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Morris P.G.,Sloan Kettering Cancer Center
Anti-Cancer Drugs | Year: 2012

High-grade gliomas (HGGs), including glioblastoma, are a heterogeneous group of primary brain tumors, associated with devastating neurological sequelae and limited survival. In 2005, a randomized phase III study established postoperative radiotherapy and temozolomide as the standard of care for patients with resected, newly diagnosed glioblastoma. Despite this progress, almost all patients relapse and therapeutic options in the recurrent setting are limited. The optimum approach for recurrent HGG is challenging because of tumor resistance and the worsening performance status of the patients. As glioblastoma is a highly vascular tumor and has high levels of vascular endothelial growth factor, there has been interest in the use of the vascular endothelial growth factor targeting, monoclonal antibody bevacizumab. In a series of phase II studies, bevacizumab alone or with irinotecan showed improvements in tumor response, disease control, and survival compared with historical controls. These results led to the licensing of bevacizumab for glioblastoma in the USA, but a contrasting view was adopted by the European Medicines Agency, because of (deemed) modest response rates and lack of direct comparisons with other agents. Against this background, Gil and colleagues conducted a retrospective review of 130 patients with recurrent HGG treated with bevacizumab and irinotecan and showed an encouraging median progression-free survival of 5.1 months (95% confidence interval, 4.4-5.9) and a median overall survival of 9.0 months (95% confidence interval, 6.7-11.2), in agreement with other series. In this editorial, the context and implications of these results are discussed, with a particular focus on the possible need and design of randomized phase III trials. © 2012 Wolters Kluwer Health | Lippincott Williams &Wilkins.

Mantha S.,Sloan Kettering Cancer Center
Journal of Thrombosis and Thrombolysis | Year: 2013

Dabigatran, rivaroxaban, apixaban and edoxaban administered in fixed doses and without routine laboratory monitoring have been compared to warfarin for the prevention of stoke in patients with nonvalvular atrial fibrillation (AF). Phase III data is currently available for dabigatran, rivaroxaban and apixaban. It is derived from three randomized controlled trials: RE-LY, ROCKET AF and ARISTOTLE. Dabigatran and apixaban appeared to be superior to warfarin for the primary endpoint of stroke or systemic embolism, while rivaroxaban was deemed non-inferior. The risk of major bleeding was modestly decreased overall with the new agents, while the risk of intracranial hemorrhage was substantially reduced. The results of ENGAGE AF-TIMI 48 comparing edoxaban to warfarin are still pending. Large, well designed clinical trials support the use of three new target-specific oral anticoagulants for the prevention of stroke in individuals with nonvalvular AF. © 2013 Springer Science+Business Media New York.

Mosher C.E.,Sloan Kettering Cancer Center | Danoff-Burg S.,Albany State University
Archives of Dermatology | Year: 2010

Objective: To assess the prevalence of addiction to indoor tanning among college students and its association with substance use and symptoms of anxiety and depression. Design: Two written measures, the CAGE (Cut down, Annoyed, Guilty, Eye-opener) Questionnaire, used to screen for alcoholism, and the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) (DSM-IV-TR) criteria for substance-related disorders, were modified to evaluate study participants for addiction to indoor tanning. Standardized self-report measures of anxiety, depression, and substance use also were administered. Setting: A large university (approximately 18 000 students) in the northeastern United States. Participants: A total of 421 college students were recruited from September through December 2006. Main Outcome Measures: Self-reported addiction to indoor tanning, substance use, and symptoms of anxiety and depression. Results: Among 229 study participants who had used indoor tanning facilities, 90 (39.3%) met DSM-IV-TR criteria and 70 (30.6%) met CAGE criteria for addiction to indoor tanning. Students who met DSM-IV-TR and CAGE criteria for addiction to indoor tanning reported greater symptoms of anxiety and greater use of alcohol, marijuana, and other substances than those who did not meet these criteria. Depressive symptoms did not significantly vary by indoor tanning addiction status. Conclusion: Findings suggest that interventions to reduce skin cancer risk should address the addictive qualities of indoor tanning for a minority of individuals and the relationship of this behavior to other addictions and affective disturbance. ©2010 American Medical Association. All rights reserved.

Bennette C.,University of Washington | Vickers A.,Sloan Kettering Cancer Center
BMC Medical Research Methodology | Year: 2012

Background: Quantiles are a staple of epidemiologic research: in contemporary epidemiologic practice, continuous variables are typically categorized into tertiles, quartiles and quintiles as a means to illustrate the relationship between a continuous exposure and a binary outcome. Discussion. In this paper we argue that this approach is highly problematic and present several potential alternatives. We also discuss the perceived drawbacks of these newer statistical methods and the possible reasons for their slow adoption by epidemiologists. Summary. The use of quantiles is often inadequate for epidemiologic research with continuous variables. © 2012 Bennette and Vickers; licensee BioMed Central Ltd.

Gillies R.J.,H. Lee Moffitt Cancer Center and Research Institute | Kinahan P.E.,University of Washington | Hricak H.,Sloan Kettering Cancer Center
Radiology | Year: 2016

In the past decade, the field of medical image analysis has grown exponentially, with an increased number of pattern recognition tools and an increase in data set sizes. These advances have facilitated the development of processes for high-throughput extraction of quantitative features that result in the conversion of images into mineable data and the subsequent analysis of these data for decision support; this practice is termed radiomics. This is in contrast to the traditional practice of treating medical images as pictures intended solely for visual interpretation. Radiomic data contain first-, second-, and higher-order statistics. These data are combined with other patient data and are mined with sophisticated bioinformatics tools to develop models that may potentially improve diagnostic, prognostic, and predictive accuracy. Because radiomics analyses are intended to be conducted with standard of care images, it is conceivable that conversion of digital images to mineable data will eventually become routine practice. This report describes the process of radiomics, its challenges, and its potential power to facilitate better clinical decision making, particularly in the care of patients with cancer. © RSNA, 2015.

Brogi E.,Sloan Kettering Cancer Center
Genes and Development | Year: 2011

The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival. This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response. © 2011 by Cold Spring Harbor Laboratory Press.

Lichtman S.M.,Sloan Kettering Cancer Center
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting | Year: 2013

Cancer is the leading cause of death worldwide. In 2008, 7.6 million deaths were attributable to cancer, representing 13% of all deaths. It is estimated that approximately 30% of cancer deaths are attributable to the five leading behavioral and dietary risks. These include high body mass index, low fruit and vegetable intake, lack of physical activity, and tobacco and alcohol use. A number of viral infections, such as hepatitis B and C and HPV, are responsible for approximately 20% of cancer deaths. Approximately 70% of cancer deaths occurred in low- and middle-income countries. Because of the increased numbers of elderly individuals and improved control of comorbidity, deaths from cancer worldwide are projected to continue rising, with an estimated 13.1 million deaths in 2030. To meet this need, the American Society of Clinical Oncology (ASCO) has evolved into a truly international organization. Over one-third of ASCO members practice in over 100 countries, representing the world's largest collection of expertise and insight into the treatment of cancer. More than one-half of ASCO's Annual Meeting attendees come from outside the United States. The Journal of Clinical Oncology is read by more than 24,000 subscribers worldwide and is available in a number of different languages. To fulfill its mission, ASCO has a number of international programs for sharing knowledge and providing the tools to assist clinicians worldwide in treating their patients. These programs include mentoring and knowledge exchange, education initiatives, and scientific and educational meetings. This provides ample opportunity for involvement to enhance cancer care worldwide.

Klimek V.M.,Sloan Kettering Cancer Center
Current Opinion in Hematology | Year: 2013

Purpose of Review: Therapy-related myelodysplastic syndromes and acute myelogenous leukemia (t-MDS/AML) comprise an increasingly common, poor-risk disease cohort without standard treatment options. This review describes available treatments and recent advances that may influence the clinical management of t-MDS/AML. Recent Findings: Multiple retrospective studies have identified poor-risk cytogenetics, chemotherapy resistance, comorbidities from prior cancer and therapy, and persistence of the primary malignancy as factors that contribute to poor clinical outcomes of t-MDS/AML. Recent analyses show that t-MDS/AML can respond to standard therapy, but responses are less durable. In most cases, cure is made more likely with allogeneic stem cell transplantation. These findings suggest that improved survival may result from earlier, low-intensity nontransplant therapy, and aggressive pursuit of reduced-intensity transplant approaches in eligible individuals coupled with posttransplant relapse prevention strategies. Molecular characterization of t-MDS/AML may aid future clinical management decisions and identify targets for therapy. Summary: Data emerging from recent t-MDS/AML studies are shedding light on factors that contribute to disease biology and poor clinical outcomes. These findings can be used to develop strategies to improve the treatment and survival of patients with t-MDS/AML. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Travis W.D.,Sloan Kettering Cancer Center
Annals of Oncology | Year: 2010

Pulmonary neuroendocrine (NE) tumors include a spectrum of tumors from the low-grade typical carcinoid (TC) and intermediate-grade atypical carcinoid (AC) to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCLC). Nodular NE proliferations ≥0.5 cm are classified as carcinoid tumors and smaller ones are called tumorlets. When NE cell hyperplasia and tumorlets are extensive they represent the rare preinvasive lesion for carcinoids known as diffuse idiopathic pulmonary NE cell hyperplasia. Carcinoid tumors have significant clinical, epidemiologic and genetic differences from the high-grade SCLC and LCNEC. Multiple endocrine neoplasia type I can be found in TC and AC patients but not those with LCNEC and SCLC. Also both LCNEC and SCLC can demonstrate histologic heterogeneity with other major histologic types of lung carcinoma such as adenocarcinoma or squamous cell carcinoma, but is not characteristic of TC or AC. Genetic changes are very high in SCLC and LCNEC, but usually low for TC, intermediate for AC. The diagnosis of SCLC, TC and AC can be made by light microscopy without the need for special tests in most cases, but for LCNEC it is required to demonstrate NE differentiation by immunohistochemistry or electron microscopy. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Riester M.,Sloan Kettering Cancer Center
PLoS computational biology | Year: 2010

Histopathological classification of human tumors relies in part on the degree of differentiation of the tumor sample. To date, there is no objective systematic method to categorize tumor subtypes by maturation. In this paper, we introduce a novel computational algorithm to rank tumor subtypes according to the dissimilarity of their gene expression from that of stem cells and fully differentiated tissue, and thereby construct a phylogenetic tree of cancer. We validate our methodology with expression data of leukemia, breast cancer and liposarcoma subtypes and then apply it to a broader group of sarcomas. This ranking of tumor subtypes resulting from the application of our methodology allows the identification of genes correlated with differentiation and may help to identify novel therapeutic targets. Our algorithm represents the first phylogeny-based tool to analyze the differentiation status of human tumors.

Antonescu C.,Sloan Kettering Cancer Center
Modern Pathology | Year: 2014

Although benign hemangiomas are among the most common diagnoses amid connective tissue tumors, sarcomas showing endothelial differentiation (ie, angiosarcoma and epithelioid hemangioendothelioma) represent under 1% of all sarcoma diagnoses, and thus it is likely that fewer than 500 people in the United States are affected each year. Differential diagnosis of malignant vascular tumors can be often quite challenging, either at the low end of the spectrum, distinguishing an epithelioid hemangioendothelioma from an epithelioid hemangioma, or at the high-grade end of the spectrum, between an angiosarcoma and a malignant epithelioid hemangioendothelioma. Within this differential diagnosis both clinico-radiological features (ie, size and multifocality) and immunohistochemical markers (ie, expression of endothelial markers) are often similar and cannot distinguish between benign and malignant vascular lesions. Molecular ancillary tests have long been needed for a more objective diagnosis and classification of malignant vascular tumors, particularly within the epithelioid phenotype. As significant advances have been recently made in understanding the genetic signatures of vascular tumors, this review will take the opportunity to provide a detailed update on these findings. Specifically, this article will focus on the following aspects: (1) pathological and molecular features of epithelioid hemangioendothelioma, including the more common WWTR1-CAMTA1 fusion, as well as the recently described YAP1-TFE3 fusion, identified in a morphological variant of epithelioid hemangioendothelioma; (2) discuss the heterogeneity of angiosarcoma clinical, morphological and genetic spectrum, with particular emphasis of MYC and FLT4 gene amplification in radiation-induced angiosarcoma; and (3) provide a practical guide in the differential diagnosis of epithelioid vascular tumors using molecular testing. © 2014 USCAP, Inc.

Scher H.I.,New York Medical College | Morris M.J.,New York Medical College | Larson S.,New York Medical College | Heller G.,Sloan Kettering Cancer Center
Nature Reviews Clinical Oncology | Year: 2013

To improve future drug development and patient management for patients with castration-resistant prostate cancer (CRPC), surrogate biomarkers that are linked to relevant outcomes are urgently needed. A biomarker must be measurable, reproducible, linked to relevant clinical outcomes, and demonstrate clinical utility. This area is rapidly evolving, with recent trials in patients with CRPC incorporating the detection of circulating tumour cells (CTCs), imaging, and patient-reported outcome biomarkers. We discuss the framework for the development of biomarkers for CRPC, including different categories and contexts of use. We also highlight the requirements of analytical validation, the sequence of trials needed for clinical validation and regulatory approval, and the future outlook for imaging and CTC biomarkers. ©2013 Macmillan Publishers Limited. All rights reserved.

Batlevi C.L.,Sloan Kettering Cancer Center
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013

The treatment of Hodgkin lymphoma (HL) relies on multimodality treatment with standard chemotherapy, radiation therapy, and autologous or allogeneic stem cell transplantation in cases of relapsed disease. Genomic advances in HL provided insights into deregulation of key nodal signaling pathways, including the PI3K, NF-κB, and JAK/STAT pathways, which are amenable to small-molecule targeting. Understanding how HL cells interact and depend on their microenvironment for survival signals and immune protection may uncover other such pathways. Small-molecule targeting has the potential to dramatically improve treatment outcomes, especially in patients with highly refractory disease and those with poor tolerance to existing chemotherapies. As novel therapies continue to be developed for HL, the challenge will be to address the needs of high-risk groups, reduce long-term therapy-related morbidity, position current established treatments with novel therapies, and concurrently develop biomarkers to aid in patient selection. Brentuximab vedotin, which was approved in 2011, is already shifting the treatment paradigm of HL. Undoubtedly, other novel therapeutics in the pipeline will affect positively the landscape of treatment in HL.

Dauer L.T.,Sloan Kettering Cancer Center
Health Physics | Year: 2014

Medical staff doses have increased over the past decade, as there is an increasing need for the benefits and use of radiation in medicine. While current average medical staff doses are well within limits, some doses to individuals could exceed 20 mSv y deep dose equivalent or lens dose equivalent (if unprotected), and there is the potential for some workers to exceed 500 mSv y shallow dose equivalent without careful assessment and protection. Nuclear medicine radiochemistry and patient dose preparation present challenging opportunities for improved dose control. In addition, fluoroscopically guided intervention procedures continue to represent an important area for careful protection implementation. Optimization of radiation protection in the medical setting should include tried and true principles of justification, optimization, and limitation with emphasis on training, credentialing, planning, and quality management. As newer and developing uses of radiation in medicine are tested and implemented, it is important to consider effective dosimetric monitoring, lens of eye doses, extremity doses, novel uses, and novel radionuclide characteristics. An ongoing assessment of current and future patterns of use for radiation in medicine is an essential activity to assist in prioritizing limited resources for staff protection. © 2014 Health Physics Society.

Begg C.B.,Sloan Kettering Cancer Center
American journal of epidemiology | Year: 2012

Contemporary searches for new risk factors frequently involve genome-wide explorations of very large numbers of candidate risk variants. Given that diseases can often be classified into subtypes that possess evidence of etiologic heterogeneity, the question arises as to whether or not a search for new risk factors would be improved by looking separately within subtypes. Etiologic risk heterogeneity inevitably increases the signal in at least one of the subtypes, but this advantage may be offset by smaller sample sizes and the increased chances of false discovery. In this article, the authors show that only a relatively modest degree of etiologic heterogeneity is necessary for the subtyping strategies to have improved statistical power. In practice, effective exploitation of etiologic heterogeneity requires strong evidence that the subtypes selected are likely to exhibit substantial heterogeneity. Further, defining the subtypes that demonstrate the most heterogeneous profiles is important for optimizing the search for new risk factors. The concepts are illustrated by using data from a breast cancer study in which results are available separately for estrogen receptor-positive (ER+) and -negative (ER-) tumors.

Hudis C.A.,Sloan Kettering Cancer Center
The oncologist | Year: 2011

Triple-negative breast cancer, characterized by tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or HER-2 genes, represents an important clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The metastatic potential in triple-negative breast cancer is similar to that of other breast cancer subtypes, but these tumors are associated with a shorter median time to relapse and death. One important goal is therefore the identification of prognostic factors and markers to reliably select high and low risk subsets of patients with triple-negative disease for different treatment approaches of subtypes with differential responsiveness to specific agents. However, a reliable prognostic marker has been elusive, and markers have been inconsistently useful. For example, epidermal growth factor receptor (EGFR) has been studied, but there is still a lack of agreement on a standard assay or cutoff for EGFR expression levels with respect to prognosis. Similarly, because triple-negative status is sometimes used as a surrogate for basal-like breast cancer, specific basal markers have been explored. Indeed, trials designed to accrue patients with basal-like breast cancer using ER/PR and HER-2 negativity may provide only an approximation of the triple-negative population and are sometimes reanalyzed using more specific indicators like CK 5/6, EGFR status, and others, again marred by discordances. Chemotherapy remains the mainstay of treatment of triple-negative breast cancer, but important limitations still need to be overcome in the next few years if any significant clinical strides are to be made. Current treatment strategies for triple-negative disease include anthracyclines, taxanes, ixabepilone, platinum agents, and biologic agents. More recently, EGFR inhibition has been proposed as a therapeutic mechanism in triple-negative breast cancer, again with mixed results. Agents that target poly(ADP-ribose) polymerase and androgen receptors have also been proposed in these patients or subsets of them, and ongoing trials should result in definitive guidance with respect to the value of these agents in triple-negative disease. Triple-negative breast cancer is clearly a distinct clinical subtype, from the perspective of both ER and HER-2 expression, but further subclassification is needed. At present, there is not a clear, proven effective single agent that targets a defining vulnerability in triple-negative breast cancer. This article will review the clinical problem of triple-negative disease, potential prognostic factors, demonstrated efficacy of currently available therapeutic options, and new potential therapies.

Hedvat C.V.,Sloan Kettering Cancer Center
Archives of Pathology and Laboratory Medicine | Year: 2010

Digital viewing of histologic images is moving from presentations and publications to incorporation into the daily work of practicing pathologists. Many technologic limitations have been overcome recently, which should make widespread adoption more practical. The task now is for pathologists to become actively involved in its development and implementation, to ensure that the technology is developed with the intent to optimize workflow and to maintain diagnostic accuracy. An understanding of the basic precepts of digital imaging is required to make informed decisions related to hardware and software implementation and to collaborate with vendors and professionals outside of pathology (eg, regulatory agencies) as the technology rapidly develops. Objective.-To describe the state of digital microscopy as it applies to the field of pathology and to define specific issues related to adoption of whole slide imaging systems. Data Sources.-The information is derived from the experience of the author and review of the literature. Conclusions.-Digital microscopy is an important tool for surgical pathologists. It is currently an area of intense and rapid technologic development that will likely transform the workflow of many laboratories during the next several years.

Niethammer P.,Sloan Kettering Cancer Center
Current Opinion in Genetics and Development | Year: 2016

Wounding of tissue barriers, such as epithelia, disrupts homeostasis and allows infection. Within minutes, animals detect injury and respond to it by recruitment of phagocytes and barrier breach closure. The signals that activate these first events are scarcely known. Commonly considered are cytoplasmic factors released into the extracellular space by lysing cells (Damage Associated Molecular Patterns, DAMPs). DAMPs activate inflammatory gene transcription through pattern recognition receptors. But the promptness of wound responses is difficult to explain by transcriptional mechanisms alone. This review highlights the emerging role of nonlytic stress signals in the rapid detection of wounds. © 2016 Elsevier Ltd.

Scher H.I.,Sloan Kettering Cancer Center
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting | Year: 2014

Developing systemic therapies for advanced prostate cancer has significant challenges, including the difficulty of assessing baseline disease status, disease heterogeneity, and the lack of standards for assessing treatment effects that reliably reflect clinical benefit. To address these issues, the Prostate Cancer Working Group (PCWG2) took three actions. First, the Group incorporated a prostate cancer clinical states model framework for patient management and drug development. Second was establishing a two-objective paradigm in which trials are designed to evaluate a drug's ability to either (a) control, relieve, or eliminate present disease manifestations or (b) prevent or delay future disease manifestations. Third was the development of consensus criteria for eligibility, outcomes, and reporting in prostate cancer clinical trials. Now that the molecular interrogation of prostate cancer has led to a more complex understanding of disease biology, drug development has transitioned from evaluating cytotoxic agents with activity in multiple tumor types to the rational development of therapies targeting different aspects of the malignant process. In addition, the current availability of multiple therapies for advanced prostate cancer that prolong life brings a new mandate: that we define, validate, and qualify predictive biomarkers of sensitivity to guide treatment selection and establish endpoints short of survival that can lead to drug approval. Optimization of outcomes in future trials will require revised guidance on how to align clinically relevant objectives and eligibility with an evolving disease framework.

Amar D.,Sloan Kettering Cancer Center
The Journal of thoracic and cardiovascular surgery | Year: 2012

Postoperative atrial fibrillation (POAF) complicating general thoracic surgery is a marker of increased morbidity and stroke risk. Our goal was to determine whether increased preoperative brain natriuretic peptide (BNP) levels are able to stratify patients by the risk of POAF. Using a prospective database of 415 patients aged 60 years or older, who had undergone lung or esophageal surgery during a 1-year period, the preoperative clinical data, including BNP levels, were compared between patients who developed POAF lasting longer than 5 minutes during hospitalization and those who did not. POAF occurred in 65 (16%) of the 415 patients and was more frequent among patients who had undergone esophagectomy or anatomic lung resection (22% or 58 of 269) compared with those who did not (5% or 7 of 146; P < .0001). After esophagectomy or anatomic lung resection, 46 (34%) of the 135 patients with BNP levels greater than the median (≥ 30 pg/mL) developed POAF compared with only 12 (9%) of 134 patients with BNP levels less than 30 pg/mL (P < .0001). The rates of POAF in patients undergoing other thoracic procedures were low and not associated with the BNP levels. Multivariate logistic regression analysis showed that in patients undergoing esophagectomy or anatomic lung resection, older age (5-year increments, odds ratio [OR], 1.28; 95% confidence interval [CI], 1.01-1.61; P = .04), male gender (OR, 2.61; 95% CI, 1.12-4.17; P = .02), and BNP level 30 pg/mL or greater (OR, 4.52; 95% CI, 2.19-9.32; P < .0001) were independent risk factors for POAF. The length of hospital stay was significantly increased in patients who developed POAF compared with those who did not (P < .0001). Among patients undergoing anatomic lung resection or esophagectomy, increased age, male gender, and preoperative BNP level of 30 pg/mL or greater were significant risk factors for the development of POAF. The identification of patients who are more likely to develop POAF will allow the development of trials assessing prevention strategies aimed at reducing this complication. Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Kang H.J.,Sloan Kettering Cancer Center
Clinical nuclear medicine | Year: 2014

A previously healthy 9-year-old boy presented to an outside hospital with a history of abdominal pain and vomiting. An abdominal x-ray was unremarkable. A CT of the abdomen and pelvis performed to evaluate possible obstruction after weight loss and vomiting over a 3-week period demonstrated a large retroperitoneal mass. Laparoscopic biopsy showed diffuse large B-cell lymphoma. FDG PET/CT was performed for staging. An ileocolic intussusception was identified on the PET/CT. The intussusception was successfully managed with medical treatment. We present FDG PET/CT findings in intussusception with non-Hodgkin lymphoma as the lead point in a pediatric patient.

Hanrahan A.J.,Sloan Kettering Cancer Center
Cancer discovery | Year: 2012

Effective oncoprotein-targeted therapies have not yet been developed for ovarian cancer. To explore the role of PI3 kinase/AKT signaling in this disease, we performed a genetic and functional analysis of ovarian cancer cell lines and tumors. PI3K pathway alterations were common in both, but the spectrum of mutational changes differed. Genetic activation of the pathway was necessary, but not sufficient, to confer sensitivity to selective inhibition of AKT and cells with RAS pathway alterations or RB1 loss were resistant to AKT inhibition, whether or not they had coexistent PI3K/AKT pathway activation. Inhibition of AKT1 caused growth arrest in a subset of ovarian cell lines, but not in those with AKT3 expression, which required pan-AKT inhibition. Thus, a subset of ovarian tumors are sensitive to AKT inhibition, but the genetic heterogeneity of the disease suggests that effective treatment with AKT pathway inhibitors will require a detailed molecular analysis of each patient's tumor. SIGNIFICANCE: A subset of ovarian cancers exhibits AKT pathway activation and is sensitive to selective AKT inhibition. Ovarian tumors exhibit significant genetic heterogeneity and thus an individualized approach based on real-time, detailed genomic and proteomic characterization of individual tumors will be required for the successful application of PI3K/AKT pathway inhibitors in this disease.

Slovin S.F.,Sloan Kettering Cancer Center
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting | Year: 2015

Despite multiple immunologic approaches with peptide, protein, and DNA vaccines, no single therapy has induced complete remission or maintained durability of response in patients with castration-resistant prostate cancer (CRPC). Historically, immunotherapy has had limited effect on solid tumors with the exception of melanoma and renal cell carcinomas, which have been deemed as immunologic cancers given their potential for remissions either spontaneously or after removal of the primary lesion. There is considerable excitement about using an immunotherapy in combination with biologic agents such as checkpoint inhibitors, cytokines, other vaccines, or chemotherapy. Sipuleucel-T represents one of several novel immunologic therapeutic approaches to treat prostate cancer in addition to other solid tumors. It is the first in its class of autologous cellular therapies to demonstrate safety and an overall survival benefit in patients with asymptomatic or minimally symptomatic CRPC and represents a unique treatment method that may be further enhanced with other agents. Although sipuleucel-T can be used as a foundation on which to build and enhance future immunologic clinical trials, other exciting strategies are in development that may be easily integrated into the algorithm of current care.

Rizk N.,Sloan Kettering Cancer Center
Thoracic Surgery Clinics | Year: 2013

Determining what defines an adequate esophageal resection to optimize long-term outcomes in esophageal cancer is an elusive goal. The primary reason for this ambiguousness is the almost total lack of good quality prospective randomized surgical trials that examine this question adequately. Most available data are derived from small retrospective series typically representing single institution series and their treatment biases. The intent of this article is to identify the goals of an appropriate esophagectomy for cancer, essentially defining the targets that should be achieved from an operation. © 2013 Elsevier Inc.

Moskowitz A.J.,Sloan Kettering Cancer Center
Blood | Year: 2016

In this issue of Blood, Böll et al report on the toxicity of 2 vs 4 cycles of bleomycin-containing chemotherapy in older, early stage, favorable patients with Hodgkin lymphoma (HL) and show that 2 cycles, but no more, of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is well tolerated in this patient population. © 2016 by The American Society of Hematology.

Ballen K.K.,Massachusetts General Hospital | Barker J.N.,Sloan Kettering Cancer Center
Current Opinion in Hematology | Year: 2013

Purpose of Review: We discuss outcomes after umbilical cord blood (UCB) transplantation (UCBT) for patients with acute myeloid leukemia (AML) and compare these outcomes to results after transplantation of other allogeneic graft sources. Recent Findings: Survival after UCBT has improved considerably over the past 10 years. Multiple retrospective studies using either myeloablative or reduced intensity conditioning have shown disease-free survival after UCBT that is comparable to that of matched related or unrelated donors. Improved unit selection, conditioning, graft manipulation, and supportive care are all emerging strategies to further improve outcomes, although disease status and center expertise remain key components of successful UCBT outcome. Summary: UCBT should be considered in all high-risk AML patients in whom allogeneic stem cell transplantation is indicated but who lack a matched related or unrelated donor. UCBT can thereby now be thought of as a 'mainstream' treatment of high-risk AML. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Sarek G.,Cancer Research UK Research Institute | Vannier J.-B.,Cancer Research UK Research Institute | Panier S.,Cancer Research UK Research Institute | Petrini H.J.,Sloan Kettering Cancer Center | Boulton S.J.,Cancer Research UK Research Institute
Molecular Cell | Year: 2015

The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required toprevent catastrophic t-loop processing by structure-specific nucleases. We show that the TRF2-RTEL1 interaction is mediated by a metal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome (HHS) mutation, RTEL1R1264H. Conversely, we define a TRF2I124D substitution mutation within the TRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1R1264H mutation, giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle. These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in S phase. © 2015 The Authors.

OBJECTIVES: • To investigate the frequency of infectious complications after intravesical BCG therapy or cystoscopy in antibioticnaive patients with bladder tumours who have asymptomatic bacteriuria. • The aim was to avoid antibiotics in infected patients undergoing these common outpatient urological procedures. METHODS: • A total of 354 patients received induction BCG therapy and another 663 patients underwent cystoscopy after submitting a voided urine sample for culture. They received no antibiotics before or after the procedure. • Significant bacteriuria was defined as > 104 or > 105 colony-forming units per millilitre with a single organism. • The patients were followed for 3 months for onset of febrile UTI, defined as dysuria and fever > 38 °C requiring antibiotics. RESULTS: • Ninety BCG-treated patients (25%) and 114 cystoscopy patients (17%) had bacteriuria. • After BCG therapy, two patients with infected urine (2.2%) and three with sterile cultures (1.1%) had febrile UTIs ( P = 0.17). • After cystoscopy, four infected patients (3.5%) and five uninfected patients (1%) had febrile UTIs ( P = 0.08). • All UTIs resolved within 24 h with oral antibiotics, and none of the patients was admitted for bacterial sepsis. CONCLUSIONS: • Antibacterial prophylaxis before intravesical BCG therapy or outpatient cystoscopy does not appear to be necessary in patients with asymptomatic bacteriuria. • Such strategy avoids overuse of antibiotics, reducing drug-resistant bacterial infections. © 2012 BJU International.

Halpern N.A.,Sloan Kettering Cancer Center
Chest | Year: 2014

This third and final installment of this series on innovative designs for the smart ICU addresses the steps involved in conceptualizing, actualizing, using, and maintaining the advanced ICU informatics infrastructure and systems. The smart ICU comprehensively and electronically integrates the patient in the ICU with all aspects of care, displays data in a variety of formats, converts data to actionable information, uses data proactively to enhance patient safety, and monitors the ICU environment to facilitate patient care and ICU management. The keys to success in this complex informatics design process include an understanding of advanced informatics concepts, sophisticated planning, installation of a robust infrastructure capable of both connectivity and interoperability, and implementation of middleware solutions that provide value. Although new technologies commonly appear compelling, they are also complicated and challenging to incorporate within existing or evolving hospital informatics systems. Therefore, careful analysis, deliberate testing, and a phased approach to the implementation of innovative technologies are necessary to achieve the multilevel solutions of the smart ICU. © 2014 American College of Chest Physicians.

Slovin S.F.,Sloan Kettering Cancer Center
Immunotherapy | Year: 2013

Antibodies administered either alone or in a unique construct that can enhance targeting, immunologic recognition and cell killing, remain an area of active interest for a variety of solid tumors. Prostate cancer has unique characteristics as a target for immune-mediated therapies, particularly since it has not only a wide array of antigens expressed on its cell surface, but also has an associated biomarker, which not only can monitor the disease status but also its response to therapy. A number of unique cell surface antigens, as well as internally mediated cell molecules, have shown their clinical activity and efficacy as prostate cancer treatments. The continued evolution of novel antibody-drug and antibody-imaging constructs will probably offer more efficient ways to deliver a therapeutic to the tumor and enhance imaging of active or treated sites of disease. © 2013 Future Medicine Ltd.

Busam K.J.,Sloan Kettering Cancer Center
Seminars in Diagnostic Pathology | Year: 2013

Genetic and genomic analyses of melanocytic tumors have yielded new opportunities for improvements in diagnostic accuracy for the distinction of nevus from melanoma and better selection of patients affected by melanoma for targeted treatment. Since chromosomal copy number changes are commonly found in malignant melanoma, but rare in melanocytic nevi, cytogenetic assays have emerged as a promising ancillary study for the workup of melanocytic tumors with ambiguous light microscopic features. Comparative genomic hybridization (CGH) permits assessment of the full set of chromosomes, but requires a significant amount of lesional tissue, and may fail to detect aberrations in a minor subpopulation of tumor cells. Fluorescence in situ hybridization (FISH) is the cytogenetic assay of choice for limited amounts of tissue. FISH targets only specific chromosomes, with inherent limitations in test sensitivity and specificity. FISH analysis is also heavily dependent on individual experience. Molecular studies have identified distinct sets of mutations in melanoma and/or nevi. These mutations have become clinically relevant for targeted therapy of patients with advanced disease, especially for the treatment of patients with metastatic melanoma carrying the BRAFV600 or KIT mutations. However, mutation analysis can on occasion also be used for diagnostic purposes. © 2013.

Roobol M.J.,Erasmus Medical Center | Carlsson S.V.,Sloan Kettering Cancer Center
Nature Reviews Urology | Year: 2013

Screening for prostate cancer is a controversial topic within the field of urology. The US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial did not demonstrate any difference in prostate-cancer-related mortality rates between men screened annually rather than on an 'opportunistic' basis. However, in the world's largest trial to date - the European Randomised Study of Screening for Prostate Cancer - screening every 2-4 years was associated with a 21% reduction in prostate-cancer-related mortality rate after 11 years. Citing the uncertain ratio between potential harm and potential benefit, the US Preventive Services Task Force recently recommended against serum PSA screening. Although this ratio has yet to be elucidated, PSA testing - and early tumour detection - is undoubtedly beneficial for some individuals. Instead of adopting a 'one size fits all' approach, physicians are likely to perform personalized risk assessment to minimize the risk of negative consequences, such as anxiety, unnecessary testing and biopsies, overdiagnosis, and overtreatment. The PSA test needs to be combined with other predictive factors or be used in a more thoughtful way to identify men at risk of symptomatic or life-threatening cancer, without overdiagnosing indolent disease. A risk-adapted approach is needed, whereby PSA testing is tailored to individual risk. © 2013 Macmillan Publishers Limited. All rights reserved.

Cremers S.,Columbia University | Farooki A.,Sloan Kettering Cancer Center
Annals of the New York Academy of Sciences | Year: 2011

Osteonecrosis of the jaw (ONJ) has been hypothesized to result in part from a relative "oversuppression" of normal physiologic bone remodeling at the jaw brought about by bisphosphonate therapy. Biochemical markers of bone turnover give readily measurable information on integrated systemic bone remodeling activity, as measured by blood and urine assays. The intra- and interassay variability of most currently available assays is less than 10%, although many biological factors can influence levels of bone turnover markers. Bone turnover markers may show a dynamic response to changes in clinical status for a given disease state. Elevated bone turnover on and off treatment appears to predict adverse clinical consequences in both osteoporosis and cancer. Bisphosphonates effectively decrease the level of the bone turnover markers with a pattern depending on the marker, the bisphosphonate, the dose regimen, and the disease. However, long-term (10-year) treatment with bisphosphonates for osteoporosis does not appear to result in a progressive decline in bone turnover, as measured by markers and bone histology. The effects of long-term (greater than 2 years) treatment with monthly intravenous bisphosphonates on bone turnover markers in cancer are unknown. Discontinuation of bisphosphonate therapy appears to allow a recovery of bone turnover, which is related to the bisphosphonate, the duration of therapy, and the disease being treated. At this time, data are limited with regard to the utility of bone turnover markers in assessing risk for ONJ and whether bone marker-directed bisphosphonate holidays would be useful in prevention or treatment of ONJ. © 2010 New York Academy of Sciences.

Schuhmacher A.J.,Sloan Kettering Cancer Center | Sibilia M.,Medical University of Vienna
Cancer Cell | Year: 2012

Clinical evidence indicates that mutation/activation of EGF receptors (EGFRs) is mutually exclusive with the presence of K-RAS oncogenes in lung and colon tumors. We have validated these observations using genetically engineered mouse models. However, development of pancreatic ductal adenocarcinomas driven by K-Ras oncogenes are totally dependent on EGFR signaling. Similar results were obtained using human pancreatic tumor cell lines. EGFRs were also essential even in the context of pancreatic injury and absence of p16Ink4a/p19Arf. Only loss of p53 made pancreatic tumors independent of EGFR signaling. Additional inhibition of PI3K and STAT3 effectively prevented proliferation of explants derived from these p53-defective pancreatic tumors. These findings may provide the bases for more rational approaches to treat pancreatic tumors in the clinic. © 2012 Elsevier Inc.

Alonso C.D.,Beth Israel Deaconess Medical Center | Kamboj M.,Sloan Kettering Cancer Center
Current Infectious Disease Reports | Year: 2014

Patients undergoing solid organ and stem cell transplantation are at increased risk of Clostridium difficile infection (CDI) compared with nontransplant patients. CDI may be associated with significant morbidity in this population including prolonged hospitalization, increased hospital charges, and complications in the transplanted organ. A combination of host factors, including both B-cell and T-cell immunosuppression, in addition to traditional risk factors for CDI such as broad-spectrum antibacterial exposure, are likely to contribute to the elevated risk in this population. This article addresses the current epidemiology and risk factors for CDI in transplant recipients, the downstream complications following this infection, and current management strategies, with an emphasis on novel approaches for primary and recurrent disease including fecal microbiota transplantation. © 2014 Springer Science+Business Media.

Pedoto A.,Sloan Kettering Cancer Center
Anesthesiology Clinics | Year: 2012

Although disposable double-lumen tubes have been used for many years, there is still controversy regarding what size and which side to use for thoracic procedures requiring lung isolation. Thoracic and nonthoracic anesthesiologists often debate performance, efficiency, and outcome of small and large double-lumen tubes, and left- and right-sided tubes. This article focuses on current data in the literature and expert opinion on the topic. © 2012 Elsevier Inc.

Soslow R.A.,Sloan Kettering Cancer Center
Modern Pathology | Year: 2016

This review covers three areas in endometrial tumor pathology: International Federation of Gynecology and Obstetrics (FIGO) staging, the use of frozen section, and Lynch syndrome. The section on FIGO staging will emphasize problems that practicing pathologists often confront, such as measuring the depth of myometrial invasion, assessing for the presence of cervical stromal invasion, detecting low-volume lymph node metastases, and recognizing synchronous endometrial and ovarian tumors and artifacts. The frozen section portion of this review will focus on the performance characteristics of intraoperative examination of the uterus to determine tumor grade and depth of myometrial invasion, including suggestions for alternative methods. The last portion of this review will provide an overview of Lynch syndrome and a discussion of the rationale and methods of screening for Lynch syndrome.

Yen J.,Wellcome Trust Sanger Institute | White R.M.,Sloan Kettering Cancer Center | Stemple D.L.,Wellcome Trust Sanger Institute
Current Opinion in Genetics and Development | Year: 2014

The need for scalable strategies to probe the biological consequences of candidate cancer genes has never been more pressing. The zebrafish, with its capacity for high-throughput transgenesis, in vivo imaging and chemical/genetic screening, has ideal features for undertaking this task. Unique biological insights from zebrafish have already led to the identification of novel oncogenic drivers and small molecules being used to treat the human cancer. This review summarizes the recent main findings and describes pertinent areas where the zebrafish can greatly contribute to our understanding of cancer biology and treatment. © 2013 The Authors.

Van Calster B.,Catholic University of Leuven | Vickers A.J.,Sloan Kettering Cancer Center
Medical Decision Making | Year: 2015

Decision-analytic measures to assess clinical utility of prediction models and diagnostic tests incorporate the relative clinical consequences of true and false positives without the need for external information such as monetary costs. Net Benefit is a commonly used metric that weights the relative consequences in terms of the risk threshold at which a patient would opt for treatment. Theoretical results demonstrate that clinical utility is affected by a model';s calibration, the extent to which estimated risks correspond to observed event rates. We analyzed the effects of different types of miscalibration on Net Benefit and investigated whether and under what circumstances miscalibration can make a model clinically harmful. Clinical harm is defined as a lower Net Benefit compared with classifying all patients as positive or negative by default. We used simulated data to investigate the effect of overestimation, underestimation, overfitting (estimated risks too extreme), and underfitting (estimated risks too close to baseline risk) on Net Benefit for different choices of the risk threshold. In accordance with theory, we observed that miscalibration always reduced Net Benefit. Harm was sometimes observed when models underestimated risk at a threshold below the event rate (as in underestimation and overfitting) or overestimated risk at a threshold above event rate (as in overestimation and overfitting). Underfitting never resulted in a harmful model. The impact of miscalibration decreased with increasing discrimination. Net Benefit was less sensitive to miscalibration for risk thresholds close to the event rate than for other thresholds. We illustrate these findings with examples from the literature and with a case study on testicular cancer diagnosis. Our findings strengthen the importance of obtaining calibrated risk models. © The Author(s) 2014.

White R.M.,Sloan Kettering Cancer Center
Current Opinion in Genetics and Development | Year: 2015

The zebrafish is a relatively recent addition to cancer modeling. These models have now been extensively used in cross-species oncogenomic analyses at both the DNA and RNA levels. The goal of such studies is to identify conserved events that occur in both human and fish tumors which may act as central drivers of tumor phenotypes. Numerous comparisons of somatic DNA changes, using array CGH and exome sequencing, have demonstrated a relatively small set of conserved changes across species. In contrast, striking conservation of RNA expression patterns have been observed between the two species in models such as melanoma, leukemia, and rhabdomyosarcoma. In the future, the zebrafish will increasingly be used to model epigenetic and noncoding aspects of cancer biology. © 2015 Elsevier Ltd.

Tang J.Y.,Stanford University | Marghoob A.A.,Sloan Kettering Cancer Center
Seminars in Cutaneous Medicine and Surgery | Year: 2011

A number of therapies that target components of the Hedgehog signaling pathway currently are in clinical trials. The specific molecules that seem most promising in basal cell carcinoma and a number of other cancers are those that target the Smoothened transmembrane protein. The pivotal phase II trials have been completed on the Smoothened inhibitor known as GDC-0449; five other agents (BMS-833923, LDE225, LEQ506, IPI926, and TAK-441) have also shown promise in animal studies and early clinical trials and have shown some efficacy in a variety of cancers that are affected by the Hedgehog signaling pathway. © 2011 Elsevier Inc.

Vickers A.J.,Sloan Kettering Cancer Center
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2013

Firm evidence shows that prostate-specific antigen (PSA) velocity is statistically associated with many prostate cancer outcomes, including those related to early detection. However, the clinical use of a marker depends on clinical and statistical significance. Before PSA velocity is used to inform decisions such as whether to perform a biopsy, evidence should be clear that doing so would improve clinical outcome. A systematic review on PSA velocity found that almost no studies had evaluated whether PSA velocity aids in clinical decision-making. Since that time, several reports have indicated that including PSA in a statistical model alongside standard predictors (eg, PSA, digital rectal examination) does not improve predictive accuracy. Specifically, performing a biopsy on men with high PSA velocity in the absence of other indications, as recommended by the NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer Early Detection, would lead to many millions of unnecessary biopsies, without a corresponding number of aggressive cancers being detected. Advocates of PSA velocity have been reduced to citing a single article claiming that PSA velocity aids in clinical decision-making. The article involves selective reporting of an unusual subgroup analysis based on an extremely limited number of events. This is not to say that, in clinical practice, urologists should ignore prior PSA values: clinical judgment can be aided by careful longitudinal evaluation of PSA changes, interpreted in the context of symptoms and treatments. However, the literature clearly shows that simplistic application of PSA velocity cutoffs is not of value for early detection of prostate cancer. Copyright © 2013 by the National Comprehensive Cancer Network. All rights reserved.

Venneti S.,University of Michigan | Huse J.T.,Sloan Kettering Cancer Center
Advances in Anatomic Pathology | Year: 2015

Low-grade gliomas (LGG) constitute grades I and II tumors of astrocytic and grade II tumors of oligodendroglial lineage. Although these tumors are typically slow growing, they may be associated with significant morbidity and mortality because of recurrence and malignant progression, even in the setting of optimal resection. LGG in pediatric and adult age groups are currently classified by morphologic criteria. Recent years have heralded a molecular revolution in understanding brain tumors, including LGG. Next-generation sequencing has definitively demonstrated that pediatric and adult LGG fundamentally differ in their underlying molecular characteristics, despite being histologically similar. Pediatric LGG show alterations in FGFR1 and BRAF in pilocytic astrocytomas and FGFR1 alterations in diffuse astrocytomas, each converging on the mitogen-activated protein kinase signaling pathway. Adult LGG are characterized by IDH1/2 mutations and ATRX mutations in astrocytic tumors and IDH1/2 mutations and 1p/19q codeletions in oligodendroglial tumors. TERT promoter mutations are also noted in LGG and are mainly associated with oligodendrogliomas. These findings have considerably refined approaches to classifying these tumors. Moreover, many of the molecular alterations identified in LGG directly impact on prognosis, tumor biology, and the development of novel therapies. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Norton L.,Sloan Kettering Cancer Center
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting | Year: 2014

At the root of science lie basic rules, if we can discover or deduce them. This is not an abstract project but practical; if we can understand the why then perhaps we can rationally intervene. One of the unifying unsolved problems in physics is the hypothetical "Theory of Everything." In a similar vein, we can ask whether our own field contains such hidden fundamental truths and, if so, how we can use them to develop better therapies and outcomes for our patients. Modern oncology has developed as drugs and translational science have matured over the 50 years since ASCO's founding, but almost from that beginning tumor modeling has been a key tool. Through this general approach Norton and Simon changed our understanding of cancer biology and response to therapy when they described the fit of Gompertzian curves to both clinical and animal observations of tumor growth. The practical relevance of these insights has only grown with the development of DNA sequencing promising a raft of new targets (and drugs). In that regard, Larry Norton's contribution to this year's Educational Book reminds us to always think creatively about the fundamental problems of tumor growth and metastases as well as therapeutic response. Demonstrating the creativity and thoughtfulness that have marked his remarkable career, he now incorporates a newer concept of self-seeding to further explain why Gompertzian growth occurs and, in the process, provides a novel potential therapeutic target. As you read his elegantly presented discussion, consider how this understanding, wisely applied to the modern era of targeted therapies, might speed the availability of better treatments. But even more instructive is his personal model-not only the Norton-Simon Hypothesis-of how to live and approach science, biology, patients and their families, as well as the broader community. He shows that with energy, enthusiasm, optimism, intellect, and hard work we can make the world better. Clifford A. Hudis, MD, FACP, 2013-2014 ASCO President.

Schmitt A.M.,Sloan Kettering Cancer Center | Chang H.Y.,Stanford University
Cancer Cell | Year: 2016

Genome-wide cancer mutation analyses are revealing an extensive landscape of functional mutations within the noncoding genome, with profound effects on the expression of long noncoding RNAs (lncRNAs). While the exquisite regulation of lncRNA transcription can provide signals of malignant transformation, we now understand that lncRNAs drive many important cancer phenotypes through their interactions with other cellular macromolecules including DNA, protein, and RNA. Recent advancements in surveying lncRNA molecular mechanisms are now providing the tools to functionally annotate these cancer-associated transcripts, making these molecules attractive targets for therapeutic intervention in the fight against cancer. © 2016 Elsevier Inc.

Arvey A.,Sloan Kettering Cancer Center
Nucleic acids research | Year: 2010

Fluorescent in situ hybridization (FISH) techniques are becoming extremely sensitive, to the point where individual RNA or DNA molecules can be detected with small probes. At this level of sensitivity, the elimination of 'off-target' hybridization is of crucial importance, but typical probes used for RNA and DNA FISH contain sequences repeated elsewhere in the genome. We find that very short (e.g. 20 nt) perfect repeated sequences within much longer probes (e.g. 350-1500 nt) can produce significant off-target signals. The extent of noise is surprising given the long length of the probes and the short length of non-specific regions. When we removed the small regions of repeated sequence from either short or long probes, we find that the signal-to-noise ratio is increased by orders of magnitude, putting us in a regime where fluorescent signals can be considered to be a quantitative measure of target transcript numbers. As the majority of genes in complex organisms contain repeated k-mers, we provide genome-wide annotations of k-mer-uniqueness at http://cbio.mskcc.org/ approximately aarvey/repeatmap.

Luetke A.,University of Munster | Meyers P.A.,Sloan Kettering Cancer Center | Lewis I.,Alder Hey Childrens NHS FT | Juergens H.,University of Munster
Cancer Treatment Reviews | Year: 2014

Long-term outcome for patients with high-grade osteosarcoma has improved with the addition of systemic chemotherapy, but subsequent progress has been less marked. Modern, multiagent, dose-intensive chemotherapy in conjunction with surgery achieves a 5-year event-free survival of 60-70% in extremity localized, non-metastatic disease. A major, as yet unsolved, problem is the poor prognosis for metastatic relapse or recurrence, and for patients with axial disease. This article reviews the current state of the art of systemic osteosarcoma therapy by focusing on the experiences of cooperative osteosarcoma groups. Also, we shed light on questions and challenges posed by the aggressiveness of the tumor, and we consider potential future directions that may be critical to progress in the prognosis of high-grade osteosarcoma. © 2014.

Resh M.D.,Sloan Kettering Cancer Center
Trends in Molecular Medicine | Year: 2012

Fatty acids and/or isoprenoids are covalently attached to a variety of disease-related proteins. The distinct chemical properties of each of these hydrophobic moieties allow lipid modification to serve as a mechanism to regulate protein structure, localization and function. This review highlights recent progress in identifying inhibitors of protein lipidation and their effects on human disease. Myristoylation inhibitors have shown promise in blocking the action of human pathogens. Although inhibitors that block prenylation of Ras proteins have not yet been successful for cancer treatment, they may be efficacious in the rare premature aging syndrome progeria. Agents that alter the palmitoylation status of Ras, Wnt and Hh proteins have recently been discovered, and represent the next generation of potential chemotherapeutics. © 2012 Elsevier Ltd.

Jhanwar S.C.,Sloan Kettering Cancer Center
Advances in Biological Regulation | Year: 2015

Myelodysplastic syndromes (MDS) are a highly heterogenous group of hematopoietic tumors, mainly due to variable clinical features and diverse set of cytogenetic, molecular genetic and epigenetic lesions. The major clinical features of MDS are ineffective hematopoiesis, peripheral cytopenias, and an increased risk of transformation to acute myeloid leukemias, which in turn is most likely determined by specific genetic abnormalities and other presenting hematologic features. The risk of developing MDS is relatively higher in some genetic syndromes such as Fanconi anemia and receipt of chemotherapy and radiation treatment. In recent years a significant progress has occurred and a vast literatures has become available including the spectrum of cytogenetic abnormalities, gene mutations relating to RNA splicing machinery, epigenetic regulation of gene expression and signaling pathways associated with MDS pathogenesis, which have provided opportunities to understand the molecular mechanisms as well as employ targeted therapeutic approaches to treat MDS. The cytogenetic abnormalities detected in MDS varies from a single abnormality to complex karyotype not easily amenable to conventional cytogenetic analysis. In such cases, array based high resolution genomic analysis detected abnormalities, which are diagnostic as well as prognostic. The most common driver gene mutations detected in patients with MDS include RNA splicing (SF3B1,SRSF2,U2F1,ZRSR2), DNA methylation (TET2,DNMT3A,IDH1/IDH2), chromatin modification (ASXL1,EZH2), transcription regulation (RUNX1,BCOR) and DNA repair control p53. A small subset of MDS arise due to deregulation of RAS pathway, mainly due to NRAS/KRAS/NF1 mutations. Identification of these mutations and pathways have provided opportunities for oncologists to target these patients with specific therapies. Several drugs which either target the spliceosome, oncogenic RAS signaling, or hypomethylating agents have been employed to successfully treat MDS patients. © 2014 Published by Elsevier Ltd.

Iaea D.B.,New York Medical College | Maxfield F.R.,Sloan Kettering Cancer Center
Essays in Biochemistry | Year: 2015

Sterols are a critical component of cell membranes of eukaryotes. In mammalian cells there is approximately a six-fold range in the cholesterol content in various organelles. The cholesterol content of membranes plays an important role in organizing membranes for signal transduction and protein trafficking as well as in modulating the physiochemical properties of membranes. Cholesterol trafficking among organelles is highly dynamic and is mediated by both vesicular and non-vesicular processes. Several proteins have been proposed to mediate inter-organelle trafficking of cholesterol. However, several aspects of the mechanisms involved in regulating trafficking and distribution of cholesterol remain to be elucidated. In the present chapter, we discuss the cellular mechanisms involved in cholesterol distribution and the trafficking processes involved in maintaining sterol homoeostasis. © The Authors Journal compilation © 2015 Biochemical Society.

Finley L.W.S.,Sloan Kettering Cancer Center | Haigis M.C.,Harvard University
Trends in Molecular Medicine | Year: 2012

Cancer cells meet their needs for energy and biomass production by consuming high levels of nutrients and rewiring metabolism to support macromolecular biosynthesis. Mitochondrial enzymes play central roles in anabolic growth, and acetylation may provide a key layer of regulation over mitochondrial metabolic pathways. As a major mitochondrial deacetylase, SIRT3 regulates the activity of enzymes to coordinate global shifts in cellular metabolism. SIRT3 promotes the function of the tricarboxylic acid (TCA) cycle and the electron transport chain and reduces oxidative stress. Loss of SIRT3 triggers oxidative damage, reactive oxygen species (ROS)-mediated signaling, and metabolic reprogramming to support proliferation and tumorigenesis. Thus, SIRT3 is an intriguing example of how nutrient-sensitive, post-translational regulation may provide integrated regulation of metabolic pathways to promote metabolic homeostasis in response to diverse nutrient signals. © 2012 Elsevier Ltd.

Olson S.H.,Sloan Kettering Cancer Center
Molecular Carcinogenesis | Year: 2012

We review the current evidence for associations of several medical conditions with risk of pancreatic cancer, including allergies, pancreatitis, gall bladder disease, cholecystectomy, ulcers, gastrectomy, appendectomy, and tonsillectomy. There are consistent findings of reduced risk associated with presence of self-reported allergies, particularly hay fever but not asthma; data on other allergies are limited and inconclusive. Several studies provide evidence that patients with pancreatic cancer are more likely than comparison groups to report pancreatitis. Those studies that investigated the time between onset of pancreatitis and diagnosis of pancreatic cancer found that risk estimates declined with longer periods of time; however, increased risks were noted for long-term pancreatitis, indicating that this condition is both a risk factor and a sign of early disease. Increased risk was reported in association with cholelithiasis, but the few studies that considered time before diagnosis of cancer did not find increased risk for cholelithiasis diagnosed in the more distant past. There is weak evidence that cholecystectomy 2 or more years before cancer diagnosis is related to risk, but this is based on only a few studies. There is no consistent association between ulcers and risk, while gastrectomy may increase risk. Overall, study of these conditions, particularly those that are rare, presents methodologic challenges. Time between diagnoses is likely to be important but is not considered in most studies. Lack of adequate control in several studies for risk factors such as smoking and heavy alcohol use also makes it difficult to draw firm conclusions about these results. © 2011 Wiley Periodicals, Inc..

Cibula D.,Oncogynecological Center | Abu-Rustum N.R.,Sloan Kettering Cancer Center
Gynecologic Oncology | Year: 2010

Background: Pelvic lymphadenectomy is an integral component of gynecologic cancer surgery, yet there is a lack of standardization in the terminology used, the extent of the procedure, and the definition of anatomic landmarks. This lack of standardization if corrected will likely facilitate a more clear communication and analysis of outcomes from various institutions, and reduce confusion to trainees about the procedure being performed. Methods: We summarize the anatomic data concerning pelvic lymphatic drainage; describe the procedure based on clearly defined anatomic landmarks; and finally propose a new classification system to facilitate standardization, communication, and comparison of results. The accompanying video demonstrates the anatomic landmarks. Results: We list and define four commonly used terms related to pelvic lymph node harvesting: sentinel node mapping, excision of bulky nodes, pelvic lymph node sampling, and systematic pelvic lymphadenectomy. We list the five specific anatomic regions of the pelvic lymphatic basin: external iliac, obturator, internal iliac, common iliac, and presacral. We highlight the important neural structures located in regions of the pelvic lymphadenectomy: genitofemoral nerve, obturator nerve, cranial part of the lumbosacral plexus, hypogastric plexus, and splanchnic nerves. Finally, we propose a new, four-part classification system of types of pelvic lymph node dissection. Conclusion: In this report and video, we demonstrate anatomy and offer a new classification system for pelvic lymphadenectomy. © 2009 Elsevier Inc. All rights reserved.

Russo P.,Sloan Kettering Cancer Center
World Journal of Urology | Year: 2010

Surgical intervention in the patients with metastatic renal cancer can occur in two settings: (1) to render a patient clinically free of all sites of primary disease and metastases, termed nephrectomy/metastasectomy, or (2) to resect the primary tumor in the face of unresectable metastatic disease prior to the initiation of systemic therapy, termed cytoreductive nephrectomy. Carefully selected patients with good performance status undergoing nephrectomy and subsequent metastasectomy may experience prolonged survival in the range of 30 months, which could be attributed to a combination of patient selection factors and the surgical resections. Randomized clinical trials from the United States and Europe have demonstrated a small but significant survival benefit to cytoreductive nephrectomy and cytokine therapy versus cytokine therapy alone which is measured in the range of 3-6 months and associated with overall survival of approximately 12 months. The precise mechanism by which cytoreductive nephrectomy improves survival is not known but may relate to reduction in the large primary immunosuppressive burden. Patient selection factors including performance status and serum factors (Hgb, corrected Ca++, LDH) stratify metastatic patients into risk groups, which are strongly associated with survival time in both medically and surgically treated patients with metastatic renal cancer. The development of multi-kinase and mTOR inhibitors has markedly improved survival in treatment naïve and previously treated patients with metastatic renal cancer, and these agents are currently under active clinical investigation in the neo-adjuvant and adjuvant setting. © 2010 Springer-Verlag.

Soslow R.A.,Sloan Kettering Cancer Center
Seminars in Diagnostic Pathology | Year: 2010

Endometrial carcinomas are a heterogenous group of tumors that show variable histologies, molecular abnormalities and clinical outcomes. The idea of rigid distinctions between tumor types is appealing to pathologists, gynecologists, researchers and patients, but in a recent study where high grade endometrial carcinomas were reviewed by three experienced gynecologic pathologists, diagnostic agreement about tumor type was reached in only approximately one half of cases. In general, biologically and clinically validated diagnostic criteria are lacking for high grade endometrial carcinomas and for those that appear mixed epithelial. Until such criteria are developed, it remains important to define which morphologic patterns convey accurate clinical and biological information and which do not or might not. "Endometrial carcinomas with ambiguous features," the focus of this review, are tumors with comparatively uninformative morphologic features. Some publications indicate that gland forming and papillary endometrial carcinomas that appear morphologically low grade or ambiguous are really high grade. There are also indications that high grade endometrial carcinomas are biologically heterogeneous and that the morphologic clues we currently use to distinguish one subtype from another fail to correlate with biological data. Many tumors that appear morphologically mixed are, in fact, not biologically or clinically confused: most represent biologically "pure" tumors with variant morphology. Interesting associations between the presence of Lynch Syndrome (hereditary nonpolyposis colorectal carcinoma syndrome) and ambiguous morphology have been discussed in the literature. An apparent relationship between morphologic ambiguity and malignant mixed Müllerian tumor (MMMT) also exists. The identity of some morphologically ambiguous endometrial carcinoma can be elucidated with immunohistochemistry or other ancillary techniques at present, but the nature of many still remains undefined. This review presents the concept of morphologically ambiguous endometrial carcinomas, proposes morphological gold standard diagnostic criteria for tumors that are not ambiguous (an effort that helps define tumors that are ambiguous), provides a relevant literature review and offers practical guidance for sorting through diagnostically challenging cases. © 2010 Elsevier Inc.

Heller G.,Sloan Kettering Cancer Center
Lifetime Data Analysis | Year: 2011

The prevalence of interval censored data is increasing in medical studies due to the growing use of biomarkers to define a disease progression endpoint. Interval censoring results from periodic monitoring of the progression status. For example, disease progression is established in the interval between the clinic visit where progression is recorded and the prior clinic visit where there was no evidence of disease progression. A methodology is proposed for estimation and inference on the regression coefficients in the Cox proportional hazards model with interval censored data. The methodology is based on estimating equations and uses an inverse probability weight to select event time pairs where the ordering is unambiguous. Simulations are performed to examine the finite sample properties of the estimate and a colon cancer data set is used to demonstrate its performance relative to the conventional partial likelihood estimate that ignores the interval censoring. © 2010 Springer Science+Business Media, LLC.

Brennan C.,Sloan Kettering Cancer Center
Current Neurology and Neuroscience Reports | Year: 2011

Recent large-scale genomic profiling studies of glioma have yielded a proliferation of candidate subclasses, biomarkers and therapeutic targets for investigation. Some findings, such as that of IDH mutation in low-grade gliomas and secondary glioblastoma (GBM), fit well into established notions of different routes of gliomagenesis. Other results, such as the division of primary GBM based on signaling pathway alterations, suggest new pathogenetic routes with implications for treatment. The analysis of this data is still in the early stage. Nonetheless, several preliminary findings merit consideration in the development and interpretation of current clinical trials. © Springer Science+Business Media, LLC 2011.

Morris P.G.,Sloan Kettering Cancer Center
Anti-Cancer Drugs | Year: 2010

Despite advances in cancer biology, chemotherapy remains the backbone of treatment approaches for many patients with metastatic breast cancer (MBC). Halichondrins, derived from marine sponges, have significant potential as potent antimicrotubule agents. Eribulin, with proven preclinical activity, is a synthetic halichondrin analog with novel actions on tubulin including suppression of microtubule polymerization. Phase I and II studies in MBC identified neutropenia as the dose-limiting toxicity and a maximum tolerated dose of 1.4mg/m2 on days 1 and 8 of a 21-day cycle. An encouraging response rate of 11.5% in refractory MBC led to the launch of the phase III Eisai Metastatic Breast Cancer Study Assessing Physician's Choice versus Eribulin trial, in which heavily pretreated patients with MBC were randomized 2 : 1 to intravenous eribulin or monotherapy of the investigator's choice. Recently, it was reported that this important study of 762 patients met its primary endpoint of overall survival: Eribulin was associated with an improvement in median overall survival from 10.65 months to 13.12 months (hazard ratio 0.8; 95% confidence interval 0.66-0.99) and a response rate of 12.2%. In general, the side effect profile of eribulin seems to be acceptable, as although neutropenia occurred in 45% of the patients, febrile neutropenia was rare and the incidence of neuropathy was low. These findings show that eribulin is potentially a new active agent for MBC, although results of ongoing studies are awaited to confirm the reported benefit. Future studies will investigate the potential role of eribulin in other settings, including for early breast cancer, to ascertain how to optimally incorporate this new agent into current treatment paradigms. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Pasternak G.W.,Sloan Kettering Cancer Center
Clinical Journal of Pain | Year: 2010

Most of the opioids used in clinical practice exert their effects through μ opioid receptors. Yet, subtle but important pharmacological differences have been observed among the μ opioids. Their potency, effectiveness, and adverse effects can vary unpredictably among patients. These clinical differences among the μ opioids strongly argue against a single receptor mediating their actions. The cloning of the μ opioid receptor has greatly enhanced our understanding of the complexity of this system and has provided possible mechanisms to explain these observations. A single μ opioid receptor gene has been identified, but we now know that it generates a multitude of different μ opioid receptor subtypes through a mechanism commonly used to enhance protein diversity, alternative splicing. Early studies identified a number of splice variants involving the tip of the C-terminus. This region of the receptor is far away from the binding pocket, explaining why these variants still exhibit the same selectivity for μ opioids. However, the differences in structure at the C-terminus influence the activation patterns of the μ opioids. In addition, a second series of variants has been isolated that involves alternative splicing at the N-terminus. Together, these sets of μ opioid receptor splice variants may help explain the clinical variability of the μ drugs among patients and provide insights into why it is so important to individualize therapy for every patient in pain. © 2010 Lippincott Williams & Wilkins, Inc.

Docampo M.D.,The New School | Auletta J.J.,Ohio State University | Jenq R.R.,Sloan Kettering Cancer Center
Biology of Blood and Marrow Transplantation | Year: 2015

The intestinal microbiota has many critical roles in maintaining gastrointestinal epithelial and gastrointestinal systemic immune homeostasis. This review provides insight into how allogeneic hematopoietic cell transplantation (HCT) and its associated complications and supportive care therapies affect the microbiota. Additionally, the review discusses how preservation and restoration of the microbiota might be advantageous in decreasing HCT-related morbidity and mortality. © 2015 American Society for Blood and Marrow Transplantation.

Cheung and colleagues demonstrate that amplified CRKL can function as a driver oncogene in lung adenocarcinoma, activating both RAS and RAP1 to induce mitogen-activated protein kinase signaling. In addition, they show that CRKL amplification may be another mechanism for primary or acquired resistance to epidermal growth factor receptor kinase inhibitors. © 2011 American Association for Cancer Research.

Otlowski M.,University of Tasmania | Taylor S.,University of Tasmania | Bombard Y.,Yale University | Bombard Y.,Sloan Kettering Cancer Center
Annual Review of Genomics and Human Genetics | Year: 2012

Genetic discrimination (GD) is a complex, multifaceted ethical, psychosocial, and legal phenomenon. It is defined as the differential treatment of asymptomatic individuals or their relatives on the basis of their real or assumed genetic characteristics. This article presents an overview of GD within the contemporary international context. It describes the concept of GD and its contextual features, reviews research evidence regarding people's experiences of GD and the impact of GD within a range of domains, and provides an overview of legal and policy responses to GD that have emerged globally. We argue that GD is a significant and internationally established phenomenon that requires multilevel responses to ensure social justice and equitable outcomes for all citizens. Future research should monitor GD and its impacts within the community as well as institutions and should evaluate the effectiveness of legislative, policy, community education, and systemic responses. © 2012 by Annual Reviews. All rights reserved.

Krejci L.,Masaryk University | Krejci L.,St Annes University Hospital In Brno | Altmannova V.,Masaryk University | Altmannova V.,St Annes University Hospital In Brno | And 2 more authors.
Nucleic Acids Research | Year: 2012

Homologous recombination (HR) is critical both for repairing DNA lesions in mitosis and for chromosomal pairing and exchange during meiosis. However, some forms of HR can also lead to undesirable DNA rearrangements. Multiple regulatory mechanisms have evolved to ensure that HR takes place at the right time, place and manner. Several of these impinge on the control of Rad51 nucleofilaments that play a central role in HR. Some factors promote the formation of these structures while others lead to their disassembly or the use of alternative repair pathways. In this article, we review these mechanisms in both mitotic and meiotic environments and in different eukaryotic taxa, with an emphasis on yeast and mammal systems. Since mutations in several proteins that regulate Rad51 nucleofilaments are associated with cancer and cancer-prone syndromes, we discuss how understanding their functions can lead to the development of better tools for cancer diagnosis and therapy. © 2012 The Author(s).

Deberardinis R.J.,University of Texas Southwestern Medical Center | Thompson C.B.,Sloan Kettering Cancer Center
Cell | Year: 2012

An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states - often genetically programmed - that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is now a crucial frontier in disease-oriented research. This Review discusses the broad impact of metabolism in cellular function and how modern concepts of metabolism can inform our understanding of common diseases like cancer and also considers the prospects of developing new metabolic approaches to disease treatment. © 2012 Elsevier Inc.

Chou T.-C.,Sloan Kettering Cancer Center
Cancer Research | Year: 2010

This brief perspective article focuses on the most common errors and pitfalls, as well as the do's and don'ts in drug combination studies, in terms of experimental design, data acquisition, data interpretation, and computerized simulation. The Chou-Talalay method for drug combination is based on the median-effect equation, derived from the mass-action law principle, which is the unified theory that provides the common link between single entity and multiple entities, and first order and higher order dynamics. This general equation encompasses the Michaelis-Menten, Hill, Henderson-Hasselbalch, and Scatchard equations in biochemistry and biophysics. The resulting combination index (CI) theorem of Chou-Talalay offers quantitative definition for additive effect (CI = 1), synergism (CI < 1), and antagonism (CI > 1) in drug combinations. This theory also provides algorithms for automated computer simulation for synergism and/or antagonism at any effect and dose level, as shown in the CI plot and isobologram, respectively. ©2010 AACR.

Panageas K.S.,Sloan Kettering Cancer Center
Expert Review of Clinical Pharmacology | Year: 2015

Major recent advances in the diagnosis, treatment, prevention and screening of cancer have led to improvements in survival and other outcomes for cancer patients. When the 198 identified rare cancers are taken in aggregate, rare cancers account for 22% of all cancer diagnoses, higher than any single common cancer. Yet median survival for patients with rare cancer patients remains poor as clinical trial and treatment advancements trail those achieved for common cancer. Overcoming the challenges inherent in the study of rare diseases is critical to achieve improvements in outcomes for patients. Combining a redesign of clinical trial protocols with the new paradigm for the treatment of all cancers, may lead to improvements in survival benefits for rare cancers in line with those achieved in the treatment of more common types. © 2015 Taylor & Francis.

Serganov A.,New York University | Patel D.J.,Sloan Kettering Cancer Center
Annual Review of Biophysics | Year: 2012

Riboswitches are mRNA elements capable of modulating gene expression in response to specific binding by cellular metabolites. Riboswitches exert their function through the interplay of alternative ligand-free and ligand-bound conformations of the metabolite-sensing domain, which in turn modulate the formation of adjacent gene expression controlling elements. X-ray crystallography and NMR spectroscopy have determined three-dimensional structures of virtually all the major riboswitch classes in the ligand-bound state and, for several riboswitches, in the ligand-free state. The resulting spatial topologies have demonstrated the wide diversity of riboswitch folds and revealed structural principles for specific recognition by cognate metabolites. The available three-dimensional information, supplemented by structure-guided biophysical and biochemical experimentation, has led to an improved understanding of how riboswitches fold, what RNA conformations are required for ligand recognition, and how ligand binding can be transduced into gene expression modulation. These studies have greatly facilitated the dissection of molecular mechanisms underlying riboswitch action and should in turn guide the anticipated development of tools for manipulating gene regulatory circuits. © 2012 by Annual Reviews. All rights reserved.

Chi P.,Rockefeller University | Chi P.,Sloan Kettering Cancer Center | Allis C.D.,Rockefeller University | Wang G.G.,Rockefeller University
Nature Reviews Cancer | Year: 2010

Post-translational modification of histones provides an important regulatory platform for processes such as gene transcription and DNA damage repair. It has become increasingly apparent that the misregulation of histone modification, which is caused by the deregulation of factors that mediate the modification installation, removal and/or interpretation, actively contributes to human cancer. In this Review, we summarize recent advances in understanding the interpretation of certain histone methylations by plant homeodomain finger-containing proteins, and how misreading, miswriting and mis-erasing of histone methylation marks can be associated with oncogenesis and progression. These observations provide us with a greater mechanistic understanding of epigenetic alterations in human cancers and might also help direct new therapeutic interventions in the future. © 2010 Macmillan Publishers Limited. All rights reserved.

Cassileth B.R.,Sloan Kettering Cancer Center
The oncologist | Year: 2010

Integrative oncology is the synthesis of mainstream cancer care and evidence-based complementary therapies. Complementary strategies include massage therapies, acupuncture, fitness, and mind-body techniques, which take advantage of the reciprocal relationship between the mind and body. Neuropathic pain--and pain more generally--is part of a complex process involving the whole physical and psychosocial being, therefore requiring an integrative management approach. Several studies have demonstrated, for example, that social context plays an important role in the perception of pain and that a patient's coping strategies can influence the persistence of pain. In this article, we briefly describe research illustrating the promise of integrative approaches for the treatment of cancer-related neuropathic pain.

Huse J.T.,Sloan Kettering Cancer Center | Aldape K.D.,University of Toronto
Clinical Cancer Research | Year: 2014

While the classification of diffuse gliomas has relied on the examination of morphologic features supplemented with techniques such as immunohistochemistry, there is an increasing recognition of substantial biologic diversity within morphologically defined entities. High-throughput technologies, in particular studies that integrate genome-wide data from diverse molecular platforms, increasingly identify the existence of robust and distinct glioma subtypes. While treatment advances and improvement of outcomes for patients with diffuse glioma have been modest, there may be benefit to integrate findings from biologic studies into clinical practice to enhance the precision of treatment for these diseases. Recent examples such as the identification of mutations in IDH1 and IDH2 as an early genetic event that is predominantly in lower-grade gliomas (grades 2 and 3) underscore the importance of molecular discovery leading to the ability to develop subclassifications with prognostic and potentially therapeutic implications. In contrast, glioblastoma (grade 4), the most common and aggressive glioma, typically arises without IDH mutation, supporting the need for different therapeutic approaches. Additional genomic and epigenomic signatures are generally nonoverlapping between IDH-mutant and IDH wild-type diffuse glioma, and despite comparable histopathology, IDH-mutant gliomas can be considered as biologically distinct from IDH wild-type gliomas. In this CCR Focus article, we highlight and summarize the current understanding of recent molecular findings and the relationships of these findings to clinical trials and clinical management. © 2014 AACR.

Marks P.A.,Sloan Kettering Cancer Center
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2010

There are eleven zinc dependent histone deacetylases (HDAC) in humans which have histones and many non-histone substrates. The substrates of these enzymes include proteins that have a role in regulation of gene expression, cell proliferation, cell migration, cell death, immune pathways and angiogenesis. Inhibitors of HDACs (HDACi) have been developed which alter the structure and function of these proteins, causing molecular and cellular changes that induce transformed cell death. The HDACi are being developed as anti-cancer drugs and have therapeutic potential for many non-oncologic diseases. © 2010 Elsevier B.V.

Marks D.S.,Harvard University | Hopf T.A.,Harvard University | Sander C.,Sloan Kettering Cancer Center
Nature Biotechnology | Year: 2012

Genomic sequences contain rich evolutionary information about functional constraints on macromolecules such as proteins. This information can be efficiently mined to detect evolutionary couplings between residues in proteins and address the long-standing challenge to compute protein three-dimensional structures from amino acid sequences. Substantial progress has recently been made on this problem owing to the explosive growth in available sequences and the application of global statistical methods. In addition to three-dimensional structure, the improved understanding of covariation may help identify functional residues involved in ligand binding, protein-complex formation and conformational changes. We expect computation of covariation patterns to complement experimental structural biology in elucidating the full spectrum of protein structures, their functional interactions and evolutionary dynamics. © 2012 Nature America, Inc.

Schejter E.D.,Weizmann Institute of Science | Baylies M.K.,Sloan Kettering Cancer Center
Current Opinion in Cell Biology | Year: 2010

From the muscles that control the blink of your eye to those that allow you to walk, the basic architecture of muscle is the same: muscles consist of bundles of the unit muscle cell, the muscle fiber. The unique morphology of the individual muscle fiber is dictated by the functional demands necessary to generate and withstand the forces of contraction, which in turn leads to movement. Contractile muscle fibers are elongated, syncytial cells, which interact with both the nervous and skeletal systems to govern body motion. In this review, we focus on three key cell-cell and cell-matrix contact processes, that are necessary to create this exquisitely specialized cell: cell fusion, cell elongation, and establishment of a myotendinous junction. We address these processes by highlighting recent findings from the Drosophila model system. © 2010 Elsevier Ltd.

Beauchamp K.A.,Sloan Kettering Cancer Center | Pande V.S.,Stanford University | Das R.,Stanford University
Biophysical Journal | Year: 2014

Predicting biological structure has remained challenging for systems such as disordered proteins that take on myriad conformations. Hybrid simulation/experiment strategies have been undermined by difficulties in evaluating errors from computational model inaccuracies and data uncertainties. Building on recent proposals from maximum entropy theory and nonequilibrium thermodynamics, we address these issues through a Bayesian energy landscape tilting (BELT) scheme for computing Bayesian hyperensembles over conformational ensembles. BELT uses Markov chain Monte Carlo to directly sample maximum-entropy conformational ensembles consistent with a set of input experimental observables. To test this framework, we apply BELT to model trialanine, starting from disagreeing simulations with the force fields ff96, ff99, ff99sbnmr-ildn, CHARMM27, and OPLS-AA. BELT incorporation of limited chemical shift and 3J measurements gives convergent values of the peptide's α, β, and PPII conformational populations in all cases. As a test of predictive power, all five BELT hyperensembles recover set-aside measurements not used in the fitting and report accurate errors, even when starting from highly inaccurate simulations. BELT's principled framework thus enables practical predictions for complex biomolecular systems from discordant simulations and sparse data. © 2014 Biophysical Society.

Herr H.W.,Sloan Kettering Cancer Center
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2015

Repeat transurethral resection (TUR) is indicated for high-grade non-muscle-invasive bladder tumors. Repeat TUR is a diagnostic, therapeutic, prognostic, and predictive procedure. Repeat TUR achieves optimal local control by removing residual tumors after initial TUR, improves staging accuracy, provides additional histologic material favoring accurate diagnosis, allocates appropriate therapy with improved outcomes, facilitates response to intravesical therapy, and provides important prognostic information. © JNCCN - Journal of the National Comprehensive Cancer Network.

Wu P.,Rockefeller University | van Overbeek M.,Rockefeller University | van Overbeek M.,Sloan Kettering Cancer Center | Rooney S.,Rockefeller University | de Lange T.,Rockefeller University
Molecular Cell | Year: 2010

Mammalian telomeres contain a single-stranded 3' overhang that is thought to mediate telomere protection. Here we identify the TRF2-interacting factor Apollo as a nuclease that contributes to the generation/maintenance of this overhang. The function of mouse Apollo was determined using Cre-mediated gene deletion, complementation with Apollo mutants, and the TRF2-F120A mutant that cannot bind Apollo. Cells lacking Apollo activated the ATM kinase at their telomeres in S phase and showed leading-end telomere fusions. These telomere dysfunction phenotypes were accompanied by a reduction in the telomeric overhang signal. The telomeric functions of Apollo required its TRF2-interaction and nuclease motifs. Thus, TRF2 recruits the Apollo nuclease to process telomere ends synthesized by leading-strand DNA synthesis, thereby creating a terminal structure that avoids ATM activation and resists end-joining. These data establish that the telomeric overhang is required for the protection of telomeres from the DNA damage response. © 2010 Elsevier Inc.

Wang S.Q.,Sloan Kettering Cancer Center
Seminars in cutaneous medicine and surgery | Year: 2011

Commercial sunscreen based on nano-sized titanium dioxide (TiO(2)) and zinc oxide (ZnO) delivers superior UV protection and reduces whitening on skin compared to the older generations of inorganic sunscreens. This review discusses the historical use of nano-sized TiO(2) and ZnO in sunscreen and the relationship between UV attenuation and the primary particles, aggregates and agglomerates that make up these inorganic oxides. In addition we reviewed the recent safety concerns surrounding these materials, specifically, percutaneous penetration of TiO(2) and ZnO nanoparticles through human skin and their potential to cause phototoxicity. Copyright © 2011 Elsevier Inc. All rights reserved.

Mo Q.,Sloan Kettering Cancer Center
Biostatistics | Year: 2012

Chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) is a powerful technique that is being used in a wide range of biological studies including genome-wide measurements of protein-DNA interactions, DNA methylation, and histone modifications. The vast amount of data and biases introduced by sequencing and/or genome mapping pose new challenges and call for effective methods and fast computer programs for statistical analysis. To systematically model ChIP-seq data, we build a dynamic signal profile for each chromosome and then model the profile using a fully Bayesian hidden Ising model. The proposed model naturally takes into account spatial dependency and global and local distributions of sequence tags. It can be used for one-sample and two-sample analyses. Through model diagnosis, the proposed method can detect falsely enriched regions caused by sequencing and/or mapping errors, which is usually not offered by the existing hypothesis-testing-based methods. The proposed method is illustrated using 3 transcription factor (TF) ChIP-seq data sets and 2 mixed ChIP-seq data sets and compared with 4 popular and/or well-documented methods: MACS, CisGenome, BayesPeak, and SISSRs. The results indicate that the proposed method achieves equivalent or higher sensitivity and spatial resolution in detecting TF binding sites with false discovery rate at a much lower level. © The Author 2011.

Gupta V.,University of Toronto | Tallman M.S.,Sloan Kettering Cancer Center | Weisdorf D.J.,University of Minnesota
Blood | Year: 2011

Progress in the last decade has improved the understanding of leukemia biology. Molecular markers in combinations with cytogenetics have improved the risk stratification of acute myeloid leukemia (AML) and informed decision-making. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning have improved the safety as well as access of allogeneic hematopoietic cell transplantation (HCT) for a larger number of patients. In this review, the positioning of HCT in the management of patients with AML is evaluated in view of changing risk/benefit ratios associated with both conventional treatments and transplantation, and some of the controversies are addressed in light of emerging data. Increasing data demonstrate outcomes of alternative donor transplantation approaching HLA-identical sibling donors in high-risk AML supporting the inclusion of alternative donors in trials of prospective studies evaluating post remission strategies for high-risk AML. The use of reduced-intensity conditioning has expanded the eligibility of HCT to older patients with AML, and outcome data are encouraging. Continued study of HCT versus alternative therapies is required to optimize patients' outcomes in AML. © 2011 by The American Society of Hematology.

Penack O.,Charite - Medical University of Berlin | Socie G.,Hopital Saint Louis | Van Den Brink M.R.M.,Sloan Kettering Cancer Center
Blood | Year: 2011

GVHD and tumor relapse are fundamental problems in allogeneic HSCT. Recent research has linked neovascularization to GVHD, tumor growth, and graft-versus-tumor (GVT) activity. Damage of the endothelium by the conditioning regimen provides the initiation stimulus for recruitment of donor-derived endothelial cells and their progenitors. During the early inflammatory phase of GVHD there is considerable neovascularization facilitating migration of inflammatory cells to target organs. In the course of GVHD, however, the vasculature itself becomes a target of alloreactive donor T cells. As a consequence, later stages of GVHD are characterized by fibrosis and rarefaction of blood vessels. Importantly, the inhibition of tumor-neovascularization by activated donor T cells that release antiangiogenic substances contributes to GVT and may be enhanced by pharmacologic inhibition of neovascularization. Furthermore, the therapeutic inhibition of neovascularization may improve immunotherapy for cancer by enhancing leukocyte infiltration in tumor tissue because of normalization of tumor vessels and stimulation of leukocyte-vessel wall interactions. These insights identify important mechanisms underlining the importance of neovascularization for allogeneic immune responses and move therapeutic approaches targeting neovascularization into the spotlight. This perspective covers current knowledge of the role of neovascularization during GVHD as well as GVT and its implications for HSCT. © 2011 by The American Society of Hematology.

van Loosdregt J.,University Utrecht | Coffer P.J.,University Utrecht | Coffer P.J.,Sloan Kettering Cancer Center
Trends in Immunology | Year: 2014

Forkhead box (FOX)P3 is a requisite transcription factor for the development and maintenance of immunosuppressive function of regulatory T (Treg) cells, and therefore for immune homeostasis. Post-translational modifications (PTMs) can transiently alter the functionality of transcription factors, and recent evidence reveals that FOXP3 can be regulated by various PTMs including acetylation, ubiquitination, and phosphorylation. Here, we review the current understanding of how these modifications control FOXP3, including regulation of DNA binding, transactivation potential, and proteasomal degradation. We place these findings in the context of the biology of Treg cells, and discuss both limitations in translating biochemical findings into in vivo functions and the opportunities presented by a better understanding of the molecular mechanisms that can transiently control FOXP3 activity in response to environmental cues. © 2014 Elsevier Ltd.

Tew W.P.,Sloan Kettering Cancer Center | Fleming G.F.,University of Chicago
Gynecologic Oncology | Year: 2015

Half of ovarian cancer patients are over the age of 65, and as the population ages, the number of older women with ovarian cancer is increasing. Older women with ovarian cancer receive less surgery and chemotherapy than younger women, suffer worse toxicity from surgery and chemotherapy than younger women, and have worse survival. Performance status has been shown to be an inadequate tool to predict toxicity of older patients from therapy. Use of formal geriatric assessment tools is a promising direction for stratifying older patients on trials. We review current data on outcomes with surgery and chemotherapy in the older population, and discuss geriatric assessment tools being studied to aid decisions regarding which older patients will tolerate standard therapy and which will not. Modified treatment regimens and interventions to decrease morbidities in the vulnerable older population should be useful. © 2014 Elsevier Inc. All rights reserved.

Grabocka E.,New York University | Pylayeva-Gupta Y.,New York University | Jones M.,Sloan Kettering Cancer Center | Lubkov V.,New York University | And 4 more authors.
Cancer Cell | Year: 2014

Mutations in KRAS are prevalent in human cancers and universally predictive of resistance to anticancer therapeutics. Although it is widely accepted that acquisition of an activating mutation endows RAS genes with functional autonomy, recent studies suggest that the wild-type forms of Ras may contribute to mutant Ras-driven tumorigenesis. Here, we show that downregulation of wild-type H-Ras or N-Ras in mutant K-Ras cancer cells leads to hyperactivation of the Erk/p90RSK and PI3K/Akt pathways and, consequently, the phosphorylation of Chk1 at an inhibitory site, Ser 280. The resulting inhibition of ATR/Chk1 signaling abrogates the activation of the G2 DNA damage checkpoint and confers specific sensitization of mutant K-Ras cancer cells to DNA damage chemotherapeutic agents invitro and invivo. © 2014 Elsevier Inc.

Glare P.A.,Sloan Kettering Cancer Center
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2013

Patients with cancer experience many complex issues throughout the trajectory of the disease. These range from the physical consequences of cancer and treatment to the psychological, social, and spiritual issues associated with living with the disease. An individualized, comprehensive, and interdisciplinary approach is needed to reduce patient suffering and ensure appropriate symptom management and support from the time of first diagnosis to end of life. Data from randomized clinical trials prove that patients provided with early palliative care can experience relief of symptoms and improvements in quality of life, mood, satisfaction, resource use, and advanced care planning. Professional organizations such as ASCO have begun to develop recommendations that integrate palliative care into standard oncologic care from the time a person is diagnosed with metastatic or advanced cancer. NCCN has a palliative care guideline that recommends early and ongoing assessment of palliative care needs and referral to specialist palliative care services in more complex cases. In turn, oncologists need to consider how best to screen patients and integrate early palliative care with routine oncologic care, within the context of their busy clinics, to ensure that patients, families, and caregivers receive timely support. Copyright © 2013 by the National Comprehensive Cancer Network. All rights reserved.

Resh M.D.,Sloan Kettering Cancer Center
Progress in Lipid Research | Year: 2016

Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty acylation to regulate intracellular trafficking, subcellular localization, protein-protein and protein-lipid interactions. Myristate and palmitate represent the most common fatty acid modifying groups. New insights into how fatty acylation reactions are catalyzed, and how fatty acylation regulates protein structure and function continue to emerge. Myristate is typically linked to an N-terminal glycine, but recent studies reveal that lysines can also be myristoylated. Enzymes that remove N-terminal myristoyl-glycine or myristate from lysines have now been identified. DHHC proteins catalyze S-palmitoylation, but the mechanisms that regulate substrate recognition by individual DHHC family members remain to be determined. New studies continue to reveal thioesterases that remove palmitate from S-acylated proteins. Another area of rapid expansion is fatty acylation of the secreted proteins hedgehog, Wnt and Ghrelin, by Hhat, Porcupine and GOAT, respectively. Understanding how these membrane bound O-acyl transferases recognize their protein and fatty acyl CoA substrates is an active area of investigation, and is punctuated by the finding that these enzymes are potential drug targets in human diseases. © 2016 Elsevier B.V. All rights reserved.

Laursen K.B.,Cornell University | Wong P.-M.,Sloan Kettering Cancer Center | Gudas L.J.,Cornell University
Nucleic Acids Research | Year: 2012

Retinoic acid receptors (RARs) α, β and γ are key regulators of embryonic development. Hematopoietic differentiation is regulated by RARα, and several types of leukemia show aberrant RARα activity. Through microarray expression analysis, we identified transcripts differentially expressed between F9 wild-type (Wt) and RARα knockout cells cultured in the absence or presence of the RAR-specific ligand all trans retinoic acid (RA). We validated the decreased Mest, Tex13, Gab1, Bcl11a, Tcfap2a and HMGcs1 transcript levels, and increased Slc38a4, Stmn2, RpL39l, Ref2L, Mobp and Rlf1 transcript levels in the RARa knockout cells. The decreased Mest and Tex13 transcript levels were associated with increased promoter CpG-island methylation and increased repressive histone modifications (H3K9me3) in RARα knockout cells. Increased Slc38a4 and Stmn2 transcript levels were associated with decreased promoter CpG-island methylation and increased permissive histone modifications (H3K9/K14ac, H3K4me3) in RARα knockout cells. We demonstrated specific association of RARα and RXRα with the Mest promoter. Importantly, stable expression of a dominant negative, oncogenic PML-RARα fusion protein in F9 Wt cells recapitulated the decreased Mest transcript levels observed in RARα knockout cells. We propose that RARα plays an important role in cellular memory and imprinting by regulating the CpG methylation status of specific promoter regions. © 2011 The Author(s).

Chodera J.D.,Sloan Kettering Cancer Center
Journal of Chemical Theory and Computation | Year: 2016

Molecular simulations intended to compute equilibrium properties are often initiated from configurations that are highly atypical of equilibrium samples, a practice which can generate a distinct initial transient in mechanical observables computed from the simulation trajectory. Traditional practice in simulation data analysis recommends this initial portion be discarded to equilibration, but no simple, general, and automated procedure for this process exists. Here, we suggest a conceptually simple automated procedure that does not make strict assumptions about the distribution of the observable of interest in which the equilibration time is chosen to maximize the number of effectively uncorrelated samples in the production timespan used to compute equilibrium averages. We present a simple Python reference implementation of this procedure and demonstrate its utility on typical molecular simulation data. © 2016 American Chemical Society.

Lee C.J.,Sloan Kettering Cancer Center | Ansell J.E.,New Hill
British Journal of Clinical Pharmacology | Year: 2011

Heparins and vitamin K antagonists have been the primary agents used for anticoagulation in certain cardiovascular and thromboembolic diseases for over 50 years. However, they can be difficult to administer and are fraught with limitations. In response to the need for new anticoagulants, direct thrombin inhibitors (DTIs) have been developed and investigated for their utility in prophylaxis and treatment of venous thromboembolism (VTE), heparin-induced thrombocytopenia (HIT), acute coronary syndromes (ACS), secondary prevention of coronary events after ACS, and nonvalvular atrial fibrillation. Currently, four parenteral direct inhibitors of thrombin activity are FDA-approved in North America: lepirudin, desirudin, bivalirudin and argatroban. Of the new oral DTIs, dabigatran etexilate is the most studied and promising of these agents. This review discusses the clinical indications and efficacy of these direct thrombin inhibitors as well as future directions in anticoagulant therapy. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Bejar R.,University of California at San Diego | Abdel-Wahab O.,Sloan Kettering Cancer Center
Blood | Year: 2013

In this issue of Blood, Papaemmanuil et al present results from the largest single targeted sequencing effort in myelodysplastic syndrome (MDS) to date both in terms of number of patients studied (738 patients, of which 603 had MDS) and genes sequenced (111 genes). © 2013 by The American Society of Hematology.

Begg C.B.,Sloan Kettering Cancer Center
International Journal of Cancer | Year: 2011

Much attention is directed currently to identifying subtypes of cancers that are genetically and clinically distinct. The expectation is that subtyping on the basis of somatic genomic characteristics will supplant traditional pathological subtypes with respect to relevance for targeted therapies and clinical course. Less attention has been paid to the goal of validating subtypes on the basis of the distinctiveness of their etiologies. In this article it is shown that studies of individuals with double primary malignancies provide uniquely valuable information for establishing the etiologic distinctiveness of candidate tumor subtypes. Studies of double primaries have the potential to definitively rank candidate taxonomic systems with respect to their etiological relevance by determining which subtypes are most highly correlated in the double primaries. The concept is illustrated with data from studies of the concordance of estrogen and progestin status in bilateral breast cancers, where it is shown that double primaries are much more likely to be concordant with respect to estrogen receptor (ER) status than for PR status. The high concordance of ER status is consistent with a growing literature demonstrating the etiologic distinctiveness of ER+ and ER- tumors. Copyright © 2010 UICC.

Mutations in genes encoding splicing factors (which we refer to as spliceosomal genes) are commonly found in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations recurrently affect specific amino acid residues, leading to perturbed normal splice site and exon recognition. Spliceosomal gene mutations are always heterozygous and rarely occur together with one another, suggesting that cells may tolerate only a partial deviation from normal splicing activity. To test this hypothesis, we engineered mice to express a mutated allele of serine/arginine-rich splicing factor 2 (Srsf2P95H)—which commonly occurs in individuals with MDS and AML—in an inducible, hemizygous manner in hematopoietic cells. These mice rapidly succumbed to fatal bone marrow failure, demonstrating that Srsf2-mutated cells depend on the wild-type Srsf2 allele for survival. In the context of leukemia, treatment with the spliceosome inhibitor E7107 (refs. 7,8) resulted in substantial reductions in leukemic burden, specifically in isogenic mouse leukemias and patient-derived xenograft AMLs carrying spliceosomal mutations. Whereas E7107 treatment of mice resulted in widespread intron retention and cassette exon skipping in leukemic cells regardless of Srsf2 genotype, the magnitude of splicing inhibition following E7107 treatment was greater in Srsf2-mutated than in Srsf2-wild-type leukemia, consistent with the differential effect of E7107 on survival. Collectively, these data provide genetic and pharmacologic evidence that leukemias with spliceosomal gene mutations are preferentially susceptible to additional splicing perturbations in vivo as compared to leukemias without such mutations. Modulation of spliceosome function may thus provide a new therapeutic avenue in genetically defined subsets of individuals with MDS or AML. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Xavier J.B.,Sloan Kettering Cancer Center
Molecular Systems Biology | Year: 2011

Social interaction among cells is essential for multicellular complexity. But how do molecular networks within individual cells confer the ability to interact? And how do those same networks evolve from the evolutionary conflict between individual- and population-level interests? Recent studies have dissected social interaction at the molecular level by analyzing both synthetic and natural microbial populations. These studies shed new light on the role of population structure for the evolution of cooperative interactions and revealed novel molecular mechanisms that stabilize cooperation among cells. New understanding of populations is changing our view of microbial processes, such as pathogenesis and antibiotic resistance, and suggests new ways to fight infection by exploiting social interaction. The study of social interaction is also challenging established paradigms in cancer evolution and immune system dynamics. Finding similar patterns in such diverse systems suggests that the same 'social interaction motifs' may be general to many cell populations. © 2011 EMBO and Macmillan Publishers Limited All rights reserved.

Rajkumar S.V.,Mayo Medical School | Landgren O.,Sloan Kettering Cancer Center | Mateos M.-V.,University of Salamanca
Blood | Year: 2015

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an ≥80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM. © 2015 by The American Society of Hematology.

Hanash A.M.,Sloan Kettering Cancer Center
Blood | Year: 2015

In this issue of Blood, Wikstrom and colleagues highlight antigen-presenting cell (APC) dysfunction as a potential cause of impaired antiviral immunity in graft-versus-host disease (GVHD). © 2015 by The American Society of Hematology.

Li M.O.,Sloan Kettering Cancer Center
Cell Research | Year: 2016

Asymmetric division in CD8 T cells produces two daughter cells expressing different levels of c-Myc with distinct metabolic profiles. Manipulating this asymmetric partitioning of c-Myc skews T cell responses and potentially allows the development of more effective vaccines and cancer immunotherapies. © 2016 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

Weber W.A.,Sloan Kettering Cancer Center
Journal of Nuclear Medicine | Year: 2014

Despite considerable excitement about the potential of PET/MR imaging for the detection, staging, and functional characterization of cancer, this new technology is evolving significantly more slowly than PET/CT. This slower evolution is due partly to ongoing technologic challenges (e.g., accurate attenuation correction of PET images) but also to the complex logistics of combining a whole-body PET scan with whole-body or organ-specific MR imaging. Most PET/MR imaging research published so far has focused on cancer staging and restaging in patients undergoing 18F-FDG PET/CT as the standard of care. These studies have demonstrated the feasibility of clinical 18F-FDG PET/MR imaging but so far have not shown substantial improvements in staging. This situation may not be unexpected in view of the fact that MR imaging has not replaced CT for staging of the malignancies for which 18F-FDG PET/CT is most commonly used. Given the widespread concerns about rising health care costs in general and the costs of advanced imaging techniques in particular, establishing 18F-FDG PET/MR imaging for whole-body cancer staging may be challenging because it requires more expensive equipment and longer acquisition times than 18F-FDG PET/CT. An alternative approach to developing clinical PET/MR imaging is to study how stand-alone, organ-specific MR imaging can be improved by PET/MR imaging. Unfortunately, however, 18F-FDG PET has significant limitations for the tumors that are most commonly studied with MR imaging (brain, liver, pancreatic, and prostate tumors). However, this situation may change with the development of new radiopharmaceuticals, such as prostate-specific membrane or gastrin-releasing peptide receptor ligands for the imaging of prostate cancer. In conclusion, PET/MR imaging has many potential advantages over PET/CT (lower radiation exposure, higher soft-tissue contrast, and multiparametric imaging). Realizing this potential in clinics likely will require new radiopharmaceuticals and applications other than whole-body cancer staging. COPYRIGHT © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Dickson M.A.,Sloan Kettering Cancer Center
Clinical Cancer Research | Year: 2014

Unrestrained growth is the hallmark of cancer, and disrupted cell-cycle regulation is, therefore, common. CDK4 is the key regulator of the G 1-S transition. In complex with cyclin D, CDK4 phosphorylates retinoblastoma protein (Rb) and drives cell-cycle progression, a process inhibited by pl6. The pl6-CDK4-cyclin D-Rb is aberrant in the majority of cancers and is, thus, a logical target for anticancer therapy. Previous attempts to block CDK4 with nonselective cyclin-dependent kinase (CDK) inhibitors led to toxicity and little efficacy. However, the recent development of selective CDK4 inhibitors launched the first successful efforts to target the pathway for cancer therapy. Three oral selective CDK4 inhibitors have entered clinical trials: palbociclib (PD0332991), LEEOll, and LY2835219. CDK4 inhibitors have in vitro activity against a broad range of cancers and in patients have shown antitumor activity in breast cancer, lymphoma, sarcoma, and other tumors. Major efforts are under way to develop biomarkers of response, understand potential mechanisms of resistance, and develop rational combinations of CDK4 inhibitors with chemotherapy and other targeted drugs. © 2014 American Association for Cancer Research.

Vickers A.J.,Sloan Kettering Cancer Center
CA Cancer Journal for Clinicians | Year: 2011

Prediction is ubiquitous across the spectrum of cancer care from screening to hospice. Indeed, oncology is often primarily a prediction problem; many of the early stage cancers cause no symptoms, and treatment is recommended because of a prediction that tumor progression would ultimately threaten a patient's quality of life or survival. Recent years have seen attempts to formalize risk prediction in cancer care. In place of qualitative and implicit prediction algorithms, such as cancer stage, researchers have developed statistical prediction tools that provide a quantitative estimate of the probability of a specific event for an individual patient. Prediction models generally have greater accuracy than reliance on stage or risk groupings, can incorporate novel predictors such as genomic data, and can be used more rationally to make treatment decisions. Several prediction models are now widely used in clinical practice, including the Gail model for breast cancer incidence or the Adjuvant! Online prediction model for breast cancer recurrence. Given the burgeoning complexity of diagnostic and prognostic information, there is simply no realistic alternative to incorporating multiple variables into a single prediction model. As such, the question should not be whether but how prediction models should be used to aid decision-making. Key issues will be integration of models into the electronic health record and more careful evaluation of models, particularly with respect to their effects on clinical outcomes. © 2011 American Cancer Society, Inc.

Baselga J.,Sloan Kettering Cancer Center
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Epidermal growth factor receptor is overexpressed in metastatic triple-negative breast cancers (mTNBCs), an aggressive subtype of breast cancer. Our randomized phase II study investigated cisplatin with or without cetuximab in this setting. Patients who had received no more than one previous chemotherapy regimen were randomly assigned on a 2:1 schedule to receive no more than six cycles of cisplatin plus cetuximab or cisplatin alone. Patients receiving cisplatin alone could switch to cisplatin plus cetuximab or cetuximab alone on disease progression. The primary end point was overall response rate (ORR). Secondary end points studied included progression-free survival (PFS), overall survival (OS), and safety profiles. Analyses included a significance level of α = .10 with no adjustments for multiplicity. The full analysis set comprised 115 patients receiving cisplatin plus cetuximab and 58 receiving cisplatin alone; 31 patients whose disease progressed on cisplatin alone switched to cetuximab-containing therapy. The ORR was 20% (95% CI, 13 to 29) with cisplatin plus cetuximab and 10% (95% CI, 4 to 21) with cisplatin alone (odds ratio, 2.13; 95% CI, 0.81 to 5.59; P = .11). Cisplatin plus cetuximab resulted in longer PFS compared with cisplatin alone (median, 3.7 v 1.5 months; hazard ratio [HR], 0.67; 95% CI, 0.47 to 0.97; P = .032). Corresponding median OS was 12.9 versus 9.4 months (HR, 0.82; 95% CI, 0.56 to 1.20; P = .31). Common grade 3/4 adverse events included acne-like rash, neutropenia, and fatigue. While the primary study end point was not met, adding cetuximab to cisplatin doubled the ORR and appeared to prolong PFS and OS, warranting further investigation in mTNBC.

Veselis R.A.,Sloan Kettering Cancer Center | Veselis R.A.,New York Medical College
British Journal of Anaesthesia | Year: 2015

As opposed to conscious, personally relevant (explicit) memories that we can recall at will, implicit (unconscious) memories are prototypical of 'hidden' memory; memories that exist, but that we do not know we possess. Nevertheless, our behaviour can be affected by thesememories; in fact, thesememories allowus to function inan ever-changing world. It is still unclear frombehavioural studies whether similar memories can be formed during anaesthesia. Thus, a relevant question is whether implicit memory formation is a realistic possibility during anaesthesia, considering the underlying neurophysiology. A different conceptualization of memory taxonomy is presented, the serial parallel independentmodel of Tulving,which focuses on dynamic information processing with interactions among different memory systems rather than static classification of different types of memories. The neurophysiological basis for subliminal information processing is considered in the context of brain function as embodied in network interactions. Function of sensory cortices and thalamic activity during anaesthesia are reviewed. The role of sensory and perisensory cortices, in particular the auditory cortex, in support of memory function is discussed. Although improbable, with the current knowledge of neurophysiology one cannot rule out the possibility of memory formation during anaesthesia. © 2015 The Author Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.

Vakiani E.,Sloan Kettering Cancer Center
Advances in Anatomic Pathology | Year: 2015

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 10% to 35% of gastric and gastroesophageal junction (GEJ) adenocarcinomas. In 2010, the phase III Trastuzumab for Gastric Cancer (ToGA) trial showed that addition of the anti-HER2 monoclonal antibody trastuzumab to chemotherapy significantly improved survival of patients with advanced or metastatic tumors that were positive for HER2 overexpression. As a result, HER2 testing is now recommended for all patients with advanced or metastatic disease, although there is still some debate as to the optimal methods of assessment. HER2 expression in gastric and GEJ tumors shows several differences compared with breast tumors and, for this reason, the proposed criteria for scoring HER2 expression in biopsies and resections of gastric and GEJ carcinomas differ from those used in breast carcinomas. This review discusses what is currently known about the patterns of HER2 expression in gastric and GEJ adenocarcinomas, summarizes the findings of the ToGA trial and its clinical implications, and provides an overview of the recommended guidelines for the most accurate evaluation of HER2 status in gastric and GEJ cancer. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Pamer E.G.,Sloan Kettering Cancer Center
Mucosal Immunology | Year: 2014

The mammalian colon is home to a microbial ecosystem that enhances resistance to infection, stimulates mucosal immune defenses, synthesizes essential vitamins, and promotes caloric uptake by hydrolyzing complex carbohydrates. The bacterial populations inhabiting the gut are complex and vary between different individuals. Clinical and experimental studies reveal that the colonic microbiota can enhance or ameliorate intestinal and systemic inflammatory diseases. Because of its potential to enhance resistance to infection and to reduce inflammatory diseases, targeted manipulation of microbial populations is a growing focus of investigation. The most dramatic manipulation of the intestinal microbiota involves fecal microbiota transplantation (FMT) from healthy donors to individuals with specific diseases. Remarkable clinical effectiveness of FMT has been demonstrated for recurrent Clostridium difficile infection and ongoing studies are investigating FMT for other diseases. Transplantation of complex microbial populations to recipients likely triggers mucosal immune responses that, depending on the microbiota composition and the recipient's genotype, could range from pro- to anti-inflammatory. The impact of FMT on the recipient immune system is complex and unpredictable. Ongoing discovery of commensal microbes and investigations of their impact on the host will lead to the development of new probiotic agents and microbial consortia that will eventually replace FMT. © 2014 Society for Mucosal Immunology.

Straus D.J.,Sloan Kettering Cancer Center
Journal of Internal Medicine | Year: 2011

Radiation therapy (RT) alone and more recently in combination with chemotherapy (combined modality therapy; CMT) has been the cornerstone of curative treatment for early-stage Hodgkin lymphoma (HL) for over 40years. Because of increasing awareness of the late morbidity and mortality associated with RT, recent treatment regimens have attempted to limit its use. Chemotherapy only has been demonstrated to be a treatment option for most patients with localized HL. Current clinical trials have targeted subgroups of such patients who may be at an increased risk of recurrence for the addition of limited RT to chemotherapy. © 2011 The Association for the Publication of the Journal of Internal Medicine.

Iasonos A.,Sloan Kettering Cancer Center | O'Quigley J.,University Paris - Sud
Statistics in Medicine | Year: 2012

Model-based dose-finding designs such as the continual reassessment method (CRM) rely on some basic working model. In the Bayesian setting, these take the form of 'guess estimates' of the probabilities of toxicity at each level. In the likelihood setting, these estimates simply take the form of a model as operational characteristics are unaffected by arbitrary positive power transformations. These initial estimates are often referred to as the model skeleton. The impact of any prior distribution on the model parameter that describes the dose-toxicity curve will itself depend on the skeleton being used. We study the interplay between prior assumptions and skeleton choice in the context of two-stage CRM designs. We consider the behavior of a two-stage design at the point of transition from a 3+3 design to CRM. We study how use can be made of stage1 data to construct a more efficient skeleton in conjunction with any prior information through an example of a clinical trial. We evaluate to what extent stage1 data might be down weighted when the maximum tolerated dose (MTD) is far from the starting level and stage1 data is strongly informative. The results show no improvement in accuracy; thus, weighting is not necessary unless the investigators feel strongly about the location of the MTD and wish to accelerate into the vicinity of the MTD. In general, because this information is not available, we recommend that the design of two-stage trials utilize stage1 data to establish a skeleton. © 2012 John Wiley & Sons, Ltd.

Nielsen T.O.,University of British Columbia | Poulin N.M.,University of British Columbia | Ladanyi M.,Sloan Kettering Cancer Center
Cancer Discovery | Year: 2015

Oncogenesis in synovial sarcoma is driven by the chromosomal translocation t(X,18; p11,q11), which generates an in-frame fusion of the SWI/SNF subunit SS18 to the C-terminal repression domains of SSX1 or SSX2. Proteomic studies have identified an integral role of SS18–SSX in the SWI/SNF complex, and provide new evidence for mistargeting of polycomb repression in synovial sarcoma. Two recent in vivo studies are highlighted, providing additional support for the importance of WNT signaling in synovial sarcoma: One used a conditional mouse model in which knockout of β-catenin prevents tumor formation, and the other used a small-molecule inhibitor of β-catenin in xenograft models. Significance: Synovial sarcoma appears to arise from still poorly characterized immature mesenchymal progenitor cells through the action of its primary oncogenic driver, the SS18–SSX fusion gene, which encodes a multifaceted disruptor of epigenetic control. The effects of SS18–SSX on polycomb-mediated gene repression and SWI/SNF chromatin remodeling have recently come into focus and may offer new insights into the basic function of these processes. A central role for deregulation of WNT–β-catenin signaling in synovial sarcoma has also been strengthened by recent in vivo studies. These new insights into the the biology of synovial sarcoma are guiding novel preclinical and clinical studies in this aggressive cancer. © 2015 American Association for Cancer Research.

The FilmArray Respiratory Panel (RP) (BioFire™ Diagnostics, Inc., Salt Lake City, UT, USA) is the first multiplex molecular panel cleared by the US FDA for the detection of both bacterial and viral respiratory pathogens in nasopharygeal swabs. The FilmArray RP targets 20 pathogens including 17 viruses and subtypes and three bacteria, and is performed with minimal sample manipulation. The FilmArray RP has a fully automated sample-to-answer workflow with a turn-around-time of approximately 1 h. The reported sensitivity and specificity of the assay ranges from 80 to 100 and 100%, respectively, with the sensitivity for the adenovirus as low as 46%. A new version of the FilmArray RP assay (version 1.7) with improved sensitivity for the adenovirus was released in 2013. The performance characteristics and simplified workflow have allowed its implementation in a wide range of laboratories. The FilmArray RP has changed the diagnostic landscape and will have a significant impact on the care of patients with respiratory tract infection. © 2013 Informa UK Ltd.

McCormick B.,Sloan Kettering Cancer Center
Current Opinion in Obstetrics and Gynecology | Year: 2012

Purpose of Review: This review is to provide an update on the current status of partial breast irradiation (PBI) for women presenting with early-stage breast cancer, as an alternate radiation technique to fractionated, whole breast radiation, following conservation surgery. As more women are asking for and receiving this treatment, both on and off protocols, understanding recent additions to the literature is important to physicians caring for this patient population. Recent Findings: Newly published retrospective studies, with follow-up times out to 10 years and the status of both recently completed and still open large prospective phase III trials will be covered, with emphasis on unexpected side effects reported, and some hypothesis-generating radiobiology observations. A recent consensus treatment guideline for PBI use is also discussed. Summary: Selected retrospective studies continue to report outcomes matching those achieved with whole breast radiation; however, results from large prospective randomized trials comparing PBI to whole breast radiation have been reported only with short follow-up times, or in two studies, are still pending. A recent consensus guideline is useful at present in selecting patients for discussion of this treatment. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologicmalignancies that arise fromclonal proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs. The vinca alkaloid vincristine is a standard component of chemotherapy regimens used to treat ALL, because of its well-defined mechanism of action, demonstrated anticancer activity, and ability to be combined with other agents. However, the dosage of vincristine is frequently capped because of neurotoxicity concerns, and patients with large body surface areas are, therefore, almost always underdosed. Liposomal formulations have the ability to "passively" accumulate at sites of increased vasculature permeability and reduce the adverse effects of encapsulated relative to free drug. Vincristine sulfate liposome injection (VSLI) is a sphingomyelin/cholesterol-based liposome-encapsulated formulation that is delivered weekly in a 1-hour infusion. Based on the pharmacokinetics of the liposomal delivery system, vincristine is slowly released from the liposome and delivered into the tissues more efficiently than with the standard preparation, allowing a higher dose. This increase in therapeutic index from reduced toxicity is a valuable difference between the two formulations. VSLI is indicated for the treatment of adultswith second or greater relapse and clinically advanced Philadelphia chromosomenegativeALL. For the first time, studieswill be able to exploit the delivery of higher and uncapped doses of vincristine in randomized studies comparing first-line chemotherapy with standard vincristine versus VSLI in both ALL and lymphoma to determine whether VSLI is superior to conventional vincristine. © AlphaMed Press 2016.

Motzer R.J.,Sloan Kettering Cancer Center
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial targeted therapy in patients with metastatic renal cell carcinoma (RCC). Patients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review. A total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio [HR], 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%). Tivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC.

Berman E.,Sloan Kettering Cancer Center
Current Opinion in Hematology | Year: 2012

Purpose of review: The review will appraise the literature concerning ABL kinase domain mutations that has appeared over the last year and identify new questions, answers to old questions, and discuss new trends in clinical and laboratory based research. Recent findings: A concise summary of European LeukemiaNet guidelines for kinase domain mutation studies was published this year. A new controversial topic emerged: the relevance of IC 50 data to guide second-line tyrosine kinase inhibitor (TKI) therapy. Although flaws in the methodology have been acknowledged, one group summarily rejected IC 50 data and recommended that clinicians use individual patient comorbidities and drug safety profiles. The influence of kinase domain mutations on response to second-line and third-line TKI therapy was also published this year; unexpectedly, kinase domain mutations were found to have no effect on response or survival. However, the presence of a kinase domain mutation did influence survival following hematopoietic stem cell transplantation. Lastly, new findings from laboratories identified transcription factors BCL6 and STAT5 as potential new treatment targets. Summary: The last 12 months has brought much attention to clinical management of patients with kinase domain mutations and identified a new controversy concerning IC50 data use in the clinic. Kinase domain mutations do not appear to influence response to second-line and third-line response to TKI therapy. New targets that do not directly involve BCR-ABL added potential new therapeutic approaches. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Background:RECORD-3 assessed non-inferiority of progression-free survival (PFS) with everolimus vs sunitinib in previously untreated patients with metastatic renal cell carcinoma. Baseline plasma sample collection and randomised design enabled correlation of circulating biomarkers with efficacy.Methods:Samples were analysed for 121 cancer-related biomarkers. Analyses of biomarkers categorised patients as high or low (vs median) to assess association with first-line PFS (PFS1L) for each treatment arm. A composite biomarker score (CBS) incorporated biomarkers potentially predictive of PFS1L with everolimus.Results:Plasma samples from 442 of the 471 randomised patients were analysed. Biomarkers were associated with PFS1L for everolimus alone (29), sunitinib alone (9) or both (12). Everolimus-specific biomarkers (CSF1, ICAM1, IL-18BP, KIM1, TNFRII) with hazard ratio ⩾1.8 were integrated into a CBS (range 0–5). For CBS low (0–3, n=291) vs high (4–5, n=151), PFS1L differed significantly for everolimus but not for sunitinib. There was no significant difference in PFS1L between everolimus and sunitinib in the high CBS patient cohort.Conclusions:Baseline levels of multiple soluble biomarkers correlated with benefit from everolimus and/or sunitinib, independent of clinical risk factors. A similar PFS1L was observed for both treatments among patients with high CBS score.British Journal of Cancer advance online publication, 23 February 2016; doi:10.1038/bjc.2016.21 www.bjcancer.com. © 2016 Cancer Research UK

Al-Ahmadie H.A.,Sloan Kettering Cancer Center
Nature Genetics | Year: 2016

Plasmacytoid bladder cancer is an aggressive histologic variant with a high risk of disease-specific mortality. Using whole-exome and targeted sequencing, we find that truncating somatic alterations in the CDH1 gene occur in 84% of plasmacytoid carcinomas and are specific to this histologic variant. Consistent with the aggressive clinical behavior of plasmacytoid carcinomas, which frequently recur locally, CRISPR/Cas9-mediated knockout of CDH1 in bladder cancer cells enhanced cell migration. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Morrow M.,Sloan Kettering Cancer Center
Breast | Year: 2013

The molecular subtype of breast cancer is the major determinant of the type of systemic therapy, but less attention has been paid to the impact of subtype on local therapy outcomes. Presenting features of breast cancer vary with hormone receptor status, with triple negative cancers being significantly less likely than hormone receptor positive cancers to have nodal metastases, and HER2 overexpressing cancers being more likely to be multifocal or multicentric and to have an extensive intraductal component. The risk of local recurrence varies with subtype as well, with triple negative cancers having the highest risk of local recurrence after both breast-conserving therapy and mastectomy, indicating that bigger surgery does not overcome bad biology. © 2013 Elsevier Ltd.

Katabi N.,Sloan Kettering Cancer Center
Archives of Pathology and Laboratory Medicine | Year: 2010

Diagnosis of biliary neoplasia can be challenging but is essential for the appropriate clinical management of patients. Therefore, it is important to recognize the morphologic features of the biliary neoplasms to report a correct diagnosis. Objectives.-(1) To discuss the differential diagnosis of dysplasia in the gallbladder and differentiate dysplasia from reactive atypia and invasive carcinoma, (2) review the histologic features of adenoma and polypoid biliary lesions, (3) highlight the differential diagnosis of adenocarcinoma in liver biopsy, and (4) discuss the differential diagnosis of atypical biliary glandular lesions. Data Sources.-Current English literature related to gallbladder and biliary neoplasia. Conclusions.-Biliary glandular neoplasms show a wide spectrum of morphology and have many mimics. Careful examination of the histologic features of these lesions and familiarity with their morphology can help to achieve the correct diagnosis.

Carlson D.,Sloan Kettering Cancer Center
Archives of Pathology and Laboratory Medicine | Year: 2010

Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting. Parathyroid adenomas are common, unlike other parathyroid tumors. This review presents a brief summary of current updates in parathyroid pathology. Objective.-To review parathyroid development and discuss issues in hyperparathyroidism and diagnosis of parathyroid lesions, including the application of immunohistochemistry and molecular biology. Data Sources.-Current texts, PubMed (National Library of Medicine) articles, and Memorial Sloan-Kettering Cancer Center archives. Conclusions.-Primary hyperparathyroidism is most commonly seen with sporadic adenomas, followed by hyperplasia, multiple adenomas, and carcinoma. Autosomal dominant familial hyperparathyroidism syndromes should be considered in the evaluation of patients with parathyroid lesions, particularly in associationwith parathyroid carcinoma.While the incidence of parathyroid carcinoma is quite low, it is seen with a greater frequency in those patients with hyperparathyroidism- jaw tumor syndrome. Inactivation of the tumor suppressor gene HRPT2 can be identified in a large number of parathyroid carcinomas. Hence, germline HRPT2 gene mutations may reflect unrecognized syndromic patients.

Tang L.H.,Sloan Kettering Cancer Center
Archives of Pathology and Laboratory Medicine | Year: 2010

The appendix gives rise to an array of epithelial neoplasms showing glandular or neuroendocrine differentiation, and some tumors with elements of both cell types. Although some appendiceal neoplasms resemble their counterparts in the small and large intestines (conventional adenocarcinoma and carcinoid tumor), the appendix also gives rise to relatively unique entities including mucinous neoplasms and goblet cell carcinoid tumors, which present a challenge in pathologic classification and clinical management. Objective.-To review clinical and diagnostic issues for 3 pathologic types of epithelial neoplasms of the appendix: (1) adenocarcinoma, with specific focus on mucinous neoplasm; (2) goblet cell carcinoid tumor and associated adenocarcinoma; and (3) typical carcinoid tumor. Data Sources.-Case-derived material and literature review. Conclusion. The most important issue in pathologic assessment of epithelial tumors of the appendix is to understand the clinical implications inherent in the diagnosis.

Shia J.,Sloan Kettering Cancer Center
Archives of Pathology and Laboratory Medicine | Year: 2010

The anal canal possesses complex anatomy and histology and gives rise to a variety of tumor types. Challenging issues remain with regard to both the pathologic diagnosis and the clinical management of these tumors. Objectives.-To provide an updated overview of the histogenesis, clinical and pathologic characteristics, diagnostic terminology, and relevant clinical management of the various types of anal canal tumors. Data Sources.-Recent literature on clinical and pathologic characteristics of anal canal tumors. Conclusions.-Although most anal canal tumors are of squamous lineage, a complex variety ofother tumors also occurs. Recognition of such diverse tumor entitieswill allow accurate pathologic diagnosis and most optimal clinical management.

Rekhtman N.,Sloan Kettering Cancer Center
Archives of Pathology and Laboratory Medicine | Year: 2010

The 2004 World Health Organization (WHO) classification recognizes 4 major types of lung neuroendocrine tumors: typical carcinoid, atypical carcinoid, small cell lung cancer, and large cell neuroendocrine carcinoma. Markedly different prognostic implications and treatment paradigms for these tumors underscore the importance of accurate pathologic diagnosis. Objective.-To detail the clinical and pathologic features of lung neuroendocrine tumors, with emphasis on diagnostic criteria, differential diagnoses, and application of immunohistochemistry. The emerging evidence for the utility of Ki- 67 (MIB1) in the diagnosis of lung neuroendocrine tumors, particularly in small biopsy and cytology, is emphasized. Data Sources.-The 2004 WHO classification, other published literature, and primary material from the author's institution. Conclusions.-The current WHO classification of neuroendocrine tumors is based on morphologic features in combination with precisely defined mitotic rate and absence or presence of necrosis. Ki-67 (MIB1) is emerging as a useful ancillary tool in the diagnosis of these tumors. Continued research efforts are needed to identify additional immunohistochemical and molecular biomarkers that can serve as ancillary diagnostic tools and as potential therapeutic targets for these diseases.

Travis W.D.,Sloan Kettering Cancer Center
Archives of Pathology and Laboratory Medicine | Year: 2010

Sarcomatoid neoplasms of the lung and pleura are rare tumors that present a complex differential diagnosis, making them challenging for surgical pathologists. In the lung, the main tumors are the sarcomatoid carcinomas, including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma. They are characterized by histologic heterogeneity; molecular data support their origin from a pluripotent stem cell that undergoes neoplastic transformation with divergent epithelial and sarcomatous differentiation. Diagnosis is difficult in small biopsy specimens and typicallyrequires a resection specimen. Despite the presence of sarcomatoid features, these tumors are classified as lung carcinomas. Pulmonary blastomas must be distinguished from pleuropulmonary blastomas, which are a unique type of thoracic sarcoma typically occurring in young children. In the pleura, the main tumors to consider are the sarcomatoid and desmoplastic types of malignant mesothelioma, solitary fibrous tumor, and desmoid tumor. While light microscopy is sufficient to diagnose most of these tumors, immunohistochemistry can be useful in selected settings. In particular, it can aid to confirm epithelial differentiation in spindle cell carcinomas and the presence of rhabdomyosarcoma in sarcomatoid carcinomas, mesotheliomas, or pleuropulmonary blastomas. For sarcomatoid and desmoplastic mesothelioma, keratin is the most useful stain because it can highlight invasive growth and mesothelial markers are positive in only the minority of cases. Clinical and radiologic correlation is needed to separate some pleomorphic carcinomas with pleural involvement from sarcomatoid malignant mesothelioma, since these poorly differentiated tumors may not express the usual immunohistochemical markers for carcinoma or mesothelioma.

Zardavas D.,University of Waterloo | Baselga J.,Sloan Kettering Cancer Center | Piccart M.,University of Waterloo
Nature Reviews Clinical Oncology | Year: 2013

Extensive preclinical experimentation has conceptually changed the way we perceive breast cancer, with the wide spectrum of genomic alterations governing its malignant progression now being recognized. Functional genomics has helped us identify important genetic defects that can be pharmaceutically targeted in the setting of metastatic disease. Rationally chosen combination regimens are now under clinical investigation. Recent data underline the functional importance of the tumour-associated stroma, with several candidate molecular targets now emerging. Data elucidating a cellular hierarchy within the breast cancer cellular compartment support the existence of a therapy-resistant subpopulation of breast cancer stem cells. Identification of the developmental pathways that dictate their malignant phenotype and use of high-throughput screening techniques are leading to new therapeutic avenues. In this Review, we present the biological rationale for the clinical development of more than 15 different classes of targeted agents in breast cancer, along with evidence supporting rational combinations. However, metastatic breast cancer resembles a Darwinian evolutionary system, with 'driver' mutations and epigenetic changes determining clonal selection according to branching trajectories. This evolution is reflected in the molecular heterogeneity of the disease and poses severe impediments to the successful clinical development of emerging targeted agents. ©2013 Macmillan Publishers Limited. All rights reserved.

Ahmad U.,Sloan Kettering Cancer Center
The Journal of thoracic and cardiovascular surgery | Year: 2015

OBJECTIVES: The objectives of this collaborative study were to characterize patients with thymic carcinoma, their treatment patterns, and association with overall survival (OS) and recurrence-free survival (RFS).METHODS: Clinical, pathologic, treatment, and follow-up information were analyzed. OS and RFS were the primary outcome measures.RESULTS: In 1042 cases of thymic carcinoma, 42 (5%) patients had pathologic Masaoka stage I, 138 (17%) had stage II, 370 (45%) had stage III, and 274 (33%) had stage IV disease. Overall, 166 patients (22%) underwent induction chemotherapy and 48 (6%) had preoperative radiation therapy. An R0 resection was performed in 447 cases (61%), R1 in 102 cases (14%), and R2 in 184 cases (25%). Squamous cell carcinoma was the predominant histologic subtype (n = 560; 79%). Adjuvant chemotherapy was administered to 237 (31%) patients, and 449 (60%) received adjuvant radiation therapy. The median OS was 6.6 years (95% confidence interval [CI], 5.8-8.3) and the cumulative incidence of recurrence at 5 years was 35% (95% CI, 30%-40%). In univariate analysis, early Masaoka stage, R0 resection, chemotherapy, and radiation therapy were associated with OS. Early Masaoka stage and R0 resection were also associated with RFS. On multivariable analysis, R0 resection and radiation therapy were associated with prolonged OS. Radiation therapy and male gender were associated with prolonged RFS.CONCLUSIONS: R0 resection and radiation therapy are associated with improved OS, whereas radiation therapy and male gender are associated with longer RFS. Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Halpern N.A.,Sloan Kettering Cancer Center
Chest | Year: 2014

Successfully designing a new ICU requires clarity of vision and purpose and the recognition that the patient room is the core of the ICU experience for patients, staff, and visitors. The ICU can be conceptualized into three components: the patient room, central areas, and universal support services. Each patient room should be designed for single patient use and be similarly confi gured and equipped. The design of the room should focus upon functionality, ease of use, healing, safety, infection control, communications, and connectivity. All aspects of the room, includ ing its infrastructure; zones for work, care, and visiting; environment, medical devices, and approaches to privacy; logistics; and waste management, are important elements in the design process. Since most medical devices used at the ICU bedside are really sophisticated computers, the ICU needs to be capable of supporting the full scope of medical informatics. The patient rooms, the central ICU areas (central stations, corridors, supply rooms, pharmacy, laboratory, staff lounge, visitor waiting room, on-call suite, conference rooms, and offices), and the universal support services (infection prevention, fi nishings and fl ooring, staff communications, signage and wayfi nding, security, and fi re and safety) work best when fully interwoven. This coordination helps establish effi-cient and safe patient throughput and care and fosters physical and social cohesiveness within the ICU. A balanced approach to centralized and decentralized monitoring and logistics also offers great fl exibility. Synchronization of the universal support services in the ICU with the hospital's existing systems maintains unity of purpose and continuity across the enterprise and avoids unnecessary duplication of efforts. © 2014 American College of Chest Physicians.

Morris C.D.,Sloan Kettering Cancer Center
Instructional course lectures | Year: 2012

There is considerable overlap in the clinical and imaging presentation of general orthopaedic conditions and musculoskeletal neoplasms. At centers that treat orthopaedic oncologic conditions, it is not uncommon to see patients with spine and extremity tumors previously treated for presumed general orthopaedic ailments. It is important for orthopaedic surgeons to understand how to interpret commonly ordered radiographic studies (radiographs, MRIs, and CT scans) as they relate to bone and soft-tissue tumors, to be familiar with the imaging appearance of common musculoskeletal lesions in the extremities and spine, and to understand what imaging findings should trigger a referral to an orthopaedic oncologist.

Yahalom J.,Sloan Kettering Cancer Center
Current Treatment Options in Oncology | Year: 2014

Radiation is established as one of the most powerful, highly effective treatments for non-Hodgkin lymphoma (NHL). Unfortunately, in recent years the medical oncology community has improperly underutilized radiotherapy (RT) in the management of NHL. Replacing RT with longer chemotherapy and/or immunotherapy may not necessarily be a good alternative approach and may lead to suboptimal outcome and more toxicity, particularly in patients with localized disease. Some misconceptions regarding the use of RT emanated from the ways RT has been utilized in the past - as a single therapy and in high doses and large fields. Major developments in imaging technology, radiation planning concepts, and RT precision and delivery have been revolutionized RT for NHL over the past two decades. Modern proper administration should result with very minimal acute or late side effects. Some of the controversial issues of the use of RT borrowed from Hodgkin lymphoma, such as risk of secondary tumors, are irrelevant to patients with NHL but cause unnecessary patient and physician scare. Many lymphoma types are notoriously sensitive to RT, especially the indolent types. When localized, like in most marginal zone lymphoma (MZL) and almost a third of follicular lymphomas (FL), RT is potentially curative, even with low dose and small volumes. In more aggressive lymphomas, RT often is an effective consolidation after chemotherapy in complete or even incomplete responders. It also is an important component of salvage and palliation. In older patients, RT is particularly valuable, because chemotherapy tolerance and salvage options may be limited. The International Lymphoma Radiation Oncology Group (ILROG) developed and published modern guidelines for using RT in NHL, including FL. The guidelines emphasize the new concept of RT field: involved site radiotherapy (ISRT). These modern ILROG principles and several relevant studies that looked into the proper integration of RT in the management of NHL patients are the focus of this manuscript. © 2014 The Author(s).

Weitzel J.N.,Cancer Genetics Education Program | Blazer K.R.,Cancer Genetics Education Program | MacDonald D.J.,Cancer Genetics Education Program | Culver J.O.,Cancer Screening and Prevention Program | Offit K.,Sloan Kettering Cancer Center
CA Cancer Journal for Clinicians | Year: 2011

Scientific and technologic advances are revolutionizing our approach to genetic cancer risk assessment, cancer screening and prevention, and targeted therapy, fulfilling the promise of personalized medicine. In this monograph, we review the evolution of scientific discovery in cancer genetics and genomics, and describe current approaches, benefits, and barriers to the translation of this information to the practice of preventive medicine. Summaries of known hereditary cancer syndromes and highly penetrant genes are provided and contrasted with recently discovered genomic variants associated with modest increases in cancer risk. We describe the scope of knowledge, tools, and expertise required for the translation of complex genetic and genomic test information into clinical practice. The challenges of genomic counseling include the need for genetics and genomics professional education and multidisciplinary team training, the need for evidence-based information regarding the clinical utility of testing for genomic variants, the potential dangers posed by premature marketing of first-generation genomic profiles, and the need for new clinical models to improve access to and responsible communication of complex disease risk information. We conclude that given the experiences and lessons learned in the genetics era, the multidisciplinary model of genetic cancer risk assessment and management will serve as a solid foundation to support the integration of personalized genomic information into the practice of cancer medicine. © 2011 American Cancer Society.

Gonen M.,Sloan Kettering Cancer Center
Academic Radiology | Year: 2013

Rationale and Objectives: Receiver operating characteristic (ROC) curves are ubiquitous in the analysis of imaging metrics as markers ofboth diagnosis and prognosis. While empirical estimation of ROC curves remains the most popular method, there are several reasons to consider smooth estimates based on a parametric model. Materials and Methods: A mixture model is considered for modeling the distribution of the marker in the diseased population motivated by the biological observation that there is more heterogeneity in the diseased population than there is in the normal one. It is shown that this model results in an analytically tractable ROC curve which is itself a mixture of ROC curves. Results: The use of creatine kinase-BB isoenzyme in diagnosis of severe head trauma is used as an example. ROC curves are fit using the direct binormal method, ROCKIT software, and the Box-Cox transformation as well as the proposed mixture model. The mixture model generates an ROC curve that is much closer to the empirical one than the other methods considered. Conclusions: Mixtures of ROC curves can be helpful in fitting smooth ROC curves in datasets where the diseased population has higher variability than can be explained by a single distribution. © 2013 AUR.

Comstock C.,Sloan Kettering Cancer Center
Ultrasound Clinics | Year: 2011

Static or compressive elastography (ultrasound [US] strain imaging) and acoustic radiation force impulse, of which shear wave elastography is a subtype, are the 2 main methods of breast US elastography and they differ by the type of stress or vibration applied. This article discusses using elastographic information for lesion analysis as an adjunct to the standard gray-scale morphologic and color Doppler information. © 2011 Published by Elsevier Inc.

Rice T.W.,Cleveland Clinic | Rusch V.W.,Sloan Kettering Cancer Center | Ishwaran H.,Cleveland Clinic | Blackstone E.H.,Cleveland Clinic
Cancer | Year: 2010

BACKGROUND: Previous American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) stage groupings for esophageal cancer have not been data driven or harmonized with stomach cancer. At the request of the AJCC, worldwide data from 3 continents were assembled to develop data-driven, harmonized esophageal staging for the seventh edition of the AJCC/UICC cancer staging manuals. METHODS: All-cause mortality among 4627 patients with esophageal and esophagogastric junction cancer who underwent surgery alone (no preoperative or postoperative adjuvant therapy) was analyzed by using novel random forest methodology to produce stage groups for which survival was monotonically decreasing, distinctive, and homogeneous. RESULTS: For lymph node-negative pN0M0 cancers, risk-adjusted 5-year survival was dominated by pathologic tumor classification (pT) but was modulated by histopathologic cell type, histologic grade, and location. For lymph node-positive, pN+M0 cancers, the number of cancer-positive lymph nodes (a new pN classification) dominated survival. Resulting stage groupings departed from a simple, logical arrangement of TNM. Stage groupings for stage I and II adenocarcinoma were based on pT, pN, and histologic grade; and groupings for squamous cell carcinoma were based on pT, pN, histologic grade, and location. Stage III was similar for histopathologic cell types and was based only on pT and pN. Stage 0 and stage IV, by definition, were categorized as tumor in situ (Tis) (high-grade dysplasia) and pM1, respectively. CONCLUSIONS: The prognosis for patients with esophageal and esophagogastric junction cancer depends on the complex interplay of TNM classifications as well as nonanatomic factors, including histopathologic cell type, histologic grade, and cancer location. These features were incorporated into a data-driven staging of these cancers for the seventh edition of the AJCC/UICC cancer staging manuals. © 2010 American Cancer Society.

Cohen N.A.,Sloan Kettering Cancer Center
Annals of Surgery | Year: 2016

OBJECTIVE:: We aimed to identify key principles of targeted therapy of protein kinases and their application to the management of solid tumors. BACKGROUND:: Concurrent advances in tumor genomic analysis and molecular inhibitor development have dramatically impacted the diagnosis and treatment of solid tumors, and common themes regarding the use of kinase inhibitors are developing. METHODS:: The list of kinase inhibitors that have been approved by the US Food and Drug Administration was reviewed and articles related to the agents were searched in the PubMed database up until December 2015. We included pivotal, randomized controlled phase 2 and 3 trials, and also pertinent preclinical studies. RESULTS:: Small molecule inhibitors targeted against driver kinases, overactive in selected subsets of solid tumors, elicit improved response rates and survival compared with standard chemotherapy. Disease control has been proven in the metastatic and, to a limited extent, the adjuvant setting. However, tumor eradication is rare, and duration of treatment response is limited by the development of drug resistance. CONCLUSIONS:: Kinase inhibitors induce response in diverse types of solid tumors. Although the agents are often effective in defined molecular subsets, cure is rare and resistance is common. This broad review provides rationale for further investigation of multimodality therapy combining kinase inhibitors with additional systemic and local therapies, including surgery. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Kao Y.-C.,Sloan Kettering Cancer Center
American Journal of Surgical Pathology | Year: 2016

With the advent of next-generation sequencing, an increasing number of novel gene fusions and other abnormalities have emerged recently in the spectrum of EWSR1-negative small blue round cell tumors (SBRCTs). In this regard, a subset of SBRCTs harboring either BCOR gene fusions (BCOR-CCNB3, BCOR-MAML3), BCOR internal tandem duplications (ITD), or YWHAE-NUTM2B share a transcriptional signature including high BCOR mRNA expression, as well as similar histologic features. Furthermore, other tumors such as clear cell sarcoma of kidney (CCSK) and primitive myxoid mesenchymal tumor of infancy also demonstrate BCOR ITDs and high BCOR gene expression. The molecular diagnosis of these various BCOR genetic alterations requires an elaborate methodology including custom BAC fluorescence in situ hybridization (FISH) probes and reverse transcription polymerase chain reaction assays. As these tumors show high level of BCOR overexpression regardless of the genetic mechanism involved, either conventional gene fusion or ITD, we sought to investigate the performance of an anti-BCOR monoclonal antibody clone C-10 (sc-514576) as an immunohistochemical marker for sarcomas with BCOR gene abnormalities. Thus we assessed the BCOR expression in a pathologically and genetically well-characterized cohort of 25 SBRCTs, spanning various BCOR-related fusions and ITDs and YWHAE-NUTM2B fusion. In addition, we included related pathologic entities such as 8 CCSKs and other sarcomas with BCOR gene fusions. As a control group we included 20 SBRCTs with various (non-BCOR) genetic abnormalities, 10 fusion-negative SBRCTs, 74 synovial sarcomas, 29 rhabdomyosarcomas, and other sarcoma types. In addition, we evaluated the same study group for SATB2 immunoreactivity, as these tumors also showed SATB2 mRNA upregulation. All SBRCTs with BCOR-MAML3 and BCOR-CCNB3 fusions, as well as most with BCOR ITD (93%), and all CCSKs showed strong and diffuse nuclear BCOR immunoreactivity. Furthermore, all SBRCTs with YWHAE-NUTM2B also were positive. SATB2 stain was also positive in tumors with YWHAE-NUTM2B, BCOR-MAML3, BCOR ITD (75%), BCOR-CCNB3 (71%), and a subset of CCSKs (33%). In conclusion, BCOR immunohistochemical stain is a highly sensitive marker for SBRCTs and CCSKs with BCOR abnormalities and YWHAE-rearrangements and can be used as a useful diagnostic marker in these various molecular subsets. SATB2 immunoreactivity is also present in the majority of this group of tumors. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Younes A.,Sloan Kettering Cancer Center
Hematology/Oncology Clinics of North America | Year: 2014

Hodgkin lymphoma (HL) is a relatively rare but highly curable human cancer. Because very few patients relapse and will require subsequent therapy, new drug development for HL has not been seen as a high priority by the pharmaceutical industry. Brentuximab vedotin, an antibody-drug conjugate that targets CD30 receptors, became the first drug to be approved by regulatory agencies for the treatment of HL in more than 30years. This review summarizes the current and future directions of incorporating brentuximab vedotin in the management of patients with HL. © 2014 Elsevier Inc.

Haynes C.M.,New York University | Haynes C.M.,Sloan Kettering Cancer Center | Yang Y.,New York University | Blais S.P.,New York University | And 2 more authors.
Molecular Cell | Year: 2010

Genetic analyses previously implicated the matrix-localized protease ClpP in signaling the stress of protein misfolding in the mitochondrial matrix to activate nuclear-encoded mitochondrial chaperone genes in C. elegans (UPRmt). Here, we report that haf-1, a gene encoding a mitochondria-localized ATP-binding cassette protein, is required for signaling within the UPRmt and for coping with misfolded protein stress. Peptide efflux from isolated mitochondria was ATP dependent and required HAF-1 and the protease ClpP. Defective UPRmt signaling in the haf-1-deleted worms was associated with failure of the bZIP protein, ZC376.7, to localize to nuclei in worms with perturbed mitochondrial protein folding, whereas zc376.7(RNAi) strongly inhibited the UPRmt. These observations suggest a simple model whereby perturbation of the protein-folding environment in the mitochondrial matrix promotes ClpP-mediated generation of peptides whose haf-1-dependent export from the matrix contributes to UPRmt signaling across the mitochondrial inner membrane. © 2010 Elsevier Inc. All rights reserved.

Chen M.,Columbia University | Chen M.,Rockefeller University | David C.J.,Sloan Kettering Cancer Center | Manley J.L.,Columbia University
Nature Structural and Molecular Biology | Year: 2012

Expression of the mammalian pyruvate kinase M (PKM) gene provides an important example of mutually exclusive splicing. We showed previously that the hnRNP proteins A1, A2 and PTB have a crucial role in this process. Here we provide evidence that concentration-dependent interactions involving a network of these proteins are sufficient to determine the outcome of PKM splicing. At high concentrations, such as those found in most cancer cells, hnRNPA1 binding to two sites in the upstream regulated exon (exon 9) orchestrates cooperative interactions leading to exon 9 exclusion. At lower concentrations, binding shifts to downstream intronic sites, such that exon 9 is included and exon 10 mainly excluded, with any mRNA including both exons degraded by nonsense-mediated decay. Together, our results provide a mechanism by which a few general factors control alternative splicing of a widely expressed transcript. © 2012 Nature America, Inc. All rights reserved.

Neff T.,University of Colorado at Denver | Armstrong S.A.,Sloan Kettering Cancer Center
Blood | Year: 2013

The importance of epigenetic gene regulatory mechanisms in normal and cancer development is increasingly evident. Genome-wide analyses have revealed the mutation, deletion, and dysregulated expression of chromatin-modifying enzymes in a number of cancers, including hematologic malignancies. Genome-wide studies of DNA methylation and histone modifications are beginning to reveal the landscape of cancer-specific chromatin patterns. In parallel, recent genetic loss-of-function studies in murine models are demonstrating functional involvement of chromatin-modifying enzymes inmalignant cell proliferation and self-renewal. Paradoxically, the same chromatin modifiers can, depending on cancer type, be either hyperactive or inactivated. Increasingly, cross talk between epigenetic pathways is being identified. Leukemias carrying MLL rearrangements are quintessential cancers driven by dysregulated epigenetic mechanisms in which fusion proteins containing N-terminal sequences of MLL require few or perhaps no additional mutations to cause human leukemia. Here, we review how recent progress in the field of epigenetics opens potential mechanism-based therapeutic avenues. © 2013 by The American Society of Hematology.

Landgren O.,Sloan Kettering Cancer Center
Blood | Year: 2015

In this issue of Blood, Hjalgrim et al1 used the Scandinavian Donations and Transfusions (SCANDAT2) database,2 which includes comprehensive information on donors and recipients of >20 million blood products handled by the Danish and Swedish blood banks between 1968 and 2010, to address the clinically relevant question of whether chronic lymphocytic leukemia (CLL) is transmitted through blood transfusions. © 2015 by The American Society of Hematology.

Nakanishi K.,Sloan Kettering Cancer Center
Methods in molecular biology (Clifton, N.J.) | Year: 2011

DNA interstrand cross-links (ICLs) covalently link both strands of the DNA duplex, impeding cellular processes like DNA replication. Homologous recombination (HR) is considered to be a major pathway for the repair of ICLs in mammalian cells as mutants for HR components are highly sensitive to DNA-damaging agents that cause ICLs. This chapter describes GFP assays to measure HR following site-specific ICL formation with psoralen through DNA triplex technology. This approach can be used to determine the genetic requirements for ICL-induced HR in relation to those involved in HR repair of other DNA lesions such as double-strand breaks.

Brentjens R.J.,Sloan Kettering Cancer Center
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

The ability of immune-competent donor T cells to mediate a beneficial graft-versus-leukemia (GVL) effect was first identified in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematologic malignancies. Unfortunately, with the exception of chronic myelogenous leukemia and EBV-induced lymphoproliferative disease, allo-HSCT GVL lacks the potency to significantly affect disease progression or recurrence in most other hematologic malignancies. The inadequacy of a GVL effect using past approaches is particularly evident in patients with lymphoid malignancies. However, with the advent of improved gene transfer technology, genetically modified tumor-specific immune effectors have extended cellular immunotherapy to lymphoid malignancies. One promising strategy entails the introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs), which redirect the specificity and function of immune effectors. CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials, supporting further investigation in patients with B-cell cancers. However, disparities in clinical trial design and CAR structure have complicated the discovery of the optimal application of this technology. Recent preclinical studies support additional genetic modifications of CAR-modified T cells to achieve optimal clinical efficacy using this novel adoptive cellular therapy.

Patel J.P.,Sloan Kettering Cancer Center
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults, and the majority of patients with AML die from relapsed disease. Although many studies over the past 4 decades have identified disease alleles in AML, recent genome-wide and candidate gene studies have identified additional recurrent somatic mutations in AML patients with biologic, clinical, and therapeutic importance. Herein we review our current understanding of the molecular pathogenesis of AML and discuss how mutational profiling can be used to refine prognostication in AML and to inform therapeutic approaches. We also review the current challenges in translating genomic studies to the clinical setting, which remains a significant challenge and an urgent priority.

Polotsky H.N.,Sloan Kettering Cancer Center | Polotsky A.J.,Yeshiva University
Seminars in Reproductive Medicine | Year: 2010

The incidence of metabolic syndrome increases substantially during perimenopause and early menopause. Postmenopausal women are at a higher risk of hypertension, proatherogenic lipid changes, diabetes, and severe cardiovascular disease as compared with their premenopausal counterparts. Whether or not menopause has a causative contribution to the deteriorating metabolic profile that is independent of chronological aging has been a subject of many studies. Menopausal transition is associated with significant weight gain (2 to 2.5 kg over 3 years on average), which is not dissimilar to that in premenopausal women of like age. Concomitantly, there is an increase in abdominal adiposity and a decrease in energy expenditure, phenomena that have been postulated to explain the higher risk of metabolic syndrome and increases in cholesterol and triglycerides. Hypertension and diabetes become more prevalent with age and should be timely diagnosed and treated. Lifestyle changes including moderately decreased caloric intake and aerobic exercise could prevent proatherogenic changes and weight gain observed with aging. Accurate prediction of cardiovascular risk in midlife women is essential to help identify the subset of women who are likely to benefit from intensive management of metabolic risk factors. This review focuses on metabolic changes associated with menopausal transition, specifically alterations in weight, waist circumference, body fat distribution, energy expenditure, and circulating biomarkers including adipokines. Copyright © 2010 by Thieme Medical Publishers, Inc.

Comen E.A.,Sloan Kettering Cancer Center
Discovery medicine | Year: 2012

Metastasis, the process whereby cancer cells spread from their primary site of origin and grow in adjacent or distant sites, is the primary cause of death in cancer patients. The last 30 years has witnessed significant progress in decreasing cancer mortality rates--largely as a result of improved screening and prevention, practical applications of cancer genomics, and less toxic, more targeted therapies. Despite these improvements, metastasis relentlessly drives mortality. The pervasive mortality from metastasis highlights the shortcomings of traditionally accepted hypotheses on the metastatic process. Historically, metastasis has been described as a unidirectional process, whereby cancer cells leave a primary tumor and seed metastasis in regional lymph nodes or distant sites. This anatomically based hypothesis has dictated much of our medical, and in particular, surgical approach to treating cancers. Alternatively, recent research indicates that metastasis is a multidirectional process whereby cancer cells can seed distant sites as well as the primary tumor itself. The multidirectional pathway of cancer cells, termed "self-seeding," has been corroborated in several experimental and clinical models. This review will evaluate the "self-seeding" hypothesis with attention both to the "seed" (cancer cells) as well as the "soil" (premetastatic niche). Increasingly, the role of the microenvironment surrounding metastases appears essential to the survival of metastatic colonies. The self-seeding model depends not only on the inherent mobility of cancer cells, but also on the supporting non-cancerous cells which enable circulating tumors cells to migrate to and survive in distant sites. The recognition that some of these non-cancerous cells include key components of the immune system has re-ignited the field of immunotherapy in cancer. One particular area of immunotherapy research, tumor entrained neutrophils, will be reviewed in more depth. Ultimately, understanding the dynamic interplay between cancer cells and the metastatic niche offers fertile ground for progress both in the treatment and prevention of metastasis.

Nehmeh S.A.,Sloan Kettering Cancer Center
PET Clinics | Year: 2013

PET-CT scanners allow robust and synergistic fusion of anatomic and functional information, which has improved sensitivity, specificity, and enhancement in the value of PET and CT when assessing tumor response to therapy. Breathing motion and the difference in time resolutions commonly cause motion artifacts and spatial mismatch between the corresponding image sets. Correction for the breathing-induced artifacts represents a particular challenge. This article summarizes the materials, methods, and results involved in multiple investigations of the correction for respiratory motion in PET-CT imaging of the thorax. Some methods use respiratory-phase data selection, whereas others have adopted sophisticated software techniques. © 2013 Elsevier Inc.

Giralt S.,Sloan Kettering Cancer Center
Hematology | Year: 2012

High-dose melphalan with autologous stem cell support has been an integral part of myeloma therapy for more than 25 years either as salvage therapy or as consolidation of an initial remission. Although multiple phase III trials have demonstrated that this therapy results in higher response rates and longer remission duration than conventional chemotherapy the use of thalidomide, lenalidomide and bortezomib as induction therapy have limited the clinical relevance of these trials. In this manuscript, we will summarize the results of ongoing and recently published clinical trials and describe how they have impacted current transplant recommendations, and their relevance to the treatment of myeloma patients in developing countries. © W. S. Maney & Son Ltd 2012.

Correa D.D.,Sloan Kettering Cancer Center | Hess L.M.,Indiana University
Gynecologic Oncology | Year: 2012

Objectives: As advances in treatment have prolonged survival for many patients with ovarian cancer, there has been growing interest in assessing the adverse effects of disease and treatment. The aim of this study was to review the literature on cognitive function and quality of life (QOL) in this population. Methods: A review of published studies including formal assessment of neurocognitive functions and self-reported domains of quality of life, with an emphasis on cognitive function, was performed. Results: The small number of studies including formal evaluations of neurocognitive function suggests that many ovarian cancer patients experience cognitive difficulties associated with their disease and treatment. Several studies described declines in self-reported cognitive function that may impact QOL, but the results were not consistent across studies. Conclusions: Adequately powered longitudinal studies including formal neurocognitive and QOL assessments are needed to advance our understanding of the incidence of cognitive dysfunction and its impact on functional ability and QOL in ovarian cancer patients. These research efforts may ultimately contribute to treatment decision-making through the identification of vulnerable patients, and to the development of appropriate intervention strategies to improve cognitive function and QOL. © 2011 Elsevier Inc. All rights reserved.

Houssami N.,University of Sydney | Turner R.,University of Sydney | Morrow M.,Sloan Kettering Cancer Center
Annals of Surgery | Year: 2013

BACKGROUND AND OBJECTIVE: The role of breast magnetic resonance imaging (MRI) in women newly diagnosed with breast cancer (BC) is controversial. This meta-analysis examines the effect of preoperative MRI compared with standard preoperative assessment on surgical outcomes, focusing on studies that used a controlled design. METHODS: Using random-effects logistic meta-regression modeling, we estimated the proportion of women with each outcome in the MRI versus no-MRI groups, and calculated the odds ratio (OR) and adjusted OR (adjusted for study-level median age, and, where appropriate, for temporal effect) for each model. RESULTS: There were 9 eligible studies (2 randomized trials; 7 comparative cohorts). Outcomes in 3112 patients with BC (any histological tumor type) for MRI versus no-MRI (referent) were as follows: initial mastectomy 16.4% versus 8.1% [OR, 2.22 (P < 0.001); adjusted OR, 3.06 (P < 0.001)]; re-excision after initial breast conservation 11.6% versus 11.4% [OR, 1.02 (P = 0.87); adjusted OR, 0.95 (P = 0.71)]; overall mastectomy 25.5% versus 18.2% [OR, 1.54 (P < 0.001); adjusted OR, 1.51 (P < 0.001)]. In 766 patients with invasive lobular cancer (ILC), outcomes were as follows: initial mastectomy 31.1% versus 24.9% [OR, 1.36 (P = 0.056); adjusted OR, 2.12 (P = 0.008)]; re-excision after initial breast conservation 10.9% versus 18.0% [OR, 0.56 (P = 0.031); adjusted OR, 0.56 (P = 0.09)]; overall mastectomy 43.0% versus 40.2% [OR, 1.12 (P = 0.45); adjusted OR, 1.64 (P = 0.034)]. CONCLUSIONS: Our summary of the evidence showed that MRI significantly increased mastectomy rates and suggests an unfavorable harm-benefit ratio for routine use of preoperative MRI in BC. We found weak evidence that MRI reduced re-excision surgery in patients with ILC - although this was at the expense of increased mastectomies - and overall patient benefit from MRI in ILC is not clear from this study. Copyright © 2013 by Lippincott Williams & Wilkins.

Pike M.C.,Sloan Kettering Cancer Center | Pike M.C.,University of Southern California | Pearce C.L.,University of Southern California
Annals of Oncology | Year: 2013

Mammographic density (MD), representing connective and epithelial tissue (fibroglandular tissue, FGT) is a major risk factor for breast cancer. In an analysis of an autopsy series (Bartow SA, Pathak DR, Mettler FA. Radiographic microcalcification and parenchymal patterns as indicators of histologic "high-risk" benign breast disease. Cancer 1990; 66: 1721-1725, Bartow SA, Pathak DR, Mettler FA et al. Breast mammographic pattern: a concatenation of confounding and breast cancer risk factors. Am J Epidemiol 1995; 142: 813-819), MD was found to be strongly correlated with the collagen and epithelial content of the breast (Li T, Sun L, Miller N et al. The association of measured breast tissue characteristics with MD and other risk factors for breast cancer. Cancer Epidemiol Biomarkers Prev 2005; 14: 343-349), and another report showed that breast epithelium was highly concentrated in the areas of collagen concentration (Hawes D, Downey S, Pearce CL et al. Dense breast stromal tissue shows greatly increased concentration of breast epithelium but no increase in its proliferative activity. Breast Cancer Res 2006; 8: R24). Collagen comprises the overwhelming majority of the FGT, occupying an area on the slides obtained from the autopsy series some 15 times the area of glandular tissue. The relationship of MD with breast cancer risk appears likely to be due to a major extent to increasing epithelial cell numbers with increasing MD. FGT is also seen in breast magnetic resonance imaging (breast MRI) and, as expected, it has been shown that this measure of FGT (MRI-FGT) is highly correlated with MD. A contrast-enhanced breast MRI shows that normal FGT 'enhances' (background parenchymal enhancement, BPE) after contrast agent is administered(Morris EA. Diagnostic breast MR imaging: current status and future directions. Radiol Clin North Am 2007; 45: 863-880, vii., Kuhl C. The current status of breast MR imaging. Part I. Choice of technique, image interpretation, diagnostic accuracy, and transfer to clinical practice. Radiology 2007; 244: 356-378), and a recent study suggests that BPE is also a major breast cancer risk factor, possibly as important as, and independent of MD (King V, Brooks JD, Bernstein JL et al. BPE at breast MR imaging and breast cancer risk. Radiology 2011; 260: 50-60). BPE is much more sensitive to the effects of menopause and tamoxifen than is FGT (King V, Gu Y, Kaplan JB et al. Impact of menopausal status on BPE and fibroglandular tissue on breast MRI. Eur Radiol 2012; 22: 2641-2647, King V, Kaplan J, Pike MC et al. Impact of tamoxifen on amount of fibroglandular tissue, BPE, and cysts on breast MRI. Breast J 2012; 18: 527-534). Changes in MD and BPE may be most useful in predicting response to chemopreventive agents aimed at blocking breast cell proliferation. More study of the biological basis of the effects of MD and BPE is needed if we are to fully exploit these factors in developing chemopreventive approaches to breast cancer. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Lee L.H.,Sloan Kettering Cancer Center
Modern Pathology | Year: 2016

Immune checkpoint blockade targeting the programmed death-1 (PD-1) pathway has shown efficacy in several types of cancers including mismatch-repair-deficient colorectal carcinoma. In some tumor types, programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry has shown utility as a predictive marker for response to anti-PD-1 therapies. This utility, however, remains to be determined in colorectal carcinoma. In addition, although tumor-infiltrating lymphocytes have been associated with better prognosis in colorectal carcinoma, the prognostic value of PD-1 expression in these lymphocytes and its interaction with PD-L1 expression still await investigation. To address these questions, we performed a pilot study to evaluate the patterns of PD-L1 and PD-1 immunohistochemical expression on colorectal carcinoma cells and their tumor-infiltrating lymphocytes, respectively. Using tissue microarray, we found that 5% (19/394) of colorectal carcinomas exhibited high tumor PD-L1 expression, and 19% (76/392) had elevated numbers of PD-1-positive tumor-infiltrating lymphocytes. PD-L1 levels correlated with PD-1 levels (P<0.001), and mismatch-repair-deficient tumors had significantly higher rates of high PD-L1 and PD-1 expression when compared with mismatch-repair-proficient tumors (18% vs 2% and 50% vs 13%, respectively; P<0.001 for both). Staining intensity was also stronger for both markers in mismatch-repair-deficient tumors. Furthermore, we observed that among patients with mismatch-repair-deficient colorectal carcinoma, PD-1/PD-L1 expression stratified recurrence-free survival in an inter-dependent manner: an association between high PD-1-positive tumor-infiltrating lymphocytes and improved recurrence-free survival (P=0.041) was maintained only when the tumors had low-level PD-L1 expression (P=0.006); patients whose tumors had both high PD-1-positive tumor-infiltrating lymphocytes and high PD-L1 expression had a significantly worse recurrence-free survival (P<0.001). Thus, our results not only provide a foundation for further assessment of PD-L1 immunohistochemistry as a predictive marker for anti-PD-1 therapy in colorectal carcinoma, they also shed light on the prognostic impact of tumor-infiltrating lymphocytes in different subsets of mismatch-repair-deficient colorectal carcinomas.Modern Pathology advance online publication, 22 July 2016; doi:10.1038/modpathol.2016.139. © 2016 United States & Canadian Academy of Pathology

Valente K.,Sloan Kettering Cancer Center
American Journal of Surgical Pathology | Year: 2016

Diffuse malignant peritoneal mesothelioma (MPeM) is rare and arises from peritoneal serosal surfaces. Although it shares similar histomorphology with its counterpart, malignant pleural mesothelioma, etiologies, clinical courses, and therapies differ. Nuclear grading and level of mitoses have been correlated with prognosis in malignant pleural mesothelioma with epithelioid subtype. Whether nuclear grading and level of mitoses correlate with prognosis in MPeM is still unknown. Our study utilizes a 2 tier system incorporating nuclear features and level of the mitoses to stratify cases of MPeM with epithelioid subtype. Fifty-one cases of MPeM with clinical follow-up underwent retrospective microscopic review. From that subset, 46 cases were of epithelioid subtype, which were then stratified into a low-grade or high-grade tier. Survival times were calculated on the basis of Kaplan-Meier analysis. The low-grade tier had higher overall survival with a median of 11.9 years and 57% at 5 years when compared with the high-grade tier with a median of 3.3 years and 21% at 5 years (P=0.002). Although not statistically significant, the low-grade tier had higher progression-free survival with a median of 4.7 years and 65% at 5 years when compared with the high-grade tier with a median of 1.9 years and 35% at 5 years (P=0.089). Our study is first to specifically evaluate and correlate nuclear features and level of mitoses with overall survival in MPeM with epithelioid subtype.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0/ Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Chemotherapy-resistant B-cell hematologic malignancies may be cured with allogeneic hematopoietic stem cell transplantation (HSCT), demonstrating the potential susceptibility of these tumors to donor T-cell mediated immune responses. However, high rates of transplant-related morbidity and mortality limit this approach. For this reason, there is an urgent need for less-toxic forms of immune-based cellular therapy to treat these malignancies. Adoptive transfer of autologous T cells genetically modified to express chimeric antigen receptors (CARs) targeted to specific tumor-associated antigens represents an attractive means of overcoming the limitations of conventional HSCT. To this end, investigators have generated CARs targeted to various antigens expressed by B-cell malignancies, optimized the design of these CARs to enhance receptor mediated T cell signaling, and demonstrated significant anti-tumor efficacy of the resulting CAR modified T cells both in vitro and in vivo mouse tumor models. These encouraging preclinical data have justified the translation of this approach to the clinical setting with currently 12 open clinical trials and one completed clinical trial treating various B-cell malignancies utilizing CAR modified T cells targeted to either the CD19 or CD20 B-cell specific antigens.

Sun J.C.,Sloan Kettering Cancer Center
Current Topics in Microbiology and Immunology | Year: 2016

Natural killer (NK) cells are innate lymphocytes that survey the environment and protect the host from infected and cancerous cells. As their name implies, NK cells represent an early line of defense during pathogen invasion by directly killing infected cells and secreting inflammatory cytokines. Although the function of NK cells was first described more than four decades ago, the development of this cytotoxic lineage is not well understood. In recent years, we have begun to identify specific transcription factors that control each stage of development and maturation, from ontogeny of the NK cell progenitor to the effector functions of activated NK cells in peripheral organs. This chapter highlights the transcription factors that are unique to NK cells, or shared between NK cells and other hematopoietic cell lineages, but govern the biology of this cytolytic lymphocyte. © Springer International Publishing Switzerland 2015.

Klotz M.W.,Sloan Kettering Cancer Center
The International journal of oral & maxillofacial implants | Year: 2011

The purpose of this study was to use a clinical simulation to determine whether wear of the internal surface of a titanium implant was greater following connection and loading of a one-piece zirconia implant abutment or a titanium implant abutment. Two implants received zirconia abutments and two received titanium abutments. The implants were secured into four fiber-reinforced epoxy resin disks that had been prepared to receive the internal-connection implants. The assemblies were cyclically loaded off-axis for a total of 1,000,000 cycles. At various intervals, the abutments were removed, photographed, examined using scanning electron microscopy (SEM), and returned to the implants for further testing. The area of titanium transfer from the implants to the abutments observed in the SEM images was quantified using image analysis software. The method was able to quantify the area of material transferred to the abutments. There was considerably more wear associated with the zirconia abutments, but the rate of wear slowed after about 250,000 cycles. Parabolic curves were fit to the data. The projected mean ± standard deviation maximum area (wear) values associated with the titanium and zirconia abutments were 15.8 ± 3.3 x 10 3 Μm 2 and 131.8 ± 14.5 x 10 3 Μm 2, respectively, and this difference was statistically significant (P = .0081). The implants with the zirconia abutments showed a greater initial rate of wear and more total wear than the implants with the titanium abutments following cyclic loading. The amount of titanium transfer seen on the zirconia abutment increased with the number of loading cycles but appeared to be self-limiting. The clinical ramifications of this finding are unknown at this time; however, the potential for component loosening and subsequent fracture and/or the release of particulate titanium debris may be of concern.

Cheung N.-K.V.,Sloan Kettering Cancer Center | Dyer M.A.,St Jude Childrens Research Hospital | Dyer M.A.,University of Tennessee Health Science Center | Dyer M.A.,Howard Hughes Medical Institute
Nature Reviews Cancer | Year: 2013

Neuroblastoma is a solid tumour that arises from the developing sympathetic nervous system. Over the past decade, our understanding of this disease has advanced tremendously. The future challenge is to apply the knowledge gained to developing risk-based therapies and, ultimately, improving outcome. In this Review we discuss the key discoveries in the developmental biology, molecular genetics and immunology of neuroblastoma, as well as new translational tools for bringing these promising scientific advances into the clinic. © 2013 Macmillan Publishers Limited. All rights reserved.

White R.,Sloan Kettering Cancer Center | White R.,New York Medical College | Rose K.,Childrens Hospital Boston | Rose K.,Howard Hughes Medical Institute | And 4 more authors.
Nature Reviews Cancer | Year: 2013

The zebrafish is a recent addition to animal models of human cancer, and studies using this model are rapidly contributing major insights. Zebrafish develop cancer spontaneously, after mutagen exposure and through transgenesis. The tumours resemble human cancers at the histological, gene expression and genomic levels. The ability to carry out in vivo imaging, chemical and genetic screens, and high-throughput transgenesis offers a unique opportunity to functionally characterize the cancer genome. Moreover, increasingly sophisticated modelling of combinations of genetic and epigenetic alterations will allow the zebrafish to complement what can be achieved in other models, such as mouse and human cell culture systems. © 2013 Macmillan Publishers Limited. All rights reserved.

Yu A.F.,Sloan Kettering Cancer Center | Ky B.,University of Pennsylvania
Heart | Year: 2016

Contemporary cancer treatment uses multiple modalities such as chemotherapy, targeted therapy and radiotherapy. These therapies, often used in combination, are aociated with an increased risk of cardiotoxicity, specifically cardiomyopathy and heart failure. Cardiologists and oncologists are faced with the challenge of maximising the clinical benefit from cancer therapy while minimising the risk of early and late-onset cardiotoxicity. The current paradigm for cardiotoxicity detection and management relies primarily upon the aement of left ventricular ejection fraction (LVEF). However, LVEF alone is limited in both diagnostic and prognostic ability. There is growing enthusiasm over the identification of newer biomarkers of cardiotoxicity that can detect cardiac injury at earlier stages of disease and could be used as an adjunctive prognostic measure to routine LVEF aement. Thus, imaging and circulating biomarkers are currently under active investigation for use throughout the continuum of cancer care-for risk stratification of cardiotoxicity prior to treatment, detection of early cardiotoxicity during treatment and diagnosis of late cardiotoxicity in survivorship. Myocardial strain, cardiac troponin and brain natriuretic peptide are the most prominent biomarkers currently being studied, although data on novel circulating biomarkers are emerging.

Hall A.,Sloan Kettering Cancer Center
Biochemical Society Transactions | Year: 2012

Rho GTPases comprise a family of molecular switches that control signal transduction pathways in eukaryotic cells. A conformational change induced upon binding GTP promotes an interaction with target (effector) proteins to generate a cellular response. A highly conserved function of Rho GTPases from yeast to humans is to control the actin cytoskeleton, although, in addition, they promote a wide range of other cellular activities. Changes in the actin cytoskeleton drive many dynamic aspects of cell behaviour, including morphogenesis, migration, phagocytosis and cytokinesis, and the dysregulation of Rho GTPases is associated with numerous human diseases and disorders. ©The Authors Journal compilation ©2012 Biochemical Society.

Pasternak G.W.,Sloan Kettering Cancer Center
Pain Medicine | Year: 2012

Although effective alone, opioids are often used in combination with other drugs for relief of moderate to severe pain. Guidelines for acute perioperative pain recommend the use of multimodal therapy for pain management, although combinations of opioids are not specifically recommended. Mu opioid drugs include morphine, heroin, fentanyl, methadone, and morphine 6β-glucuronide (M6G). Their mechanism of action is complex, resulting in subtle pharmacological differences among them and with unpredictable differences in their potency, effectiveness, and tolerability among patients. Highly selective mu opioids do not bind to a single receptor. Rather, they interact with a large number of mu receptor subtypes with different activation profiles for the various drugs. Thus, mu-receptor-based drugs are not all the same and it may be possible to utilize these differences for enhanced pain control in a clinical setting. These differences among the drugs raise the question of whether combinations might result in better pain relief with fewer side effects. This concept has already been demonstrated between two mu opioids in preclinical studies and clinical trials on other combinations are ongoing. This article reviews the current state of knowledge about mu opioid receptor pharmacology, summarizes preclinical evidence for synergy from opioid combinations, and highlights the complex nature of the mu opioid receptor pharmacology. © 2012.

Katz S.J.,University of Michigan | Morrow M.,Sloan Kettering Cancer Center
Cancer | Year: 2013

Patients with favorable prognosis of breast cancer are vulnerable to overtreatment because the absolute net benefit of different treatments may be small and difficult to quantify in individual cases. Advances in personalized treatment hold the promise of increasing the certainty of the treatment benefit of different treatments in individual patients, but insufficient attention has been paid to the challenges to treatment decision-making. Copyright © 2013 American Cancer Society.

Rudensky A.Y.,Sloan Kettering Cancer Center
Immunological Reviews | Year: 2011

Regulatory T (Treg) cells play central role in regulation of immune responses to self-antigens, allergens, and commensal microbiota as well as immune responses to infectious agents and tumors. Transcriptional factor Foxp3 serves as a lineage specification factor of Treg cells. Paucity of Treg cells due to loss-of-function mutations of the Foxp3 gene is responsible for highly aggressive, fatal, systemic immune-mediated inflammatory lesions in mice and humans. Recent studies of Foxp3 expression and function provided critical novel insights into biology of Treg cells and into cellular mechanisms of the immune homeostasis. © 2011 John Wiley & Sons A/S.

Chernichenko N.,Sloan Kettering Cancer Center
Current opinion in oncology | Year: 2012

To provide a critical review of recent literature on the role of tracheal resection in thyroid cancer. The current body of literature is centered on the controversy regarding how radical the extent of tracheal resection needs to be to achieve long-term control of thyroid carcinoma with tracheal invasion. Proponents of shave excision are guided by the reported survival outcomes comparable to segmental resections in a selected group of patients. Others believe that all patients should have a segmental sleeve resection to ensure clearance of transmural disease. Recent advances in microsurgical reconstruction may allow selected patients to undergo tracheal resection when a large tracheal defect is anticipated. Tracheal invasion by well differentiated carcinoma is a marker of a more aggressive tumor behavior, defining a subpopulation of patients at a greater risk of recurrence and death. The goal of surgical intervention in this scenario is complete resection with no gross residual disease. A well designed prospective multi-institutional trial, taking into account depth of invasion, risk group stratification, histology, presence of distant metastasis, radioactive iodine trapping ability, adjuvant treatment, and long-term survival data, is needed to compare the outcomes following more conservative shave excision and segmental tracheal resection.

Conti R.M.,University of Chicago | Bach P.B.,Sloan Kettering Cancer Center
Health Affairs | Year: 2014

The federal 340B program gives participating hospitals and other medical providers deep discounts on outpatient drugs. Named for a section of the Veterans Health Care Act of 1992, the program's original intent was to help low-income and uninsured patients. But the program has come under scrutiny by critics who contend that some hospitals exploit the drug discounts to generate profits instead of either investing in programs for the poor or passing the discounts along to patients and insurers.We examined whether the program is expanding in ways that could maximize hospitals' ability to generate profits from the 340B drug discounts. We matched data for 960 hospitals and 3,964 affiliated clinics registered with the 340B program in 2012 with the socioeconomic characteristics of their communities from the US Census Bureau's American Community Survey.We found that hospital-affiliated clinics that registered for the 340B program in 2004 or later served communities that were wealthier and had higher rates of health insurance compared to communities served by hospitals and clinics that registered for the program before 2004. Our findings support the criticism that the 340B program is being converted from one that serves vulnerable patient populations to one that enriches hospitals and their affiliated clinics. © 2014 Project HOPE- The People-to-People Health Foundation, Inc.

Serganov A.,Sloan Kettering Cancer Center
RNA Biology | Year: 2010

Riboswitches are gene control elements typically located in the 5′ untranslated regions of bacterial mRNAs where they modulate the expression of associated genes in response to elevated concentrations of cellular metabolites. Metabolite binding stabilizes the evolutionarily conserved receptor domains and affects the folding of the downstream gene-controlling modules. About 20 classes of riboswitches display a large number of RNA sequences perfectly adjusted to bind their cognate cellular metabolites. The question of how riboswitches achieve exquisite specificity for various ligands has been answered for almost all major classes of known riboswitches by structural and biochemical studies of their metabolite-sensing domains. Here I outline the most recent additions to the growing collection of riboswitch structures, review the principles of riboswitch folding and metabolite recognition, and discuss whether this information can help us understand the details of genetic control and metabolite recognition in the riboswitches whose three-dimensional structures are not available. © 2010 Landes Bioscience.

Omelchenko T.,Sloan Kettering Cancer Center
Small GTPases | Year: 2012

Collective cell migration is a key process during epithelial morphogenesis, tissue regeneration and tumor dissemination. During collective epithelial migration, anterior-posterior polarity, apical-basal polarity and cell-cell junctions must be dynamically coordinated, but the underlying molecular mechanisms controlling this complex behavior are unclear. Rho GTPases regulate the actin cytoskeleton, in particular protrusive and contractile activities at cell-cell contacts. Recently, a number of regulators - nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) - have been identified and suggested to provide spatio-temporal control of Rho GTPases at cell-cell contacts. One of these is myosin IXA, a member of class IX, single-headed actin motors having a conserved RhoGAP domain. Using its actin-binding and motor activities, myosin IX interacts with actin filaments and moves toward filament plus ends. At the plasma membrane, myosin IX's RhoGAP activity negatively regulates Rho to facilitate localized reorganization of the actin cytoskeleton. Here, I discuss how myosin IXA regulates Rho and the actin cytoskeleton during the assembly of nascent cell-cell contacts and how this might contribute to collective epithelial migration.© 2012 Landes Bioscience.

Morrow M.,Sloan Kettering Cancer Center
Cancer Research | Year: 2013

Axillary lymph node dissection (ALND) has been a part of breast cancer management since the 1900s. The idea that axillary metastases do not require surgical removal is a repudiation of the Halstedian concept of breast cancer biology, yet multiple prospective randomized studies show that the incidence of nodal recurrence in patients not having ALND is substantially lower than expected, based on the incidence of axillary metastases in patients having ALND, and survival does not differ based on axillary treatment. Avoidance of axillary dissection significantly reduces the morbidity of breast cancer surgery. As the use of systemic therapy has increased and targeted therapies have become available, the incidence of axillary recurrence in patients not having dissection has decreased to approximately 1% at 5 years, making routine axillary dissection difficult to justify. ALND is no longer standard management for patients with T1 and T2, clinically node-negative cancers undergoing breast-conserving therapy and found to have a positive sentinel node, and can also be avoided in patients with these tumor features having mastectomy if the need for postmastectomy radiotherapy is clear with the finding of a positive sentinel node. © 2013 American Association for Cancer Research.

Lichtman S.M.,Sloan Kettering Cancer Center
Journal of Geriatric Oncology | Year: 2012

Increasing age is directly associated with an increasing risk of cancer, and persons over 65 constitute the fastest growing group in the United States. Not only do older adults comprise the majority of cancer patients, at the same time, they have also been vastly underrepresented in clinical trials. As a result, little evidence-based data exist to guide their course of treatment. Alternative trial designs and expanded research evaluations are needed to guide cancer therapy in this population, which is estimated to account for 20% of all Americans by the year 2030. In this review, after examining the status quo, we propose ways to correct the widespread underreporting and underrepresentation of older adults in cancer trials, and highlight existing barriers to trial enrollment. We also outline specific issues of treatment and survivorship as they pertain to older adults, including function, clinical benefit, quality of life, polypharmacy, toxicity, and comorbidity. © 2012 Elsevier Ltd.

Maluccio M.,Indiana University | Covey A.,Sloan Kettering Cancer Center
CA Cancer Journal for Clinicians | Year: 2012

Hepatocellular carcinoma (HCC) is one of the few cancers in which a continued increase in incidence has been observed over several years. As such, there has been a focus on safe and accurate diagnosis and the development of treatment algorithms that take into consideration the unique complexities of this patient population. In the past decade, there have been improvements in nonsurgical treatment platforms and better standardization with respect to the diagnosis and patient eligibility for liver transplant. How to navigate patients through the challenges of treatment is difficult and depends on several factors: 1) patient-related variables such as comorbid conditions that influence treatment eligibility; 2) liver-related variables such as Child-Pugh score; and 3) tumor-related variables such as size, number, pattern of spread within the liver, and vascular involvement. The objectives of this review are to put into perspective the current treatment options for patients with HCC, the unique advantages and disadvantages of each treatment approach, and the evidence that supports the introduction of sorafenib into the multidisciplinary management of HCC. CA Cancer J Clin 2012;. © 2012 American Cancer Society. Copyright © 2012 American Cancer Society, Inc.

Kircher M.F.,Sloan Kettering Cancer Center | Willmann J.K.,Stanford University
Radiology | Year: 2012

Molecular imaging, generally defined as noninvasive imaging of cellular and subcellular events, has gained tremendous depth and breadth as a research and clinical discipline in recent years. The coalescence of major advances in engineering, molecular biology, chemistry, immunology, and genetics has fueled multi- and interdisciplinary innovations with the goal of driving clinical noninvasive imaging strategies that will ultimately allow disease identification, risk stratification, and monitoring of therapy effects with unparalleled sensitivity and specificity. Techniques that allow imaging of molecular and cellular events facilitate and go hand in hand with the development of molecular therapies, offering promise for successfully combining imaging with therapy. While traditionally nuclear medicine imaging techniques, in particular positron emission tomography (PET), PET combined with computed tomography (CT), and single photon emission computed tomography, have been the molecular imaging methods most familiar to clinicians, great advances have recently been made in developing imaging techniques that utilize magnetic resonance (MR), optical, CT, and ultrasonographic (US) imaging. In the first part of this review series, we present an overview of the principles of MR imaging-, CT-, and US-based molecular imaging strategies. © RSNA, 2012.

Giancotti F.G.,Sloan Kettering Cancer Center
Cell | Year: 2013

Many cancer patients suffer from metastatic relapse several years after they have undergone radical surgery. Early cancer cell dissemination followed by a protracted period of dormancy potentially explains this prevalent clinical behavior. Increasing evidence suggests that the metastasis-initiating cells are cancer stem cells or revert to this functional state upon infiltrating a target organ. Their entry into dormancy and subsequent reactivation are governed by intrinsic programs and by contextual cues, which resemble those regulating the self-renewal capability of adult stem cells. In addition, metastatic cells undergoing reactivation are nursed by specialized extracellular matrix niches, which support positive signals, such as Wnt and Notch, and attenuate negative signals, such as BMP. In spite of significant remaining uncertainties, these findings provide a framework to understand the logic of metastatic dormancy and reactivation and open new avenues for therapeutic intervention. © 2013 Elsevier Inc.

Pamer E.G.,Sloan Kettering Cancer Center
Science | Year: 2016

The intestinal microbiota, which is composed of diverse populations of commensal bacterial species, provides resistance against colonization and invasion by pathogens. Antibiotic treatment can damage the intestinal microbiota and, paradoxically, increase susceptibility to infections. Reestablishing microbiota-mediated colonization resistance after antibiotic treatment could markedly reduce infections, particularly those caused by antibiotic-resistant bacteria. Ongoing studies are identifying commensal bacterial species that can be developed into next-generation probiotics to reestablish or enhance colonization resistance. These live medicines are at various stages of discovery, testing, and production and are being subjected to existing regulatory gauntlets for eventual introduction into clinical practice. The development of next-generation probiotics to reestablish colonization resistance and eliminate potential pathogens from the gut is warranted and will reduce health care-associated infections caused by highly antibiotic-resistant bacteria. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved.

Abdel-Wahab O.,Sloan Kettering Cancer Center
Current Opinion in Hematology | Year: 2011

Purpose of Review: Since the discovery of the JAK2V617F mutation in 2005, an increasing number of somatic and germline genetic events responsible for myeloproliferative neoplasm (MPN) pathogenesis have been uncovered. The purpose of this review is to outline the most recent discoveries of the genetic alterations found in patients with MPNs. Recent Findings: In addition to the JAK2V617F mutation, additional mutations in the JAK-STAT pathway have been discovered including a series of mutations in exon 12 of JAK2, the thrombopoietic receptor gene MPL, and in the gene encoding the JAK-STAT inhibitory adaptor protein LNK. Additionally, mutations in genes which appear to affect the epigenome of MPN patients have been discovered including mutations in TET2, IDH1/2, EZH2, and ASXL1. Lastly, some insights into the genetic events which contribute to transformation of a chronic MPN phenotype to acute myeloid leukemia have been elucidated, including deletion of the transcription factor Ikaros. Summary: The spectrum of genetic abnormalities found in the classic MPNs has increased over the last 6 years and somatic mutations in JAK2, MPL, LNK, TET2, EZH2, ASXL1, and IDH1/2 have all been described. Despite this, the initiating genetic events responsible for the development of MPNs is still not totally understood. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Sung J.S.,Sloan Kettering Cancer Center
Radiologic Clinics of North America | Year: 2014

Ultrasonography is an important modality that is frequently used in all aspects of breast imaging, including breast cancer screening, the evaluation of palpable abnormalities, further characterization of lesions seen mammographically, and for determining the method of percutaneous biopsy. Understanding the basic technical aspects of ultrasonography equipment is critical to ensure high breast ultrasonography image quality. © 2014 Elsevier Inc.

Every malignant tumor has a unique spectrum of genomic alterations including numerous protein mutations. There are also hundreds of personal germline variants to be taken into account. The combinatorial diversity of potential cancer-driving events limits the applicability of statistical methods to determine tumor-specific "driver" alterations among an overwhelming majority of "passengers". An alternative approach to determining driver mutations is to assess the functional impact of mutations in a given tumor and predict drivers based on a numerical value of the mutation impact in a particular context of genomic alterations.Recently, we introduced a functional impact score, which assesses the mutation impact by the value of entropic disordering of the evolutionary conservation patterns in proteins. The functional impact score separates disease-associated variants from benign polymorphisms with an accuracy of ~80%. Can the score be used to identify functionally important non-recurrent cancer-driver mutations? Assuming that cancer-drivers are positively selected in tumor evolution, we investigated how the functional impact score correlates with key features of natural selection in cancer, such as the non-uniformity of distribution of mutations, the frequency of affected tumor suppressors and oncogenes, the frequency of concurrent alterations in regions of heterozygous deletions and copy gain; as a control, we used presumably non-selected silent mutations. Using mutations of six cancers studied in TCGA projects, we found that predicted high-scoring functional mutations as well as truncating mutations tend to be evolutionarily selected as compared to low-scoring and silent mutations. This result justifies prediction of mutations-drivers using a shorter list of predicted high-scoring functional mutations, rather than the "long tail" of all mutations.

Durack J.C.,Sloan Kettering Cancer Center
American Journal of Roentgenology | Year: 2014

OBJECTIVE. The purposes of this article are to provide a brief overview of structured radiology reporting and to emphasize the anticipated benefits from a new generation of standardized interventional radiology procedure reports. CONCLUSION. Radiology reporting standards and tools have evolved to enable automated data integration from multiple institutions using structured templates. In interventional radiology, data aggregated into clinical, research and quality registries from enriched structured reports could firmly establish the interventional radiology value proposition. © American Roentgen Ray Society.

Thompson C.B.,Sloan Kettering Cancer Center
EMBO Journal | Year: 2014

One of the most common abnormalities of cancer cells is their predilection to engage in a high rate of glycolysis despite the continued availability of oxygen. First described by Otto Warburg, this phenomenon of aerobic glycolysis (or the Warburg effect) has recently been proposed to result from cancer-associated alterations in signal transduction pathways. In this issue of The EMBO Journal, Pate et al provide further support for this hypothesis by demonstrating that Wnt signaling plays an important role in establishing aerobic glycolysis as a mechanism to support in vivo cancer cell proliferation. © 2014 The Author.

Couch F.J.,Mayo Medical School | Nathanson K.L.,University of Pennsylvania | Offit K.,Sloan Kettering Cancer Center | Offit K.,New York Medical College
Science | Year: 2014

The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.

Rampal R.,Sloan Kettering Cancer Center | Mascarenhas J.,Mount Sinai School of Medicine
Current Opinion in Hematology | Year: 2014

Purpose of review The myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera and primary myelofibrosis (PMF), are a heterogeneous group of myeloid-derived chronic haematopoietic malignancies. Frequent clinical consequences of these diseases include not only an increased risk of thrombosis but also leukemic transformation, which carries a particularly poor prognosis. Here, we discuss the recent identification of risk factors for leukemic transformation, elucidate mechanisms contributing to leukemic transformation, as well as highlight the development of new treatment strategies. Recent findings Significant progress in the understanding of the biology of MPNs has been made in recent years, particularly with the discovery that mutations in the JAK-STAT signaling pathway cause unregulated activation. These genetic insights have been extended to leukemic transformation and have revealed a host of genetic alterations that occur at the time of transformation, and that may identify patients at risk for leukemic transformation. Such studies have demonstrated that acute myeloid leukemia (AML) evolved from a chronic phase MPN is distinct from de-novo AML both genetically and clinically given its resistance to conventional antileukemic therapy. Summary Leukemic transformation of an MPN remains a significant clinical challenge. Recent advances in the understanding of the molecular events that contribute to the development of leukemic transformation will need to be utilized in order to produce rational therapeutic approaches for this largely fatal disease. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Howe L.R.,New York Medical College | Subbaramaiah K.,New York Medical College | Hudis C.A.,New York Medical College | Hudis C.A.,Sloan Kettering Cancer Center | Dannenberg A.J.,New York Medical College
Clinical Cancer Research | Year: 2013

The increasing rate of obesity worldwide is predicted to be associated with a surge in diseases. Notably, obesity has been linked to approximately 20% of cancer cases in the United States; obesity is associated with both increased risk and worse outcomes after diagnosis. Altered levels of circulating factors are strongly implicated, including insulin, insulin-like growth factor 1, leptin, adiponectin, and interleukin-6 (IL-6). In addition, increasing attention has focused on the consequences of local adipose inflammation. Inflammatory foci characterized by crown-like structures consisting of dead adipocytes encircled by macrophages occur in white adipose depots, including the breast tissue, of most overweight and obese women. Saturated fatty acids, released as a consequence of obesity-associated lipolysis, induce macrophage activation via Toll-like receptor 4, thereby stimulating NF-κB signaling. This, in turn, activates transcription of proinflammatory genes including COX-2, IL-6, IL-1β, and TNFα. Elevated levels of proinflammatory mediators cause both local and systemic effects. Of particular relevance with regard to breast cancer is increased transcription of the CYP19 gene encoding aromatase, the ratelimiting enzyme for estrogen synthesis. Notably, this obesity-inflammation- aromatase axis provides a plausible explanation for increased rates of postmenopausal, hormone receptor-positive breast cancer associated with obesity and hence may offer targets for interventions to attenuate risk or improve prognosis. Potential approaches include weight reduction, exercise, and suppression of obesity-driven signaling pathways using pharmaceutical or dietary agents. A key future goal is to identify biomarkers that accurately report adipose inflammation, both for identification of at-risk individuals and to assess the efficacy of interventions. © 2013 American Association for Cancer Research.

Zauber A.G.,Sloan Kettering Cancer Center
Digestive Diseases and Sciences | Year: 2015

About sixty percent of the US population of those age fifty and older are currently up to date with colorectal cancer screening recommendations. Has this level of screening made a difference for reducing colorectal cancer (CRC) incidence and/or mortality? Randomized controlled trials of guaiac-based fecal occult blood tests, which have relatively low sensitivity but high specificity for CRC, have shown a modest effect but with a long-term reduction in CRC mortality. Newer fecal immunochemical tests are expected to have a greater effect. Randomized controlled trials of flexible sigmoidoscopy have also demonstrated a reduction in CRC mortality. Observational studies of screening colonoscopy suggest an effect of greater than fifty percent reduction in CRC mortality. We have assessed past trends of colorectal cancer screening in the US population which suggest that more than fifty percent of the decline in colorectal cancer mortality can be attributed to the increased acceptance and uptake in colorectal cancer screening. Current and future levels of increased screening could provide for even larger reductions for the USA. Colorectal cancer screening has and will continue to make a significant impact on reducing colorectal cancer mortality. © 2015, Springer Science+Business Media New York.

Halpern N.A.,Sloan Kettering Cancer Center
Chest | Year: 2014

Designing a smart ICU is a time-consuming, complex, multiphased, political, and costly exercise. This process begins with two notions: First, all hospital parties agree that a new or renovated ICU is required, and second, the hospital has agreed to allocate space, personnel, and fi scal resources for the project. In this fi rst of a three-part series on innovative designs for the smart ICU, we will explore the roles of the ICU design team in managing the design process. The team must be administratively empowered, knowledgeable, and forward thinking. The fi rst charge of the design team is to develop a clear vision for the goals, look and feel, and functionality of the new ICU. This vision must be guided by the imperative to positively impact patients, staff, and visitors. The team must concentrate on innovative but practical ideas that are in compliance with building codes and design guidelines and address issues related to renovation vs new construction. Mock-ups, both physical and computer generated, and a simulation laboratory for advanced technologies should be used to test design assumptions and reveal problems well in advance of actual ICU construction and technology implementation. Technology platforms need to be standardized within the ICU and equipment purchases protected against early obsolescence. The ramifi cations and expectations of the new ICU must be thoughtfully considered and dealt with during the design process. Last, it is essential that the design group continue its involvement in the new ICU during construction, occupancy, and post occupancy. © 2014 American College of Chest Physicians.

Sonoda Y.,Sloan Kettering Cancer Center
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society | Year: 2010

Cytoreduction of all visible disease has been associated with improved survival in patients with advanced-stage ovarian or peritoneal cancer. This is best achieved by minimizing injury to normal tissues. We report on the tumor destruction potential, in an ex vivo model, of a novel energy source that uses an electrically neutral beam of pure plasma to vaporize tissue. Tumors were harvested from patients undergoing primary surgical cytoreduction for ovarian or peritoneal cancer. Specimens were divided into 1-cm sections and treated with pure plasma energy for 2 or 4 seconds using standardized power settings. Bright-field microscopy was used to measure the depth of tissue vaporization and lateral thermal damage (LTD). The mean (SD) tissue vaporization depth was 2.7 (1.3) mm (n = 96). Lateral thermal damage was minimal at all tissue interaction settings (0.13 [0.031] mm). Lateral thermal damage was approximately 5% of the depth of tissue vaporization. Tissue interaction time was a more powerful predictor of vaporization than power. When tissue interaction time increased from 2 to 4 seconds, depth of vaporization and LTD increased by 1.7 and 0.03 mm, respectively (P < 0.001 for both). When power was increased from low to high settings, depth of vaporization increased by 0.6 mm (P = 0.02), and LTD did not change. Plasma energy can effectively vaporize ovarian and peritoneal cancer cells. Greater power and tissue interaction time results in more tumor vaporization while maintaining minimal LTD. This is an attractive characteristic of plasma energy that may be useful for eradicating tumor from visceral surfaces.

Levine R.L.,Sloan Kettering Cancer Center
Best Practice and Research: Clinical Haematology | Year: 2013

Specific combinations of mutations, including FLT3 and IDH1/IDH2/TET2, frequently co-occur in acute myeloid leukemia (AML) and are associated with poor prognosis. These mutation combinations can be modeled in mice to provide a more genetically accurate model of AML. Within these models, stem cells may be different depending on how experiments are conducted and based on context. No one mutation can turn on a gene; rather the perfect storm of the right genes in the right cell is necessary to produce AML. Furthermore, this understanding is therapeutically relevant. Rapid and accurate targeted DNA sequencing will identify mutations of prognostic and therapeutic significance and will guide treatment choices in the future. © 2013 Elsevier Ltd. All rights reserved.

Estey E.,University of Washington | Estey E.,Fred Hutchinson Cancer Research Center | Levine R.L.,Sloan Kettering Cancer Center | Lowenberg B.,Erasmus Medical Center
Blood | Year: 2015

A fundamental difficulty in testing "targeted therapies" in acute myeloid leukemia (AML) is the limitations of preclinical models in capturing inter- and intrapatient genomic heterogeneity. Clinical trials typically focus on single agents despite the routine emergence of resistant subclones and experience in blast-phase chronic myeloid leukemia and acute promyelocytic leukemia arguing against this strategy. Inclusion of only relapsed-refractory, or unfit newly diagnosed, patients risks falsely negative results. There is uncertainty as to whether eligibility should require demonstration of the putative target and regarding therapeutic end points. Although use of in vivo preclinical models employing primary leukemic cells is first choice, newer preclinical models including "organoids" and combinations of pharmacologicandgenetic approaches may better align models with human AML. We advocate earlier inclusion of combinations ± chemotherapy and of newly diagnosed patients into clinical trials. When a drug plausibly targets a pathway uniquely related to a specific genetic aberration, eligibility should begin with this subset, including patients with other malignancies, with subsequent extension to other patients. In other cases, a more open-minded approach to initial eligibility would facilitate quicker identification of responsive subsets. Complete remission without minimal residual disease seems a particularly useful short-term end point. Genotypic and phenotypic studies should be prespecified and performed routinely to distinguish responders from nonresponders. © 2015 by The American Society of Hematology.

Winawer S.J.,Sloan Kettering Cancer Center
Digestive Diseases and Sciences | Year: 2015

The present explosive interest in screening for colorectal cancer (CRC), one of the most prevalent and preventable cancers, had its beginnings at a hospital in London and an Internist’s office in Ohio. Demonstrated there were the concepts that CRC did not occur de-novo but arose from a premalignant polyp, that detection of the resultant cancer at an earlier stage was associated with better survival and that cancer could be detected at an early presymptomatic stage by screening. Many years later, the introduction of colonoscopy and colonoscopic polypectomy provided the opportunity for randomized trials to prove that these concepts were true. The sequence of rigorous science followed by guidelines consensus and then multilevel national efforts of screening implementation has resulted in a decline in the CRC incidence and mortality worldwide, most significantly in the USA. Campaigns have been initiated to maximize population screening and further investigate its optimal approach. Some historical details of this success story and many of the key participants are presented in this paper. © 2015, Springer Science+Business Media New York.

Levine R.L.,Sloan Kettering Cancer Center
Current Topics in Microbiology and Immunology | Year: 2012

Although the Janus family of kinases (JAK1, JAK2, JAK3, and TYK2) has been extensively characterized and investigated, the role of Janus kinase activation in the pathogenesis and therapy of human malignancies was not fully appreciated until recently when multiple studies identified a recurrent somatic mutation in the JAK2 tyrosine kinase (JAK2V617F) in the majority of patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), polycythemia vera, essential thrombocytosis, and primary myelofibrosis. Other mutations that activate the JAK-STAT signaling pathway have since been identified in JAK2V617F-negative MPN patients and in a subset of patients with acute myeloid leukemia and acute lymphoid leukemia. In addition, dysregulated JAK-STAT signaling has been implicated in the pathogenesis of a spectrum of epithelial neoplasms. In this chapter, we will review the recent studies that identified genetic alterations that activate JAK signaling in different malignancies, and discuss the recent efforts aimed at developing small-molecule inhibitors of JAK kinase activity for the treatment of MPNs and other malignancies. © 2012 Springer-Verlag Berlin Heidelberg.

Antonescu C.R.,Sloan Kettering Cancer Center | Dal Cin P.,Brigham and Womens Hospital
Pathology | Year: 2014

Soft tissue tumours represent a heterogeneous group of mesenchymal lesions and their classification continues to evolve as a result of incorporating advances in cytogenetic and molecular techniques. In the last decade, traditional diagnostic approaches were supplemented with a significant number of reliable molecular diagnostic tools, detecting tumour type specific genetic alterations. Additionally, the successful application of some of these techniques to formalin fixed, paraffin embedded tissue enabled a broader range of clinical material to be subjected to molecular analysis. However, despite all these remarkable advances, the realisation that some of the genetic abnormalities are not fully histotype specific and that certain gene aberrations can be shared among different sarcoma types, otherwise completely unrelated clinically or immunophenotypically, has introduced some drawbacks in surgical pathology practice. One such common example is the presence of EWSR1 gene rearrangements by fluorescence in situ hybridisation (FISH), a test now preferred over the elaborate RT-PCR testing, in a variety of benign and highly malignant soft tissue tumours, in addition to a subset of carcinomas. Furthermore, the presence of identical gene fusions in completely different sarcoma types (i.e., EWSR1-ATF1, EWSR1-CREB1) or in nonmesenchymal malignancies (epithelial or haematological) has raised skepticism as to their diagnostic utility, and their lack of specificity has been compared to the limitations of other ancillary techniques, in particular immunohistochemistry. This review catalogues the main groups of genes that behave in a promiscuous manner within recurrent fusion events in soft tissue tumours. Although we acknowledge that the present molecular classification of soft tissue tumours is much more complex than two decades ago, when EWSR1 gene rearrangements had been described as the hallmark of Ewing sarcoma, we make the strong argument that with very few exceptions, the prevalence of fusion transcripts in most sarcomas is such that they come to define these entities and can be used as highly specific molecular diagnostic markers in the right clinical and pathological context. © 2013 Royal College of Pathologists of Australasia.

Background Antimicrobial resistance is a major health problem, caused primarily by overuse of antibiotics in clinical situations in which they are not necessary. Practice guidelines recommend that antibiotics be given before outpatient cystoscopy to prevent symptomatic urinary tract infection (UTI). Objective To determine the frequency of febrile UTI after outpatient flexible cystoscopy in antibiotic-naive bladder tumor patients. Design, setting, and participants A total of 2010 consecutive outpatients with bladder tumors were entered into a prospective registry study. All patients underwent cystoscopy after they submitted a voided urine sample for culture. Significant bacteriuria was defined as >104 colony-forming units per milliliter with a single organism. Patients were stratified for known risk factors for UTI. Intervention Patients underwent flexible cystoscopy and received no antibiotics immediately before or after cystoscopy. They were followed for 30 d for onset of febrile UTI. Outcome measurements and statistical analysis The end point was incidence of febrile UTI within 30 d of cystoscopy. Febrile UTI was defined as temperature >38 C and dysuria, or having received antibiotics from an outside physician for urinary symptoms. Results and limitations Of the 2010 patient cystoscopies, 489 (24%) had asymptomatic bacteriuria, and 1521 (76%) had sterile urine. Thirty-nine patients (1.9%) developed febrile UTI ≤30 d after cystoscopy - 4.5% in colonized patients and 1.1% in uninfected patients (p = 0.02). All UTIs resolved in ≤12-24 h with oral antibiotics. None of the patients was admitted for bacterial sepsis. Limitations of the study are that it is a single-surgeon experience in one institution, and results may not apply to other patient populations. Conclusions Antibacterial therapy before outpatient flexible cystoscopy does not appear necessary in bladder tumor patients who have no clinical signs or symptoms of acute UTI, including asymptomatic bacteriuria. Antibiotic stewardship is the responsibility of all urologists. © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Antonescu C.,Sloan Kettering Cancer Center
Current Topics in Microbiology and Immunology | Year: 2012

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. Nearly all tumors have a mutation in the KIT or, less often, platelet-derived growth factor receptor (PDGFRA) or B-rapidly Accelerated Fibrosarcoma (BRAF) gene. The discovery of constitutive KIT activation as the central mechanism of GIST pathogenesis, suggested that inhibiting or blocking KIT signaling might be the milestone in the targeted therapy of GISTs. Indeed, imatinib mesylate inhibits KIT kinase activity and represents the front line drug for the treatment of unresectable and advanced GISTs, achieving a partial response or stable disease in about 80% of patients with metastatic GIST. KIT mutation status has a significant impact on treatment response. Patients with the most common exon 11 mutation experience higher rates of tumor shrinkage and prolonged survival, as tumors with an exon 9 mutation or wild-type KIT are less likely to respond to imatinib. Although imatinib achieves a partial response or stable disease in the majority of GIST patients, complete and lasting responses are rare. About half of the patients who initially benefit from imatinib treatment eventually develop drug resistance. The most common mechanism of resistance is through polyclonal acquisition of second site mutations in the kinase domain, which highlights the future therapeutic challenges in salvaging these patients after failing kinase inhibitor monotherapies. More recently, sunitinib (Sutent, Pfizer, New York, NY), which inhibits vascular endothelial growth factor receptor (VEGFR) in addition to KIT and PDGFRA, has proven efficacious in patients who are intolerant or refractory to imatinib. This review summarizes the recent knowledge on targeted therapy in GIST, based on the central role of KIT oncogenic activation, as well as discussing mechanisms of resistance. © 2012 Springer-Verlag Berlin Heidelberg.

Yeeles J.T.,Sloan Kettering Cancer Center
Cold Spring Harbor perspectives in biology | Year: 2013

In recent years, an increasing number of studies have shown that prokaryotes and eukaryotes are armed with sophisticated mechanisms to restart stalled or collapsed replication forks. Although these processes are better understood in bacteria, major breakthroughs have also been made to explain how fork restart mechanisms operate in eukaryotic cells. In particular, repriming on the leading strand and fork regression are now established as critical for the maintenance and recovery of stalled forks in both systems. Despite the lack of conservation between the factors involved, these mechanisms are strikingly similar in eukaryotes and prokaryotes. However, they differ in that fork restart occurs in the context of chromatin in eukaryotes and is controlled by multiple regulatory pathways.

Mantha S.,Sloan Kettering Cancer Center | Ansell J.,New York University
Journal of Thrombosis and Thrombolysis | Year: 2015

Four target-specific oral anticoagulants (TSOA’s) have been compared to a vitamin K antagonist for the treatment of acute venous thromboembolism (VTE): dabigatran (D), rivaroxaban (R), apixaban (A) and edoxaban (E). We performed an indirect comparison of the TSOA’s, based on the six phase III trials identified (RE-COVER I, RE-COVER II, EINSTEIN-DVT, EINSTEIN-PE, AMPLIFY and Hokusai-VTE). There was no statistically significant difference in risk of recurrent VTE or all-cause mortality between the TSOA’s. For major bleeding, the RR of an event was 0.42 (95 % CI 0.21–0.87, p = 0.02) for A versus D, compared with 0.57 (95 % CI 0.29–1.15, p = 0.12) for A versus R, 0.37 (95 % CI 0.19–0.73, p < 0.001) for A versus E, 0.74 (95 % CI 0.42–1.30, p = 0.30) for R versus D, 0.64 (95 % CI 0.38–1.08, p = 0.10) for R versus E and 1.15 (95 % CI 0.66–2.00, p = 0.62) for E versus D. For the composite endpoint of major or clinically relevant nonmajor bleeding, the RR was 0.71 (95 % CI 0.53–0.96, p = 0.02) for A versus D, 0.47 (95 % CI 0.37–0.61, p < 0.001) for A versus R, 0.54 (95 % CI 0.42–0.70, p < 0.001) for A versus E, 1.50 (95 % CI 1.17–1.92, p = 0.001) for R versus D, 1.15 (95 % CI 0.95–1.39, p = 0.16) for R versus E and 1.31 (95 % CI 1.02–1.68, p = 0.04) for E versus D. Overall, apixaban appears to be associated with a lower risk of bleeding than the other TSOA’s. This analysis may be helpful to the clinician in trying to balance risk versus benefit in selecting a new anticoagulant. A dedicated randomized trial directly comparing the new agents would be required to confirm these results. © 2014, Springer Science+Business Media New York.

van den Brink M.R.,Sloan Kettering Cancer Center
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation | Year: 2010

Disease relapse remains a major cause of mortality following allogeneic hematopoietic cell transplantation (HCT). Over the past decade, our understanding of the biology underlying the graft-versus-tumor/leukemia (GVT) effect has increased greatly; however, several other factors affect the occurrence and outcome of relapse, including conditioning regimen, type of allograft, and the histology, status, and sensitivity to chemotherapy of the disease being treated. The mainstay of relapse treatment is donor lymphocyte infusion (DLI), but the efficacy of DLI is quite variable depending on disease histology and state. As such, there is a significant need for novel therapies and strategies for relapse following allogeneic HCT, particularly in patients for whom DLI is not an option. The National Cancer Institute is sponsoring an international workshop to address issues and research questions relative to the biology, natural history, prevention, and treatment of relapse following allogeneic HCT. Copyright 2010. Published by Elsevier Inc.

Morrow M.,Sloan Kettering Cancer Center
Annals of Surgical Oncology | Year: 2014

In September 2011, the Society of Surgical Oncology (SSO) Executive Council voted to transition to self-management. The transition was successfully completed in October 2012. This article summarizes the infrastructure changes that have occurred to facilitate the transition, the SSO goals, selected results from the 2012 Membership Survey, and future directions for the SSO. © 2014 Society of Surgical Oncology.

Gao P.,Sloan Kettering Cancer Center
Nature Chemical Biology | Year: 2016

The field of small self-cleaving nucleolytic ribozymes has been invigorated by the recent discovery of the twister, twister-sister, pistol and hatchet ribozymes. We report the crystal structure of a pistol ribozyme termed env25, which adopts a compact tertiary architecture stabilized by an embedded pseudoknot fold. The G-U cleavage site adopts a splayed-apart conformation with in-line alignment of the modeled 2′-O of G for attack on the adjacent to-be-cleaved P-O5′ bond. Highly conserved residues G40 (N1 position) and A32 (N3 and 2′-OH positions) are aligned to act as a general base and a general acid, respectively, to accelerate cleavage chemistry, with their roles confirmed by cleavage assays on variants, and an increased pKa of 4.7 for A32. Our structure of the pistol ribozyme defined how the overall and local topologies dictate the in-line alignment at the G-U cleavage site, with cleavage assays on variants revealing key residues that participate in acid-base-catalyzed cleavage chemistry. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Blasberg R.,Sloan Kettering Cancer Center | Piwnica-Worms D.,University of Washington
Clinical Cancer Research | Year: 2012

At a Clinical and Translational Cancer Research Think Tank meeting sponsored by the American Association for Cancer Research in 2010, one of the breakout groups focused on new technologies and imaging. The discussions emphasized new opportunities in translational imaging and its role in the future, rather than established techniques that are currently in clinical practice. New imaging methods under development are changing the approach of imaging science from a focus on the anatomic description of disease to a focus on the molecular basis of disease. Broadly referred to as molecular imaging, these new strategies directly embrace the incorporation of cell and molecular biology concepts and techniques into image generation and can involve the introduction of genes into cells with the explicit intent to image the end products of gene expression with external imaging devices. These new methods hold the promise of providing clinicians with (i) robust linkages between cell and animal models and clinical trials, (ii) in vivo biomarkers that can be measured repeatedly and sequentially over time to observe dynamic disease processes and responses to treatment, and (iii) tools for preselection and patient population enrichment in phase II and III trials to improve outcomes and better direct treatment. These strategies provide real-time pharmacodynamic parameters and can be powerful tools to monitor therapeutic effects in a spatially and tissue-specific manner, which may reduce cost during drug development, because pharmacodynamic studies in animals can inform clinical trials and accelerate the translation process. The Imaging Response Assessment Team (IRAT) program serves as an example of how imaging techniques can be incorporated into clinical trials. IRATs work to advance the role of imaging in assessment of response to therapy and to increase the application of quantitative anatomic, functional, and molecular imaging endpoints in clinical trials, and imaging strategies that will lead to individualized patient care. ©2012 AACR.

Joyce J.A.,Sloan Kettering Cancer Center | Fearon D.T.,Cold Spring Harbor Laboratory | Fearon D.T.,The New School
Science | Year: 2015

Effective immunotherapy promotes the killing of cancer cells by cytotoxic T cells. This requires not only that cancer-specific Tcells be generated, but also that these Tcells physically contact cancer cells. The coexistence in some patients of cancer cells and T cells that recognize them indicates that tumors may exhibit the phenomenon of immune privilege, in which immunogenic tissue is protected from immune attack. Here, we review the evidence that stromal cells of the tumor microenvironment mediate this restriction by excluding T cells from the vicinity of cancer cells. Overcoming this T cell checkpoint may thus enable optimal immunotherapy.

Abu-Rustum N.R.,Sloan Kettering Cancer Center
Journal of Obstetrics and Gynaecology Research | Year: 2014

Endometrial cancer is the most common gynecologic malignancy. In the majority of patients, the disease will present at an early stage, without metastasis, and with an excellent prognosis. Although the rate of metastasis in patients with early stage endometrial cancer is low, the standard of treatment still includes a complete or selective pelvic and para-aortic lymphadenectomy for staging. Many patients will undergo a comprehensive lymphadenectomy despite having disease confined to the uterus, resulting in detrimental side-effects, including lower extremity lymphedema. Recent studies, such as 'A Study in the Treatment of Endometrial Cancer', have shown that there is no therapeutic benefit to a complete lymphadenectomy in early stage endometrial cancer, although further study is needed to confirm these findings. The use of sentinel lymph node (SLN) mapping in endometrial cancer may provide an appropriate middle ground between the two schools of thought of complete lymphadenectomy versus no nodal evaluation. SLN mapping, which is gaining everincreasing acceptance in many cancer types, is based on the concept that lymph node metastasis is the result of an orderly process, that is, the lymph drains in a specific pattern away from the tumor, and therefore if the SLN, or first node, is negative for metastasis, then the nodes after the SLN should also be negative.We present here the Memorial Sloan-Kettering Cancer Center experience with SLN mapping in uterine cancer, a technique we first began using in 2003 and have improved over the years. © 2014 Japan Society of Obstetrics and Gynecology.

Krebs P.,Sloan Kettering Cancer Center | Prochaska J.O.,University of Rhode Island | Rossi J.S.,University of Rhode Island
Preventive Medicine | Year: 2010

Objective: Computer-tailored interventions have become increasingly common for facilitating improvement in behaviors related to chronic disease and health promotion. A sufficient number of outcome studies from these interventions are now available to facilitate the quantitative analysis of effect sizes, permitting moderator analyses that were not possible with previous systematic reviews. Method: The present study employs meta-analytic techniques to assess the mean effect for 88 computer-tailored interventions published between 1988 and 2009 focusing on four health behaviors: smoking cessation, physical activity, eating a healthy diet, and receiving regular mammography screening. Effect sizes were calculated using Hedges g. Study, tailoring, and demographic moderators were examined by analyzing between-group variance and meta-regression. Results: Clinically and statistically significant overall effect sizes were found across each of the four behaviors. While effect sizes decreased after intervention completion, dynamically tailored interventions were found to have increased efficacy over time as compared with tailored interventions based on one assessment only. Study effects did not differ across communication channels nor decline when up to three behaviors were identified for intervention simultaneously. Conclusion: This study demonstrates that computer-tailored interventions have the potential to improve health behaviors and suggests strategies that may lead to greater effectiveness of these techniques. © 2010 Elsevier Inc.

Abdeen A.,Beth Israel Deaconess Medical Center | Healey J.H.,Sloan Kettering Cancer Center
Journal of Bone and Joint Surgery - Series A | Year: 2010

BACKGROUND: Limb salvage following resection of a tumor in the proximal part of the humerus poses many challenges. Reconstructive options are limited because of the loss of periarticular soft-tissue stabilizers of the glenohumeral joint in addition to the loss of bone and articular cartilage. The purpose of this study was to evaluate the functional outcome and survival of the reconstruction following use of a humeral allograft-prosthesis composite for limb salvage. METHODS: An allograft-prosthesis composite was used to reconstruct a proximal humeral defect following tumor resection in thirty-six consecutive patients at one institution over a sixteen-year period. The reconstruction was performed at the time of a primary tumor resection in thirty cases, after a failure of a reconstruction following a previous tumor resection in five patients, and following excision of a local recurrence in one patient. The mean duration of follow-up of the living patients was five years. Glenohumeral stability, function, implant survival, fracture rate, and union rate following the reconstructions were measured. Functional outcome and implant survival were analyzed on the basis of the amount of deltoid resection, whether the glenohumeral resection had been extra-articular or intra-articular, and the length of the humerus that had been resected. RESULTS: One patient sustained a glenohumeral dislocation. Deltoid resection (partial or complete) resulted in a reduced postoperative range of motion in flexion and abduction but had no effect on the mean Musculoskeletal Tumor Society score. Extraarticular resections were associated with lower Musculoskeletal Tumor Society scores. All patients had either mild or no pain and normal hand function at the time of final follow-up. The overall estimated rate of survival of the construct, with revision as the end point, was 88% at ten years. There were three failures due to progressive prosthetic loosening that necessitated removal of the construct. Four patients required an additional bone-grafting procedure to treat a delayed union of the osteosynthesis site. CONCLUSIONS: An allograft-prosthesis composite used for limb salvage following tumor resection in the proximal part of the humerus is a durable construct associated with an acceptable complication rate. Deltoid preservation and intra-articular resection are associated with a greater range of shoulder motion and a superior functional outcome, respectively. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence. Copyright © 2010 by The Journal of Bone and Joint Surgery, Incorporated.

Rathkopf D.E.,Sloan Kettering Cancer Center
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ARN-509 in men with metastatic CRPC. Thirty patients with progressive CRPC received continuous daily oral ARN-509 at doses between 30 and 480 mg, preceded by administration of a single dose followed by a 1-week observation period with pharmacokinetic sampling. Positron emission tomography/computed tomography imaging was conducted to monitor [(18)F]fluoro-α-dihydrotestosterone (FDHT) binding to AR in tumors before and during treatment. Primary objective was to determine pharmacokinetics, safety, and recommended phase II dose. Pharmacokinetics were linear and dose proportional. Prostate-specific antigen declines at 12 weeks (≥ 50% reduction from baseline) were observed in 46.7% of patients. Reduction in FDHT uptake was observed at all doses, with a plateau in response at ≥ 120-mg dose, consistent with saturation of AR binding. The most frequently reported adverse event was grade 1/2 fatigue (47%). One dose-limiting toxicity event (grade 3 abdominal pain) occurred at the 300-mg dose. Dose escalation to 480 mg did not identify a maximum-tolerated dose. ARN-509 was safe and well tolerated, displayed dose-proportional pharmacokinetics, and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data.

Gofton T.E.,Sloan Kettering Cancer Center
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques | Year: 2011

Delirium affects a diverse patient population, may present with highly variable clinical features, is a source of distress for patients and their caregivers, prolongs hospital stays and may herald a poor prognosis. Many cases of delirium are reversible and therefore a full history, physical examination and investigations should be performed. Ahigh degree of suspicion is required for detecting delirium and thorough investigations are necessary in order to determine the underlying etiology and to maximize the potential for reversibility. The following review outlines important aspects of a clinical approach to delirium, the differential diagnosis of delirium, investigation of a patient presenting with delirium, management of delirium, the pathophysiology of delirium and the prognosis accompanying delirium.

Roper N.,New York Medical College | Korenstein D.,Sloan Kettering Cancer Center
Journal of General Internal Medicine | Year: 2015

BACKGROUND: Journals have increased disclosure requirements in recent years, in part to deter guest authorship. The prevalence of guest authorship among primary authors (first and last) in the current era of increased disclosure requirements is unknown. OBJECTIVES: Our aim was to examine the self-reported prevalence of guest authorship among primary authors from a sample of randomized clinical trials with and without industry funding and industry collaboration in the design, analysis or reporting of trials. DESIGN: Cross-sectional analysis of randomized, drug/device clinical trials with published details on the “Role of the Funding Source/Sponsor” published in high-impact biomedical journals between 1 December 2011 and 31 November 2012. Phase 1 or 2 trials, secondary trial analyses, and trials that were not listed on ClinicalTrials.gov were excluded. Primary guest authorship was defined, based on International Committee of Medical Journal Editors (ICMJE) criteria, when neither the first nor last author contributed to either of the following: 1) the design of the trial or the analysis/interpretation of data; or 2) drafting part or all of the manuscript. PARTICIPANTS: One hundred and sixty-eight randomized clinical trials that met inclusion criteria were included. MAIN OUTCOME MEASURES: We measured differences in the prevalence of guest authorship between trials with neither industry funding nor collaboration and 1) trials with industry funding without collaboration, and 2) trials with industry funding with collaboration. RESULTS: The overall prevalence of primary guest authorship was 6 % (10/168). Primary guest authorship was significantly more common in trials with industry funding with collaboration than in those with neither industry funding nor collaboration [13.2 % (10/76) vs. 0 % (0/39); p < 0.02]. Primary guest authorship did not differ between trials with industry funding without collaboration and trials with neither industry funding nor collaboration. CONCLUSIONS: Among a sample of randomized, drug/device clinical trials in high-impact biomedical journals, primary guest authorship was overall uncommon and occurred exclusively among trials with industry funding with collaboration. © 2015, Society of General Internal Medicine.

McCarthy C.M.,Sloan Kettering Cancer Center
Plastic and reconstructive surgery | Year: 2012

Current efficacy data supporting the routine use of acellular dermal matrices in postmastectomy tissue expander/implant reconstruction are limited. A multicenter, blinded, randomized controlled study was designed to evaluate the effectiveness of acellular dermal matrix in the setting of tissue expander/implant reconstruction. The primary objective of the study was to determine whether the use of matrix would decrease patient-reported postoperative pain. The secondary objective was to determine whether its use would accelerate the rate of postoperative expansion. The randomized controlled trial was conducted at two U.S. centers from 2008 to 2011. Immediately following mastectomy, all patients were randomized to one of two treatment arms: (1) acellular dermal matrix-assisted, tissue expander/implant reconstruction; and (2) submuscular tissue expander/implant placement. All patients were blinded to their treatment arm. One hundred eight consented to participate; 38 were excluded prior to randomization. In total, 70 patients were randomized. There were no differences seen in immediate postoperative pain (p = 0.19) or pain during the expansion phase (p = 0.65) between treatment arms. There was similarly no difference in postoperative narcotic use (p = 0.38). The rate of postoperative expansion did not differ between groups (p = 0.83). The results suggest that the use of acellular dermal matrix in the setting of tissue expander/implant reconstruction neither reduces postoperative pain nor accelerates the rate of postoperative expansion. An examination of its efficacy in improving long-term outcomes following tissue expander/implant reconstruction is warranted.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This reply has been retracted at the request of the Editor-in-Chief and the Author following the retraction of the original article (Eur Urol 67 (2015) 605–608, http://dx.doi.org/10.1016/j.eururo.2014.06.049). © 2016 European Association of Urology

Banerjee S.C.,Sloan Kettering Cancer Center | Greene K.,Rutgers University
Journal of Health Communication | Year: 2012

This study examined transportation effects of first- and third-person narratives as well as the role of transportation in the persuasion process. In particular, the authors evaluated the role of transportation in affecting cognitive and affective responses. Last, they addressed the relation between (a) cognitive and affective responses and (b) antidrug expectancies. Participants were 500 undergraduate students at a large northern university in the United Kingdom who were randomly assigned to 1 of 2 conditions: first- or third-person narratives on cocaine use. The results demonstrated that there was no difference between first- and third-person narratives in terms of transportation. However, overall, greater transportation was associated with more favorable cognitive responses, and more favorable cognitive response was associated with stronger anticocaine expectancies. In terms of affective responses, results indicated the mediating role of sadness and contentment in the association between transportation and anticocaine expectancies. In particular, increased transportation was associated with greater sadness and lower contentment. Lower sadness and contentment were associated with stronger anticocaine expectancies. Important theoretical and empirical implications are discussed. © 2012 Copyright Taylor and Francis Group, LLC.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The author of this paper has requested that it be retracted because of an incorrect representation of the study methodology. Contrary to the manuscript contents, patients were randomly assigned to narrow band or white light cystoscopy in the order of their attendance, rather than in a permuted block allocation. Patients were individually consented for the clinical procedures, but not to a prospective randomized clinical trial where randomization occurred by permuted block. An appropriate waiver was obtained from the Institutional Review Board to analyze and publish anonymized data from the clinical database. © 2016

Morris C.D.,Sloan Kettering Cancer Center
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2010

Treatment of pelvic bone sarcomas remains one of the most challenging areas of orthopedic oncology for all members of the disease management team. Although considerable advances have been made in all aspects of sarcoma treatment, the prognosis for patients with primary sarcomas of the pelvis continues to be guarded, and therefore, much controversy exists regarding optimal surgical management, radiation therapy, and systemic therapy. This article summarizes the current treatment paradigms for the 3 most common bone sarcomas (osteosarcoma, Ewing's sarcoma, and chondrosarcoma), highlighting the unresolved issues in their management as they pertain to the pelvis. © Journal of the National Comprehensive Cancer Network.

Gollub M.J.,Sloan Kettering Cancer Center
American Journal of Roentgenology | Year: 2011

OBJECTIVE. The purpose of this article is to comprehensively survey all CT-detected ileocolic and colocolic intussusceptions at a cancer institute. MATERIALS AND METHODS. Using the free-text string "intus," the radiology information database of Memorial Sloan-Kettering Cancer Center was searched over a 13.5-year period for abdominopelvic CT scan reports. Images were rereviewed by an attending radiologist for the presence of a bowel-within-bowel appearance involving the colon. The reference standard for a lead point was histopathologic examination or, if the tumor was not resected, an identifiable mass persisting on follow-up CT scans. Transient intussusception was defined as intussusception that resolved on follow-up CT scan without surgical removal or as intussusception with an intermittent presence on serial CT scans. Idiopathic intussusception was defined as the absence of mass or mural thickening at CT or surgery. RESULTS. Four hundred sixty-one CT scan reports were retrieved, 138 of which mentioned intussusception as a pertinent negative. From the remaining 323 scan reports, after all exclusions (small bowel - small bowel intussusception, incomplete imaging, pediatric patients, and misinterpretations on rereview), 33 patients were shown to have 34 intussusceptions, including ileocolic (n = 11) and colocolic (n = 23) intussusceptions, on 34 CT scans. Seven intussusceptions were transient (i.e., intermittent). No patient had idiopathic intussusception. Histopathologic results were available for 22 of 34 intussusceptions. Intussusceptions were caused by colorectal cancer (n = 12), lymphoma (n = 5), metastases to the colon (n = 8), colon polyps (n = 4), and nonneoplastic causes, including lipoma (n = 3), hematoma (n = 1), and edema (n = 1). CONCLUSION. In patients with cancer, intussusceptions involving the colon are never idiopathic. Most are due to primary colon cancer or metastatic disease and most require surgical removal. Although seven intussusceptions were transient, six were caused by neoplasia. © American Roentgen Ray Society.

Jaulin F.,Cornell University | Jaulin F.,Sloan Kettering Cancer Center | Kreitzer G.,Cornell University
Journal of Cell Biology | Year: 2010

Epithelial polarization is associated with selective stabilization and reorganization of microtubule (MT) arrays. However, upstream events and downstream consequences of MT stabilization during epithelial morphogenesis are still unclear. We show that the anterograde kinesin KIF17 localizes to MT plus ends, stabilizes MTs, and affects epithelial architecture. Targeting of KIF17 to plus ends of growing MTs requires kinesin motor activity and interaction with EB1. In turn, KIF17 participates in localizing adenomatous polyposis coli (APC) to the plus ends of a subset of MTs. We found that KIF17 affects MT dynamics, polymerization rates, and MT plus end stabilization to generate posttranslationally acetylated MTs. Depletion of KIF17 from cells growing in three-dimensional matrices results in aberrant epithelial cysts that fail to generate a single central lumen and to polarize apical markers. These findings implicate KIF17 in MT stabilization events that contribute to epithelial polarization and morphogenesis. © 2010 Jaulin and Kreitzer.

Kelvin J.F.,Sloan Kettering Cancer Center
Clinical journal of oncology nursing | Year: 2012

A key concern for young patients with cancer and survivors is the desire to parent a child. With infertility being a well-established long-term effect of many oncologic regimens, patients who want to have children often become distressed when faced with the possibility of losing their fertility. Several organizations have recommended that oncology professionals discuss options for fertility preservation when planning treatment; however, this does not routinely occur. Oncology nurses play a significant role in filling this practice gap by identifying patients who are interested in future parenting and ensuring they get the information and referrals they need to decide whether to pursue fertility preservation. This article outlines the available options, challenges in discussing fertility, and strategies to incorporate fertility education into practice.

Chen J.X.,Sloan Kettering Cancer Center | Yan S.S.,Columbia University
Journal of Alzheimer's Disease | Year: 2010

Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Abnormalities in mitochondrial properties include impaired energy metabolism, defects in key respiratory enzyme activity/function, accumulation/generation of mitochondrial reactive oxygen species, and formation of membrane permeability transition pore. While the mechanisms underlying mitochondrial dysfunction remain incompletely understood, recent studies provide substantial evidence for the progressive accumulation of mitochondrial Aβ, which directly links to mitochondria-mediated toxicity. In this review, we describe recent studies addressing the following key questions: 1) Does Aβ accumulate in mitochondria of AD brain and AD mouse models?; 2) How does Aβ gain access to the mitochondria?; 3) If mitochondria are loaded with Aβ, do they develop similar evidence of dysfunction?; 4) What are the mechanisms underlying mitochondrial Aβ-induced neuronal toxicity?; and 5) What is the impact of interaction of mitochondrial Aβ with its binding partners (cyclophilin D and ABAD) on mitochondrial and neuronal properties/function in an Aβ milieu? The answers to these questions provide new insights into mechanisms of mitochondrial stress related to the pathogenesis of AD and information necessary for developing therapeutic strategy for AD. © 2010 IOS Press and the authors. All rights reserved.

Zanzonico P.,Sloan Kettering Cancer Center
Radiation Research | Year: 2012

The underlying principles of nuclear medicine imaging involve the use of unsealed sources of radioactivity in the form of radiopharmaceuticals. The ionizing radiations that accompany the decay of the administered radioactivity can be quantitatively detected, measured, and imaged in vivo with instruments such as gamma cameras. This paper reviews the design and operating principles, as well as the capabilities and limitations, of instruments used clinically and preclinically for in vivo radionuclide imaging. These include gamma cameras, single-photon emission computed tomography (SPECT) scanners, and positron emission tomography (PET) scanners. The technical basis of autoradiography is reviewed as well. © 2012 by Radiation Research Society.

Molina A.M.,Sloan Kettering Cancer Center
The oncologist | Year: 2011

In the U.S. and Europe, clinical practice guidelines for metastatic renal cell carcinoma have undergone several revisions as a result of the introduction of molecular-targeted therapies. Recently, the National Comprehensive Cancer Network (NCCN) and the European Association of Urology (EAU) published updated guidelines to reflect these new treatment approaches that provide greater efficacy and better tolerability than the previous standard of care, cytokine therapy with interleukin-2 or interferon-α. Recommendations are classified by line of therapy, Memorial Sloan-Kettering Cancer Center risk level for survival, and level of evidence. Although many similarities exist, levels of evidence between the NCCN and EAU guidelines have differing designations and definitions, and timing of updates varies. New research developments, such as identification of effective combinations of targeted agents, optimal regimens for sequential therapy, newly designed targeted agents, benefits in special populations, and identification of additional prognostic factors and biomarkers, will prompt continued updates and refinements of today's clinical practice guidelines, with the goal of providing physicians with the most up-to-date clinical consensus upon which to base treatment decisions. Because clinical trial populations may not represent real-life patient populations, recommendations should serve only as a guide and must be tailored to the needs of each patient.

Marks P.A.,Sloan Kettering Cancer Center
Expert Opinion on Investigational Drugs | Year: 2010

Importance of the field: Histone deacetylase (HDAC) inhibitors are being developed as a new, targeted class of anticancer drugs. Area covered in this review: This review focuses on the mechanisms of action of the HDAC inhibitors, which selectively induce cancer cell death. What the reader will gain: There are 11 zinc-dependent HDACs in humans and the biological roles of these lysine deacetylases are not completely understood. It is clear that these different HDACs are not redundant in their activity. This review focuses on the mechanisms by which HDAC inhibitors can induce transformed cell growth arrest and cell death, inhibit cell mobility and have antiangiogenesis activity. There are more than a dozen HDAC inhibitors, including hydroxamates, cyclic peptides, benzamides and fatty acids, in various stages of clinical trials and many more compounds in preclinical development. The chemically different HDAC inhibitors may target different HDACs. Take home message: There are extensive preclinical studies with transformed cells in culture and tumor-bearing animal models, as well as limited clinical studies reported to date, which indicate that HDAC inhibitors will be most useful when used in combination with cytotoxic or other targeted anticancer agents. © 2010 Informa UK, Ltd.

Pedoto A.,Sloan Kettering Cancer Center
Anesthesiology Research and Practice | Year: 2012

Obesity is a worldwide health problem affecting 34% of the American population. As a result, more patients requiring anesthesia for thoracic surgery will be overweight or obese. Changes in static and dynamic respiratory mechanics, upper airway anatomy, as well as multiple preoperative comorbidities and altered drug metabolism, characterize obese patients and affect the anesthetic plan at multiple levels. During the preoperative evaluation, patients should be assessed to identify who is at risk for difficult ventilation and intubation, and postoperative complications. The analgesia plan should be executed starting in the preoperative area, to increase the success of extubation at the end of the case and prevent reintubation. Intraoperative ventilatory settings should be customized to the changes in respiratory mechanics for the specific patient and procedure, to minimize the risk of lung damage. Several non invasive ventilatory modalities are available to increase the success rate of extubation at the end of the case and to prevent reintubation. The goal of this review is to evaluate the physiological and anatomical changes associated with obesity and how they affect the multiple components of the anesthetic management for thoracic procedures. Copyright © 2012 Alessia Pedoto.

Mohrin M.,University of California at Berkeley | Shin J.,University of California at Berkeley | Liu Y.,University of California at Berkeley | Brown K.,University of California at Berkeley | And 5 more authors.
Science | Year: 2015

Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. How stem cells maintain metabolic homeostasis remains elusive. Here, we identified a regulatory branch of the mitochondrial unfolded protein response (UPRmt), which is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress (PFSmt), and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 up-regulation improved the regenerative capacity of aged HSCs. These findings define the deregulation of a UPRmt-mediated metabolic checkpoint as a reversible contributing factor for HSC aging. © 2015 American Association for the Advancement of Science. All rights reserved.

O'Neill J.P.,Royal College of Surgeons in Ireland | Shaha A.R.,Sloan Kettering Cancer Center
Oral Oncology | Year: 2013

Purpose Anaplastic thyroid cancer (ATC) is a lethal disease causing a global disproportionate number of thyroid cancer-related deaths. The American Thyroid Association (ATA) has recently produced clear and comprehensive guidelines to assist physicians treating ATC. Methods The recent ATA guideline publication was reviewed. A systematic review of studies indexed in Medline and Pubmed was also undertaken using search terms relevant to ATC. Results Patients with ATC have a median survival of 5 months and less than 20% survive 1 year. Early tumor dissemination results in 20-50% percent of patients having distant metastases and 90% having adjacent tissue invasion on presentation. This highlights the necessity for effective combined therapy. Stage IVA/ IVB, resectable disease may benefit from a multimodal (surgery, IMRT for loco regional control, and systemic therapy) approach. However, a majority of patients present with unresectable locoregional disease. Early palliative care involvement is inclusive of life-prolonging therapies. ATC management demands rapid, complex and integrated multidisciplinary decision making. Conclusion In this article we discuss the multidisciplinary strategies that exist to optimize the management of these patients in accordance with the recent guidelines from The American Thyroid Association. © 2013 Elsevier Ltd. All rights reserved.

Teruya-Feldstein J.,Sloan Kettering Cancer Center
Archives of Pathology and Laboratory Medicine | Year: 2010

Surgical and subspecialty pathologists rely heavily on the patient's clinical context, imaging studies, morphology, and on ancillary studies such as immunohistochemistry (IHC), cytogenetics, and molecular diagnostics in arriving at accurate, contemporary diagnoses. Lymphoma/ leukemia classification has led the way in the number of antibodies used in IHC algorithmic diagnostic approaches to distinguish more than 40 diseases. As the era of genomics, transcriptomics, proteomics, and targeted pathway therapeutics unfolds-and as infusion of federal funds to programs such as Accelerating Clinical Trials of Novel Oncologic PathWays (ACTNOW) requires that correlative biomarker assays be performed in Clinical Laboratory Improvement Amendments of 1988 (CLIA)-certified IHC laboratories-we face changes and challenges for the future. Objective.-To discuss the laboratory, pertinent daily diagnostic, prognostic, and therapeutic uses of IHC, and future directions and challenges. Data Sources.-Recent literature review and ongoing current activities in our laboratory and institution. Conclusions.-Meticulous attention at the microscope by expert subspecialty pathologists using ancillary methods is important in making correct diagnoses. Awareness of the literature and interactions with our research colleagues, including clinical, basic, and translational scientists, continue to expand our insights into and understanding of complex diseases; this will ultimately provide prognostic information to assist in appropriate clinical management of our patients and development of new targeted or combination therapies. Multimodality correlations will continue, with morphology, imaging data, immunophenotyping, and genetics as well as steadily increasing integration of pathway signaling, genome, sequenome, transcriptome, and proteome data used in clinical settings.

Moskowitz C.,Sloan Kettering Cancer Center
Best Practice and Research: Clinical Haematology | Year: 2012

Clinically this chapter will focus on 3 important issues critical in the management of diffuse large B cell lymphoma (DLBCL) in 2012: risk stratification, interim PET-CT scanning and the role of high dose therapy and ASCT in the rituximab era for patients with relapsed and primary refractory disease. © 2012 Elsevier Ltd. All rights reserved.

Lamanna N.,Sloan Kettering Cancer Center
Current Hematologic Malignancy Reports | Year: 2012

Chronic lymphocytic leukemia (CLL) is typically a disease of older individuals. Yet most of the literature on various chemotherapeutic regimens includes patients who are 10 to 15 years younger than the median age at diagnosis of this disease. The older patient population is grossly underrepresented in clinical trials. Currently available therapies are often too toxic for this older patient population, so their efficacy is reduced. This review discusses some of the results of treatment in older patients with CLL. A discussion of factors that often affect outcome, such as comorbidities, renal function, bone marrow reserve, and infection, are also reviewed, along with quality of life. © 2012 Springer Science+Business Media, LLC.

Herr H.W.,Sloan Kettering Cancer Center
Current Urology Reports | Year: 2014

Narrow-band imaging (NBI) is a novel optical method designed to enhance visual detection of bladder tumors over conventional white-light imaging (WLI) cystoscopy. Current experience with NBI cystoscopy in evaluating and treating non-muscle-invasive bladder tumors is reviewed. A comprehensive literature search was conducted including all published studies and abstracts investigating NBI cystoscopy in patients with bladder cancer. Comprehensive cystoscopic images are provided to illustrate differences between NBI and WLI cystoscopy. Early experience suggests that NBI cystoscopy detects more bladder tumors than does WLI cystoscopy, and NBI-assisted fulguration and transurethral resection (TUR) appear to result in fewer tumor recurrences. Questions remain, however, such as the following: Does NBI cystoscopy detect high-grade tumors, such as carcinoma in situ, that are missed by WLI cystoscopy? Would false positives lead to an unaccepted number of negative biopsies? And how might observer bias skew results? In addition, a major drawback of current studies is that the quality of cystoscopy and TUR by individual surgeons has not been addressed. Although clinical trials are just beginning, NBI cystoscopy holds promise that this new optical method may improve visualization of bladder tumors over conventional WLI cystoscopy. Further prospective and comparative trials are required to determine whether NBI will play a role in evaluating and treating urothelial tumors in individual patients. © 2014 Springer Science+Business Media.

Stubblefield M.D.,Sloan Kettering Cancer Center | Keole N.,10264 E Rosemary Lane
PM and R | Year: 2014

Upper body pain and dysfunction are common in survivors of breast cancer. Disorders of the upper body can result directly from breast cancer or from the surgery, chemotherapy, radiotherapy, or hormonal therapies used in its treatment. Although considerable information is available regarding impairments such as pain and restricted shoulder range of motion associated with breast cancer and its treatment, relatively little information is available about the specific neuromuscular, musculoskeletal, lymphovascular, and other diagnostic entities that underlie those impairments. This article will detail the common and specific causes of upper body pain and dysfunction in breast cancer survivors, including postsurgical pain, rotator cuff disease, adhesive capsulitis, arthralgias, cervical radiculopathy, brachial plexopathy, mononeuropathy, postmastectomy pain syndrome, lymphedema, axillary web syndrome, deep vein thrombosis, and cellulitis. Diagnostic specificity is a key first step to safely and effectively restore function and quality of life to breast cancer survivors. © 2014 American Academy of Physical Medicine and Rehabilitation.

Abu-Rustum N.R.,Sloan Kettering Cancer Center
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2014

Most patients with endometrial cancer will present with early-stage disease. Although the rate of metastasis in these patients is low, proffering excellent prognoses, the standard of treatment in many practices still includes a complete or selective pelvic and para-aortic lymphadenectomy for staging; and accurate surgical staging is the most important prognostic factor. Many patients will undergo a comprehensive lymphadenectomy despite having disease confined to the uterus, resulting in prolonged operating time, additional cost, and potential side effects, such as lower extremity lymphedema. However, recent studies show that a complete lymphadenectomy may have no therapeutic benefit in patients with early-stage endometrial cancer. Sentinel lymph node (SLN) mapping, which has been used in other cancer types, may be an acceptable surgical strategy between a complete lymphadenectomy and no nodal evaluation in patients with endometrial cancer. SLN mapping is based on the concept that lymph node metastasis is the result of an orderly process; that is, lymph drains in a specific pattern away from the tumor, and therefore, if the SLN, or first node, is negative for metastasis, then the nodes after the SLN should also be negative. This approach can help patients avoid the side effects associated with a complete lymphadenectomy, although disease must be thoroughly staged for accurate prognosis and determination of appropriate treatment approach. Surgeon experience, adherence to an SLN algorithm, and the use of pathologic "ultrastaging" are key factors for successful SLN mapping.

Gilks C.B.,University of British Columbia | Oliva E.,Massachusetts General Hospital | Soslow R.A.,Sloan Kettering Cancer Center
American Journal of Surgical Pathology | Year: 2013

Patients with high-grade subtypes of endometrial carcinoma (grade 3 endometrioid, serous, clear cell, or carcinosarcoma) have a relatively poor prognosis. The specific subtype may be used to guide patient management, but there is little information on the reproducibility of subtype diagnosis in cases of high-grade endometrial carcinoma. Fifty-six cases diagnosed as a high-grade subtype of endometrial carcinoma were identified from the pathology archives of Vancouver General Hospital. All slides for each case were reviewed independently by 3 pathologists, who diagnosed the specific tumor subtype(s) and assigned the percentage of each subtype for mixed tumors. Agreement between observers was categorized as follows: major disagreement: (A) no consensus for low-grade endometrioid versus high-grade carcinoma (any subtype), or (B) no consensus with respect to the predominant high-grade subtype present; minor disagreement: consensus was reached about the cell type of the predominant component of a mixed tumor, but there was disagreement about the subtype of the minor component. A tissue microarray was constructed from these cases and immunostained for p16, ER, PR, PTEN, and p53. In 35 of 56 (62.5%) cases, there was agreement between all 3 reviewers regarding the subtype diagnosis of the exclusive (in pure tumors) or predominant (in mixed tumors) high-grade component. Of these cases, there was a minor disagreement (ie, disagreement about the minor high-grade component subtype in a mixed tumor) in 4 cases (4/56, 7.1%). In 20 of 56 (35.8%) cases there was a major disagreement; in 17 (30.4%) of these cases there was no consensus about the major subtype diagnosis, whereas in 3 (5.4%) cases there was disagreement about whether a component of high-grade endometrial carcinoma was present. In the final case, all 3 reviewers diagnosed the case as low-grade endometrioid carcinoma, disagreeing with the original diagnosis of high-grade carcinoma. The most frequent areas of disagreement were serous versus clear cell (7 cases) and serous versus grade 3 endometrioid (6 cases). Immunostaining results using the 5-marker immunopanel were then used to adjudicate in the 6 cases in which there was disagreement between reviewers with respect to serous versus endometrioid carcinoma, and these supported a diagnosis of serous carcinoma in 4 of 6 cases and endometrioid carcinoma in 2 of 6 cases. Pairwise comparison between the reviewers for the 20 cases classified as showing major disagreement was as follows: reviewer 1 and reviewer 2 agreed in 5/20 cases, reviewer 1 and reviewer 3 agreed in 7/20 cases, and reviewer 2 and reviewer 3 agreed in 8/20 cases, indicating that disagreements were not because of a single reviewer holding outlier opinions. Diagnostic consensus among 3 reviewers about the exclusive or major subtype of high-grade endometrial carcinoma was reached in only 35/56 (62.5%) cases, and in 4 of these cases there was disagreement about the minor component present. This poor reproducibility did not reflect systematic bias on the part of any 1 reviewer. There is a need for molecular tools to aid in the accurate and reproducible diagnosis of high-grade endometrial carcinoma subtype. Copyright © 2013 by Lippincott Williams & Wilkins.

Satagopan J.M.,Sloan Kettering Cancer Center | Elston R.C.,Case Western Reserve University
Statistics in Medicine | Year: 2013

This paper is concerned with evaluating whether an interaction between two sets of risk factors for a binary trait is removable and, when it is removable, fitting a parsimonious additive model using a suitable link function to estimate the disease odds (on the natural logarithm scale). Statisticians define the term 'interaction' as a departure from additivity in a linear model on a specific scale on which the data are measured. Certain interactions may be eliminated via a transformation of the outcome such that the relationship between the risk factors and the outcome is additive on the transformed scale. Such interactions are known as removable interactions. We develop a novel test statistic for detecting the presence of a removable interaction in case-control studies. We consider the Guerrero and Johnson family of transformations and show that this family constitutes an appropriate link function for fitting an additive model when an interaction is removable. We use simulation studies to examine the type I error and power of the proposed test and to show that, when an interaction is removable, an additive model based on the Guerrero and Johnson link function leads to more precise estimates of the disease odds parameters and a better fit. We illustrate the proposed test and use of the transformation by using case-control data from three published studies. Finally, we indicate how one can check that, after transformation, no further interaction is significant. © 2012 John Wiley & Sons, Ltd.

Brennan S.B.,Sloan Kettering Cancer Center
Techniques in Vascular and Interventional Radiology | Year: 2014

Magnetic resonance Imaging-guided breast biopsy is an essential component of breast imaging practices offering breast magnetic resonance imaging. Careful planning and preparation allow for an efficient and successful biopsy. Deliberate positioning and controlled compression are keys to a comfortable and cooperative patient. The biopsy is only complete once imaging-histologic correlation has been made by the radiologist. © 2014 Elsevier Inc.

Rathkopf D.,New York Medical College | Scher H.I.,Sloan Kettering Cancer Center
Cancer Journal (United States) | Year: 2013

Persistent androgen receptor (AR) signaling despite low levels of serum androgens has been identified as a critical target for drug discovery in castration-resistant prostate cancer (CRPC). As proof of principle that the AR remains relevant in CRPC, 2 AR-targeted agents recently approved by the Food and Drug Administration-abiraterone and enzalutamide-have increased overall survival for patients with CRPC in the setting of prior chemotherapy. This review focuses on the AR and 2 direct antagonists, enzalutamide and ARN-509. These next-generation AR antagonists offer great promise for patients with advanced disease. Relative to conventional antiandrogens such as bicalutamide, they bind to the receptor with higher affinity, prevent nuclear translocation and DNA binding, and induce apoptosis without agonist activity in preclinical models. The success of these AR-targeted agents in the clinic has changed the landscape of therapy for patients with CRPC, and further therapeutic options building on this platform are currently in development. Copyright © 2013 Lippincott Williams &Wilkins.

Arcila M.E.,Sloan Kettering Cancer Center
Acta Cytologica | Year: 2012

A high proportion of patients with lung carcinoma present at a late stage of disease or have significant comorbidities which preclude treatment by aggressive surgical approaches. Consequently, many of these patients must be diagnosed and treated based on the assessment of cytologic samples or very small biopsies. Molecular testing, now an integral part of this assessment, introduces an additional level of complexity in the triaging of limited tissue for maximal diagnostic yield. Archived and previously stained cytologic samples provide a robust source of material for molecular studies. However, optimal techniques of tissue retrieval and DNA extraction are crucial to maximize the DNA yield. In this communication, we outline our protocol for obtaining DNA from archival cytologic material. The method is simple, requires no destaining steps or extensive manipulation of the sample, and yields sufficient DNA for the standard performance of routine molecular studies. © 2012 S. Karger AG, Basel.

Shia J.,Sloan Kettering Cancer Center
Seminars in Diagnostic Pathology | Year: 2015

The last two decades have seen significant advancement in our understanding of colorectal tumors with DNA mismatch repair (MMR) deficiency. The ever-emerging revelations of new molecular and genetic alterations in various clinical conditions have necessitated constant refinement of disease terminology and classification. Thus, a case with the clinical condition of hereditary non-polyposis colorectal cancer as defined by the Amsterdam criteria may be one of Lynch syndrome characterized by a germline defect in one of the several MMR genes, one of the yet-to-be-defined "Lynch-like syndrome" if there is evidence of MMR deficiency in the tumor but no detectable germline MMR defect or tumor MLH1 promoter methylation, or "familial colorectal cancer type X" if there is no evidence of MMR deficiency. The detection of these conditions carries significant clinical implications. The detection tools and strategies are constantly evolving. The Bethesda guidelines symbolize a selective approach that uses clinical information and tumor histology as the basis to select high-risk individuals. Such a selective approach has subsequently been found to have limited sensitivity, and is thus gradually giving way to the alternative universal approach that tests all newly diagnosed colorectal cancers. Notably, the universal approach also has its own limitations; its cost-effectiveness in real practice, in particular, remains to be determined. Meanwhile, technological advances such as the next-generation sequencing are offering the promise of direct genetic testing for MMR deficiency at an affordable cost probably in the near future. This article reviews the up-to-date molecular definitions of the various conditions related to MMR deficiency, and discusses the tools and strategies that have been used in detecting these conditions. Special emphasis will be placed on the evolving nature and the clinical importance of the disease definitions and the detection strategies. © 2015 Elsevier Inc.

Pencheva N.,Rockefeller University | Buss C.G.,Rockefeller University | Posada J.,Rockefeller University | Merghoub T.,Sloan Kettering Cancer Center | Tavazoie S.F.,Rockefeller University
Cell | Year: 2014

Melanoma metastasis is a devastating outcome lacking an effective preventative therapeutic. We provide pharmacologic, molecular, and genetic evidence establishing the liver-X nuclear hormone receptor (LXR) as a therapeutic target in melanoma. Oral administration of multiple LXR agonists suppressed melanoma invasion, angiogenesis, tumor progression, and metastasis. Molecular and genetic experiments revealed these effects to be mediated by LXRβ, which elicits these outcomes through transcriptional induction of tumoral and stromal apolipoprotein-E (ApoE). LXRβ agonism robustly suppressed tumor growth and metastasis across a diverse mutational spectrum of melanoma lines. LXRβ targeting significantly prolonged animal survival, suppressed the progression of established metastases, and inhibited brain metastatic colonization. Importantly, LXRβ activation displayed melanoma-suppressive cooperativity with the frontline regimens dacarbazine, B-Raf inhibition, and the anti-CTLA-4 antibody and robustly inhibited melanomas that had acquired resistance to B-Raf inhibition or dacarbazine. We present a promising therapeutic approach that uniquely acts by transcriptionally activating a metastasis suppressor gene. © 2014 Elsevier Inc.

Kircher M.F.,Sloan Kettering Cancer Center | Willmann J.K.,Stanford University
Radiology | Year: 2012

Molecular imaging is expected to have a major impact on the early diagnosis of diseases and disease monitoring in the next decade. Traditionally, nuclear imaging techniques have been the mainstay of molecular imaging in the clinical arena. However, with continued development of molecularly targeted contrast agents for nonnuclear imaging techniques such as magnetic resonance (MR), computed tomography (CT), and ultrasonography (US), the spectrum of clinical molecular imaging applications is expanding. In the second part of this review series, an overview of applications of molecular MR imaging-, CT-, and US-based imaging strategies that show promise for clinical translation is presented, and key challenges that need to be addressed to successfully translate these promising techniques in the future are discussed. © RSNA, 2012.

Stewart M.,Sloan Kettering Cancer Center
Social Work in Health Care | Year: 2014

Spirituality is central to many people's lives, yet social workers often defer discussing the topic with patients. Their avoidance can be linked to the lack of training on how to speak with patients about spiritual matters (Lemmer, 2010) With further education, clinical social workers are empowered to assess this significant aspect of the patient's cancer experience as they progress along the illness continuum. The social worker's comfort and familiarity with spiritual assessment, spiritual language, and various forms of religious and/or spiritual practices will improve their clinical work with patients who have chronic cancer by providing insight to guide appropriate social work interventions designed to enhance spiritual well-being. © 2014 Copyright Taylor & Francis Group, LLC.

Shaha A.R.,Sloan Kettering Cancer Center
Endocrine Practice | Year: 2012

Objective: To discuss the risk of recurrence in patients with differentiated thyroid cancer and emphasize the importance of risk-group stratification.Methods: Common risk factors associated with recurrent thyroid cancer are outlined, and appropriate management strategies are reviewed.Results: The overall prognosis in patients with differentiated thyroid cancer is excellent. Factors associated with recurrent thyroid cancer include extrathyroidal extension of the primary tumor, bulky nodal metastatic lesions, macroscopic local invasion, and aggressive histologic subtypes. The locoregional recurrence and mortality are higher in patients with high-risk thyroid cancers. Patients initially presenting with locally aggressive and advanced thyroid cancer have a higher incidence of recurrent disease in the thyroid bed or nodal metastasis. These patients also have a high incidence of distant metastatic lesions. Locally recurrent thyroid cancer may be seen in more than 25% of patients with aggressive differentiated thyroid cancer. Recurrent disease in the thyroid bed can be a difficult problem to manage because of the proximity of the tumor to the recurrent laryngeal nerve, visceral structures in the central compartment, and occasional involvement of the trachea or larynx. External beam radiation therapy after surgical treatment may be important for better local control in the thyroid bed region, especially in patients with poorly differentiated histologic features. The role of additional radioiodine therapy remains undefined at this stage.Conclusion: Management of patients with recurrent thyroid cancer necessitates a true multidisciplinary approach. These patients require close follow-up, with cross-sectional imaging and positron emission tomographic scanning in selected individuals. Copyright © 2012 AACE.

Pusic A.L.,Sloan Kettering Cancer Center
Plastic and Reconstructive Surgery | Year: 2013

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Differentiate among the various techniques available to reconstructive breast surgeons. 2. Perform a comprehensive assessment of the breast reconstruction candidate. 3. Gain knowledge about the indications and contraindications for different breast reconstructive procedures. 4. Understand the complications inherent in different reconstructive breast procedures. 5. Summarize the long-term objective and subjective implications of surgery. SUMMARY: This article was prepared to accompany practice-based assessment with ongoing surgical education for the Maintenance of Certification for the American Board of Plastic Surgery. It is structured to outline the care of the patient with the postmastectomy breast deformity. Copyright © 2013 by the American Society of Plastic Surgeons.

Joensuu H.,University of Helsinki | Dematteo R.P.,Sloan Kettering Cancer Center
Annual Review of Medicine | Year: 2012

Gastrointestinal stromal tumor (GIST) has become a model for targeted therapy in cancer. The vast majority of GISTs contain an activating mutation in either the KIT or platelet-derived growth factor A (PDGFRA) gene. GIST is highly responsive to several selective tyrosine kinase inhibitors. In fact, this cancer has been converted to a chronic disease in some patients. Considerable progress has been made recently in our understanding of the natural history and molecular biology of GIST, risk stratification, and drug resistance. Despite the efficacy of targeted therapy, though, surgery remains the only curative primary treatment and cures >50% of GIST patients who present with localized disease. Adjuvant therapy with imatinib prolongs recurrence-free survival and may improve overall survival. Combined or sequential use of tyrosine kinase inhibitors with other agents following tumor molecular subtyping is an attractive next step in the management of GIST. © 2012 by Annual Reviews. All rights reserved.

Pietanza M.C.,Sloan Kettering Cancer Center
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

In clinical trials, traditional monitoring methods, paper documentation, and outdated collection systems lead to inaccuracies of study information and inefficiencies in the process. Integrated electronic systems offer an opportunity to collect data in real time. We created a computer software system to collect 13 patient-reported symptomatic adverse events and patient-reported Karnofsky performance status, semi-automated RECIST measurements, and laboratory data, and we made this information available to investigators in real time at the point of care during a phase II lung cancer trial. We assessed data completeness within 48 hours of each visit. Clinician satisfaction was measured. Forty-four patients were enrolled, for 721 total visits. At each visit, patient-reported outcomes (PROs) reflecting toxicity and disease-related symptoms were completed using a dedicated wireless laptop. All PROs were distributed in batch throughout the system within 24 hours of the visit, and abnormal laboratory data were available for review within a median of 6 hours from the time of sample collection. Manual attribution of laboratory toxicities took a median of 1 day from the time they were accessible online. Semi-automated RECIST measurements were available to clinicians online within a median of 2 days from the time of imaging. All clinicians and 88% of data managers felt there was greater accuracy using this system. Existing data management systems can be harnessed to enable real-time collection and review of clinical information during trials. This approach facilitates reporting of information closer to the time of events, and improves efficiency, and the ability to make earlier clinical decisions.

Shi C.,Sloan Kettering Cancer Center | Shi C.,Rockefeller University
Immunology | Year: 2012

Mesenchymal stem cells (MSCs) are multipotent cells that are being clinically explored as regenerative therapeutics. Cultured MSCs secrete various modulatory factors, which contribute to the immunosuppressive effects of transplanted MSCs as a therapy. Although the in vitro phenotype of MSCs has been well characterized, identification of MSCs in vivo is made difficult by the lack of specific markers. Current advances in murine MSC research provide valuable tools for studying the localization and function of MSCs in vivo. Recent findings suggest that MSCs exert diverse functions depending on tissue context and physiological conditions. This review focuses on bone marrow MSCs and their roles in haematopoiesis and immune responses. © 2012 The Author. Immunology © 2012 Blackwell Publishing Ltd.

Abdel-Wahab O.,Sloan Kettering Cancer Center
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

The myelodysplastic syndromes (MDS) are a clinically and cytogenetically heterogeneous group of clonal diseases characterized by ineffective hematopoiesis, peripheral blood cytopenias, and an increased risk of progression to acute myeloid leukemia. The precise molecular mechanisms behind the development of MDS have remained elusive; however, the distinct sensitivity of this disease to DNA methyltransferase inhibitors and the presence of markedly abnormal epigenetic profiles suggested the existence of an epigenetic mechanism underlying the disease. Recently, the advent of new technologies for the detection of genetic abnormalities has led to the description of a set of novel recurrent mutations in patients with this disease. The majority of these novel mutations have been described in genes encoding different components of the epigenetic machinery, many of which are associated with distinct clinical outcomes. Finally, mutations in mRNA splicing genes have also been described recently in MDS, underscoring the molecular complexity that underlies the development of this heterogeneous disease.

Soff G.A.,Sloan Kettering Cancer Center
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012

After more than 50 years of thrombosis treatment and prophylaxis being based on heparin and vitamin K antagonists, a new generation of oral, direct anticoagulants is now available. The past 5 years have brought a strikingly large number of trials that evaluated these new oral anticoagulants in a range of clinical trials, particularly nonvalvular atrial fibrillation, thrombosis prophylaxis after major joint replacement surgery, treatment of venous thromboembolic events, and, most recently, acute coronary syndrome. These studies have been notably similar in design between the drugs for specific indication. This review focuses on the 3 drugs that either have recently been approved by the US Food and Drug Administration (dabigatran and rivaroxaban) or have the most mature phase III clinical data (apixaban). © 2012 American Heart Association, Inc.

Rampal R.,Sloan Kettering Cancer Center
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

The use of candidate gene and genome-wide discovery studies in the last several years has led to an expansion of our knowledge of the spectrum of recurrent, somatic disease alleles, which contribute to the pathogenesis of hematologic malignancies. Notably, these studies have also begun to fundamentally change our ability to develop informative prognostic schema that inform outcome and therapeutic response, yielding substantive insights into mechanisms of hematopoietic transformation in different tissue compartments. Although these studies have already had important biologic and translational impact, significant challenges remain in systematically applying these findings to clinical decision making and in implementing new technologies for genetic analysis into clinical practice to inform real-time decision making. Here, we review recent major genetic advances in myeloid and lymphoid malignancies, the impact of these findings on prognostic models, our understanding of disease initiation and evolution, and the implication of genomic discoveries on clinical decision making. Finally, we discuss general concepts in genetic modeling and the current state-of-the-art technology used in genetic investigation.

Strong V.E.,Sloan Kettering Cancer Center
Surgical Oncology Clinics of North America | Year: 2012

There has been much speculation regarding differences in outcome for patients who have gastric cancer in the Eastern versus Western world. Among other factors, th