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Dana–Farber Cancer Institute is a center for cancer treatment and research in Boston, Massachusetts. It is a major affiliate of Harvard Medical School, and a founding member of Dana–Farber/Harvard Cancer Center, a Comprehensive Cancer Center designated by the National Cancer Institute. Wikipedia.

Rabbani P.,New York University | Takeo M.,New York University | Chou W.,New York University | Myung P.,Case Western Reserve University | And 4 more authors.
Cell | Year: 2011

Melanocyte stem cells (McSCs) intimately interact with epithelial stem cells (EpSCs) in the hair follicle bulge and secondary hair germ (sHG). Together, they undergo activation and differentiation to regenerate pigmented hair. However, the mechanisms behind this coordinated stem cell behavior have not been elucidated. Here, we identified Wnt signaling as a key pathway that couples the behavior of the two stem cells. EpSCs and McSCs coordinately activate Wnt signaling at the onset of hair follicle regeneration within the sHG. Using genetic mouse models that specifically target either EpSCs or McSCs, we show that Wnt activation in McSCs drives their differentiation into pigment-producing melanocytes, while EpSC Wnt signaling not only dictates hair follicle formation but also regulates McSC proliferation during hair regeneration. Our data define a role for Wnt signaling in the regulation of McSCs and also illustrate a mechanism for regeneration of complex organs through collaboration between heterotypic stem cell populations. PaperFlick: © 2011 Elsevier Inc. All Rights Reserved.

Mao Y.,Dana-Farber Cancer Institute | Zhang J.,Northeastern University
Journal of the American Chemical Society | Year: 2012

Cooperativity is a hallmark of spontaneous biopolymer folding. The presence of intermolecular interactions could create off-pathway misfolding structures and suppress folding cooperativity. This raises the hypothesis that thermodynamic competitivity between off-pathway misfolding and on-pathway folding may intervene with cooperativity and govern biopolymer folding dynamics under conditions permitting large-scale intermolecular interactions. Here we report direct imaging and theoretical modeling of thermodynamic competitivity between biopolymer folding and misfolding under such conditions, using a two-dimensional array of proton-fueled DNA molecular motors packed at the maximal density as a model system. Time-resolved liquid-phase atomic force microscopy with enhanced phase contrast revealed that the misfolding and folding intermediates transiently self-organize into spatiotemporal patterns on the nanoscale in thermodynamic states far away from equilibrium as a result of thermodynamic competitivity. Computer simulations using a novel cellular-automaton network model provide quantitative insights into how large-scale intermolecular interactions correlate the structural dynamics of individual biomolecules together at the systems level. © 2011 American Chemical Society.

Pardee A.B.,Dana-Farber Cancer Institute
Journal of Cellular Physiology | Year: 2015

During the 20th century great progress was made in genetics and biochemistry, and these were combined into a molecular biological understanding of functions of macromolecules. Further great discoveries will be made about bioregulations, applicable to scientific problems such as cell development and evolution, and to illnesses including heart disease through defective control of cholesterol production, and to neurological cell-based diseases. The "War Against Cancer" is still far from won. The present generation of scientists can develop clinical applications from recent basic science discoveries. © 2015 Wiley Periodicals, Inc.

Cohen J.,Tufts University | Malins A.,Dana-Farber Cancer Institute | Shahpurwala Z.,University of Mississippi
Health Affairs | Year: 2013

In Europe drug reimbursement decisions often weigh how new drugs perform relative to those already on the market and how costeffective they are relative to certain metrics. In the United States such comparative-effectiveness and cost-effectiveness evidence is rarely considered.Which approach allows patients greater access to drugs? In 2000-11 forty-one oncology drugs were approved for use in the United States and thirty-one were approved in Europe. We compared patients" access to the twenty-nine cancer drugs introduced into the health care systems of the United States and four European countries. Relative to the approach used in the US Medicare program in particular, the European evidence-based approach appears to have led to reduced prices for those drugs deemed worthy of approval and reimbursement. The result is improved affordability for payers and increased access for patients to those drugs that were available. The United States lacks a systematic approach to assessing such evidence in the coverage decision-making process, which may prove inadequate for controlling costs, improving outcomes, and reducing inequities in access to care. © 2013 Project HOPE- The People-to-People Health Foundation, Inc.

Mayers J.R.,Massachusetts Institute of Technology | Vander Heiden M.G.,Massachusetts Institute of Technology | Vander Heiden M.G.,Dana-Farber Cancer Institute | Vander Heiden M.G.,The Broad Institute of MIT and Harvard
Trends in Biochemical Sciences | Year: 2015

To fuel unregulated proliferation, cancer cells alter metabolism to support macromolecule biosynthesis. Cell culture studies have revealed how different oncogenic mutations and nutrients impact metabolism. Glucose and glutamine are the primary fuels used in vitro; however, recent studies have suggested that utilization of other amino acids as well as lipids and protein can also be important to cancer cells. Early investigations of tumor metabolism are translating these findings to the biology of whole tumors and suggest that additional complexity exists beyond nutrient availability alone in vivo. Whole-body metabolism and tumor heterogeneity also influence the metabolism of tumor cells, and successful targeting of metabolism for cancer therapy will require an understanding of tumor metabolism in vivo. © 2015 Elsevier Ltd.

Thomas J.D.,Dana-Farber Cancer Institute | Arnold R.M.,University of Pittsburgh
Journal of Palliative Medicine | Year: 2011

Background: Giving feedback is a core element of medical education, one that is gaining attention but with a thin evidence base to guide medical educators. This review provides a definition of feedback and its purpose, selectively reviews the literature regarding educators' and learners' attitudes toward feedback, and provides an algorithm for giving feedback. Discussion: The authors discuss the parallels between giving feedback and breaking bad news, emphasizing the importance of titrating the amount of information given, attending to affect, and making a plan for next steps. Special considerations for giving feedback in palliative care are highlighted, including the effect of heightened emotion in the clinical encounter and the difficulties of giving feedback about communication skills. © Copyright 2011, Mary Ann Liebert, Inc.

Shammas M.A.,Dana-Farber Cancer Institute
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2011

Purpose of review: There has been growing evidence that lifestyle factors may affect the health and lifespan of an individual by affecting telomere length. The purpose of this review was to highlight the importance of telomeres in human health and aging and to summarize possible lifestyle factors that may affect health and longevity by altering the rate of telomere shortening. Recent findings: Recent studies indicate that telomere length, which can be affected by various lifestyle factors, can affect the pace of aging and onset of age-associated diseases. Summary: Telomere length shortens with age. Progressive shortening of telomeres leads to senescence, apoptosis, or oncogenic transformation of somatic cells, affecting the health and lifespan of an individual. Shorter telomeres have been associated with increased incidence of diseases and poor survival. The rate of telomere shortening can be either increased or decreased by specific lifestyle factors. Better choice of diet and activities has great potential to reduce the rate of telomere shortening or at least prevent excessive telomere attrition, leading to delayed onset of age-associated diseases and increased lifespan. This review highlights the role of telomeres in aging and describes the lifestyle factors which may affect telomeres, human health, and aging. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Whittaker S.R.,Dana-Farber Cancer Institute
Cancer discovery | Year: 2013

RAF inhibitors such as vemurafenib and dabrafenib block BRAF-mediated cell proliferation and achieve meaningful clinical benefit in the vast majority of patients with BRAF(V600E)-mutant melanoma. However, some patients do not respond to this regimen, and nearly all progress to therapeutic resistance. We used a pooled RNA interference screen targeting more than 16,500 genes to discover loss-of-function events that could drive resistance to RAF inhibition. The highest ranking gene was NF1, which encodes neurofibromin, a tumor suppressor that inhibits RAS activity. NF1 loss mediates resistance to RAF and mitogen-activated protein kinase (MAPK) kinase kinase (MEK) inhibitors through sustained MAPK pathway activation. However, cells lacking NF1 retained sensitivity to the irreversible RAF inhibitor AZ628 and an ERK inhibitor. NF1 mutations were observed in BRAF-mutant tumor cells that are intrinsically resistant to RAF inhibition and in melanoma tumors obtained from patients exhibiting resistance to vemurafenib, thus showing the clinical potential for NF1-driven resistance to RAF/MEK-targeted therapies.

Jaffe A.E.,Lieber Institute for Brain Development | Irizarry R.A.,Dana-Farber Cancer Institute
Genome Biology | Year: 2014

Background: Epigenome-wide association studies of human disease and other quantitative traits are becoming increasingly common. A series of papers reporting age-related changes in DNA methylation profiles in peripheral blood have already been published. However, blood is a heterogeneous collection of different cell types, each with a very different DNA methylation profile.Results: Using a statistical method that permits estimating the relative proportion of cell types from DNA methylation profiles, we examine data from five previously published studies, and find strong evidence of cell composition change across age in blood. We also demonstrate that, in these studies, cellular composition explains much of the observed variability in DNA methylation. Furthermore, we find high levels of confounding between age-related variability and cellular composition at the CpG level.Conclusions: Our findings underscore the importance of considering cell composition variability in epigenetic studies based on whole blood and other heterogeneous tissue sources. We also provide software for estimating and exploring this composition confounding for the Illumina 450k microarray. © 2014 Jaffe and Irizarry; licensee BioMed Central Ltd.

Vickers A.J.,Sloan Kettering Cancer Center | Cronin A.M.,Dana-Farber Cancer Institute | Begg C.B.,Sloan Kettering Cancer Center
BMC Medical Research Methodology | Year: 2011

Background. We have observed that the area under the receiver operating characteristic curve (AUC) is increasingly being used to evaluate whether a novel predictor should be incorporated in a multivariable model to predict risk of disease. Frequently, investigators will approach the issue in two distinct stages: first, by testing whether the new predictor variable is significant in a multivariable regression model; second, by testing differences between the AUC of models with and without the predictor using the same data from which the predictive models were derived. These two steps often lead to discordant conclusions. Discussion. We conducted a simulation study in which two predictors, X and X*, were generated as standard normal variables with varying levels of predictive strength, represented by means that differed depending on the binary outcome Y. The data sets were analyzed using logistic regression, and likelihood ratio and Wald tests for the incremental contribution of X* were performed. The patient-specific predictors for each of the models were then used as data for a test comparing the two AUCs. Under the null, the size of the likelihood ratio and Wald tests were close to nominal, but the area test was extremely conservative, with test sizes less than 0.006 for all configurations studied. Where X* was associated with outcome, the area test had much lower power than the likelihood ratio and Wald tests. Summary. Evaluation of the statistical significance of a new predictor when there are existing clinical predictors is most appropriately accomplished in the context of a regression model. Although comparison of AUCs is a conceptually equivalent approach to the likelihood ratio and Wald test, it has vastly inferior statistical properties. Use of both approaches will frequently lead to inconsistent conclusions. Nonetheless, comparison of receiver operating characteristic curves remains a useful descriptive tool for initial evaluation of whether a new predictor might be of clinical relevance. © 2011 Vickers et al; licensee BioMed Central Ltd.

Patenaude A.F.,Dana-Farber Cancer Institute | Pelletier W.,Alberta Childrens Hospital | Bingen K.,Medical College of Wisconsin
Pediatric Blood and Cancer | Year: 2015

As part of a larger effort to create standards for psychosocial care of children with cancer, we document consensus and evidence-based data on interprofessional communication, documentation, and training for professionals providing psycho-oncology services. Six databases were searched. Sixty-five articles and six guidelines and consensus-based documents were identified; 35 met inclusion criteria. Data support strong recommendations for standards of care in communication/collaboration, documentation of patient information, and training in pediatric psycho-oncology. These are areas where extensive research is unlikely to be conducted; however, professional expectations and qualifications may be further clarified and strengthened with time. Pediatr Blood Cancer. © 2015 Wiley Periodicals, Inc.

Takezawa K.,Kinki University | Okamoto I.,Kinki University | Nishio K.,Kinki University | Janne P.A.,Dana-Farber Cancer Institute | Nakagawa K.,Kinki University
Clinical Cancer Research | Year: 2011

Purpose: EML4-ALK (echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase) was recently identified as a transforming fusion gene in non-small cell lung cancer. The purpose of the present study was to characterize the mechanism of malignant transformation by EML4-ALK. Experimental Design: We established NIH 3T3 cells that stably express variant 1 or 3 of EML4-ALK and examined the signaling molecules that function downstream of EML4-ALK. Results: Forced expression of EML4-ALK induced marked activation of extracellular signal-regulated kinase (ERK) and STAT3, but not that of AKT. Inhibition of ERK or STAT3 signaling resulted in substantial attenuation of the proliferation of cells expressing either variant of EML4-ALK, suggesting that these signaling pathways function downstream of EML4-ALK in lung cancer cells. The specific ALK inhibitor TAE684 induced apoptosis that was accompanied both by upregulation of BIM, a proapoptotic member of the Bcl-2 family, and by downregulation of survivin, a member of the inhibitor of apoptosis protein (IAP) family, in EML4-ALK-expressing NIH 3T3 cells as well as in H3122 human lung cancer cells harboring endogenous EML4-ALK. Depletion of BIM and overexpression of survivin each inhibited TAE684-induced apoptosis, suggesting that both upregulation of BIM and downregulation of survivin contribute to TAE684-induced apoptosis in EML4-ALK-positive lung cancer cells. Furthermore, BIM and survivin expression was found to be independently regulated by ERK and STAT3 signaling pathways, respectively. Conclusions: ALK inhibitor-induced apoptosis is mediated both by BIM upregulation resulting from inhibition of ERK signaling as well as by survivin downregulation resulting from inhibition of STAT3 signaling in EML4-ALK-positive lung cancer cells. © 2011 American Association for Cancer Research.

Brown J.R.,Dana-Farber Cancer Institute
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2011

Despite the widespread use of highly effective chemoimmunotherapy (CIT), fludarabine-refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical problem associated with poor overall survival (OS). The traditional definition, which includes those patients with no response or relapse within 6 months of fludarabine, is evolving with the recognition that even patients with longer remissions of up to several years after CIT have poor subsequent treatment response and survival. Approved therapeutic options for these patients remain limited, and the goal of therapy for physically fit patients is often to achieve adequate cytoreduction to proceed to allogeneic stem cell transplantation (alloSCT). Fortunately, several novel targeted therapeutics in clinical trials hold promise of significant benefit for this patient population. This review discusses the activity of available and novel therapeutics in fludarabine-refractory or fludarabine-resistant CLL as well as recently updated data on alloSCT in CLL.

Guinan E.C.,Dana-Farber Cancer Institute
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2011

Aplastic anemia remains a diagnosis of exclusion. Our ability to reliably diagnose, and therefore exclude, a variety of inherited or acquired diseases with similar phenotypes has improved markedly. An efficient diagnostic plan is important because time from diagnosis to treatment is related to outcome regardless of the therapeutic option chosen. HSCT remains the mainstay of therapy for those with matched sibling donors, and results have improved even further in recent years. For those without a sibling donor, the high response and overall survival rates of combined immunosuppressive therapy (IST) have proven robust. Nonetheless, incomplete response, relapse, and progression to myelodysplasia/leukemia have more clearly emerged as significant long-term issues. Improvements in outcome of alternative donor transplantation and the use of established and novel immunosuppressive agents provide multiple alternatives for treating refractory or relapsed patients. Best practices in this regard are not yet clearly established and may vary by a variety of demographic and treatment-specific factors. Regardless of the type of therapeutic approach, patients require ongoing monitoring for occurrence of disease and/or therapy-related side effects.

Qiang L.,Columbia University | Banks A.S.,Dana-Farber Cancer Institute | Accili D.,Columbia University
Journal of Biological Chemistry | Year: 2010

The activity of transcription factor FoxO1 is regulated by phosphorylation-dependent nuclear exclusion and deacetylation-dependent nuclear retention. It is unclear whether and how these two post-translational modifications affect each other. To answer this question, we expressed FoxO1 cDNAs with combined mutations of phosphorylation and acetylation sites in HEK-293 cells and analyzed their subcellular localization patterns. We show that mutations mimicking the acetylated state (KQ series) render FoxO1 more sensitive to Akt-mediated phosphorylation and nuclear exclusion and can reverse the constitutively nuclear localization of phosphorylation-defective FoxO1. Conversely, mutations mimicking the deacetylated state (KR series) promote FoxO1 nuclear retention. Oxidative stress and the Sirt1 activator resveratrol are thought to promote FoxO1 deacetylation and nuclear retention, thus increasing its activity. Accordingly, FoxO1 deacetylation was required for the effect of oxidative stress (induced by H 2O 2) to retain FoxO1 in the nucleus. H 2O 2 also inhibited FoxO1 phosphorylation on Ser-253 and Thr-24, the key insulin-regulated sites, irrespective of its acetylation. In contrast, the effect of resveratrol was independent of FoxO1 acetylation and its phosphorylation on Ser-253 and Thr-24, suggesting that resveratrol acts on FoxO1 in a Sirt1- and Akt-independent manner. The dissociation of deacetylation from dephosphorylation in H 2O 2-treated cells indicates that the two modifications can occur independently of each other. It can be envisaged that FoxO1 exists in multiple nuclear forms with distinct activities depending on the balance of acetylation and phosphorylation. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Steensma D.P.,Dana-Farber Cancer Institute
Current Hematologic Malignancy Reports | Year: 2012

Just as a pawnshop owner who is unable to distinguish a genuine Rolex watch from a cheap knockoff courts financial ruin, the physician who fails to discriminate between authentic myelodysplastic syndromes (MDS) and conditions resembling MDS risks misinforming or harming patients. This review summarizes minimal criteria for diagnosing MDS and discusses common diagnostic challenges. MDS needs to be separated from numerous neoplastic and non-clonal hematologic disorders that can mimic MDS, including other myeloid neoplasms, nutritional deficiencies, toxin exposures, aplastic anemia, and inherited disorders (e.g., congenital sideroblastic anemia). Some distinctions are more critical therapeutically than others; e.g., recognizing B12 deficiency is more important than parsing high-risk MDS from erythroleukemia. Diagnostically ambiguous cases may be assigned holding-pattern terms, "idiopathic cytopenia(s) of undetermined significance" (ICUS) or "idiopathic dysplasia of undetermined significance" (IDUS), while awaiting clarifying information or further clinical developments. In the future, advances in molecular pathology will improve diagnostic accuracy, especially in morphologically non-descript cases. © Springer Science+Business Media, LLC 2012.

Elfiky A.A.,Dana-Farber Cancer Institute
Discovery medicine | Year: 2012

Emerging from a largely cytokine-based era, the last several years have witnessed a dramatic change in the therapeutic landscape of renal cancer. Molecularly targeted and antiangiogenic agents now form the backbone of most therapeutic strategies for patients with metastatic renal cell carcinoma (mRCC). Although the next few years may not see such broad paradigm shifts, there are ongoing areas of development including vaccine and immunotherapies which do diverge from this paradigm and hold promise to improve therapeutic outcomes for patients with mRCC.

Chau N.G.,Dana-Farber Cancer Institute
Current Treatment Options in Oncology | Year: 2014

Human papillomavirus-associated oropharynx cancer (HPV-OPC) is growing in incidence and has distinct clinical, pathologic, molecular, and epidemiologic features. However, the management of HPV-OPC does not presently differ from HPV-negative OPC based on the current evidence and requires complex multidisciplinary approaches. The superior prognosis of HPV-OPC and the toxicities of current multimodality treatment in a young population serve as the impetus to evaluate de-intensification treatment regimens aimed at reducing toxicity while maintaining therapeutic efficacy. Clinical trials are underway to evaluate reduced doses of radiation or less toxic systemic therapy regimens in HPV-OPC. Minimally invasive surgical approaches in the HPV-OPC population with early tumor stage also are being investigated. De-intensification strategies should only be employed in the context of clinical trials, and HPV-OPC patients should be offered clinical trials’ participation. Appropriate patient selection is critical to the development of de-intensification regimens, and this requires greater understanding of risk factors within the HPV-OPC population, HPV-OPC biology, and how HPV modulates response to specific therapies. Smoking history and bulky nodal disease have been shown to impact negatively the favorable prognosis of HPV association. Validated biomarkers within the HPV-OPC population are lacking, although alterations in the PI3K pathway and markers of immune response may emerge as important considerations in the future. Novel therapeutic strategies are desperately needed particularly for HPV-OPC patients who fail definitive therapy, and select patients with recurrent or metastatic disease may benefit from aggressive approaches. © 2014, Springer Science+Business Media New York.

Luke J.J.,University of Chicago | Ott P.A.,Dana-Farber Cancer Institute
Oncotarget | Year: 2015

Checkpoint inhibitors are revolutionizing treatment options and expectations for patients with melanoma. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was the first approved checkpoint inhibitor. Emerging long-term data indicate that approximately 20% of ipilimumabtreated patients achieve long-term survival. The first programmed death 1 (PD-1) inhibitor, pembrolizumab, was recently approved by the United States Food and Drug Administration for the treatment of melanoma; nivolumab was previously approved in Japan. PD-1 inhibitors are also poised to become standard of care treatment for other cancers, including non-small cell lung cancer, renal cell carcinoma and Hodgkin's lymphoma. Immunotherapy using checkpoint inhibition is a different treatment approach to chemotherapy and targeted agents: instead of directly acting on the tumor to induce tumor cell death, checkpoint inhibitors enhance or de novostimulate antitumor immune responses to eliminate cancer cells. Initial data suggest that objective anti-tumor response rates may be higher with anti-PD-1 agents compared with ipilimumab and the safety profile may be more tolerable. This review explores the development and next steps for PD-1 pathway inhibitors, including discussion of their novel mechanism of action and clinical data to-date, with a focus on melanoma.

Matulonis U.A.,Dana-Farber Cancer Institute
Future Oncology | Year: 2011

Bevacizumab is a monoclonal antibody that binds to VEGF, a circulating protein involved in the promotion of angiogenesis and probably tumor growth and progression. Bevacizumab has demonstrated anticancer activity in several cancers, either combined with chemotherapy or when used as a single agent, and has been approved by the US FDA as a treatment for several cancers. As VEGF has been implicated in ovarian cancer progression and ascites formation, and high levels of VEGF have been found in plasma and ascites in women with ovarian cancer, bevacizumab has been tested as an anticancer therapy in ovarian cancer. Documented single-agent activity of bevacizumab in recurrent ovarian cancer has led to combination studies with both biologic agents as well as other chemotherapy agents in both recurrent and newly diagnosed cancer. One trial in patients with recurrent, heavily pretreated ovarian cancer demonstrated a higher than predicted risk of gastrointestinal perforation, and although a lower incidence of gastrointestinal perforation has been reported in less heavily pretreated patients, patients and their physicians must be aware of this risk. Upfront studies testing the impact of adding bevacizumab to carboplatin and paclitaxel chemotherapy for the treatment of newly diagnosed cancer are currently underway, and one Phase III randomized study (Gynecologic Oncology Group study 218) was recently presented and will be discussed in this article. © 2011 Future Medicine Ltd.

Trevino K.M.,Dana-Farber Cancer Institute
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Patients who develop a strong alliance with their health care providers have been shown to have higher levels of psychosocial well-being and rates of treatment adherence. Young adults with cancer have lower levels of psychosocial well-being and treatment adherence relative to patients with cancer in other age groups. This study sought to evaluate the relationships between the patient-oncologist alliance, psychosocial well-being, and treatment adherence in young adults with advanced cancer. Ninety-five young adults (age 20 to 40 years) with advanced cancer were administered measures of alliance, psychosocial well-being, willingness to adhere to treatment, and treatment adherence. Relationships between alliance and psychosocial well-being were examined bivariately. Multiple linear regression models examined the relationship between alliance and adherence, controlling for confounding influences (eg, psychosocial well-being). Alliance was significantly (P ≤ .01) and positively associated with greater perceived social support and less severe illness-related grief. After controlling for significant confounding influences (ie, metastases, appraised support, and grief), alliance remained significantly (P ≤ .01) associated with greater willingness to adhere to treatment and greater adherence to oral medication. By developing a strong alliance, oncologists may enhance psychosocial well-being and increase treatment adherence in young adult patients with advanced cancer.

Castillo J.J.,Dana-Farber Cancer Institute | Reagan J.L.,The Miriam Hospital | Sikov W.M.,Brown University | Winer E.S.,The Miriam Hospital
British Journal of Haematology | Year: 2015

Plasmablastic lymphoma (PBL) is a rare and aggressive CD20-negative lymphoma. Despite improvements of the biology behind PBL, it still represents a challenge from the diagnostic and therapeutic perspectives for pathologists and clinicians. PBL is characterized by high rates of relapse and short median survival with standard approaches. Here, we report the use of the combination of bortezomib and infusional etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (V-EPOCH) in three patients with PBL; two were HIV-positive and one was HIV-negative. All three patients obtained a durable complete response to V-EPOCH with survival times of 24, 18 and 12 months respectively. © 2015 John Wiley & Sons Ltd.

Janeway K.A.,Dana-Farber Cancer Institute | Walkley C.R.,St. Vincents Institute
Bone | Year: 2010

Osteosarcoma (OS) is the most common primary tumour of bone, occurring predominantly in the second decade of life. High-dose cytotoxic chemotherapy and surgical resection have improved prognosis, with long-term survival for patients with localized (non-metastatic) disease approaching 70%. At presentation approximately 20% of patients have metastases and almost all patients with recurrent OS have metastatic disease and cure rates for patients with metastatic or recurrent disease remain poor (< 20% survival). Over the past 20 years, considerable progress has been made in the understanding of OS pathogenesis, yet these insights have not translated into substantial therapeutic advances and clinical outcomes. Further progress is essential in order to develop molecularly based therapies that target both primary lesions as well as metastatic disease. The increasing sophistication with which gene expression can be modulated in the mouse, both positively and negatively in addition to temporally, has allowed for the recent generation of more faithful OS models than have previously been available. These murine OS models can recapitulate all aspects of the disease process, from initiation and establishment to invasion and dissemination to distant sites. The development and utilisation of murine models that faithfully recapitulate human osteosarcoma, complementing existing approaches using human and canine disease, holds significant promise in furthering our understanding of the genetic basis of the disease and, more critically, in advancing pre-clinical studies aimed at the rational development and trialing of new therapeutic approaches. © 2010 Elsevier Inc.

Shulman L.N.,Dana-Farber Cancer Institute
Nature Reviews Cancer | Year: 2014

The knowledge and tools to cure many cancer patients exist in developed countries but are unavailable to many who live in the developing world, resulting in unnecessary loss of life. Bringing cancer care to the poor, particularly to low-income countries, is a great challenge, but it is one that we believe can be met through partnerships, careful planning and a set of guiding principles. Alongside vaccinations, screening and other cancer-prevention efforts, treatment must be a central component of any cancer programme from the start. It is also critical that these programmes include implementation research to determine programmatic efficacy, where gaps in care still exist and where improvements can be made. This article discusses these issues using the example of Rwanda's expanding national cancer programme. © 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Castillo J.J.,Dana-Farber Cancer Institute | Winer E.S.,The Miriam Hospital | Olszewski A.J.,Memorial Hospital of Rhode Island
American Journal of Hematology | Year: 2014

Approximately a third of the patients with diffuse large B-cell lymphoma present with extranodal involvement. Our study aims to identify primary extranodal sites of disease associated with prognosis in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era. A secondary objective is to describe epidemiological and clinical characteristics of patients with extranodal DLBCL. We included adult patients from the Surveillance, Epidemiology and End Results (SEER) database (2004-2009) in whom DLBCL was the first malignancy diagnosed. Extranodal primary sites were divided into 12 groups according to the topography code reported by SEER. Multivariate overall survival (OS) analyses were performed using Cox proportional-hazard regression models adjusted for age, sex, race, and stage. From a total of 25,992 adult DLBCL patients included in our analysis, 32% presented with extranodal primary sites. Gastrointestinal tract (34%), head/neck (H&N; 14%), and skin/soft tissue (11%) were the most common. In comparison with nodal DLBCL, patients with extranodal involvement were older (with exception of skeletal sites) and presented with earlier stages. In the multivariate analysis, sites associated with worse OS rates were gastrointestinal (Hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.15-1.33; P <0.001), pulmonary (HR 1.59, 95% CI 1.38-1.83; P <0.001), and liver/pancreas (HR 1.58, 95% CI 1.35-1.85; P <0.001), whereas H&N was associated with better survival (HR 0.79, 95% CI 0.70-0.89; P <0.001). In this population-based study, primary extranodal sites of involvement are associated with distinct outcomes in patients with DLBCL. Gastrointestinal, pulmonary, and liver/pancreas sites had a significant worse outcome than nodal sites. © 2013 Wiley Periodicals, Inc.

Tomasetti C.,Dana-Farber Cancer Institute
Bulletin of Mathematical Biology | Year: 2012

In this work, we consider the problem of estimating the probability for a specific random genetic mutation to be present in a tumor of a given size. Previous mathematical models have been based on stochastic methods where the tumor was assumed to be homogeneous and, on average, growing exponentially. In contrast, we are able to obtain analytical results for cases where the exponential growth of cancer has been replaced by other, arguably more realistic types of growth of a heterogeneous tumor cell population. Our main result is that the probability that a given random mutation will be present by the time a tumor reaches a certain size, is independent of the type of curve assumed for the average growth of the tumor, at least for a general class of growth curves. The same is true for the related estimate of the expected number of mutants present in a tumor of a given size, if mutants are indeed present. © 2012 Society for Mathematical Biology.

Toschi L.,Dana-Farber Cancer Institute
Targeted oncology | Year: 2010

Chemotherapy represents the mainstay of non-small cell lung cancer (NSCLC) treatment, but response is usually observed in only one out of three patients. Massive efforts have been carried out to identify biomarkers that might help clinicians to choose appropriate drugs, by identifying potentially sensitive subjects and spare toxicities in patients who are unlikely to benefit from treatment. Low excision repair cross-complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) levels have been associated with increased sensitivity to cisplatin and gemcitabine, respectively, while reduced class III beta-tubulin expression has been associated with taxane activity. Initial prospective studies showed the feasibility of a customized approach based on biomarker assessment, and phase III trials will hopefully provide further validation of this approach. The impact of biomarkers for patient selection has now been well established for tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), with EGFR mutations emerging as the most reliable predictor for improved outcome. Relevant clinical issues are represented by the identification of patients who can be reasonably excluded from treatment and by the development of therapeutic approaches able to overcome acquired resistance to anti-EGFR strategies.

Orkin S.H.,Dana-Farber Cancer Institute | Higgs D.R.,Weatherall Institute of Molecular Medicine
Science | Year: 2010

Effective strategies to treat sickle cell disease could involve manipulating the type of hemoglobin produced in patients.

Klempner S.J.,University of California at Irvine | Myers A.P.,Beth Israel Deaconess Medical Center | Myers A.P.,Dana-Farber Cancer Institute | Cantley L.C.,Beth Israel Deaconess Medical Center | Cantley L.C.,New York Medical College
Cancer Discovery | Year: 2013

The phosphoinositide 3-kinase (PI3K) pathway is one of the most frequently mutated pathways in cancer, and is actively being pursued as a therapeutic target. Despite the importance of the PI3K pathway in cancer, durable responses to PI3K pathway-targeted therapies are uncommon with monotherapy. Several in vitro and xenograft models have elucidated compensatory signaling and genomic changes which may limit the therapeutic effectiveness of PI3K inhibitors in the clinic. Future clinical trials with prospective evaluation of tumor signaling and genomic changes are likely to identify novel resistance mechanisms as well as subsets of patients who may derive maximal benefit from PI3K pathway inhibitors. Significance: There are multiple ongoing clinical trials targeting the PI3K pathway members in several malignancies. This review summarizes the known mechanisms of resistance to targeting the PI3K pathway. Understanding of resistance mechanisms will help to inform more rational clinical trial design to optimize the clinical impact of targeting the PI3K pathway in cancer. © 2013 American Association for Cancer Research.

Kimmelman A.C.,Dana-Farber Cancer Institute
Clinical Cancer Research | Year: 2015

The ability to inhibit the RAS oncogene has been the holy grail of oncology because of the critical role of this gene in a multitude of tumor types. In addition, RAS-mutant tumors are among the most aggressive and refractory to treatment. Although directly targeting the RAS oncogene has proven challenging, an alternative approach for treating RAS-driven cancers is to inhibit critical downstream events that are required for tumor maintenance. Indeed, much focus has been put on inhibiting signaling cascades downstream of RAS. Recent studies have shown that oncogenic RAS promotes a metabolic reprogramming of tumor cells, shifting them toward an anabolic metabolism necessary to produce biomass to support unconstrained proliferation. These cancers also use a diverse set of fuel sources to meet their metabolic needs and have even developed a variety of mechanisms to act as metabolic scavengers to obtain necessary metabolic substrates from both extracellular and intracellular sources. Collectively, these adaptations can create "metabolic bottlenecks" whereby tumor cells rely on particular pathways or rate-limiting metabolites. In this regard, inhibiting individual or combinations of these metabolic pathways can attenuate growth in preclinical models. Because these dependencies are tumor selective and downstream of oncogenic RAS, there is the opportunity for therapeutic intervention. Although targeting tumor metabolism is still in the early days of translation to patients, our continued advances in understanding critical metabolic adaptations in RAS-driven cancers, as well as the ability to study this altered metabolism in relevant tumor models, will accelerate the development of new therapeutic approaches. ©2015 American Association for Cancer Research.

Foo J.,Dana-Farber Cancer Institute
Physical biology | Year: 2011

Most human cancer types result from the accumulation of multiple genetic and epigenetic alterations in a single cell. Once the first change (or changes) have arisen, tumorigenesis is initiated and the subsequent emergence of additional alterations drives progression to more aggressive and ultimately invasive phenotypes. Elucidation of the dynamics of cancer initiation is of importance for an understanding of tumor evolution and cancer incidence data. In this paper, we develop a novel mathematical framework to study the processes of cancer initiation. Cells at risk of accumulating oncogenic mutations are organized into small compartments of cells and proliferate according to a stochastic process. During each cell division, an (epi)genetic alteration may arise which leads to a random fitness change, drawn from a probability distribution. Cancer is initiated when a cell gains a fitness sufficiently high to escape from the homeostatic mechanisms of the cell compartment. To investigate cancer initiation during a human lifetime, a 'race' between this fitness process and the aging process of the patient is considered; the latter is modeled as a second stochastic Markov process in an aging dimension. This model allows us to investigate the dynamics of cancer initiation and its dependence on the mutational fitness distribution. Our framework also provides a methodology to assess the effects of different life expectancy distributions on lifetime cancer incidence. We apply this methodology to colorectal tumorigenesis while considering life expectancy data of the US population to inform the dynamics of the aging process. We study how the probability of cancer initiation prior to death, the time until cancer initiation, and the mutational profile of the cancer-initiating cell depends on the shape of the mutational fitness distribution and life expectancy of the population.

PGC1α is a key transcriptional coregulator of oxidative metabolism and thermogenesis. Through a high-throughput chemical screen, we found that molecules antagonizing the TRPVs (transient receptor potential vanilloid), a family of ion channels, induced PGC1α expression in adipocytes. In particular, TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance. Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. This role of TRPV4 as a cell-autonomous mediator for both the thermogenic and proinflammatory programs in adipocytes could offer a target for treating obesity and related metabolic diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

Richardson P.G.,Dana-Farber Cancer Institute | Mark T.M.,New York Medical College | Lacy M.Q.,Rochester College
Critical Reviews in Oncology/Hematology | Year: 2013

New treatment options are urgently needed for patients with relapsed multiple myeloma (MM) who are refractory to thalidomide, lenalidomide, and bortezomib therapy. Pomalidomide, a second-generation immunomodulatory agent, has been shown to exert direct antiproliferative actions on MM cells, effects on the bone-marrow microenvironment, and immunomodulation. In phase I clinical trials, pomalidomide has demonstrated promising response rates in patients with relapsed and/or refractory MM, with manageable toxicity. In phase II trials pomalidomide, 2-4. mg/daily, given continuously or on days 1-21 of a 28-day cycle, in combination with dexamethasone, has been associated with high quality and durable clinical responses in patients who are refractory to lenalidomide, bortezomib, or both. Pomalidomide appears to be well tolerated; hematologic toxicities are the most commonly reported adverse events and peripheral neuropathy is rare. Phase III trials are currently underway to determine the optimal dose and combination regimen of pomalidomide in the treatment of MM. © 2013.

Chen H.,CAS Beijing Institute of Genomics | Hey J.,Temple University | Chen K.,Dana-Farber Cancer Institute
Molecular Biology and Evolution | Year: 2015

Large-sample or population-level sequencing data provide unprecedented opportunities for inferring detailed population histories, especially recent demographic histories. On the other hand, it challenges most existing population genetic methods: Simulation-based approaches require intensive computation, and analytical approaches are often numerically intractable when the sample size is large. We propose a computationally efficient method for simultaneous estimation of population size, the rate, and onset time of population growth in the very recent history, using the pattern of the total number of segregating sites as a function of sample size. Coalescent simulation shows that it can accurately and efficiently estimate the parameters of recent population growth from large-scale data. This approach has the flexibility to model population history with multiple growth stages or other epochs, and it is robust when the sample size is very large or at the population scale, for which the Kingman's coalescent assumption is not valid. This approach is applied to recently published data and estimates the recent population growth rate in the European population to be 1.49% with the onset time 7.26 ka, and the rate in the African population to be 0.735% with the onset time 10.01 ka. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Colleoni M.,Italian National Cancer Institute | Giobbie-Hurder A.,Dana-Farber Cancer Institute
Annals of Oncology | Year: 2010

Endocrine-responsive tumors that are small and without nodal involvement (i.e. tumors classified as pT1 pN0) are a heterogeneous group of tumors that are associated with a low risk of relapse in the majority of the cases. Therefore, the costs and benefits of adjuvant endocrine therapy should be carefully considered within this subgroup of patients. Treatment decisions should take into consideration co-morbidities as well as the presence of other classical risk factors such as HER2 overexpression or extensive peritumoral vascular invasion. Tamoxifen or tamoxifen plus ovarian function suppression should be considered as proper endocrine therapies in premenopausal patients. Ovarian function suppression alone or ovarian ablation might also be considered adequate in selected patients (e.g. very low-risk patients, in the presence of co-morbidities or patient preference). An aromatase inhibitor should form part of standard endocrine therapy for most postmenopausal women with receptor-positive breast cancer, although patients at low risk or with co-morbid musculoskeletal or cardiovascular risk factors may be considered suitable for tamoxifen alone. Tailored endocrine treatments should be considered in patients with endocrine-responsive tumors classified as pT1 pN0. Issues focusing on safety, quality of life and subjective side effects should be routinely discussed. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Tsao H.,Massachusetts General Hospital | Tsao H.,The Wellman Center for Photomedicine | Chin L.,University of Houston | Garraway L.A.,Dana-Farber Cancer Institute | Fisher D.E.,Massachusetts General Hospital
Genes and Development | Year: 2012

Melanoma is often considered one of the most aggressive and treatment-resistant human cancers. It is a disease that, due to the presence of melanin pigment, was accurately diagnosed earlier than most other malignancies and that has been subjected to countless therapeutic strategies. Aside from early surgical resection, no therapeutic modality has been found to afford a high likelihood of curative outcome. However, discoveries reported in recent years have revealed a near avalanche of breakthroughs in the melanoma field-breakthroughs that span fundamental understanding of the molecular basis of the disease all the way to new therapeutic strategies that produce unquestionable clinical benefit. These discoveries have been born from the successful fruits of numerous researchers working in many-sometimes-related, although also distinct- biomedical disciplines. Discoveries of frequent mutations involving BRAF(V600E), developmental and oncogenic roles for the microphthalmia-associated transcription factor (MITF) pathway, clinical efficacy of BRAF-targeted small molecules, and emerging mechanisms underlying resistance to targeted therapeutics represent just a sample of the findings that have created a striking inflection in the quest for clinically meaningful progress in the melanoma field. © 2012 by Cold Spring Harbor Laboratory Press.

Anderson K.C.,Dana-Farber Cancer Institute
Journal of Clinical Oncology | Year: 2012

Multiple myeloma (MM) is a remarkable example of rapid bench-to-bedside translation in new drug development. The proteasome inhibitor bortezomib and immunomodulatory drug lenalidomide targeted MM cells in the bone marrow (BM) microenvironment to overcome conventional drug resistance in laboratory and animal models and were rapidly translated into clinical trials demonstrating their efficacy in patients with relapsed and then newly diagnosed MM, with a doubling of the median survival as a direct result. The future is even brighter. First, immune-based therapies are being developed (eg, elotuzumab monoclonal antibody [MoAb]; CD138DM immunotoxin; MM cell- dendritic cell vaccines; CD138, CS-1, and XBP-1 peptide vaccines; anti-17 MoAb; and other treatments to overcome causes of immune dysfunction). Second, promising next-generation agents target the MM cell in its microenvironment (eg, deubiquitinating enzyme inhibitors; chymotryptic [carfilzomib, Onyx 0912, MLN 9708] and broader [NPI-0052] proteasome inhibitors; immunoproteasome inhibitors; and pomalidamide). Moreover, agents targeting bone biology (eg, zoledronic acid, anti-DKK-1 MoAb, anti-B-cell activating factor MoAb and bortezomib, Btk inhibitor) show promise not only in preserving bone integrity but also against MM. Third, rationally based combination therapies, including bortezomib with Akt, mammalian target of rapamycin, or histone deacetylase inhibitors, are active even in bortezomib-refractory MM. Finally, genomics is currently being used in the definition of MM heterogeneity, new target discovery, and development of personalized therapy. Myeloma therefore represents a paradigm for targeting the tumor in its microenvironment, which has already markedly improved patient outcome in MM and has great potential in other hematologic malignancies and solid tumors as well. © 2012 by American Society of Clinical Oncology.

Flaherty K.T.,Massachusetts General Hospital | Hodi F.S.,Dana-Farber Cancer Institute | Fisher D.E.,Massachusetts General Hospital
Nature Reviews Cancer | Year: 2012

The past decade has revealed that melanoma is comprised of multiple subclasses that can be categorized on the basis of key features, including the clinical stage of disease, the oncogenic molecular 'drivers', the anatomical location or the behaviour of the primary lesion and the expression of specific biomarkers. Although exercises in subclassification are not new in oncology, progress in this area has produced both conceptual and clinical breakthroughs, which, for melanoma, are unprecedented in the modern history of the disease. This Review focuses on these recent striking advances in the strategy of molecularly targeted approaches to the therapy of melanoma in humans. © 2012 Macmillan Publishers Limited. All rights reserved.

Qi J.,Dana-Farber Cancer Institute
Cold Spring Harbor Perspectives in Biology | Year: 2014

In cancer, epigenetic proteins are intensely studied targets for therapeutic drug discovery, showing great promise. These proteins include the chromatin-modifying enzymes that “write” and “erase” histone posttranslational modifications (PTM), and those that “read” these marks through binding modules. In an effort to find a compound that could disrupt the protein– protein interactions between a PTM and reader, JQ1 has proven to be a first-in-class, drug-like inhibitor of the “bromodomain and extraterminal domain” epigenetic readers (BETs), which recognize histone lysine acetylation marks. JQ1 has facilitated the mechanistic study and therapeutic application in cancer of this kind of epigenetic inhibition. By using this chemical probe, we have discovered that the bromodomain inhibitors (BETi) have compelling activity in preclinical models of multiple myeloma and acute myeloid leukemia. In particular, BETi down-regulates the MYC, IL-7R, and E2F transcriptional programs. We are continuously integrating the transcriptional consequences of BETi with changes in the epigenomic landscapes of cancer cells to elucidate the mechanisms underlying response to BETi using chemical and genetic perturbations. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Schrag D.,Dana-Farber Cancer Institute
Current Treatment Options in Oncology | Year: 2013

Opinion statement: Management of locally advanced rectal cancer is complex because curative treatment routinely involves administration of surgery, chemotherapy, and radiation. Optimal treatment delivery sequencing and timing are challenging, and moreover, there is considerable heterogeneity in risk based on rectal tumor location, extent, and nodal involvement. The goal in rectal cancer treatment is to optimize disease-free and overall survival while minimizing the risk of local recurrence and toxicity from both radiation and systemic therapy. Currently, the standard approach to management of locally advanced (T3 or T2) rectal cancer involves careful staging with a pelvic MRI and proctoscopic evaluation by a surgeon experienced in total mesorectal excision. MRI can help to distinguish between patients in low-, intermediate-, and high-risk categories. Low-risk tumors have no evidence of either extramural spread or nodal involvement and proximal location in the rectum. For such patients, R0 resection is almost always possible and immediate surgery often is reasonable. In the minority of cases where unanticipated lymph node involvement is detected at surgical pathology, postoperative radiation can be administered. Patients who opt for up-front rectal surgery need to understand that although there is a chance that radiation can be avoided, if it is necessary, it is less well tolerated when administered postoperatively. Initial surgical treatment should be reserved for low-risk patients for whom imaging indicates and multidisciplinary team members feel is able to undergo an R0 resection with low chance for regional spread of disease. For patients with high-risk disease based on distal tumor location requiring an APR, threatened radial margins, or T4 tumors, preoperative chemoradiation is essential. Indeed, this approach increases the likelihood of complete surgical resection with negative margins. For some high-risk patients, for example those with T4 or bulky nodal disease, preoperative systemic therapy followed by preoperative chemoradiation and then surgery may be optimal. The feasibility of this approach is well established based on nonrandomized trials, but it has not been evaluated in a randomized study. Preoperative administration of systemic therapy can achieve clinical downstaging, optimize rates of sphincter preservation, and establish tumor responsiveness, which may be valuable for incorporation into future treatment decisions. For patients with intermediate-risk T3 rectal cancers, for example, a cT3N1 tumor 7 cm from the anal verge with two to three regional lymph nodes in the 7-mm range, we encourage participation in the PROSPECT randomized trial, which is now open and accruing at numerous centers in North America, and shortly in Europe and South America as well. This study will determine in the era of optimal imaging, surgical technique, and better systemic chemotherapy, whether pelvic radiation remains an essential component of curative treatment. The PROSPECT study uses chemoradiation selectively rather than automatically and customizes subsequent treatment based on response to neoadjuvant FOLFOX. Clinical trials with interventions that tailor treatment to more precisely defined clinical subgroups based on both initial features and tumor responsiveness are expected to become the norm. Although this trend is likely to make clinical trial design more complex, customized treatment strategies are likely to achieve the optimal balance between under- and overtreatment and will address the heterogeneity of both tumor biology and disease presentation. For now, treatment for a patient with clinical T3N1 tumor in the mid rectum consists of the following components: Neoadjvuant chemoradiation with either 5-fluorouracil or capecitabine as sensitizing therapy. Low anterior resection with total mesorectal excision. Typically a temporary diverting ostomy is required. Postoperative administration of adjuvant systemic therapy, 8 cycles of FOLFOX is appropriate, although oxaliplatin should be omitted for early signs of peripheral neuropathy or on the basis of age/comorbidity. Although this is the current care standard, there is concern that such extensive treatment is not necessary for all patients to prevent local recurrence and to optimize cure. To determine if therapy can be streamlined, participation in PROSPECT or other clinical trials asking compelling clinical questions is a priority. © 2013 Springer Science+Business Media New York.

Chalancon G.,University of Cambridge | Ravarani C.N.J.,University of Cambridge | Balaji S.,Dana-Farber Cancer Institute | Martinez-Arias A.,University of Cambridge | And 3 more authors.
Trends in Genetics | Year: 2012

Complex regulatory networks orchestrate most cellular processes in biological systems. Genes in such networks are subject to expression noise, resulting in isogenic cell populations exhibiting cell-to-cell variation in protein levels. Increasing evidence suggests that cells have evolved regulatory strategies to limit, tolerate or amplify expression noise. In this context, fundamental questions arise: how can the architecture of gene regulatory networks generate, make use of or be constrained by expression noise? Here, we discuss the interplay between expression noise and gene regulatory network at different levels of organization, ranging from a single regulatory interaction to entire regulatory networks. We then consider how this interplay impacts a variety of phenomena, such as pathogenicity, disease, adaptation to changing environments, differential cell-fate outcome and incomplete or partial penetrance effects. Finally, we highlight recent technological developments that permit measurements at the single-cell level, and discuss directions for future research. © 2012 Elsevier Ltd.

Freedman A.,Dana-Farber Cancer Institute
American Journal of Hematology | Year: 2015

Disease overview: Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma (FL) is characterized by diffuse lymphoadenopathy, bone marrow involvement, splenomegaly, and less commonly other extranodal sites of involvement. In general, cytopenias can occur but constitutional symptoms of fever, night sweats, and weight loss are uncommon. Diagnosis: Diagnosis is based on histology of preferably a biopsy of a lymph node. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes. Risk stratification: The Follicular Lymphoma International Prognostic Index prognostic model for FL uses five independent predictors of inferior survival: age >60 years, hemoglobin <12 g/dL, serum LDH>normal, Ann Arbor stage III/IV, number of involved nodal areas>4. The presence of 0, 1, 2, and≥3 adverse factors defines low, intermediate, and high-risk disease. With the use of more modern therapies, outcomes have improved. Risk-adapted therapy: Observation continues to be adequate for asymptomatic patients with low bulk disease and no cytopenias, with no survival advantage for early treatment with either chemotherapy or rituximab alone. For patients needing therapy, most patients are treated with chemotherapy plus rituximab, which has improved response rates, duration of response and overall survival. Randomized studies have shown additional benefit for maintenance rituximab both following chemotherapy-rituximab and single agent rituximab. Experimental therapies as well as stem cell transplantation (SCT) are considered for recurrent disease. © 2015 Wiley Periodicals, Inc.

Hammerman P.S.,Dana-Farber Cancer Institute | Hammerman P.S.,The Broad Institute of MIT and Harvard | Neil Hayes D.,University of North Carolina at Chapel Hill | Grandis J.R.,University of Pittsburgh
Cancer Discovery | Year: 2015

Large and comprehensive genomic surveys of head and neck squamous cell carcinomas (HNSCC) are now greatly increasing our understanding of the diversity of this disease and the key genomic changes that drive these tumors. The results from these studies are beginning to inform the introduction of novel therapies for patients with HNSCCs. Here, we review some of the key findings from recent genomic studies of head and neck cancers, including the most comprehensive study to date from The Cancer Genome Atlas Network. © 2015 American Association for Cancer Research.

Arnason J.E.,Beth Israel Deaconess Medical Center | Brown J.R.,Dana-Farber Cancer Institute
Drugs | Year: 2015

The majority of patients with chronic lymphocytic leukemia (CLL) respond to chemo-immunotherapy. However, long-term remission remains elusive and the majority of patients will die of complications related to CLL. In this review we discuss the recent developments in targeted therapy for CLL. Targeted therapy has evolved beyond the cell surface targeting of CD20 with rituximab. Our review focuses on the evolution of antibody therapy in CLL, strategies to target effector T cells to the tumor, inhibition of the B-cell receptor signaling pathway, and finally targeting the mediators of apoptosis. With our improved understanding of the biology of CLL, the evolution of targeted therapy has resulted in significant clinical responses in patients who are refractory to traditional treatment options and holds the potential for a future where we can manage this disease without chemotherapy. © 2015 Springer International Publishing Switzerland.

Wan Y.,Dana-Farber Cancer Institute
Blood | Year: 2013

SF3B1 is a critical component of the splicing machinery, which catalyzes the removal of introns from precursor messenger RNA (mRNA). Next-generation sequencing studies have identified mutations in SF3B1 in chronic lymphocytic leukemia (CLL) at high frequency. In CLL, SF3B1 mutation is associated with more aggressive disease and shorter survival, and recent studies suggest that it can be incorporated into prognostic schema to improve the prediction of disease progression. Mutations in SF3B1 are predominantly subclonal genetic events in CLL, and hence are likely later events in the progression of CLL. Evidence of altered pre-mRNA splicing has been detected in CLL cases with SF3B1 mutations. Although the causative link between SF3B1 mutation and CLL pathogenesis remains unclear, several lines of evidence suggest SF3B1 mutation might be linked to genomic stability and epigenetic modification.

Field J.J.,Blood Research Institute | Nathan D.G.,Dana-Farber Cancer Institute | Linden J.,La Jolla Institute for Allergy and Immunology
Clinical Immunology | Year: 2011

Sickle cell disease (SCD) causes widely disseminated vaso-occlusive episodes. Building on evidence implicating invariant NKT (iNKT) cells in the pathogenesis of ischemia/reperfusion injury, recent studies demonstrate that blockade of iNKT cell activation in mice with SCD reduces pulmonary inflammation and injury. In patients with SCD, iNKT cells in blood are increased in absolute number and activated in comparison to healthy controls. iNKT cell activation is reduced by agonists of adenosine 2A receptors (A2ARs) such as the clinically approved coronary vasodilator, regadenoson. An ongoing multi-center, dose-finding and safety trial of infused regadenoson, has been initiated and is providing preliminary data about its safety and efficacy to treat SCD. Very high accumulation of adenosine may have deleterious effects in SCD through activation of adenosine 2B receptors that are insensitive to regadenoson. Future possible therapeutic approaches for treating SCD include selective A2BR antagonists and antibodies that deplete iNKT cells. © 2011 Elsevier Inc.

Viswanathan A.N.,Dana-Farber Cancer Institute | Erickson B.A.,Medical College of Wisconsin
Gynecologic Oncology | Year: 2015

Despite a concerning decline in the use of brachytherapy over the past decade, no other therapy is able to deliver a very high dose of radiation into or near a tumor, with a rapid fall-off of dose to adjacent structures. Compared to traditional X-ray-based brachytherapy that relies on points, the use of CT and MR for 3D planning of gynecologic brachytherapy provides a much more accurate volume-based calculation of dose to an image-defined tumor and to the bladder, rectum, sigmoid, and other pelvic organs at risk (OAR) for radiation complications. The publication of standardized guidelines and an online contouring teaching atlas for performing 3D image-based brachytherapy has created a universal platform for communication and training. This has resulted in a uniform approach to using image-guided brachytherapy for treatment and an internationally accepted format for reporting clinical outcomes. Significant improvements in survival and reductions in toxicity have been reported with the addition of image guidance to increase dose to tumor and decrease dose to the critical OAR. Future improvements in individualizing patient treatments should include a more precise definition of the target. This will allow dose modulation based on the amount of residual disease visualized on images obtained at the time of brachytherapy. © 2015 Elsevier Inc.

Janeway K.A.,Dana-Farber Cancer Institute | Maki R.G.,Mount Sinai School of Medicine
Clinical Cancer Research | Year: 2012

The ability to better interrogate the genetic state of a given cancer is giving rise to a new paradigm in cancer therapeutics in which the specific genetic alterations that give rise to the cancer inform the therapeutic decision-making for that specific patient. Sarcomas of soft tissue and bone represent model diseases that underscore this paradigm. However,many barriers prevent linkage of one of the 75 or more different types of sarcoma to novel therapeutic agents. In the present perspective, the authors outline key therapeutic opportunities and hurdles in clinical sarcoma research, focusing on specific examples of sarcomas that are on the verge of new breakthroughs, as well as those in which promise has not lived up to expectations. Focused clinical trial design, ideally with several biomarker or histology-specific arms, is one means to be simultaneously parsimonious and inclusive. ©2012 AACR.

Michelson A.D.,Dana-Farber Cancer Institute
Platelets | Year: 2013

PLATELETS is the definitive current source of state-of-the-art knowledge about platelets and covers the entire field of platelet biology, pathophysiology, and clinical medicine. Recently there has been a rapid expansion of knowledge in both basic biology and the clinical approach to platelet-related diseases including thrombosis and hemorrhage. Novel platelet function tests, drugs, blood bank storage methods, and gene therapies have been incorporated into patient care or are in development. This book draws all this information into a single, comprehensive and authoritative resource. First edition won Best Book in Medical Science Award from the Association of American Publishers Contains fourteen new chapters on topics such as platelet genomics and proteomics, inhibition of platelet function by the endothelium, clinical tests of platelet function, real time in vivo imaging of platelets, and inherited thrombocytopenias A comprehensive full color reference comprising over 70 chapters, 1400 pages, and 16,000 references. © 2013 Elsevier Inc. All rights reserved.

Choueiri T.K.,Dana-Farber Cancer Institute
Current Clinical Pharmacology | Year: 2011

Metastatic renal cell carcinoma (RCC) is predominantly refractory to treatment with traditional cytotoxic chemotherapies, and until recently management options were limited to immunotherapy, palliative care, or phase I trials. The past five years have witnessed a major change in the treatment of advanced RCC with the introduction of targeted therapies that derive their efficacy through affecting angiogenesis. The main class of agents involves drugs that target the vascular endothelial growth factor (VEGF). Several VEGF inhibitors are now approved for the treatment of metastatic RCC. The field is expanding rapidly with goals including 1) developing novel more potent and better tolerated agents and 2) defining the role of combination and sequential anti-VEGF regimens. © 2011 Bentham Science Publishers.

Colson K.,Dana-Farber Cancer Institute
Supportive Care in Cancer | Year: 2015

Purpose: Recent therapeutic advancements have significantly improved overall survival of patients with multiple myeloma (MM). As a result, the impact of disease- and treatment-related symptoms must be managed effectively to improve patient quality of life, given prolonged survival after diagnosis. This review discusses current MM treatment options, effective symptom management approaches, and practical strategies for supportive care. Methods: A literature search was performed using MEDLINE/PubMed and scientific congress databases, focusing on clinical trials, review articles, clinical practice guidelines, and other guidance documents on treatment paradigms and supportive care strategies in MM. Additionally, clinical practice worksheets were developed from published sources, and nursing “pearls of wisdom” were gathered from practical experience in the clinic. Results: Current therapeutic regimens for relapsed/refractory MM include proteasome inhibitors (i.e., bortezomib, carfilzomib) and immunomodulatory agents (i.e., thalidomide, lenalidomide, pomalidomide), alone or in combination with chemotherapy or corticosteroids. Toxicities associated with agents and combination regimens used in the treatment of MM include myelosuppression, venous thromboembolism, peripheral neuropathy, infections, fatigue, gastrointestinal disorders, and/or cardiac events. Treatment-specific tools and clinical assessments can be useful for optimizing dosing and schedule adjustments to increase therapy duration, and implementing supportive care strategies (e.g., growth factors, transfusional support, intravenous hydration, bisphosphonates, antiviral therapies) to manage treatment-related symptoms. Conclusions: Improved survival after MM diagnosis has led to increased patient susceptibility to other diseases and comorbidities due to advanced age. In addition to appropriate drug dosing and administration, effective supportive care and health maintenance are crucial for maximizing quality of life and disease control. © 2015, Springer-Verlag Berlin Heidelberg.

Janeway K.A.,Dana-Farber Cancer Institute | Weldon C.B.,Childrens Hospital Boston
Seminars in Pediatric Surgery | Year: 2012

Pediatric gastrointestinal stromal tumor (GIST) is a rare entity that can be quite different from its adult counterpart. This report provides a comprehensive review on the diagnosis and management of this tumor in children and adolescents, including its oncogenesis and associated syndromes. Surgery remains a mainstay of treatment, but there are no standard guidelines available at this time regarding the best practice for multimodality therapy as our understanding of the biology of GIST is still in evolution. Therefore, pediatric patients with GIST should be ideally treated in the context of clinical trials at specialized, multidisciplinary centers throughout the course of their disease, especially because these patients may live for years after diagnosis. © 2012 Elsevier Inc.

Thoreen C.C.,Dana-Farber Cancer Institute
Biochemical Society Transactions | Year: 2013

The process of cell growth depends on a complex co-ordinated programme of macromolecular synthesis that can be tuned to environmental constraints. In eukaryotes, the mTOR [mammalian (or mechanistic) target of rapamycin] signalling pathway is a master regulator of this process, in part by regulating mRNA translation through control of the eIF4F (eukaryotic initiation factor 4F) initiation complex. The present review discusses the role of this relationship in mTOR-regulated gene expression, and its contribution to phenotypes associated with deregulated mTOR signalling, such as cancer. © 2013 Biochemical Society.

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments. Clinicaltrials.gov ID: NCT00004205.

Motta S.,University of Catania | Pappalardo F.,University of Catania | Pappalardo F.,Dana-Farber Cancer Institute
Briefings in Bioinformatics | Year: 2013

Mathematical and computational models are increasingly used to help interpret biomedical data produced by high-throughput genomics and proteomics projects. The application of advanced computer models enabling the simulation of complex biological processes generates hypotheses and suggests experiments. Appropriately interfaced with biomedical databases, models are necessary for rapid access to, and sharing of knowledge through data mining and knowledge discovery approaches. © The Author 2012. Published by Oxford University Press.

Truog R.D.,Childrens Hospital Boston | Kesselheim A.S.,Brigham and Womens Hospital | Joffe S.,Dana-Farber Cancer Institute
Science | Year: 2012

The intuition that tissue donors are owed fi nancial compensation is mistaken as a matter of policy and ethics.

Cutler C.,Dana-Farber Cancer Institute
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

Transplantation is the only known cure for myelodysplastic syndrome (MDS). While some comparative analyses have demonstrated early transplantation to be the preferred strategy for all MDS patients, many of these analyses are biased. Using newly identified prognostic factors and models, a rational approach to transplantation can be undertaken. Factors such as transfusion dependency, cytogenetics, medical comorbidity, and World Health Organization (WHO) histologic subtype should all be considered when deciding on the role of transplantation for the MDS patient. Unresolved issues in transplantation include the impact of pre-transplant tumor debulking with traditional chemotherapeutic agents or the new DNA hypomethylating agents, and the optimal timing of reduced-intensity conditioning transplantation for older patients or for those with medical comorbidities.

For decades, lymphoma has been considered a dreaded and untoward complication of autoimmune disorders, including inflammatory bowel disease (IBD). Yet until recently, the data linking inflammatory bowel disease with an increased risk for lymphoma has been equivocal. With the publication of the CESAME trial in 2009, a greater understanding of lymphoma risk has begun to emerge. In this Falk Symposium paper, I discuss the available data from studies that interrogated the relationship between lymphoma and IBD, thiopurines and TNF α-directed agents. While recent data has clarified some aspects of lymphoma epidemiology in patients with IBD, causality and the mechanisms that underlie it remain very poorly understood. © 2010 S. Karger AG, Basel.

Koreth J.,Dana-Farber Cancer Institute
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.

Stone R.M.,Dana-Farber Cancer Institute
Journal of Clinical Oncology | Year: 2013

A 42-year-old woman presented with bruising and fatigue. Her WBC count was 10,370/μL, with a differential showing 5% polys, 5% monos, 10% lymphocytes, and 80% myeloid-appearing blasts, some of which contained Auer rods (Fig 1). Bone marrow examination revealed 90% infiltration with myeloid-appearing blasts, and flow cytometry analysis confirmed the diagnosis of acute myeloid leukemia (AML) with expression of CD33, CD13, and CD117. Cytogenetics revealed a normal female karyotype; molecular testing for NPM1, FLT3-ITD, and CEBPα mutations revealed wild-type status for each gene. The patient received induction therapy with daunorubicin 90 mg/m2 per day for 3 days and continuous-infusion cytarabine 100 mg/m2 per day for 7 days. After an induction course complicated by Gram-negative bacterial sepsis, her counts recovered by day 32, and bone marrow examination 6 weeks after diagnosis showed a complete remission. One week later she feels well and has normal physical and laboratory examinations. She is an only child (but has a common HLA type) and presents for discussion of postremission therapy options. © 2013 by American Society of Clinical Oncology.

Ma Q.,Dana-Farber Cancer Institute
Journal of Clinical Investigation | Year: 2010

The somatic sensory system responds to stimuli of distinct modalities, including touch, pain, itch, and temperature sensitivity. In the past century, great progress has been made in understanding the coding of these sensory modalities. From this work, two major features have emerged. First, there are specific neuronal circuits or labeled lines transmitting specific sensory information from the skin to the brain. Second, the generation of specific sensations often involves crosstalk among distinct labeled lines. These features suggest that population coding is the mechanism underlying somatic sensation.

Cutler C.,Dana-Farber Cancer Institute | Ballen K.K.,Massachusetts General Hospital
Blood Reviews | Year: 2012

Only 30% of patients who require an allogeneic hematopoietic cell transplant will have a HLA matched sibling donor. Many patients, particularly those patients with diverse racial and ethnic backgrounds, may not be able to identify a suitably matched unrelated donor. Over 25,000 umbilical cord blood transplant procedures have been performed in the last 25. years. Considerable challenges exist in defining the appropriate conditioning regimen and graft vs host disease prophylaxis, surmounting issues of cell dose and delayed engraftment, and improving immune recovery. In this review, we discuss strategies to improve umbilical cord blood transplant outcomes, focusing on cord blood unit selection, expansion, and homing efficiency. © 2012 Elsevier Ltd.

Ng K.,Dana-Farber Cancer Institute
Current Colorectal Cancer Reports | Year: 2014

Vitamin D insufficiency is highly prevalent in the U.S., particularly among colorectal cancer (CRC) patients. These low levels of vitamin D are concerning given increasing evidence that vitamin D may have health benefits beyond skeletal outcomes. Prospective observational studies suggest that higher vitamin D levels are associated with lower risk of incident CRC and improved survival for patients with established CRC, and randomized clinical trials are urgently needed to establish causality. Moreover, there remains a great need to improve prognosis for patients with CRC, and investigating vitamin D as a potential therapy is an attractive option in regards to safety and cost, particularly in this era of expensive and often toxic anti-neoplastic agents. In this review the evidence regarding the activity of vitamin D in CRC will be summarized, spanning preclinical, epidemiological, and clinical studies, and future research directions will be discussed. © 2014 Springer Science+Business Media New York.

Cohen P.,Rockefeller University | Spiegelman B.M.,Dana-Farber Cancer Institute
Diabetes | Year: 2015

The epidemic of obesity and type 2 diabetes has increased interest in pathways that affect energy balance in mammalian systems. Brown fat, in all of its dimensions, can increase energy expenditure through the dissipation of chemical energy in the form of heat, using mitochondrial uncoupling and perhaps other pathways. We discuss here some of the thermodynamic and cellular aspects of recent progress in brown fat research. This includes studies of developmental lineages of UCP1+ adipocytes, including the discovery of beige fat cells, a new thermogenic cell type. We also discuss the physiology and transcriptional control of brown and beige cells in rodents and the state of current knowledge about human brown fat. © 2015 by the American Diabetes Association.

Lam A.Q.,Brigham and Womens Hospital | Humphreys B.D.,Brigham and Womens Hospital | Humphreys B.D.,Dana-Farber Cancer Institute
Clinical Journal of the American Society of Nephrology | Year: 2012

AKI is common in patients with cancer, and it causes interruptions in therapy and increased hospital length of stay, cost, and mortality. Although cancer patients are susceptible to all of the usual causes of AKI in patients without cancer, there are a number of AKI syndromes that occur more frequently or are unique to this patient population. AKI also confers substantially increased risk of short-term death, and the ability to reverse AKI portends a better outcome in some cancers, such as multiple myeloma. Several trends in oncology, including increased survival, better supportive care, older patients who have received multiple chemotherapy regimens, and new therapeutic options, are driving an increase in the numbers of cancer patients who develop AKI. As a result, nephrologists should be increasingly familiar with the diagnosis, management, and treatment of AKI in this setting. Here, we summarize recent data on epidemiology of AKI in cancer patients, describe the most common AKI syndromes in this population, and highlight emerging areas in the growing field of onconephrology. © 2012 by the American Society of Nephrology.

Zhou F.,Dana-Farber Cancer Institute
Nature communications | Year: 2013

Advances in chemistry and massively parallel detection underlie DNA-sequencing platforms that are poised for application in personalized medicine. In stark contrast, systematic generation of protein-level data lags well behind genomics in virtually every aspect: depth of coverage, throughput, ease of sample preparation and experimental time. Here, to bridge this gap, we develop an approach based on simple detergent lysis and single-enzyme digest, extreme, orthogonal separation of peptides and true nanoflow liquid chromatography-tandem mass spectrometry that provides high peak capacity and ionization efficiency. This automated, deep efficient peptide sequencing and quantification mass spectrometry platform provides genome-scale proteome coverage equivalent to RNA-seq ribosomal profiling and accurate quantification for multiplexed isotope labels. In a model of the embryonic to epiblast transition in murine stem cells, we unambiguously quantify 11,352 gene products that span 70% of Swiss-Prot and capture protein regulation across the full detectable range of high-throughput gene expression and protein translation.

Lee J.,Yonsei University | Jeon J.Y.,Yonsei University | Meyerhardt J.A.,Dana-Farber Cancer Institute
Hematology/Oncology Clinics of North America | Year: 2015

Much research supports the association between diet and lifestyle in the development of colorectal cancer. Recent studies have demonstrated an association between various energy balance host factors (obesity, physical inactivity, and certain dietary factors) and outcomes. This review summarizes the impact of modifiable lifestyle factors, including prediagnosis and postdiagnosis adiposity, physical activity, and diet, on the prognosis of patients with colorectal cancer. The article focuses on associations of these factors in survivors of stage I to III colorectal cancer, and summarizes the possible mechanisms for the association between modifiable lifestyle factors and the prognosis of patients with colorectal cancer. © 2015 Elsevier Inc.

Brown J.R.,Dana-Farber Cancer Institute
Clinical Advances in Hematology and Oncology | Year: 2010

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Currently, the most effective treatment for CLL consists of a combination of fludarabine, cyclophosphamide, and rituximab. Although this approach has encouraging results, patients with CLL eventually relapse and require additional therapies. Many of the current therapeutic regimens for CLL are myelotoxic, immunosuppressive, and associated with infectious complications. Targeted therapies can often minimize these complications. The US Food and Drug Administration has recently approved 2 agents, bendamustine and ofatumumab, for the treatment of CLL. Emerging therapies ranging from new monoclonal antibodies to small molecules that interfere with vital pathways in signal transduction and cell cycle regulation are currently being developed. This article will focus on novel agents in earlier development phases for CLL, including the immunomodulator lenalidomide; monoclonal antibodies, such as lumiliximab, GA-101, and small molecule immunopharmaceuticals; BCL-2 inhibitors, such as oblimersen, obatoclax, and ABT-263; and protein kinase inhibitors, such as flavopiridol, spleen tyrosine kinase inhibitors, and phosphatidylinositol 3-kinase inhibitors.

Fruhwirth-Schnatter S.,Johannes Kepler University | Pyne S.,Dana-Farber Cancer Institute
Biostatistics | Year: 2010

Skew-normal and skew-t distributions have proved to be useful for capturing skewness and kurtosis in data directly without transformation. Recently, finite mixtures of such distributions have been considered as a more general tool for handling heterogeneous data involving asymmetric behaviors across subpopulations. We consider such mixture models for both univariate as well as multivariate data. This allows robust modeling of high-dimensional multimodal and asymmetric data generated by popular biotechnological platforms such as flow cytometry.We develop Bayesian inference based on data augmentation and Markov chain Monte Carlo (MCMC) sampling. In addition to the latent allocations, data augmentation is based on a stochastic representation of the skew-normal distribution in terms of a random-effects model with truncated normal random effects. For finite mixtures of skew normals, this leads to a Gibbs sampling scheme that draws from standard densities only. This MCMC scheme is extended to mixtures of skew-t distributions based on representing the skew-t distribution as a scale mixture of skew normals.As an important application of our new method, we demonstrate how it provides a new computational framework for automated analysis of high-dimensional flow cytometric data. Using multivariate skew-normal and skew-t mixture models, we could model non-Gaussian cell populations rigorously and directly without transformation or projection to lower dimensions.

Freedman A.,Dana-Farber Cancer Institute
American Journal of Hematology | Year: 2012

Disease overview: Follicular lymphoma (FL) is generally an indolent B-cell lymphoproliferative disorder of transformed follicular center B cells. FL is characterized by diffuse lymphoadenopathy, involvement of bone marrow, splenomegaly, and less commonly other extranodal sites of involvement. In general, cytopenias can occur but constitutional symptoms of fever, nightsweats, and weight loss are uncommon. Diagnosis: Diagnosis is based on histology of preferably a biopsy of a lymph node. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes. Risk stratification: The FL International Prognostic Index prognostic model for FL uses five independent predictors of inferior survival: age > 60 years, hemoglobin < 12 g/dL, serum lactate dehydrogenase > normal, Ann Arbor stage III/IV, number of involved nodal areas > 4. The presence of 0, 1, 2, and ≥ 3 adverse factors defines low, intermediate, and high-risk disease with median 10-year survivals in the pre-rituximab era of ~71, 51, and 36 months, respectively. With the use of more modern therapies, specifically anti-CD20 monoclonal antibody, the outcome has improved. Risk-adapted therapy: Observation continues to be adequate for asymptomatic patients with low bulk disease and no cytopenias. For patients needing therapy, most patients are treated with chemotherapy plus rituximab, which has improved response rates, duration of response, and overall survival. Randomized studies have shown additional benefit for maintenance rituximab both following chemotherapy-rituximab and single-agent rituximab. Autologous stem cell transplantation (SCT) has not shown a survival benefit in first remission patients. SCT including both autologous and allogeneic SCT or experimental agent therapy is considered for recurrent disease. © 2012 Wiley Periodicals, Inc.

Sherr C.J.,Howard Hughes Medical Institute | Sherr C.J.,St Jude Childrens Research Hospital | Beach D.,The Blizard Institute | Shapiro G.I.,Dana-Farber Cancer Institute
Cancer Discovery | Year: 2016

Biochemical and genetic characterization of D-type cyclins, their cyclin D–dependent kinases (CDK4 and CDK6), and the polypeptide CDK4/6 inhibitor p16INK4 over two decades ago revealed how mammalian cells regulate entry into the DNA synthetic (S) phase of the cell-division cycle in a retinoblastoma protein–dependent manner. These investigations provided proof-of-principle that CDK4/6 inhibitors, particularly when combined with coinhibition of allied mitogen-dependent signal transduction pathways, might prove valuable in cancer therapy. FDA approval of the CDK4/6 inhibitor palbociclib used with the aromatase inhibitor letrozole for breast cancer treatment highlights long-sought success. The newest findings herald clinical trials targeting other cancers. Significance: Rapidly emerging data with selective inhibitors of CDK4/6 have validated these cell-cycle kinases as anticancer drug targets, corroborating longstanding preclinical predictions. This review addresses the discovery of these CDKs and their regulators, as well as translation of CDK4/6 biology to positive clinical outcomes and development of rational combinatorial therapies. © 2016 American Association for Cancer Research.

Goldberg M.S.,Dana-Farber Cancer Institute
Cell | Year: 2015

Although cancer immunotherapy can lead to durable outcomes, the percentage of patients who respond to this disruptive approach remains modest to date. Encouragingly, nanotechnology can enhance the efficacy of immunostimulatory small molecules and biologics by altering their co-localization, biodistribution, and release kinetics. © 2015 Elsevier Inc.

Jung M.,Dongduk Womens University | Jung M.,Dana-Farber Cancer Institute
Asian Pacific Journal of Cancer Prevention | Year: 2014

This study investigated how self-rated health and socioeconomic status are associated with behaviour of cancer survivors regarding desire for information. For this association, we compared survivors who did not seek information about cancer with those who did. We examined how sociodemographic, socioeconomic, cancerrelated, and health information factors are associated with self-rated health (SRH) by health information seeking/ avoiding behavior in a survey of 502 post-treatment cancer patients. In the information seeking group, all four factors exhibited significant relationships with SRH. SRH values were significantly high for women (p<0.05), non-Hispanic White (p<0.05), and educated (p<0.01) participants, and for those who had high self-efficacy to use health information by themselves (p<0.01). Furthermore, in the information avoiding group, not only were there no significant relationships between socioeconomic status (SES) and SRH, but there were negative associations between their attitude/capacity and the SRH. In terms of communication equity, the promotion of information seeking behavior can be an effective way to reduce health disparities that are caused by social inequalities. Information avoiding behavior, however, does not exhibit a negative contribution toward the relationship between SRH and SES. Information seeking behavior was positively associated with SRH, but avoiding behavior was not negatively associated. We thus need to eliminate communication inequalities using health intervention to support information seeking behavior, while simultaneously providing support for avoiders.

Travis L.B.,University of Rochester | Wahnefried W.D.,University of Alabama at Birmingham | Allan J.M.,Northumbria University | Wood M.E.,University of Vermont | Ng A.K.,Dana-Farber Cancer Institute
Nature Reviews Clinical Oncology | Year: 2013

Second and higher-order malignancies now comprise about 18% of all incident cancers in the USA, superseding first primary cancers of the breast, lung, and prostate. The occurrence of second malignant neoplasms (SMN) is influenced by a myriad of factors, including the late effects of cancer therapy, shared aetiological factors with the primary cancer (such as tobacco use, excessive alcohol intake, and obesity), genetic predisposition, environmental determinants, host effects, and combinations of factors, including gene-environment interactions. The influence of these factors on SMN in survivors of adult-onset cancer is reviewed here. We also discuss how modifiable behavioural and lifestyle factors may contribute to SMN, and how these factors can be managed. Cancer survivorship provides an opportune time for oncologists and other health-care providers to counsel patients with regard to health promotion, not only to reduce SMN risk, but to minimize co-morbidities. In particular, the importance of smoking cessation, weight control, physical activity, and other factors consonant with adoption of a healthy lifestyle should be consistently emphasized to cancer survivors. Clinicians can also play a critical role by endorsing genetic counselling for selected patients and making referrals to dieticians, exercise trainers, and others to assist with lifestyle change interventions. © 2013 Macmillan Publishers Limited. All rights reserved.

Kajimura S.,University of California at San Francisco | Spiegelman B.M.,Dana-Farber Cancer Institute | Seale P.,University of Pennsylvania
Cell Metabolism | Year: 2015

Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes. © 2015 Elsevier Inc.

Jacobson C.A.,Dana-Farber Cancer Institute | Abramson J.S.,Massachusetts General Hospital
Advances in Hematology | Year: 2012

Patients with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) are at increased risk for developing Hodgkin's lymphoma (HL), a risk that has not decreased despite the success of combination antiretroviral therapy (cART) in the modern era. HIV-associated HL (HIV-HL) differs from HL in non-HIV-infected patients in that it is nearly always associated with Epstein-Barr virus (EBV) and more often presents with high-risk features of advanced disease, systemic B symptoms, and extranodal involvement. Before the introduction of cART, patients with HIV-HL had lower response rates and worse outcomes than non-HIV-infected HL patients treated with conventional chemotherapy. The introduction of cART, however, has allowed for the delivery of full-dose and dose-intensive chemotherapy regimens with improved outcomes that approach those seen in non-HIV infected patients. Despite these significant advances, HIV-HL patients remain at increased risk for treatment-related toxicities and drug-drug interactions which require careful attention and supportive care to insure the safe administration of therapy. This paper will address the modern diagnosis, risk stratification, and therapy of HIV-associated HL. Copyright © 2012 Caron A. Jacobson and Jeremy S. Abramson.

Badalian-Very G.,Dana-Farber Cancer Institute
Annual review of pathology | Year: 2013

Langerhans cell histiocytosis (LCH) combines in one nosological category a group of diseases that have widely disparate clinical manifestations but are all characterized by accumulation of proliferating cells with surface markers and ultrastructural features similar to cutaneous Langerhans cells (LCs). Despite this unified nosology, important questions about LCH remain unanswered. First, despite having phenotypic features of LCs, LCH cell gene-expression patterns differ from those in LCs. Although this observation suggests that LCH may arise from an earlier precursor, it is not necessarily inconsistent with the hypothesis that LCs are the cell of origin for LCH. Second, LCH's prominent inflammatory component and occasional benign clinical course suggest that LCH may not be a neoplasm. However, the demonstration that LCH cells are clonal, along with the recent discovery of activating BRAF mutations in LCH cells, strongly suggests that LCH is a neoplastic disease. These new observations point the way to rationally targeted therapies.

Schlenner S.M.,Dana-Farber Cancer Institute | Rodewald H.-R.,German Cancer Research Center | Rodewald H.-R.,University of Ulm
Trends in Immunology | Year: 2010

The long-standing model for hematopoiesis, which features a dichotomy into separate lymphoid and myeloid branches, predicts that progenitor T cells arise from a lymphocyte-restricted pathway. However, experiments that have detected myeloid potential in progenitor T cells have been reported as evidence to question this model. Mapping physiological differentiation pathways has now led to opposite conclusions, by showing that T cells and thymic myeloid cells have distinct origins and that, in vivo, T cell progenitors lack significant potential for myeloid lineages including dendritic cells. Here, we review the underlying experiments that have led to such fundamentally different conclusions. The current controversy might reflect a need to distinguish between cell fates that are possible experimentally from physiological fate choices, to build a map of immunological differentiation pathways. © 2010 Elsevier Ltd.

Hosios A.M.,Massachusetts Institute of Technology | Fiske B.P.,Massachusetts Institute of Technology | Gui D.Y.,Massachusetts Institute of Technology | Vander Heiden M.G.,Massachusetts Institute of Technology | Vander Heiden M.G.,Dana-Farber Cancer Institute
Molecular Cell | Year: 2015

The role of pyruvate kinase M2 (PKM2) in cell proliferation is controversial. A unique function of PKM2 proposed to be important for the proliferation of some cancer cells involves the direct activity of this enzyme as a protein kinase; however, a detailed biochemical characterization of this activity is lacking. Using [32P]-phosphoenolpyruvate (PEP) we examine the direct substrates of PKM2 using recombinant enzyme and in vitro systems where PKM2 is genetically deleted. Labeling of some protein species from [32P]-PEP can be observed; however, most were dependent on the presence of ADP, and none were dependent on the presence of PKM2. In addition, we also failed to observe PKM2-dependent transfer of phosphate from ATP directly to protein. These findings argue against a role for PKM2 as a protein kinase. Hosios et al. use radioactive assays to investigate PEP-dependent phosphorylation. While some proteins can be labeled by phosphate from PEP, this activity is not dependent upon PKM2. They did not observe protein kinase activity involving this metabolic enzyme, and reports of PKM2 protein kinase activity may be partially explained by ATP regeneration by pyruvate kinase. © 2015 Elsevier Inc.

Hauer J.,Dana-Farber Cancer Institute
Pediatric Annals | Year: 2010

In summary, pain is commonly experienced by children with severe NI. By utilizing knowledge of the literature, medication properties, and a systematic approach, quality of life can be improved for many of these children. A summary outlining a suggested symptom management strategy for children with NI who experience pain is provided in the Sidebar (see page 204).

Turner N.H.,Hospital of Prato | Partridge A.,Dana-Farber Cancer Institute | Sanna G.,Hospital of Prato | Di Leo A.,Hospital of Prato | Biganzoli L.,Hospital of Prato
Annals of Oncology | Year: 2013

Background: Breast cancer in young women is typically characterised by aggressive disease, and treatment with adjuvant chemotherapy is generally recommended. Chemotherapy has conferred significant improvements in diseasefree and overall survival for young women with breast cancer; however, with improved cure rates, long-term adverse effects of cytotoxic treatment, such as premature ovarian failure (POF) and infertility, have become increasingly important. A potential fertility preservation strategy is administration of gonadotropin-releasing hormone agonists (GnRHas) during adjuvant chemotherapy. Design: This review analyses and summarises the current evidence for use of GnRHa in preserving ovarian function in young breast cancer patients. Results: Twelve trials, both non-randomised and randomised, have now been conducted assessing GnRHas in fertility preservation in young breast cancer patients, with conflicting results. Limitations of the current data include the use of poorly sensitive end points for fertility preservation, variable age of enrolled patients and limited pregnancy data. Conclusion: The utility of GnRHa as a fertility preservation strategy remains uncertain, and use outside of a clinical trial generally not recommended. Further research into this under-recognised issue is vital. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Abrams T.A.,Dana-Farber Cancer Institute
Journal of the National Cancer Institute | Year: 2014

Since the introduction of biologic therapies for the treatment of metastatic colorectal cancer (mCRC), few studies have examined patterns of care or predictors of specific treatment approaches. We assessed 4877 mCRC patients who received chemotherapy between January 2004 and March 2011 at academic, private, and community-based oncology practices subscribing to a US-wide chemotherapy order entry (system capturing disease, patient, provider, and treatment data. Multivariable analyses of these prospectively recorded characteristics were used to identify independent predictors of specific therapeutic choices. All statistical tests were two-sided. Throughout the study period, fluoropyrimidine/oxaliplatin combination was the most commonly used first-line chemotherapy regimen, representing 71% of first-line therapy by 2007. First-line bevacizumab use averaged 51%, peaking at 55% in 2006. Of those who received first-line bevacizumab, 34% continued to receive bevacizumab in the second-line. Only 26% of patients in our cohort ever received an anti-EGFR monoclonal antibody (cetuximab = 22%; panitumumab = 6%) at some point in their treatment course. Patients treated at academic centers, with longer duration of first-line therapy, and at sites in the western United States were statistically more likely to receive an anti-EGFR antibody. Anti-EGFR antibody use fell by 18% after the US Food and Drug Administration limited its use to patients with KRAS wild-type tumors in June 2009. Analysis of this US-wide mCRC cohort demonstrates that bevacizumab has been more consistently integrated into treatment regimens than anti-EGFR antibody therapies, particularly in first-line therapy. However, treatment choices vary substantially according to specific patient, practice, and provider characteristics.

Case M.A.B.,Dana-Farber Cancer Institute
Clinical Journal of Oncology Nursing | Year: 2011

The purpose of this integrative review is to explore the presence of the oncology nurse as navigator on measurable patient outcomes. Eighteen primary nursing research studies were found using combinations of the following key words: Advocate, cancer, case manager, coach, certification, guide, navigator, nurse, oncology, patient navigator, pivot nurse, and continuity of care. Nurse researchers identified nursing-sensitive patient outcomes related to the time to diagnosis and appropriate treatment, effect on mood states, satisfaction, support, continuity of care, and cost outcomes. Navigator roles are expanding globally, and nurses should continue to embrace opportunities to ensure the safe passage of patients with cancer along the entire trajectory of illness and to evaluate the implications for educational preparation, research, and practice of navigators of all kinds.

Goldberg M.S.,Dana-Farber Cancer Institute
Methods | Year: 2013

Short interfering RNAs (siRNAs) mediate the catalytic sequence-specific cleavage of target messenger RNA (mRNA) molecules, resulting in the silencing of gene products in an efficient and precise manner. One apparent application of this technology is the knockdown of genes responsible for cancer progression, including pro-proliferative oncogenes, inhibitors of apoptosis, and mediators of angiogenesis. Delivery of siRNAs into particular cells has remained the principal obstacle to the realization of the potential of RNA interference (RNAi) in the clinic. Several groups have worked to develop carriers that facilitate siRNA delivery into ovarian cancer cells in mouse models of ovarian cancer. The results have been promising, often leading to significant survival extension. Such benefit is critical for a disease that is characterized by very poor outcomes and demands novel treatment options. This review describes advancements in siRNA delivery for the treatment of ovarian cancer. © 2013 Elsevier Inc.

Garrett W.S.,Dana-Farber Cancer Institute
Science (New York, N.Y.) | Year: 2015

A host's microbiota may increase, diminish, or have no effect at all on cancer susceptibility. Assigning causal roles in cancer to specific microbes and microbiotas, unraveling host-microbiota interactions with environmental factors in carcinogenesis, and exploiting such knowledge for cancer diagnosis and treatment are areas of intensive interest. This Review considers how microbes and the microbiota may amplify or mitigate carcinogenesis, responsiveness to cancer therapeutics, and cancer-associated complications. Copyright © 2015, American Association for the Advancement of Science.

Corre J.,Linstitut University Du Cancer Of Toulouse Oncopole | Corre J.,French Institute of Health and Medical Research | Munshi N.,Dana-Farber Cancer Institute | Avet-Loiseau H.,Linstitut University Du Cancer Of Toulouse Oncopole | Avet-Loiseau H.,French Institute of Health and Medical Research
Blood | Year: 2015

Our knowledge of myeloma genetics remained limited and lagged behind many other hematologic malignancies because of the inherent difficulties in generating metaphases within the malignant plasma cell clone. With the development of molecular techniques (microarrays and next-generation sequencing), our understanding has been highly improved in the past 5 years. These studies have not only confirmed the prevalence of wide heterogeneity in myeloma at the molecular level, but has also provided a much clearer picture of the disease pathogenesis and progression. Whether these data will enable improvements in the therapeutic approach is still a matter of debate. The next improvement will come from detailed analyses of these molecular features to try to move from a treatment fitted to every patient to individualized therapies, taking into account the complexity of the chromosomal changes, the mutation spectrum, and subclonality evolution.

Korsgren C.,Childrens Hospital Boston | Lux S.E.,Childrens Hospital Boston | Lux S.E.,Dana-Farber Cancer Institute
Blood | Year: 2010

Spectrin and protein 4.1R crosslink Factin, forming the membrane skeleton. Actin and 4.1R bind to one end of β-spectrin. The adjacent end of α-spectrin, called the EF domain, is calmodulin-like, with calcium-dependent and calcium-independent EF hands. The severely anemic sph 1J/sph 1J mouse has very fragile red cells and lacks the last 13 amino acids in the EF domain, implying that the domain is critical for skeletal integrity. To test this, we constructed a minispectrin heterodimer from the actin-binding domain, the EF domain, and 4 adjacent spectrin repeats in each chain. The minispectrin bound to F-actin in the presence of native human protein 4.1R. Formation of the spectrinactin-4.1R complex was markedly attenuated when the minispectrin contained the shortened sph 1J α-spectrin. The α-spectrin deletion did not interfere with spectrin heterodimer assembly or 4.1R binding but abolished the binary interaction between spectrin and F-actin. The data show that the α-spectrin EF domain greatly amplifies the function of the β-spectrin actin-binding domain (ABD) in forming the spectrin-actin-4.1R complex. A model, based on the structure of α-actinin, suggests that the EF domain modulates the function of the ABD and that the C-terminal EF hands (EF 34) may bind to the linker that connects the ABD to the first spectrin repeat. © 2010 by The American Society of Hematology.

Zhang X.,Norris Cotton Cancer Center | Zhang X.,Dana-Farber Cancer Institute | Bailey S.D.,A+ Network | Bailey S.D.,University of Toronto | And 3 more authors.
Trends in Genetics | Year: 2014

Genome-wide association studies (GWAS) have identified more than 8900 genetic variants, mainly single-nucleotide polymorphisms (SNPs), associated with hundreds of human traits and diseases, which define risk-associated loci. Variants that map to coding regions can affect protein sequence, translation rate, and alternative splicing, all of which influence protein function. However, the vast majority of sequence variants map to non-coding intergenic and intronic regions, and it has been much more challenging to assess the functional nature of these variants. Recent work annotating the non-coding regions of the genome has contributed to post-GWAS studies by facilitating the identification of the functional targets of risk-associated loci. Many non-coding genetic variants within risk-associated loci alter gene expression by modulating the activity of cis-regulatory elements. We review here these recent findings, discuss their implication for the post-GWAS era, and relate their importance to the interpretation of disease-associated mutations identified through whole-genome sequencing. © 2014 Elsevier Ltd.

Kim S.Y.,Dana-Farber Cancer Institute
PloS one | Year: 2010

Aberrant beta-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate beta-catenin activity for therapeutic purposes have proven elusive to date. To uncover genetic dependencies in breast cancer cells that harbor active beta-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized beta-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1epsilon) as required specifically for the proliferation of breast cancer cells with activated beta-catenin and confirm its role as a positive regulator of beta-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated beta-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/beta-catenin signaling. We also find that expression of CK1epsilon is able to promote oncogenic transformation of human cells in a beta-catenin-dependent manner. These studies identify CK1epsilon as a critical contributor to activated beta-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active beta-catenin. More generally, these observations delineate an approach that can be used to identify druggable synthetic lethal interactions with signaling pathways that are frequently activated in cancer but are difficult to target with the currently available small molecule inhibitors.

O'Neill N.K.,Dana-Farber Cancer Institute
Nature Medicine | Year: 2016

Extensive cross-linking introduced during routine tissue fixation of clinical pathology specimens severely hampers chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) analysis from archived tissue samples. This limits the ability to study the epigenomes of valuable, clinically annotated tissue resources. Here we describe fixed-tissue chromatin immunoprecipitation sequencing (FiT-seq), a method that enables reliable extraction of soluble chromatin from formalin-fixed paraffin-embedded (FFPE) tissue samples for accurate detection of histone marks. We demonstrate that FiT-seq data from FFPE specimens are concordant with ChIP-seq data from fresh-frozen samples of the same tumors. By using multiple histone marks, we generate chromatin-state maps and identify cis-regulatory elements in clinical samples from various tumor types that can readily allow us to distinguish between cancers by the tissue of origin. Tumor-specific enhancers and superenhancers that are elucidated by FiT-seq analysis correlate with known oncogenic drivers in different tissues and can assist in the understanding of how chromatin states affect gene regulation. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Lin N.U.,Dana-Farber Cancer Institute
Current Treatment Options in Neurology | Year: 2014

Brain metastases are a major clinical problem in patients with advanced breast cancer, lung cancer, melanoma, and renal cell carcinoma. Initial treatment for patients with brain metastases typically includes radiotherapy, either whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or both. Surgical resection is generally reserved for good prognosis patients with limited/controlled extracranial metastases and a single brain lesion. Once patients progress through upfront treatment, the treatment approach is quite variable and there is no clearly defined standard-of-care. Over the past decade, the role of systemic therapies and in particular, targeted therapies has been increasingly explored in patients with brain metastases from solid tumors. For example, lapatinib has been studied as monotherapy, and in combination with capecitabine, in patients with HER2-positive breast cancer, and activity has been observed in both the upfront and refractory settings. In patients with nonsmall cell lung cancer (NSCLC), central nervous system (CNS) activity has been reported with gefinitib and erlotinib. Finally, in melanoma, the B-raf inhibitors vemurafenib and dabrafenib, and the immunomodulator, ipilumimab, have reported CNS activity. Moving forward, the challenge will be to understand how to optimize the activity of targeted agents in the CNS and how to best incorporate them into the current treatment paradigms in order to improve outcomes for this patient population. © Springer Science+Business Media New York 2013.

Chen W.,Duke University | Huang F.W.,Dana-Farber Cancer Institute | De Renshaw T.B.,Duke University | Andrews N.C.,Duke University
Blood | Year: 2011

Hepcidin, a hormone produced mainly by the liver, has been shown to inhibit both intestinal iron absorption and iron release from macrophages. Hemojuvelin, a glycophosphatidyl inositol-linked membrane protein, acts as a bone morphogenetic protein coreceptor to activate hepcidin expression through a SMAD signaling pathway in hepatocytes. In the present study, we show in mice that loss of hemojuvelin specifically in the liver leads to decreased liver hepcidin production and increased tissue and serum iron levels. Although it does not have any known function outside of the liver, hemojuvelin is expressed at very high levels in cardiac and skeletal muscle. To explore possible roles for hemojuvelin in skeletal muscle, we analyzed conditional knockout mice that lack muscle hemojuvelin. The mutant animals had no apparent phenotypic abnormalities. We found that systemic iron homeostasis and liver hepcidin expression were not affected by loss of hemojuvelin in skeletal muscle regardless of dietary iron content. We conclude that, in spite of its expression pattern, hemojuvelin is primarily important in the liver. © 2011 by The American Society of Hematology.

Ligibel J.,Dana-Farber Cancer Institute
Oncology | Year: 2011

Obesity is a growing health problem in the United States and, increasingly, around the world. Excess body weight has been linked to an increased risk of postmenopausal breast cancer, and growing evidence also suggests that obesity is associated with poor prognosis in women diagnosed with early-stage breast cancer. Dozens of studies demonstrate that women who are overweight or obese at the time of breast cancer diagnosis are at increased risk of cancer recurrence and death compared with leaner women, and some evidence suggests that women who gain weight after breast cancer diagnosis may also be at increased risk of poor outcomes. In this review, we describe the evidence linking obesity to breast cancer recurrence, discuss the potential biological mechanisms through which weight could impact breast cancer prognosis, and review the weight-loss intervention studies that have been performed in breast cancer populations to date.

Mack J.W.,Dana-Farber Cancer Institute
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Medicare patients with advanced cancer have low rates of hospice use. We sought to evaluate hospice use among patients in Medicaid, which insures younger and indigent patients, relative to those in Medicare. Using linked patient-level data from California (CA) and New York (NY) state cancer registries, state Medicaid programs, NY Medicare, and CA Surveillance, Epidemiology, and End Results-Medicare data, we identified 4,797 CA Medicaid patients and 4,001 NY Medicaid patients ages 21 to 64 years, as well as 27,416 CA Medicare patients and 16,496 NY Medicare patients ages ≥ 65 years who were diagnosed with stage IV lung cancer between 2002 and 2006. We evaluated hospice use, timing of enrollment, and location of death (inpatient hospice; long-term care facility or skilled nursing facility; acute care facility; home with hospice; or home without hospice). We used multiple logistic regressions to evaluate clinical and sociodemographic factors associated with hospice use. Although 53% (CA) and 44% (NY) of Medicare patients ages ≥ 65 years used hospice, fewer than one third of Medicaid-insured patients ages 21 to 64 years enrolled in hospice after a diagnosis of stage IV lung cancer (CA, 32%; NY, 24%). A minority of Medicaid patient deaths (CA, 19%; NY, 14%) occurred at home with hospice. Most Medicaid patient deaths were either in acute-care facilities (CA, 28%; NY, 36%) or at home without hospice (CA, 39%; NY, 41%). Patient race/ethnicity was not associated with hospice use among Medicaid patients. Given low rates of hospice use among Medicaid enrollees and considerable evidence of suffering at the end of life, opportunities to improve palliative care delivery should be prioritized.

Lewis C.A.,Massachusetts Institute of Technology | Parker S.J.,University of California at San Diego | Fiske B.P.,Massachusetts Institute of Technology | McCloskey D.,University of California at San Diego | And 7 more authors.
Molecular Cell | Year: 2014

Eukaryotic cells compartmentalize biochemical processes in different organelles, often relying on metabolic cycles to shuttle reducing equivalents across intracellular membranes. NADPH serves as the electron carrier for the maintenance of redox homeostasis and reductive biosynthesis, with separate cytosolic and mitochondrial pools providing reducing power in each respective location. This cellular organization is critical for numerous functions but complicates analysis of metabolic pathways using available methods. Here we develop an approach to resolve NADP(H)-dependent pathways present within both the cytosol and the mitochondria. By tracing hydrogen in compartmentalized reactions that use NADPH as a cofactor, including the production of 2-hydroxyglutarate by mutant isocitrate dehydrogenase enzymes, we can observe metabolic pathway activity in these distinct cellular compartments. Using this system we determine the direction of serine/glycine interconversion within the mitochondria and cytosol, highlighting the ability of this approach to resolve compartmentalized reactions in intact cells. © 2014 Elsevier Inc.

Overmoyer B.,Dana-Farber Cancer Institute
Journal of Clinical Oncology | Year: 2015

A 64-year-old healthy postmenopausal woman with an intact uterus had been diagnosed with mammographically detected invasive ductal carcinoma of the right breast at the age of 59 years. She underwent breast-conservation surgery, with an excisional biopsy and sentinel lymph node sampling revealing a 1.2-cm Bloom-Richardson grade 2 invasive ductal carcinoma with negative surgical margins and one negative sentinel lymph node. Immunohistochemical testing showed that the tumor was estrogen receptor positive (strong intensity, > 95%) and progesterone receptor positive (strong intensity, 90%) but negative for human epidermal growth factor receptor 2 overexpression. The Oncotype DX (Genomic Health, Redwood City, CA) recurrence score was 13, associated with a 10-year risk of distant recurrence equaling 8% with 5 years of tamoxifen adjuvant treatment. On the basis of this result, she declined chemotherapy and received hypofractionated whole-breast irradiation in 16 fractions without a boost, receiving 42.5 Gy of radiation to the breast. At the time of her diagnosis, baseline bone density demonstrated osteopenia, with a T-score average of -1.5 for the lumbar spine and a T-score average of -1.9 for the left hip. The patient was concerned about the risk of osteoporosis associated with aromatase inhibitors and therefore chose to receive tamoxifen alone as adjuvant endocrine therapy. Serial bone-mineral density evaluation over the subsequent years has shown stable T scores (lumbar spine, -1.3; hip, -1.7). She has tolerated tamoxifen well for 5 years, without experiencing menopausal symptoms or vaginal bleeding. She is requesting an opinion on whether she should receive extended endocrine therapy for an additional 5 years. © 2015 by American Society of Clinical Oncology.

Sullivan L.B.,Massachusetts Institute of Technology | Gui D.Y.,Massachusetts Institute of Technology | Hosios A.M.,Massachusetts Institute of Technology | Bush L.N.,Massachusetts Institute of Technology | And 3 more authors.
Cell | Year: 2015

Mitochondrial respiration is important for cell proliferation; however, the specific metabolic requirements fulfilled by respiration to support proliferation have not been defined. Here, we show that a major role of respiration in proliferating cells is to provide electron acceptors for aspartate synthesis. This finding is consistent with the observation that cells lacking a functional respiratory chain are auxotrophic for pyruvate, which serves as an exogenous electron acceptor. Further, the pyruvate requirement can be fulfilled with an alternative electron acceptor, alpha-ketobutyrate, which provides cells neither carbon nor ATP. Alpha-ketobutyrate restores proliferation when respiration is inhibited, suggesting that an alternative electron acceptor can substitute for respiration to support proliferation. We find that electron acceptors are limiting for producing aspartate, and supplying aspartate enables proliferation of respiration deficient cells in the absence of exogenous electron acceptors. Together, these data argue a major function of respiration in proliferating cells is to support aspartate synthesis. © 2015 Elsevier Inc.

Ghobrial I.M.,Dana-Farber Cancer Institute
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Waldenström macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by the presence of lymphoplasmacytic cells in the BM and IgM monoclonal protein in the serum. The origin of the malignant clone is thought to be a B cell arrested after somatic hypermutation in the germinal center and before terminal differentiation to plasma cells. In this review, recent advances in the genetic and epigenetic regulators of tumor progression are discussed. Risk factors include IgM-monoclonal gammopathy of undermined significance, familial disease, and immunological factors. The clinical manifestations of the disease include those related to clonal infiltration of the BM, lymph nodes, and, rarely, other sites such as pulmonary or CNS infiltration (Bing-Neel syndrome). Other manifestations are related to the IgM monoclonal protein, including hyperviscosity, cryoglobulinemia, protein-protein interactions, Ab-mediated disorders such as neuropathy, hemolytic anemia, and Schnitzler syndrome. IgM deposition in organs can lead to amyloidogenic manifestations in WM. The diagnostic workup for a patient with WM and rare presentations of WM are described herein. Prognosis of WM depends on 5 major factors in the International Staging System, including age, anemia, thrombocytopenia, β-2 microglobulin, and IgM level. The differential diagnosis of WM includes IgM-multiple myeloma, marginal zone lymphoma, mantle cell lymphoma, and follicular lymphoma.

Gross A.H.,Dana-Farber Cancer Institute
Clinical Journal of Oncology Nursing | Year: 2015

On the occasion of the Oncology Nursing Society’s 40th anniversary, it is fitting to look back and appreciate how far we have come in the area of quality cancer care. So much has changed, fueled in part by advances in health- care quality improvement across the United States.At a Glance• The past 40 years have brought many improvements in the quality and safety of oncology nursing practice.• Beyond the technical aspects of care, advances in patient-centered care have improved patient experiences and outcomes. Consistent, personalized, human caring may be the focus of change in the next 40 years. © 2015 by the Oncology Nursing Society.

Steensma D.P.,Dana-Farber Cancer Institute
Seminars in Oncology | Year: 2011

Hematopoietic growth factors (HGFs) continue to be the most widely prescribed class of medications for patients with myelodysplastic syndromes (MDS), despite the advent of disease-modifying therapies for MDS (eg, azacitidine, decitabine, and lenalidomide) and the current absence of an MDS-specific US Food and Drug Administration (FDA)-approved indication for any of the HGFs. Erythropoiesis-stimulating agents (ESAs: epoetin alfa, darbepoetin alfa), myeloid growth factors (MGFs: filgrastim, pegfilgrastim, sargramostim), and the newest group of HGFs, thrombopoiesis-stimulating agents (TSAs: romiplostim, eltrombopag), can increase peripheral blood counts in some patients, and may ameliorate some of the signs and symptoms of MDS-associated bone marrow failure. Although HGFs are generally considered "supportive care" measures, recent data suggest that HGFs may alter the natural history of disease in MDS, either for better or worse. This review examines data on the safety and effectiveness of HGFs for patients with MDS. © 2011 Elsevier Inc. All rights reserved.

Haining W.N.,Dana-Farber Cancer Institute | Haining W.N.,The Broad Institute of MIT and Harvard | Pulendran B.,Emory Vaccine Center
Current Opinion in Immunology | Year: 2012

Molecular predictors of the response to vaccination could transform vaccine development. They would allow larger numbers of vaccine candidates to be rapidly screened, shortening the development time for new vaccines. Gene-expression based predictors of vaccine response have shown early promise. However, a limitation of gene-expression based predictors is that they often fail to reveal the mechanistic basis of their ability to classify response. Linking predictive signatures to the function of their component genes would advance basic understanding of vaccine immunity and also improve the robustness of vaccine prediction. New analytic tools now allow more biological meaning to be extracted from predictive signatures. Functional genomic approaches to perturb gene expression in mammalian cells permit the function of predictive genes to be surveyed in highly parallel experiments. The challenge for vaccinologists is therefore to use these tools to embed mechanistic insights into predictors of vaccine response. © 2012 Elsevier Ltd.

Ma Q.,Dana-Farber Cancer Institute
Neuroscience Bulletin | Year: 2012

The somatic sensory system includes a variety of sensory modalities, such as touch, pain, itch, and temperature sensitivity. The coding of these modalities appears to be best explained by the population-coding theory, which is composed of the following features. First, an individual somatic sensory afferent is connected with a specific neural circuit or network (for simplicity, a sensory-labeled line), whose isolated activation is sufficient to generate one specific sensation under normal conditions. Second, labeled lines are interconnected through local excitatory and inhibitory interneurons. As a result, activation of one labeled line could modulate, or provide gate control of, another labeled line. Third, most sensory fibers are polymodal, such that a given stimulus placed onto the skin often activates two or multiple sensory-labeled lines; crosstalk among them is needed to generate one dominant sensation. Fourth and under pathological conditions, a disruption of the antagonistic interaction among labeled lines could open normally masked neuronal pathways, and allow a given sensory stimulus to evoke a new sensation, such as pain evoked by innocuous mechanical or thermal stimuli and itch evoked by painful stimuli. As a result of this, some sensory fibers operate along distinct labeled lines under normal versus pathological conditions. Thus, a better understanding of the neural network underlying labeled line crosstalk may provide new strategies to treat chronic pain and itch. © 2012 Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg.

Jacobson C.A.,Dana-Farber Cancer Institute
Oncology (Williston Park, N.Y.) | Year: 2010

Post-transplant lymphoproliferative disorder (PTLD) is a common and serious complication of solid organ transplantation. It is a heterogeneous collection of diagnoses with varied clinical courses and outcomes. The majority of PTLD is Epstein-Barr virus (EBV)-driven as a result of loss of immune control of EBV-positive B lymphocytes. Risk factors for the development of PTLD thus reflect loss or absence of EBV immunity; they include younger age and pre-transplant EBV naivety, as well as the degree and type of immune suppression, type of organ transplantation, and time from transplantation. Identifying patients at risk for PTLD and developing strategies to prevent PTLD is the subject of much research, and the use of antiviral medications and EBV vaccines has yielded intriguing, albeit preliminary, results. As we learn more about the prognostic factors affecting outcome and the pathogenesis of individual diseases, we are better able to tailor therapy to the individual. Further clinical investigation, including randomized controlled trials, will be important in reaching this goal.

Shindiapina P.,Dartmouth Hitchcock Medical Center | Brown J.R.,Dana-Farber Cancer Institute | Danilov A.V.,Dartmouth Hitchcock Medical Center
British Journal of Haematology | Year: 2014

Chronic lymphocytic leukaemia (CLL) is an indolent B-cell malignancy with heterogeneous outcomes. Chromosomal abnormalities in CLL are predictive of the natural disease course; del(11q) and del(17p) are recognized as high risk genetic lesions. Del(17p) is associated with an impaired function of TP53, a key tumour suppressor, and is particularly problematic. Such patients respond poorly to chemo-immunotherapy and have significantly shorter survival compared to patients with standard and low-risk cytogenetics. While TP53 pathway defects are rare at initial diagnosis, their frequency increases in relapsed CLL. Until very recently, this group of patients represented an unmet clinical need with few therapeutic options. However, the advent of targeted therapies has expanded the drug armamentarium and introduced new hope for these highly refractory patients. Agents that target B-cell receptor signalling, BH3-mimetics and others induce apoptosis of the neoplastic B-cells in a TP53-independent manner. Their use in the clinic is associated with remarkable activity in patients with del(17p). In this review we discuss the frequency and clinical significance of del(17p) and genetic mutations leading to disrupted TP53, the putative role of other TP53 homologues, and the results of key clinical trials involving both conventional chemotherapy and novel agents. © 2014 John Wiley & Sons Ltd.

van Kruchten M.,University of Groningen | de Vries E.G.E.,University of Groningen | Brown M.,Dana-Farber Cancer Institute | de Vries E.F.J.,University of Groningen | And 4 more authors.
The Lancet Oncology | Year: 2013

Oestrogen receptors are overexpressed in around 70% of all breast cancers, and are a target for endocrine therapy. These receptors can be visualised on PET with use of 16α-[18F]-fluoro-17β-oestradiol (18F-FES) as a tracer. Compared with biopsy, which enables assessment of individual sites, whole-body 18F-FES-PET enables quantification of oestrogen-receptor expression in all metastases. In several studies, measurement of tumour protein expression in oestrogen receptors by 18F-FES-PET, concurrent with biopsy, detected oestrogen-receptor-positive tumour lesions with a sensitivity of 84% and specificity of 98%. Roughly 45% of patients with metastatic breast cancer have discordant oestrogen-receptor expression across lesions (ie, 18F-FES-positive and 18F-FES-negative metastases). Low tumour 18F-FES uptake in metastases can predict failure of hormonal therapy in patients with oestrogen-receptor-positive primary tumours. Finally, 18F-FES-PET has shown that oestrogen-receptor binding capacity changes after intervention with hormonal drugs, but findings need to be confirmed. Factors other than oestrogen-receptor expression, including menopausal status and concomitant therapies, that can affect tumour 18F-FES uptake must be taken into account. © 2013 Elsevier Ltd.

Demetri G.D.,Dana-Farber Cancer Institute
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.

Chen Y.-B.,Massachusetts General Hospital | Cutler C.S.,Dana-Farber Cancer Institute
Bone Marrow Transplantation | Year: 2013

Acute GVHD remains an important complication after allogeneic hematopoietic cell transplantation (HCT). Many efforts have been devoted to identifying potential noninvasive peripheral blood biomarkers to help improve the diagnosis or management of acute GVHD while avoiding invasive tissue biopsies. Early attempts to identify biomarkers focused on inflammatory cytokines, especially IL-2 or TNF-α, however, both of these and others were not specific for GVHD, often being elevated in the setting of generalized inflammation, accompanying other major complications of HCT as well. More recent efforts have focused on additional cytokines and other cell-surface molecules, which function in leukocyte trafficking and activation with the hope that these can also serve as targets for novel therapeutic approaches. Modern proteomic methods have allowed the screening of large numbers of patient samples and yielded several novel candidate biomarkers, including elafin and reg3α, which may not be directly involved in the immunological pathogenesis of GVHD, but may be unique biomarkers for end-organ injury. Combining these new molecules with traditionally identified cytokines to form an acute GVHD biomarker panel has recently shown the ability to predict outcomes in patients who develop acute GVHD. The ultimate goals of identifying a specific biomarker are to refine diagnosis, guide therapy and develop risk-adapted approaches in order to better treat patients and improve outcomes after allogeneic HCT. These approaches include differential treatment for patients who develop acute GVHD with a high-risk biomarker profile as well as pre-emptive therapy in patients after HCT prior to the development of symptoms. With the recent progress summarized below, these goals may soon be realized. © 2013 Macmillan Publishers Limited All rights reserved.

Moslehi J.,Dana-Farber Cancer Institute | Depinho R.A.,University of Houston | Depinho R.A.,University of Texas M. D. Anderson Cancer Center | Sahin E.,Baylor College of Medicine
Circulation Research | Year: 2012

Studies in humans and in mice have highlighted the importance of short telomeres and impaired mitochondrial function in driving age-related functional decline in the heart. Although telomere and mitochondrial dysfunction have been viewed mainly in isolation, recent studies in telomerase-deficient mice have provided evidence for an intimate link between these two processes. Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and PGC-1β in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging. © 2012 American Heart Association, Inc.

Ballen K.K.,Massachusetts General Hospital | Koreth J.,Dana-Farber Cancer Institute | Chen Y.-B.,Massachusetts General Hospital | Dey B.R.,Massachusetts General Hospital | Spitzer T.R.,Massachusetts General Hospital
Blood | Year: 2012

Only 30% of patients who require an allogeneic hematopoietic cell transplant will have an HLA-matched sibling donor. A search for an unrelated donor will be undertaken for patients without a matched family donor. However, many patients, particularly patients of diverse racial and ethnic backgrounds, may not be able to rapidly identify a suitably matched unrelated donor. Three alternative graft sources, umbilical cord blood (UCB), haploidentical (haplo)-related donor, and mismatched unrelated donor (MMUD) are available. UCB is associated with decreased GVHD, but hematologic recovery and immune reconstitution are slow. Haplo-HCT is characterized by donor availability for transplantation and after transplantation adoptive cellular immunotherapy but may be complicated by a high risk of graft failure and relapse. A MMUD transplant may also be an option, but GVHD may be of greater concern. Phase 2 studies have documented advances in HLAtyping, GVHD prophylaxis, and infection prevention, which have improved survival. The same patient evaluated in different transplant centers may be offered MMUD, UCB, or haplo-HCT depending on center preference. In this review, we discuss the rationale for donor choice and the need of phase 3 studies to help answer this important question. © 2012 by The American Society of Hematology.

Campos S.M.,Dana-Farber Cancer Institute | Dizon D.S.,Brown University
Hematology/Oncology Clinics of North America | Year: 2012

Of the agents available in the treatment of both solid and hematologic cancers, microtubule-targeted agents are among the most widely used and exploiting other mechanisms involving the microtubule and its role in mitosis is an area of continued interest. This review will focus on novel microtubule-targeted agents, both recently approved (eg, ixabepilone and eribulin) and in later-stage clinical trials, and kinase inhibitors that aim to directly inhibit the mitotic spindle, such as the aurora kinase, pololike kinase, and kinsein-spindle protein inhibitors. © 2012 Elsevier Inc..

Robinson B.G.,University of Sydney | Paz-Ares L.,Hospital Universitario Virgen Del Rocio | Krebs A.,Astrazeneca | Vasselli J.,Astrazeneca | Haddad R.,Dana-Farber Cancer Institute
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Purpose: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinases that also inhibits rearranged during transfection kinase activity. Vandetanib (300 mg/d) has previously demonstrated antitumor activity in patients with advanced hereditary medullary thyroid cancer (MTC). This study investigated the efficacy and safety of 100 mg/d vandetanib in patients with advanced hereditary MTC. Patients and Methods: Eligible patients with unresectable, measurable, locally advanced, or metastatic hereditary MTC received 100 mg/d vandetanib. Upon disease progression, eligible patients could enter postprogression treatment with 300 mg/d vandetanib until a withdrawal criterion was met. The primary objective was to assess the objective response rate by response evaluation criteria in solid tumors. Results: The study comprised 19 patients (13 males, six females; mean age 45 yr). Confirmed objective partial responses were observed in three patients, yielding an objective response rate of 16% (95% confidence interval 3.4-39.6). Stable disease lasting 24 wk or longer was reported in a further 10 patients(53%);thedisease control rate was therefore 68% (95% confidence interval 43.4-87.4). Serum levels of calcitonin and carcinoembryonic antigen showed a sustained 50% or greater decrease from baseline in 16% (three of 19) and 5% (one of 19) of patients, respectively. Adverse events were predominantly grade 1 or 2 and consistent with previous vandetanib monotherapy studies. Conclusions: Vandetanib at a once-daily dose of 100 mg has clinically relevant antitumor activity in patients with locally advanced or metastatic hereditary MTC and an overall acceptable safety profile. Copyright © 2010 by The Endocrine Society.

Lunt S.Y.,Massachusetts Institute of Technology | Vander Heiden M.G.,Massachusetts Institute of Technology | Vander Heiden M.G.,Dana-Farber Cancer Institute
Annual Review of Cell and Developmental Biology | Year: 2011

Warburg's observation that cancer cells exhibit a high rate of glycolysis even in the presence of oxygen (aerobic glycolysis) sparked debate over the role of glycolysis in normal and cancer cells. Although it has been established that defects in mitochondrial respiration are not the cause of cancer or aerobic glycolysis, the advantages of enhanced glycolysis in cancer remain controversial. Many cells ranging from microbes to lymphocytes use aerobic glycolysis during rapid proliferation, which suggests it may play a fundamental role in supporting cell growth. Here, we review how glycolysis contributes to the metabolic processes of dividing cells. We provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass. We argue that the major function of aerobic glycolysis is to maintain high levels of glycolytic intermediates to support anabolic reactions in cells, thus providing an explanation for why increased glucose metabolism is selected for in proliferating cells throughout nature. © 2011 by Annual Reviews. All rights reserved.

Moreau P.,University of Nantes | Richardson P.G.,Dana-Farber Cancer Institute | Cavo M.,University of Bologna | Orlowski R.Z.,University of Houston | And 3 more authors.
Blood | Year: 2012

Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib, and MLN9708, and trials investigating these "secondgeneration" PIs in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of PIs in the treatment of MM, focusing on developments over the past decade. © 2012 by The American Society of Hematology.

Wang J.-H.,Peking University | Wang J.-H.,Dana-Farber Cancer Institute
Cell Research | Year: 2012

The inside-out signaling of integrins regulates the ligand-binding affinity of the cell surface receptors in response to changes in the environment for cell survival. The specific binding to the cytoplasmic tail of integrin's β subunit by the intracellular protein talin is the key step of inside-out signaling. A pull-push mechanism has been proposed to explain how the PIP2-enriched membrane disrupts the dual auto-inhibition of the N-terminal talin-FERM domain by the C-terminal talin-rod domain such that activated talin-FERM can reach the β-tail for integrin activation. © 2012 IBCB, SIBS, CAS All rights reserved.

Choi Y.E.,Dana-Farber Cancer Institute | Park E.,Hannam University
Biochemical and Biophysical Research Communications | Year: 2015

Homologous-recombination (HR)-dependent repair defective cells are hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Combinations of defective HR pathway and PARP inhibitors have been an effective chemotherapeutic modality. We previously showed that knockdown of the WD40-repeat containing protein, Uaf1, causes an HR repair defect in mouse embryo fibroblast cells and therefore, increases sensitivity to PARP inhibitor, ABT-888. Similarly, here, we show that ferulic acid reduces HR repair, inhibits RAD 51 foci formation, and accumulates γ-H2AX in breast cancer cells. Moreover, ferulic acid, when combined with ABT-888, renders breast cancer cells become hypersensitive to ABT-888. Our study indicates that ferulic acid in combination with ABT-888 treatment may serve as an effective combination chemotherapeutic agent as a natural bioactive compound. © 2015 Elsevier Inc.

Padron E.,H. Lee Moffitt Cancer Center and Research Institute | Steensma D.P.,Dana-Farber Cancer Institute
Current Opinion in Hematology | Year: 2015

PURPOSE OF REVIEW: Chronic myelomonocytic leukemia (CMML) is a troublesome hematologic malignancy characterized by peripheral blood monocytosis, marrow dysplasia, cytopenias, frequent extramedullary involvement by clonal cells, and a propensity for progression to acute myeloid leukemia. Although previously considered a subtype of the myelodysplastic syndromes (MDS), CMML is now recognized as a distinct entity with unique biologic and clinical features. This change has created a scientific and clinical research landscape that makes it difficult to discern CMML-specific validated conclusions versus speculative extrapolation from more general MDS data. RECENT FINDINGS: Here, we review recent biologic observations that support the current CMML WHO classification, such as the high frequency of SRSF2 and ASXL1 mutations compared with MDS and critical dependence of CMML cells on granulocyte-macrophage colony-stimulating factor signaling. In addition, we discuss CMML-specific prognostic tools and therapeutic results of agents developed for MDS in patients with CMML. SUMMARY: The present review focuses on evidence supporting CMML ontology and identifies key clinical differences in the management of CMML and that of MDS subtypes. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Kentsis A.,Dana-Farber Cancer Institute
Pediatrics International | Year: 2011

Modern medicine has experienced a tremendous explosion in knowledge about disease pathophysiology, gained largely from understanding the molecular biology of human disease. Recent advances in mass spectrometry and proteomics now allow for simultaneous identification and quantification of thousands of unique proteins and peptides in complex biological tissues and fluids. In particular, proteomic studies of urine benefit from urine's less complex composition as compared to serum and tissues, and have been used successfully to discover novel markers of a variety of infectious, autoimmune, oncological, and surgical conditions. This perspective discusses the challenges of such studies that stem from the compositional variability and complexity of human urine, as well as instrumental sampling limitations and the effects of noise and selection bias. Strategies for the design of observational clinical trials, physical and chemical fractionation of urine specimens, mass spectrometry analysis, and functional data annotation are outlined. Rigorous translational investigations using urine proteomics are likely to discover novel and accurate markers of both rare and common diseases. This should aid the diagnosis, improve stratification of therapy, and identify novel therapeutic targets for a variety of childhood and adult diseases, all of which will be essential for the development of personalized and predictive medicine of the future. © 2011 Japan Pediatric Society.

D'Adamo D.R.,Dana-Farber Cancer Institute
Seminars in Oncology | Year: 2011

Sarcomas are a heterogeneous group of relatively rare mesenchymal neoplasms. They can be grouped into two general categories: soft tissue sarcoma (STS) and primary bone sarcoma, which are treated differently. Because sarcomas are relatively rare and complex with a wide variety of different histopathologic subtypes, evaluation by multidisciplinary teams who have expertise in the field is recommended. Treatment guidelines for the use of chemotherapy in patients with STS and bone sarcoma have been published by the National Comprehensive Cancer Network. The role of adjuvant chemotherapy in resected STS remains controversial. Although chemotherapy improves disease-free survival, the long-term overall survival benefit remains unproven. Chemotherapy is typically used as palliative treatment for most subtypes of metastatic STS. In contrast, chemotherapy has a proven role in the treatment of primary bone tumors and Ewing sarcoma, but it has not demonstrated efficacy in the treatment of chondrosarcoma. The standard chemotherapy regimens used in sarcoma are associated with significant toxicity, including long-term complications. Less intense and less toxic regimens are the focus of ongoing clinical research. Newer cytotoxic agents with an improved safety profile, such as trabectedin and palifosfamide, are currently in development. Future research needs to focus on identification of subpopulations of patients that are most likely to benefit from chemotherapy. © 2011 Elsevier Inc.

Reagan J.L.,Rhode Island Hospital | Castillo J.J.,Dana-Farber Cancer Institute
Future Oncology | Year: 2014

Ofatumumab is a fully human IgG1 type I anti-CD20 monoclonal antibody that binds to both the small and large loop of the membrane antigen CD20. Much of its therapeutic efficacy is derived through complement-dependent cytotoxicity, although it also appears to operate via induction of caspase-dependent apoptosis and shows potent antibody-dependent cellular phagocytosis. CD20 is an important but sometimes difficult antigen to effectively target in chronic lymphocytic leukemia (CLL) secondary to its overall dim expression in CLL cells. Currently, ofatumumab is approved in the USA and EU for fludarabine-and alemtuzumab-refractory CLL patients. However, the experience with ofatumumab in untreated CLL patients is mounting and shows competitive response and survival rates with an acceptable adverse event profile. Herein, we outline the efficacy and toxicities of ofatumumab alone and in combination for the front-line treatment of CLL. © 2014 Future Medicine Ltd.

Partridge A.H.,Dana-Farber Cancer Institute
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Previous research has suggested that young age at diagnosis is an independent risk factor for breast cancer recurrence and death. No prior studies have adequately controlled for human epidermal growth factor receptor 2 (HER2) status or anti-HER2 treatment. We sought to evaluate whether age was a prognostic or predictive factor in the HERA trial. We used 2-year median follow-up data and dichotomized age at 40 years to evaluate its prognostic effect on outcomes for women assigned to trastuzumab for 1 year or observation. Of the 1,703 women randomly assigned to 1 year of trastuzumab and 1,698 to observation, 722 (21%) were age ≤ 40 years at study entry. In separate Cox models, controlling for relevant prognostic and predictive factors, disease-free (DFS) and overall survival (OS) hazard ratios (HRs) were consistent for women age ≤ 40 versus > 40 years, regardless of treatment assignment (observation group: DFS HR age ≤ 40 v > 40 years, 1.18; 95% CI, 0.90 to 1.54; OS HR age ≤ 40 v > 40 years, 1.01; 95% CI, 0.60 to 1.69; trastuzumab group: DFS HR age ≤ 40 v > 40 years, 1.11; 95% CI, 0.81 to 1.51; OS HR age ≤ 40 v > 40 years, 1.18; 95% CI, 0.66 to 2.09). Interaction between age group and treatment effect was not statistically significant (DFS P = .89; OS P = .55). In a retrospective analysis of a large randomized controlled trial of women with early-stage HER2-positive breast cancer, age was not strongly associated with risk of early recurrence or prediction of benefit from trastuzumab therapy. Future research should investigate whether age is a predictor of later recurrence and evaluate the impact of age within groups with other tumor subtypes.

Metzger-Filho O.,Dana-Farber Cancer Institute
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

To evaluate the benefit of adjuvant trastuzumab in patients diagnosed with human epidermal growth factor receptor 2 (HER2) -positive invasive lobular carcinoma (ILC) enrolled onto the Herceptin Adjuvant (HERA) trial. Patients randomly assigned to receive one year of trastuzumab and one year of observation in the HERA trial were included (n = 3,401). Centrally reviewed estrogen receptor (ER), progesterone receptor (PgR), and HER2 copy numbers were used. First site-specific relapse pattern was evaluated for ILC and invasive ductal carcinoma (IDC). The magnitude of trastuzumab benefit was assessed using the Cox proportional hazards model for disease-free survival (DFS) and overall survival (OS). Median follow-up time was 4 years. A total of 187 ILC and 3,213 IDC patients were included. High Allred scores (6 to 8) were more common in patients with ILC than IDC for both ER (36.9% v 22.7%) and PgR (44.1% v 28.5%). A trend toward decreased HER2 copy number was observed in the ILC group. The ILC and IDC subgroups had similar patterns of first site of disease relapse. DFS hazard ratios (HRs) comparing 1 year of trastuzumab versus observation were 0.63 for ILC (95% CI, 0.34 to 1.15) and 0.77 for IDC (95% CI, 0.67 to 0.89; P for interaction = .49). The OS HRs comparing 1 year of trastuzumab versus observation were 0.60 for ILC (95% CI, 0.27 to 1.31) and 0.86 for IDC (95% CI, 0.71 to 1.06; P for interaction = .29). In this retrospective analysis, there was no suggestion that patients in the ILC cohort experienced a different magnitude of benefit from adjuvant trastuzumab than those in the IDC cohort.

OBJECTIVE:: The primary aim of this trial was to assess the feasibility of minimally invasive esophagectomy (MIE) in a multi-institutional setting.BACKGROUND:: Esophagectomy is an important, potentially curative treatment for localized esophageal cancer, but is a complex operation. MIE may decrease the morbidity and mortality of resection, and single-institution studies have demonstrated successful outcomes with MIE.METHODS:: We conducted a multicenter, phase II, prospective, cooperative group study (coordinated by the Eastern Cooperative Oncology Group) to evaluate the feasibility of MIE. Patients with biopsy-proven high-grade dysplasia or esophageal cancer were enrolled at 17 credentialed sites. Protocol surgery consisted of either 3-stage MIE or Ivor Lewis MIE. The primary end point was 30-day mortality. Secondary end points included adverse events, duration of hospital-stay, and 3-year outcomes.RESULTS:: Protocol surgery was completed in 95 of the 104 patients eligible for the primary analysis (91.3%). The 30-day mortality in eligible patients who underwent MIE was 2.1%; perioperative mortality in all registered patients eligible for primary analysis was 2.9%. Median intensive care unit and hospital stay were 2 and 9 days, respectively. Grade 3 or higher adverse events included anastomotic leak (8.6%), acute respiratory distress syndrome (5.7%), pneumonitis (3.8%), and atrial fibrillation (2.9%). At a median follow-up of 35.8 months, the estimated 3-year overall survival was 58.4% (95% confidence interval: 47.7%–67.6%). Locoregional recurrence occurred in only 7 patients (6.7%).CONCLUSIONS:: This prospective multicenter study demonstrated that MIE is feasible and safe with low perioperative morbidity and mortality and good oncological results. This approach can be adopted by other centers with appropriate expertise in open esophagectomy and minimally invasive surgery. © 2015 by Lippincott Williams & Wilkins.

Ni M.,University of Southern California | Ni M.,Dana-Farber Cancer Institute | Zhang Y.,University of Southern California | Lee A.S.,University of Southern California
Biochemical Journal | Year: 2011

GRP78 (glucose-regulated protein of 78 kDa) is traditionally regarded as a major ER (endoplasmic reticulum) chaperone facilitating protein folding and assembly, protein quality control, Ca2+ binding and regulating ER stress signalling. It is a potent anti-apoptotic protein and plays a critical role in tumour cell survival, tumour progression and angiogenesis, metastasis and resistance to therapy. Recent evidence shows that GRP78 can also exist outside the ER. The finding that GRP78 is present on the surface of cancer but not normal cells in vivo represents a paradigm shift on how GRP78 controls cell homoeostasis and provides an opportunity for cancer-specific targeting. Cell-surface GRP78 has emerged as an important regulator of tumour cell signalling and viability as it forms complexes with a rapidly expanding repertoire of cell-surface protein partners, regulating proliferation, PI3K (phosphoinositide 3-kinase)/Akt signalling and cell viability. Evidence is also emerging that GRP78 serves as a receptor for viral entry into host cells. Additionally, a novel cytosolic form of GRP78 has been discovered prominently in leukaemia cells. These, coupled with reports of nucleus- and mitochondria-localized forms of GRP78, point to the previously unanticipated role of GRP78 beyond the ER that may be critical for cell viability and therapeutic targeting. © The Authors Journal compilation © 2011 Biochemical Society.

Sheng Q.,Novartis | Liu J.,Dana-Farber Cancer Institute
British Journal of Cancer | Year: 2011

The epithelial growth factor receptor (EGFR) family of receptor tyrosine kinases has been reported to have an active role in a number of malignancies. Amplifications and overexpression of various EGFR family members, including EGFR, Her2, and ErbB3, have been reported in epithelial ovarian cancer. Although anti-EGFR-targeted therapy has shown limited clinical activity in ovarian cancer to date, a recent report suggests that activation of ErbB3, one of the members of the EGFR family, may support the growth and proliferation of ovarian cancer cells and that ErbB3 may therefore serve as a potential therapeutic target in this disease. Here, we review the EGFR family and the clinical experience with anti-EGFR family member-directed therapies in ovarian cancer to date. © 2011 Cancer Research UK All rights reserved.

Vander Heiden M.G.,Massachusetts Institute of Technology | Vander Heiden M.G.,Dana-Farber Cancer Institute
Journal of Clinical Investigation | Year: 2013

The metabolism of cancer cells differs from most normal cells, but how to exploit this difference for patient benefit is incompletely understood. Cancer cells require altered metabolism to efficiently incorporate nutrients into biomass and support abnormal proliferation. In addition, the survival of tumor cells outside of a normal tissue context requires adaptation of metabolism to different microenvironments. Some existing chemotherapies target metabolic enzymes, and there is a resurgent interest in developing new cancer drugs that interfere with metabolism. Success with this approach depends on understanding why specific metabolic pathways are important for cancer cells, determining how best to select patients, and developing technologies for monitoring patient response to therapies that target metabolic enzymes. The articles in this Review series address these issues, with a focus on how altered metabolism might influence tumor progression and how this knowledge might inform the use of new therapies targeting cancer metabolism. Emerging biomarker strategies to guide drug development are also highlighted.

Deangelo D.J.,Dana-Farber Cancer Institute
Blood Cancer Journal | Year: 2012

The outcomes for patients with chronic myeloid leukemia have improved dramatically with the development and availability of BCR-ABL1 tyrosine kinase inhibitors (TKIs) over the past decade. TKI therapy has a superior safety profile compared with the previous standard of care, interferon-a, and most adverse events (AEs) observed with front-line and second-line TKI treatment are managed with supportive care. However, some patients are intolerant to TKI therapy and experience AEs that cannot be managed through dose reduction or symptomatic treatment. Careful management of AEs helps patients to remain adherent with treatment and increases their chances for successful outcomes. Proactive vigilance for potential AEs and treatment strategies that reduce symptom burden will help to minimize patient intolerance. This review discusses the most common AEs associated with intolerance to TKI therapy and treatment strategies to help manage patients at risk for or experiencing these events. © 2012 Macmillan Publishers Limited All rights reserved.

Joffe S.,Dana-Farber Cancer Institute | Miller F.G.,U.S. National Institutes of Health
Nature Reviews Clinical Oncology | Year: 2012

Randomized controlled trials (RCTs) are central to evidence-based clinical and health-policy decisions. However, RCTs highlight the tension between the therapeutic obligations of the physician and the scientific obligations of the investigator. Clinical equipoise, defined as honest professional disagreement among expert clinicians about the preferred treatment, is often cited as the solution to this RCT dilemma. Nevertheless, there are numerous practical and conceptual problems with the notion of equipoise. These problems include its mistaken imposition of therapeutic norms on the scientific enterprise of research, the difficulty of knowing when a state of equipoise exists, the susceptibility of expert judgment to bias and weak evidence, and its inability to support evidence necessary for health-policy decisions. An alternate approach to risk - benefit assessment that is congruent with the scientific purpose of RCTs can better guide ethical evaluation of these trials, as discussed in this Perspective. © 2012 Macmillan Publishers Limited. All rights reserved.

Taylor B.S.,Sloan Kettering Cancer Center | Taylor B.S.,University of California at San Francisco | Barretina J.,Dana-Farber Cancer Institute | Barretina J.,Cambridge Broad Institute | And 4 more authors.
Nature Reviews Cancer | Year: 2011

Increasingly, human mesenchymal malignancies are being classified by the abnormalities that drive their pathogenesis. Although many of these aberrations are highly prevalent within particular sarcoma subtypes, few are currently targeted therapeutically. Indeed, most subtypes of sarcoma are still treated with traditional therapeutic modalities, and in many cases sarcomas are resistant to adjuvant therapies. In this Review, we discuss the core molecular determinants of sarcomagenesis and emphasize the emerging genomic and functional genetic approaches that, coupled with novel therapeutic strategies, have the potential to transform the care of patients with sarcoma. © 2011 Macmillan Publishers Limited. All rights reserved.

The anti-CD38 monoclonal antibody SAR650984 (SAR) is showing promising clinical activity in treatment of relapsed and refractory multiple myeloma (MM). Besides effector-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, we here define molecular mechanisms of SAR-directed MM cell death and enhanced anti-MM activity triggered by SAR with Pomalidomide (Pom). Without Fc-cross-linking agents or effector cells, SAR specifically induces homotypic aggregation (HA)-associated cell death in MM cells dependent on the level of cell surface CD38 expression, actin cytoskeleton and membrane lipid raft. SAR and its F(ab)’2 fragments trigger caspase 3/7-dependent apoptosis in MM cells highly expressing CD38, even with p53 mutation. Importantly, SAR specifically induces lysosome-dependent cell death (LCD) by enlarging lysosomes and increasing lysosomal membrane permeabilization associated with leakage of cathepsin B and LAMP-1, regardless of the presence of interleukin-6 or bone marrow stromal cells. Conversely, the lysosomal vacuolar H+-ATPase inhibitor blocks SAR-induced LCD. SAR further upregulates reactive oxygen species. Pom enhances SAR-induced direct and indirect killing even in MM cells resistant to Pom/Len. Taken together, SAR is the first therapeutic monoclonal antibody mediating direct cytotoxicity against MM cells via multiple mechanisms of action. Our data show that Pom augments both direct and effector cell-mediated MM cytotoxicity of SAR, providing the framework for combination clinical trials.Leukemia advance online publication, 25 September 2015; doi:10.1038/leu.2015.240. © 2015 Macmillan Publishers Limited

Wang X.V.,Dana-Farber Cancer Institute
BMC bioinformatics | Year: 2012

Short-read data from next-generation sequencing technologies are now being generated across a range of research projects. The fidelity of this data can be affected by several factors and it is important to have simple and reliable approaches for monitoring it at the level of individual experiments. We developed a fast, scalable and accurate approach to estimating error rates in short reads, which has the added advantage of not requiring a reference genome. We build on the fundamental observation that there is a linear relationship between the copy number for a given read and the number of erroneous reads that differ from the read of interest by one or two bases. The slope of this relationship can be transformed to give an estimate of the error rate, both by read and by position. We present simulation studies as well as analyses of real data sets illustrating the precision and accuracy of this method, and we show that it is more accurate than alternatives that count the difference between the sample of interest and a reference genome. We show how this methodology led to the detection of mutations in the genome of the PhiX strain used for calibration of Illumina data. The proposed method is implemented in an R package, which can be downloaded from http://bcb.dfci.harvard.edu/∼vwang/shadowRegression.html. The proposed method can be used to monitor the quality of sequencing pipelines at the level of individual experiments without the use of reference genomes. Furthermore, having an estimate of the error rates gives one the opportunity to improve analyses and inferences in many applications of next-generation sequencing data.

Horwitz S.M.,Sloan Kettering Cancer Center | Advani R.H.,Stanford University | Bartlett N.L.,University of Washington | Jacobsen E.D.,Dana-Farber Cancer Institute | And 5 more authors.
Blood | Year: 2014

This phase 2, open-label, multicenter study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, in relapsed/refractory CD30+ non-Hodgkin lymphomas. The primary end point was objective response rate (ORR). Key secondary end points included safety, correlation of CD30 expression with response, response duration, and progression-free survival (PFS). Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks until progression or unacceptable toxicity. This planned subset analysis included patients with peripheral T-cell lymphomas (PTCLs; n = 35), specifically angioimmunoblastic T-cell lymphoma (AITL;E = 13) and PTCL not otherwise specified (n = 22). Median age was 64 years; 63% were refractory to most recent therapy. Of 34 evaluable patients, ORR was 41% (8 complete remissions [CRs], 6 partial remissions [PRs]), and ORR was 54% in AITL (5 CRs, 2 PRs) with median PFS of 6.7 months thus far. No correlation between CD30 expression per central review and response was observed. Safety data were consistent with the known profile of brentuximab vedotin, and included at least grade 3 events of neutropenia (14%), peripheral sensory neuropathy, and hyperkalemia (9% each). In summary, brentuximab vedotin showed antitumor activity in patients with relapsed PTCL particularly AITL. © 2014 by The American Society of Hematology.

Human breast cancers that have HER2 amplification/overexpression frequently carry PIK3CA mutations, and are often associated with a worse prognosis. However, the role of PIK3CA mutations in the initiation and maintenance of these breast cancers remains elusive. In the present study, we generated a compound mouse model that genetically mimics HER2-positive breast cancer with coexisting PIK3CAH1047R. Induction of PIK3CAH1047R expression in mouse mammary glands with constitutive expression of activated Her2/Neu resulted in accelerated mammary tumorigenesis with enhanced metastatic potential. Interestingly, inducible expression of mutant PIK3CA resulted in a robust activation of phosphatidylinositol-3-kinase (PI3K)/AKT signaling but attenuation of Her2/Her3 signaling, and this can be reversed by deinduction of PIK3CAH1047R expression. Strikingly, although these Her2+ PIK3CAH1047R-initiated primary mammary tumors are refractory to HER2-targeted therapy, all tumors responded to inactivation of the oncogenic PIK3CAH1047R, a situation closely mimicking the use of a highly effective inhibitor specifically targeting the mutant PIK3CA/p110a. Notably, these tumors eventually resumed growth, and a fraction of them escaped PI3K dependence by compensatory ERK activation, which can be blocked by combined inhibition of Her2 and MEK. Together, these results suggest that PIK3CA-specific inhibition as a monotherapy followed by combination therapy targeting MAPK and HER2 in a timely manner may be an effective treatment approach against HER2-positive cancers with coexisting PIK3CA-activating mutations.Oncogene advance online publication, 7 December 2015; doi:10.1038/onc.2015.377. © 2015 Macmillan Publishers Limited

Halperin D.M.,University of Houston | Kulke M.H.,Dana-Farber Cancer Institute | Yao J.C.,University of Houston
Annual Review of Medicine | Year: 2015

Despite their perceived rarity, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rising in incidence and prevalence. The biology, natural history, and therapeutic options for GEP-NETs are heterogeneous: NETs arising in the pancreas can be distinguished from those arising elsewhere in the gastrointestinal tract, and therapy is dichotomized between these two groups. Somatostatin analogues are the mainstay of oncologic management of bowel NETs; everolimus, streptozocin, and sunitinib are approved to treat pancreatic NETs. There are significant differences in molecular genetics between pancreatic and extrapancreatic NETs, and studies are evaluating whether additional NET patients may benefit from targeted agents. We discuss the distinguishing features of these two groups of tumors, as well as the therapeutic implications of the distinction. We also examine the evolving therapeutic landscape and discuss the likelihood that treatment will be developed independently for pancreatic and extrapancreatic gastrointestinal NETs, with novel therapeutics effective for newly identified pathologically or molecularly defined subgroups. © 2015 by Annual Reviews.

Robert C.,CNRS Gustave Roussy Institute | Schadendorf D.,University of Duisburg - Essen | Messina M.,Bristol Myers Squibb | Hodi F.S.,Dana-Farber Cancer Institute | O'Day S.,Beverly Hills Cancer Center
Clinical Cancer Research | Year: 2013

Purpose: Ipilimumab is a fully human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) that has been shown to improve survival in patients with pretreated, advanced melanoma in a phase III trial. Some patients in this study who initially responded to ipilimumab treatment but later progressed were eligible for retreatment with their original randomized regimen. Here, outcomes for these patients concerning baseline characteristics, best overall response, and disease control rate are assessed and considered with respect to the overall study population. Experimental Design: In the phase III study, 676 pretreated patients were randomly allocated to treatment with ipilimumab 3 mg/kg plus gp100 vaccine, ipilimumab 3 mg/kg plus placebo, or gp100 vaccine alone. Of these patients, 32 had a partial or complete objective response or stable disease after treatment and met the eligibility criteria for retreatment, although a total of 40 patients were retreated. Results: Best overall response rates (complete responses plus partial responses) for 31 retreatmenteligible patients in the ipilimumab plus gp100 and ipilimumab plus placebo groups were 3 of 23 (13.0%) and 3 of 8 (37.5%), respectively, and disease control rates were 65.2% and 75.0%. No new types of toxicities occurred during retreatment and most events were mild-to-moderate. Conclusion: Ipilimumab provided durable objective responses and/or stable disease in qualifying patients who received retreatment upon disease progression with a similar toxicity profile to that seen during their original treatment regimen. ©2013 AACR.

Weber J.S.,H. Lee Moffitt Cancer Center and Research Institute | Dummer R.,University of Zurich | De Pril V.,Bristol Myers Squibb | Lebbe C.,Paris Public Assistance Hospital System | Hodi F.S.,Dana-Farber Cancer Institute
Cancer | Year: 2013

BACKGROUND: Ipilimumab 3 mg/kg was the first agent to demonstrate improved survival in previously treated patients with metastatic melanoma in a phase 3 trial (MDX010-20). Ipilimumab produced a characteristic spectrum of immune-related adverse events (irAEs) of special interest, consistent with its immune-based mechanism of action. METHODS: In MDX010-20, 676 previously treated patients were randomized 3:1:1 to receive ipilimumab 3 mg/kg plus the glycoprotein 100 melanoma antigen vaccine (gp100), ipilimumab 3 mg/kg + placebo, or gp100 vaccine + placebo. For the current report, the authors conducted a detailed analysis of the time to onset and resolution of irAEs associated with ipilimumab therapy. RESULTS: Grade 2 through 5 irAEs generally developed during the induction phase of treatment (0-12 weeks). Most, including grade 3/4 irAEs, were reversible when managed with treatment guidelines using vigilant monitoring and corticosteroids. The median time to resolution (to grade 1 or 0 or to the grade at baseline) of irAEs that had an onset during the induction phase was approximately 6 weeks for grade 2 through 4 irAEs and 8 weeks for grade 3 and 4 irAEs. Across the entire study duration, most grade 2 through 4 irAEs resolved within 12 weeks. CONCLUSIONS: Most ipilimumab-associated irAEs, including grade 3/4 symptoms, developed within 12 weeks of initial dosing and resolved within 12 weeks of onset. IrAEs were well characterized in their evolution and could be managed using published algorithms. Copyright © 2013 American Cancer Society.

Higuchi L.M.,Childrens Hospital | Huang E.S.,Massachusetts General Hospital | Khalili H.,Massachusetts General Hospital | Richter J.M.,Fruit Street Health | And 2 more authors.
Annals of Internal Medicine | Year: 2012

Background: Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are anti-inflammatory but have been linked in some studies to Crohn disease (CD) and ulcerative colitis (UC).Objective: To assess the association between aspirin and NSAID use and incident CD and UC.Design: Prospective cohort study.Setting: Nurses' Health Study I.Patients: 76 795 U.S. women who provided biennially updated data about aspirin and NSAID use.Measurements: Incident CD and UC between 1990 and 2008 (outcome) and NSAID and aspirin use (exposure).Results: 123 incident cases of CD and 117 cases of UC occurred over 18 years and 1 295 317 person-years of follow-up. Compared with nonusers, women who used NSAIDs at least 15 days per month seemed to have increased risk for both CD (absolute difference in age-adjusted incidence, 6 cases per 100 000 person-years [95% CI, 0 to 13]; multivariate hazard ratio, 1.59 [CI, 0.99 to2.56]) and UC (absolute difference, 7 cases per 100 000 person-years [CI, 1 to 12]; multivariate hazard ratio, 1.87 [CI, 1.16 to 2.99]). Less frequent NSAID use was not clearly associated with risk for CD or UC, and there was no clear association between aspirin use and disease.Limitations: Cohort participants were exclusively women, most of whom were white. Aspirin and NSAID use were self-reported.Conclusion: Frequent use of NSAIDs but not aspirin seemed to be associated with increased absolute incidence of CD and UC. The findings have more mechanistic than clinical implications, because the absolute incidence of CD or UC associated with NSAIDs was low and the increase in risk for CD or UC associated with NSAIDs is unlikely to alter the balance of more common and clinically significant risks and benefits associated with these agents. © 2012 American College of Physicians.

Oxnard G.R.,Dana-Farber Cancer Institute | Arcila M.E.,Sloan Kettering Cancer Center | Chmielecki J.,Sloan Kettering Cancer Center | Ladanyi M.,Sloan Kettering Cancer Center | And 2 more authors.
Clinical Cancer Research | Year: 2011

The management of non-small cell lung carcinoma (NSCLC) has been transformed by the observation that lung adenocarcinomas harboring mutations in epidermal growth factor receptor (EGFR) are uniquely sensitive to EGFR tyrosine kinase inhibitors (TKI). In these patients, acquired resistance to EGFR-TKI develops after a median of 10 to 14 months, at which time the current standard practice is to switch to conventional cytotoxic chemotherapy. Several possible mechanisms for acquired resistance have been identified, the most common being the development of an EGFR T790M gatekeeper mutation in more than 50% of cases. In this review, we discuss recent advances in the understanding of acquired TKI resistance in EGFR-mutant lung cancer and review therapeutic progress with second generation TKIs and combinations of targeted therapies. ©2011 AACR.

Ponte P.R.,Dana-Farber Cancer Institute
Annual review of nursing research | Year: 2010

Interdisciplinary collaboration is critical to excellence in patient care delivery. There is a growing consensus that the basic education for all clinical professionals should include the knowledge, skills, and attitudes required to effectively participate in interdisciplinary teams, and that health care organizations should continue this education in the practice setting. The authors examine the large and growing evidence base regarding interdisciplinary collaboration and teamwork and explore the relationship between interdisciplinary collaboration and patient, workforce, and organizational outcomes. Antecedents and attributes of the construct are presented, as well as structures, models, and programs that are being implemented by health care organizations and academic settings to facilitate and advance interdisciplinary collaboration in clinical practice.

Wong J.R.,U.S. National Cancer Institute | Harris J.K.,Washington University in St. Louis | Rodriguez-Galindo C.,Dana-Farber Cancer Institute | Johnson K.J.,Washington University in St. Louis
Pediatrics | Year: 2013

OBJECTIVE: Childhood and adolescent melanoma is rare but has been increasing. To gain insight into possible reasons underlying this observation, we analyzed trends in melanoma incidence diagnosed between the ages of 0 and 19 years among US whites by gender, stage, age at diagnosis, and primary site. We also investigated incidence trends by UV-B exposure levels. METHODS: By using Surveillance, Epidemiology, and End Results (SEER) program data (1973-2009), we calculated age-adjusted incidence rates (IRs), annual percent changes, and 95% confidence intervals for each category of interest. Incidence trends were also evaluated by using joinpoint and local regression models. SEER registries were categorized with respect to low or high UV-B radiation exposure. RESULTS: From 1973 through 2009, 1230 children of white race were diagnosed with malignant melanoma. Overall, pediatric melanoma increased by an average of 2% per year (95% confidence interval, 1.4%-2.7%). Girls, 15- to 19-year-olds, and individuals with low UV-B exposure had significantly higher IRs than boys, younger children, and those living in SEER registries categorized as high UV-B. Over the study period, boys experienced increased IRs for melanoma on the face and trunk, and females on the lower limbs and hip. The only decreased incidence trend we observed was among 15- to 19-year-olds in the high UV-B exposure group from 1985 through 2009. Local regression curves indicated similar patterns. CONCLUSIONS: These results may help elucidate possible risk factors for adolescent melanoma, but additional individual-level studies will be necessary to determine the reasons for increasing incidence trends. Copyright © 2013 by the American Academy of Pediatrics.

The term monoclonal gammopathy of undetermined significance (MGUS) was coined in 1978. The recent advances in our knowledge about MGUS and smoldering multiple myeloma (SMM) have helped us better understand the pathogenesis of myeloma. It seems that myeloma evolves from a precursor state in almost all cases. We do not completely understand the multistep process from the precursor state to myeloma, but studies like whole genome sequencing continue to improve our understanding of this process. The process of transformation may not be linear acquisition of changes, but rather a branched heterogeneous process. Clinical features that are prognostic of rapid transformation have been identified, but no specific molecular markers have been identified. Even with recent advances, multiple myeloma remains an incurable disease in the vast majority, and intervening at the precursor state provides a unique opportunity to alter the natural history of the disease. A limitation is that a vast majority of patients with precursor disease, especially low-risk MGUS, will never progress to myeloma in their lifetime, and treating these patients is not only unnecessary but may be potentially harmful. The challenge is to identify a subset of patients with the precursor state that would definitely progress to myeloma and in whom interventions will have a meaningful impact. As our understanding of the molecular and genetic processes improves, these studies will guide the selection of high-risk patients more appropriately and ultimately direct a tailored management strategy to either delay progression to symptomatic myeloma or even "cure" a person at this premalignant stage. © 2012 American Association for Cancer Research.

Mucin 1 (MUC1) is a heterodimeric protein formed by two subunits that is aberrantly overexpressed in human breast cancer and other cancers. Historically, much of the early work on MUC1 focused on the shed mucin subunit. However, more recent studies have been directed at the transmembrane MUC1-C-terminal subunit (MUC1-C) that functions as an oncoprotein. MUC1-C interacts with EGFR (epidermal growth factor receptor), ErbB2 and other receptor tyrosine kinases at the cell membrane and contributes to activation of the PI3K AKT and mitogen-activated protein kinase kinase (MEK) extracellular signal-regulated kinase (ERK) pathways. MUC1-C also localizes to the nucleus where it activates the Wnt/β-catenin, signal transducer and activator of transcription (STAT) and NF (nuclear factor)-κB RelA pathways. These findings and the demonstration that MUC1-C is a druggable target have provided the experimental basis for designing agents that block MUC1-C function. Notably, inhibitors of the MUC1-C subunit have been developed that directly block its oncogenic function and induce death of breast cancer cells in vitro and in xenograft models. On the basis of these findings, a first-in-class MUC1-C inhibitor has entered phase I evaluation as a potential agent for the treatment of patients with breast cancers who express this oncoprotein. © 2013 Macmillan Publishers Limited All rights reserved.

Tracy M.S.,Dana-Farber Cancer Institute
Breast cancer research and treatment | Year: 2013

Recent studies have revealed increasing rates of contralateral prophylactic mastectomy (CPM) among women with unilateral early stage breast cancer. This trend has raised concerns, given the lack of evidence for a survival benefit from CPM and the relatively low risk of contralateral breast cancer for most women in this setting. In this article, we review available data regarding the value of CPM, predictors, and outcomes related to CPM, and areas for future research and potential intervention.

Godinho S.A.,Queen Mary, University of London | Pellman D.,Dana-Farber Cancer Institute
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

Centrosome amplification is a hallmark of cancer. However, despite significant progress in recent years, we are still far from understanding how centrosome amplification affects tumorigenesis. Boveri's hypothesis formulated more than 100 years ago was that aneuploidy induced by centrosome amplification promoted tumorigenesis. Although the hypothesis remains appealing 100 years later, it is also clear that the role of centrosome amplification in cancer is more complex than initially thought. Here, we review how centrosome abnormalities are generated in cancer and the mechanisms cells employ to adapt to centrosome amplification, in particular centrosome clustering. We discuss the different mechanisms by which centrosome amplification could contribute to tumour progression and the new advances in the development of therapies that target cells with extra centrosomes. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Stegh A.H.,Northwestern University | DePinho R.A.,Dana-Farber Cancer Institute
Cell Cycle | Year: 2011

Malignant gliomas are the most common and lethal primary central nervous system cancer. Glioblastoma mutliforme (GBM), the most aggressive of these neoplasms, are generally lethal within two years of diagnosis due in part to the intense apoptosis resistance of its cancer cells, hence poor therapeutic response to conventional and targeted therapies. Twenty years of research has uncovered key genetic events involved in disease initiation and progression, foremost the Tp53 tumor suppressor that is mutated or deleted in 35% of GBM. The prime importance of p53 signaling for gliomapathogenesis is further evidenced by epistatic genetic events targeting additional pathway components including deletion of p14Arf (CDKN2A) and amplification of the p53-degrading ubiquitin ligases MDM2 and MDM4. Recent studies have identified and validated Bcl2-Like 12 (Bcl2L12) as a potent glioma oncoprotein with multiple strategic points in apoptosis regulatory networks, i.e. effector caspases and the p53 tumor suppressor. Bcl2L12 resides in both the cytoplasm and nucleus. In the cytoplasm, Bcl2L12 functions to inhibit caspases 3 and 7, in the nucleus, Bcl2L12 forms a complex with p53, modestly reduces p53 protein stability and prevents its binding to selected target gene promoters (e.g. p21, DR5, Noxa and PUMA), thereby inhibiting p53-directed transcriptomic changes upon DNA damage. Proteomic and multidimensional oncogenomic analyses confirmed a Bcl2L12-p53 signaling axis in GBM, as Bcl2L12 exhibited predominant genomic amplification, elevated mRNA and protein levels in GBM tumors with uncompromised p53 function. On the cell biological level, Bcl2L12 exerts robust inhibition of p53-dependent senescence and apoptosis processes in glioma cells. These multi-leveled studies establish Bcl2L12 as an important oncoprotein acting at the intersection of nuclear p53 and cytoplasmic caspase signaling and point to pharmacological disruption of the Bcl2L12:p53 complex as a promising novel therapeutic strategy for the enhanced treatment of GBM. © 2011 Landes Bioscience.

Huang H.T.,Dana-Farber Cancer Institute
Nature cell biology | Year: 2013

The initiation of cellular programs is orchestrated by key transcription factors and chromatin regulators that activate or inhibit target gene expression. To generate a compendium of chromatin factors that establish the epigenetic code during developmental haematopoiesis, a large-scale reverse genetic screen was conducted targeting orthologues of 425 human chromatin factors in zebrafish. A set of chromatin regulators was identified that target different stages of primitive and definitive blood formation, including factors not previously implicated in haematopoiesis. We identified 15 factors that regulate development of primitive erythroid progenitors and 29 factors that regulate development of definitive haematopoietic stem and progenitor cells. These chromatin factors are associated with SWI/SNF and ISWI chromatin remodelling, SET1 methyltransferase, CBP-p300-HBO1-NuA4 acetyltransferase, HDAC-NuRD deacetylase, and Polycomb repressive complexes. Our work provides a comprehensive view of how specific chromatin factors and their associated complexes play a major role in the establishment of haematopoietic cells in vivo.

Pelluru D.,Dana-Farber Cancer Institute
Leukemia | Year: 2015

We have previously demonstrated that interleukin-17A (IL-17) producing T helper 17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and the absence of BM stromal cells (BMSCs). Although IL-17A induces IL-6 production, AIN457 significantly downregulated IL-6 production and MM cell adhesion in MM–BMSC co-culture. AIN457 also significantly inhibited osteoclast cell differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared with isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report, here, that MM cells express IL-17A. We also observed that IL-17A knockdown inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.Leukemia advance online publication, 18 September 2015; doi:10.1038/leu.2015.228. © 2015 Macmillan Publishers Limited

Michor F.,Dana-Farber Cancer Institute | Liphardt J.,University of California at Berkeley | Ferrari M.,Methodist Hospital Research Institute | Widom J.,Northwestern University
Nature Reviews Cancer | Year: 2011

Large-scale cancer genomics, proteomics and RNA-sequencing efforts are currently mapping in fine detail the genetic and biochemical alterations that occur in cancer. However, it is becoming clear that it is difficult to integrate and interpret these data and to translate them into treatments. This difficulty is compounded by the recognition that cancer cells evolve, and that initiation, progression and metastasis are influenced by a wide variety of factors. To help tackle this challenge, the US National Cancer Institute Physical Sciences-Oncology Centers initiative is bringing together physicists, cancer biologists, chemists, mathematicians and engineers. How are we beginning to address cancer from the perspective of the physical sciences? © 2011 Macmillan Publishers Limited. All rights reserved.

Schneider K.A.,Dana-Farber Cancer Institute
Counseling About Cancer: Strategies for Genetic Counseling | Year: 2011

Important scientific discoveries and ever-changing guidelines for how to identify and manage patients with hereditary cancer syndromes are constantly evolving. This Third Edition of Counseling About Cancer is completely updated and expanded to feature five entirely new chapters on breast cancer, colon cancer, other solid tumors, clients and families, and genetic test results and follow-up. This is the only reference and clinical book on the market for cancer genetics counselors and other healthcare providers who must quickly assimilate complex and ever-changing data on the hereditary risk for cancer. © 2012 Wiley-Blackwell.

De S.,Dana-Farber Cancer Institute
Trends in Genetics | Year: 2011

From the fertilization of an egg until the death of an individual, somatic cells can accumulate genetic changes, such that cells from different tissues or even within the same tissue differ genetically. The presence of multiple cell clones with distinct genotypes in the same individual is referred to as 'somatic mosaicism'. Many endogenous factors such as mobile elements, DNA polymerase slippage, DNA double-strand break, inefficient DNA repair, unbalanced chromosomal segregation and some exogenous factors such as nicotine and UV exposure can contribute to the generation of somatic mutations, thereby leading to somatic mosaicism. Such changes can potentially affect the epigenetic patterns and levels of gene expression, and ultimately the phenotypes of cells. Although recent studies suggest that somatic mosaicism is widespread during normal development and aging, its implications for heightened disease risks are incompletely understood. Here, I discuss the origins, prevalence and implications of somatic mosaicism in healthy human tissues. © 2011.

Selmecki A.,Dana-Farber Cancer Institute | Forche A.,Bowdoin College | Berman J.,University of Minnesota
Eukaryotic Cell | Year: 2010

The genomic plasticity of Candida albicans, a commensal and common opportunistic fungal pathogen, continues to reveal unexpected surprises. Once thought to be asexual, we now know that the organism can generate genetic diversity through several mechanisms, including mating between cells of the opposite or of the same mating type and by a parasexual reduction in chromosome number that can be accompanied by recombination events (2, 12, 14, 53, 77, 115). In addition, dramatic genome changes can appear quite rapidly in mitotic cells propagated in vitro as well as in vivo. The detection of aneuploidy in other fungal pathogens isolated directly from patients (145) and from environmental samples (71) suggests that variations in chromosome organization and copy number are a common mechanism used by pathogenic fungi to rapidly generate diversity in response to stressful growth conditions, including, but not limited to, antifungal drug exposure. Since cancer cells often become polyploid and/or aneuploid, some of the lessons learned from studies of genome plasticity in C. albicans may provide important insights into how these processes occur in higher-eukaryotic cells exposed to stresses such as anticancer drugs. © 2010, American Society for Microbiology.

Kaelin Jr. W.G.,Dana-Farber Cancer Institute
Science | Year: 2012

Realizing the full potential of si/shRNA technology requires more sophisticated approaches to address the pitfalls.

Stan D.,Mayo Medical School | Loprinzi C.L.,Mayo Medical School | Ruddy K.J.,Dana-Farber Cancer Institute
Hematology/Oncology Clinics of North America | Year: 2013

Survivors of breast cancer are confronted with a plethora of cancer treatment-related long-term symptoms, the most common being fatigue, hot flashes, sexual dysfunction, arthralgias, neuropathy, and cognitive dysfunction. Survivors of breast cancer also face cancer treatment-related disease states, such as osteoporosis, cardiac dysfunction, obesity, infertility, and secondary cancers. Evidence-based recommendations for screening, prevention, and early intervention should be implemented to improve quality of life and decrease comorbidities in this population. © 2013 Elsevier Inc.

Fircanis S.,The Miriam Hospital | Merriam P.,The Miriam Hospital | Khan N.,The Miriam Hospital | Castillo J.J.,Dana-Farber Cancer Institute
American Journal of Hematology | Year: 2014

Smoking has been postulated as an environmental risk factor for acute myeloid leukemia (AML). The primary objective of this meta-analysis of observational studies was to evaluate the epidemiologic relationship between smoking and the risk of development of AML. Twenty-three studies published between January 1993 and December 2013 were included in our analysis, and accounted for 7,746 cases of AML. The outcome of interest was the relative risk (RR) with 95% confidence interval (CI) of developing AML in adult cigarette smokers in comparison with non-smokers, and was estimated using the random-effects model. Our results showed that current and ever smokers have 40% (RR 1.40, 95% CI 1.22-1.60; P<0.001) and 25% (RR 1.25, 95% CI 1.15-1.36; P<0.001) increased risk of developing AML when compared with non-smokers. The increased RR of AML was increased regardless of sex, study design, geographical region, and quality of the studies. Intensity of smoking of <10, 10-20, 20-30, and >30 cigarettes per day was associated with RRs of AML of 1.27, 1.36, 1.55, and 1.77, respectively (P<0.001 for trend). Duration of smoking of <20 and >20 years was associated with RRs of 1.07 and 1.44, respectively (P<0.001 for trend). Cumulative smoking of <10, 10-20, 20-30, and >30 pack-years was associated with RRs of 1.13, 1.23, 1.39, and 1.71, respectively (P<0.001 for trend). Overall, cigarette smoking proves to be a significant risk factor for the development of AML in adults. Am. J. Hematol. 89:E125-E132, 2014. © 2014 Wiley Periodicals, Inc.

Kaufmann M.,Goethe University Frankfurt | Morrow M.,Sloan Kettering Cancer Center | Von Minckwitz G.,Goethe University Frankfurt | Harris J.R.,Dana-Farber Cancer Institute
Cancer | Year: 2010

Guidelines for the locoregional treatment of primary breast cancer were last published by the US National Institutes of Health in 1991. Since then, new surgical and radiotherapeutic techniques have been developed, clinical trials have provided new evidence, and intriguing long-term effects have emerged from global metadatabases. A revision of these guidelines is therefore necessary and timely. To address this concern, in October 2008, a group of opinion leaders from Austria, Denmark, France, Germany, Italy, the Netherlands, the United Kingdom, and the United States who have worked and published in the field of locoregional treatment met and collectively prepared and approved the described set of recommendations for the use of surgery and radiotherapy in primary breast cancer outside of clinical trials. © 2010 American Cancer Society.

BACKGROUND: The cellular and molecular programs that control specific types of pain are poorly understood. We reported previously that the runt domain transcription factor Runx1 is initially expressed in most nociceptors and controls sensory neuron phenotypes necessary for inflammatory and neuropathic pain. RESULTS: Here we show that expression of Runx1-dependent ion channels and receptors is distributed into two nociceptor populations that are distinguished by persistent or transient Runx1 expression. Conditional mutation of Runx1 at perinatal stages leads to preferential impairment of Runx1-persistent nociceptors and a selective defect in inflammatory pain. Conversely, constitutive Runx1 expression in Runx1-transient nociceptors leads to an impairment of Runx1-transient nociceptors and a selective deficit in neuropathic pain. Notably, the subdivision of Runx1-persistent and Runx1-transient nociceptors does not follow the classical nociceptor subdivision into IB4+ nonpeptidergic and IB4- peptidergic populations. CONCLUSION: Altogether, we have uncovered two distinct Runx1-dependent nociceptor differentiation programs that are permissive for inflammatory versus neuropathic pain. These studies lend support to a transcription factor-based distinction of neuronal classes necessary for inflammatory versus neuropathic pain.

Morina N.,University of Amsterdam | von Lersner U.,Humboldt University of Berlin | Prigerson H.G.,Dana-Farber Cancer Institute
PLoS ONE | Year: 2011

Background: Little is known about the long-term impact of the killing of a parent in childhood or adolescence during war on distress and disability in young adulthood. This study assessed current prevalence rates of mental disorders and levels of dysfunction among young adults who had lost their father due to war-related violence in childhood or adolescence. Methods: 179 bereaved young adults and 175 non-bereaved young adults were interviewed a decade after experiencing the war in Kosovo. Prevalence rates of Major Depressive Episode (MDE), anxiety, and substance use disorders, and current suicide risk were assessed using the Mini-International Neuropsychiatric Interview. The syndrome of Prolonged Grief Disorder (PGD) was assessed with the Prolonged Grief Disorder Interview (PG-13). Somatic symptoms were measured with the Patient Health Questionnaire. General health distress was assessed with the General Health Questionnaire. Findings: Bereaved participants were significantly more likely to suffer from either MDE or any anxiety disorder than non-bereaved participants (58.7% vs. 40%). Among bereaved participants, 39.7% met criteria for Post-Traumatic Stress Disorder, 34.6% for PGD, and 22.3% for MDE. Bereaved participants with PGD were more likely to suffer from MDE, any anxiety disorder, or current suicide risk than bereaved participants without PGD. Furthermore, these participants reported significantly greater physical distress than bereaved participants without PGD. Conclusion: War-related loss during middle childhood and adolescence presents significant risk for adverse mental health and dysfunction in young adulthood in addition to exposure to other war-related traumatic events. Furthermore, the syndrome of PGD can help to identify those with the greatest degree of distress and dysfunction. © 2011 Morina et al.

Gainor J.F.,Massachusetts General Hospital | Longo D.L.,Dana-Farber Cancer Institute | Chabner B.A.,Massachusetts General Hospital
Clinical Cancer Research | Year: 2014

In recent years, the clinical development of targeted therapies has been advanced by a greater understanding of tumor biology and genomics. Nonetheless, drug development remains a slow and costly process. An additional challenge is that targeted therapies may benefit only a subset of patients treated typically those patients whose tumors are dependent on the target of interest. Thus, there is a growing need for the incorporation of both predictive and pharmacodynamic (PD) biomarkers in drug development. Predictive biomarkers are important to help guide patient selection, while PD biomarkers can provide information on the pharmacologic effects of a drug on its target. PD studies may provide insights into proof of mechanism (i.e., Does the agent hit its intended target?) and proof of concept (i.e., Does hitting the drug target result in the desired biologic effect?). PD studies may also provide information on the optimal biologic dosing or scheduling of a targeted agent. Herein, we review PD endpoints in the context of targeted drug development in non-small cell lung cancer, highlighting some of the key challenges encountered to date. In doing so, we discuss recent experiences with repeat tumor biopsies, surrogate tissue analysis, alternative clinical trial designs (e.g., window-of-opportunity trials), circulating biomarkers, and mechanism-based toxicity assessments. The application of such technologies and biomarkers in early clinical trials may facilitate rational drug development, while enhancing our understanding of why certain targeted therapies succeed or fail. © 2014 American Association for Cancer Research.

Shannon K.M.,Massachusetts General Hospital | Chittenden A.,Dana-Farber Cancer Institute
Cancer Journal (United States) | Year: 2012

Women in the United States have a 12% lifetime risk of developing breast cancer. Although only about 5% to 10% of all cases of breast cancer are attributable to a highly penetrant cancer predisposition gene, individuals who carry a mutation in one of these genes have a significantly higher risk of developing breast cancer, as well as other cancers, over their lifetime compared with the general population. The ability to distinguish those individuals at high risk allows health care providers to intervene with appropriate counseling and education, surveillance, and prevention-with the overall goal of improved survival for these individuals. This article focuses on the identification of patients at high risk for breast cancer and provides an overview of the clinical features, cancer risks, causative genes, and medical management for the most clearly described hereditary breast cancer syndromes. Newer genes that have also been implicated in familial breast cancer are also briefly reviewed. Copyright © 2012 by Lippincott Williams & Wilkins.

Viswanathan A.N.,Dana-Farber Cancer Institute | Erickson B.A.,Medical College of Wisconsin
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: To determine current practice patterns with regard to three-dimensional (3D) imaging for gynecologic brachytherapy among American Brachytherapy Society (ABS) members. Methods and Materials: Registered physician members of the ABS received a 19-item survey by e-mail in August 2007. This report excludes physicians not performing brachytherapy for cervical cancer. Results: Of the 256 surveys sent, we report results for 133 respondents who perform one or more implantations per year for locally advanced cervical cancer. Ultrasound aids 56% of physicians with applicator insertion. After insertion, 70% of physicians routinely obtain a computed tomography (CT) scan. The majority (55%) use CT rather than X-ray films (43%) or magnetic resonance imaging (MRI; 2%) for dose specification to the cervix. However, 76% prescribe to Point A alone instead of using a 3D-derived tumor volume (14%), both Point A and tumor volume (7%), or mg/h (3%). Those using 3D imaging routinely contour the bladder and rectum (94%), sigmoid (45%), small bowel (38%), and/or urethra (8%) and calculate normal tissue dose-volume histogram (DVH) analysis parameters including the D2cc (49%), D1cc (36%), D0.1cc (19%), and/or D5cc (19%). Respondents most commonly modify the treatment plan based on International Commission on Radiation Units bladder and/or rectal point dose values (53%) compared with DVH values (45%) or both (2%). Conclusions: More ABS physician members use CT postimplantation imaging than plain films for visualizing the gynecologic brachytherapy apparatus. However, the majority prescribe to Point A rather than using 3D image based dosimetry. Use of 3D image-based treatment planning for gynecologic brachytherapy has the potential for significant growth in the United States. © 2010 Elsevier Inc. All rights reserved.

Nathan D.G.,Dana-Farber Cancer Institute
Transactions of the American Clinical and Climatological Association | Year: 2012

A humanized murine sickle cell-disease (SCD) model (NY1DD) has been used to study ischemia/reperfusion injury (IRI) in sickle cell anemia, and iNKT cells (a very small subset of murine and human T cells) have been found to instigate such injury in this model. Furthermore, levels of activated iNKT cells are generally elevated in the circulation of patients with SCD. Because activated iNKT cells are rich in adenosine A2A receptors which, when agonized, down-regulate the inflammatory cytokine expression that characterizes the cells, we have conducted a phase 1 trial of a constant infusion of low-dose regadenoson (an adenosine analogue with high A2A receptor specificity) to determine its safety and the capacity of a safe dose to down-regulate circulating iNKT cells in patients with SCD. We have found two dose rates that are both safe and effective and now plan a controlled Phase 2B clinical trial to determine whether our highest dose, administered as a 48-hour constant infusion, will induce faster remission in both painful vaso-occlusive crisis (pVOC) and acute chest syndrome (ACS).

Myeloid differentiation factor 88 (MYD88) L265P somatic mutation is highly prevalent in Waldenström macroglobulinemia (WM) and supports malignant growth through nuclear factor κB (NF-κB). The signaling cascade(s) by which MYD88 L265P promotes NF-κB activation in WM remain unclear. By lentiviral knockdown or use of a MYD88 inhibitor, decreased phosphorylation of the NF-κB gatekeeper IκBα and survival occurred in MYD88 L265P-expressing WM cells. Conversely, WM cells engineered to overexpress MYD88 L265P showed enhanced survival. Coimmunoprecipitation studies identified Bruton tyrosine kinase (BTK) complexed to MYD88 in L265P-expressing WM cells, with preferential binding of MYD88 to phosphorylated BTK (pBTK). Increased pBTK was also observed in WM cells transduced to overexpress L265P vs wild-type MYD88. Importantly, MYD88 binding to BTK was abrogated following treatment of MYD88 L265P-expressing cells with a BTK kinase inhibitor. Inhibition of BTK or interleukin-1 receptor-associated kinase 1 and 4 (IRAK-1 and -4) kinase activity induced apoptosis of WM cells, and their combination resulted in more robust inhibition of NF-κB signaling and synergistic WM cell killing. The results establish BTK as a downstream target of MYD88 L265P signaling, and provide a framework for the study of BTK inhibitors alone, and in combination with IRAK inhibitors for the treatment of WM.

Cagnetta A.,Dana-Farber Cancer Institute
Blood | Year: 2013

We recently demonstrated that Nicotinamide phosphoribosyltransferase (Nampt) inhibition depletes intracellular NAD+ content leading, to autophagic multiple myeloma (MM) cell death. Bortezomib has remarkably improved MM patient outcome, but dose-limiting toxicities and development of resistance limit its long-term utility. Here we observed higher Nampt messenger RNA levels in bortezomib-resistant patient MM cells, which correlated with decreased overall survival. We demonstrated that combining the NAD+ depleting agent FK866 with bortezomib induces synergistic anti-MM cell death and overcomes bortezomib resistance. This effect is associated with (1) activation of caspase-8, caspase-9, caspase-3, poly (ADP-ribose) polymerase, and downregulation of Mcl-1; (2) enhanced intracellular NAD+ depletion; (3) inhibition of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities; (4) inhibition of nuclear factor κB signaling; and (5) inhibition of angiogenesis. Furthermore, Nampt knockdown significantly enhances the anti-MM effect of bortezomib, which can be rescued by ectopically overexpressing Nampt. In a murine xenograft MM model, low-dose combination FK866 and Bortezomib is well tolerated, significantly inhibits tumor growth, and prolongs host survival. Taken together, these findings indicate that intracellular NAD+ level represents a major determinant in the ability of bortezomib to induce apoptosis in MM cells and provide proof of concept for the combination with FK866 as a new strategy to enhance sensitivity or overcome resistance to bortezomib.

Sher D.J.,Rush University Medical Center | Punglia R.S.,Dana-Farber Cancer Institute
Seminars in Radiation Oncology | Year: 2014

Although the analysis of real-world data is the foundation of comparative effectiveness analysis, not all clinical questions are easily approached with patient-derived information. Decision analysis is a set of modeling and analytic tools that simulate treatment and disease processes, including the incorporation of patient preferences, thus generating optimal treatment strategies for varying patient, disease, and treatment conditions. Although decision analysis is informed by evidence-derived outcomes, its ability to test treatment strategies under different conditions that are realistic but not necessarily reported in the literature makes it a useful and complementary technique to more standard data analysis. Similarly, cost-effectiveness analysis is a discipline in which the relative costs and benefits of treatment alternatives are rigorously compared. With the well-recognized increase in highly technical, costly radiation therapy technologies, the cost-effectiveness of these different treatments would come under progressively more scrutiny. In this review, we discuss the theoretical and practical aspects of decision analysis and cost-effectiveness analysis, providing examples that highlight their methodology and utility. © 2014 Elsevier Inc.

Chi D.L.,University of Washington | Tucker-Seeley R.,Dana-Farber Cancer Institute
American Journal of Public Health | Year: 2013

Objectives. We evaluated the relationship between financial hardship and self-reported oral health for older men and women. Methods. We focused on adults in the 2008 Health and Retirement Study (n = 1359). The predictor variables were 4 financial hardship indicators. We used Poisson regression models to estimate the prevalence ratio of poor self-reported oral health. Results. In the non-gender-stratified model, number of financial hardships was not significantly associated with self-reported oral health. Food insecurity was associated with a 12% greater prevalence of poor self-reported oral health (95% confidence interval [CI] = 1.04, 1.21). In the gender-stratified models, women with 3 or more financial hardships had a 24% greater prevalence of poor self-reported oral health than women with zero (95% CI = 1.09, 1.40). Number of hardships was not associated with self-reported oral health for men. For men, skipping medications was associated with 50% lower prevalence of poor self-reported oral health (95% CI = 0.32, 0.76). Conclusions. Number of financial hardships was differentially associated with self-reported oral health for older men and women. Most financial hardship indicators affected both genders similarly. Future interventions to improve vulnerable older adults' oral health should account for gender-based heterogeneity in financial hardship experiences. © 2013 American Journal of Public Health.

Han K.,University of Toronto | Milosevic M.,University of Toronto | Fyles A.,University of Toronto | Pintilie M.,Princess Margaret Hospital | Viswanathan A.N.,Dana-Farber Cancer Institute
International Journal of Radiation Oncology Biology Physics | Year: 2013

Purpose: To determine the trends in brachytherapy use in cervical cancer in the United States and to identify factors and survival benefits associated with brachytherapy treatment. Methods and Materials Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 7359 patients with stages IB2-IVA cervical cancer treated with external beam radiation therapy (EBRT) between 1988 and 2009. Propensity score matching was used to adjust for differences between patients who received brachytherapy and those who did not from 2000 onward (after the National Cancer Institute alert recommending concurrent chemotherapy). Results Sixty-three percent of the 7359 women received brachytherapy in combination with EBRT, and 37% received EBRT alone. The brachytherapy utilization rate has decreased from 83% in 1988 to 58% in 2009 (P<.001), with a sharp decline of 23% in 2003 to 43%. Factors associated with higher odds of brachytherapy use include younger age, married (vs single) patients, earlier years of diagnosis, earlier stage and certain SEER regions. In the propensity score-matched cohort, brachytherapy treatment was associated with higher 4-year cause-specific survival (CSS; 64.3% vs 51.5%, P<.001) and overall survival (OS; 58.2% vs 46.2%, P<.001). Brachytherapy treatment was independently associated with better CSS (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.57-0.71), and OS (HR 0.66; 95% CI, 0.60 to 0.74). Conclusions This population-based analysis reveals a concerning decline in brachytherapy utilization and significant geographic disparities in the delivery of brachytherapy in the United States. Brachytherapy use is independently associated with significantly higher CSS and OS and should be implemented in all feasible cases. © 2013 Elsevier Inc.

Yao J.C.,University of Houston | Lagunes D.R.,Sloan Kettering Cancer Center | Kulke M.H.,Dana-Farber Cancer Institute
Oncologist | Year: 2013

In the past 3 years, we have witnessed the completion of four randomized phase III studies in neuroendocrine tumors and the approval of two new drugs, everolimus and sunitinib, for the treatment of patients with well-differentiated pancreatic neuroendocrine tumors. These studies demonstrate a shift from case series and single-arm studies toward prospective, randomized controlled clinical trials and evidence-based therapy in the neuroendocrine tumor field. However, the clinical development of these agents also highlights the potential challenges awaiting other new drugs in this area. Herein, we discuss the strengths and weaknesses of the most recent phase II and phase III neuroendocrine tumor studies and discuss how limitations inherent in current trial design can lead to potential pitfalls. We also discuss how trial design can be improved, with the hope of increasing the number of drugs successfully developed to treat patients with neuroendocrine tumors. © AlphaMed Press 2013.

Giobbie-Hurder A.,Dana-Farber Cancer Institute
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

The potential for guarantee-time bias (GTB), also known as immortal time bias, exists whenever an analysis that is timed from enrollment or random assignment, such as disease-free or overall survival, is compared across groups defined by a classifying event occurring sometime during follow-up. The types of events associated with GTB are varied and may include the occurrence of objective disease response, onset of toxicity, or seroconversion. However, comparative analyses using these types of events as predictors are different from analyses using baseline characteristics that are specified completely before the occurrence of any outcome event. Recognizing the potential for GTB is not always straightforward, and it can be challenging to know when GTB is influencing the results of an analysis. This article defines GTB, provides examples of GTB from several published articles, and discusses three analytic techniques that can be used to remove the bias: conditional landmark analysis, extended Cox model, and inverse probability weighting. The strengths and limitations of each technique are presented. As an example, we explore the effect of bisphosphonate use on disease-free survival (DFS) using data from the BIG (Breast International Group) 1-98 randomized clinical trial. An analysis using a naive approach showed substantial benefit for patients who received bisphosphonate therapy. In contrast, analyses using the three methods known to remove GTB showed no statistical evidence of a reduction in risk of a DFS event with bisphosphonate therapy.

Brown J.R.,Dana-Farber Cancer Institute
Current Hematologic Malignancy Reports | Year: 2013

Ibrutinib is a potent covalent kinase inhibitor that targets BTK. BTK, or Bruton's tyrosine kinase, is an obvious target for therapy of B cell diseases because inactivating mutations lead to B cell aplasia in humans and the disease X-linked agammaglobulinemia. Ibrutinib has modest cytotoxicity against CLL cells in vitro but also blocks trophic stimuli from the microenvironment. As with other inhibitors of the BCR pathway, ibrutinib causes rapid nodal reduction and response associated with rapid increase in lymphocytosis, which then returns to baseline over time. The ORR of ibrutinib in relapsed refractory CLL is 67 % with PFS 88 % at 15 months. In a cohort of untreated patients 65 years and over, the estimated 15 month PFS is 96 %. Registration trials have been initiated, and the difficult task that remains is to determine where in the course of CLL therapy this drug will have the greatest impact and benefit for patients. © 2013 Springer Science+Business Media New York.

Ligibel J.,Dana-Farber Cancer Institute
Journal of Clinical Oncology | Year: 2012

Lifestyle factors have been linked to the risk of developing many common malignancies and, increasingly, to prognosis. Observational evidence has shown a relationship between so-called energy balance factors (ie, diet, physical activity, and body weight) and risk of cancer recurrence and mortality in cancers of the breast, prostate, colon and, perhaps, other cancers. Interventional work has shown that individuals who make favorable changes in these lifestyle factors after cancer diagnosis feel better, experience less fatigue, and may possibly even decrease risk of cancer recurrence. Other lifestyle behaviors, such as smoking and alcohol consumption, have also been linked to the development of common cancers and may have important health consequences for cancer survivors. This article reviews the evidence that links lifestyle factors to cancer outcomes, provides clinical recommendations for cancer survivors, and describes future directions for lifestyle research in cancer survivors. © 2012 by American Society of Clinical Oncology.

Tolaney S.,Dana-Farber Cancer Institute
Current oncology reports | Year: 2014

Overexpression of human epidermal growth factor occurs in approximately 20-25 % of invasive breast cancers. This subtype of breast cancer has been associated with poor clinical outcomes. The development of trastuzumab, a humanized monoclonal antibody that binds to the extracellular domain of human epidermal growth factor receptor 2 (HER2), revolutionized outcomes of patients with HER2-positive breast cancer; however, many patients with HER2-positive metastatic breast cancer eventually become resistant to it. Several newer anti-HER2 agents have been developed, including lapatinib, pertuzumab, and trastuzumab emtansine. These exciting advances in drug development for HER2-positive breast cancer have also led to many challenges, including how to optimally sequence and combine HER2-targeted agents.

Mirabeau-Beale K.L.,Brigham and Womens Hospital | Viswanathan A.N.,Dana-Farber Cancer Institute
Gynecologic Oncology | Year: 2014

Objective To summarize the literature on quality of life for patients treated with definitive radiation for gynecologic cancers, with a specific focus on patient reported outcomes. Methods A literature review was performed to summarize studies about patient-reported outcomes and quality of life in women with gynecologic malignancies who were treated with definitive radiation therapy. Summaries are by disease site, including endometrial, cervical and vulvar cancers. Results Over 20 different survey instruments have been used to describe patient-reported outcomes for women treated with radiation for gynecologic cancer. Regardless of disease site, all patients describe a degree of compromise in physical and social functioning, as well as sexual dysfunction. Specific symptoms which are most bothersome for patients vary by disease site, such as bowel concerns predominating for endometrial cancer patients, while body image is more concerning for cervical cancer patients. Conclusions Several quality of life concerns exist for women treated with radiation therapy for gynecologic malignancies. Significant overlap exists in the QOL issues affecting these patients. Whether to combine or separate surveys by diagnosis, treatment type, age, or time point should be explored further. Assessing patients' psychological, emotional, and physical concerns helps to understand long-term adjustment, enabling incorporation of these domains into future trials that will ultimately improve patient well-being. © 2014 Elsevier Inc.

Zhou Y.-H.,University of North Carolina at Chapel Hill | Barry W.T.,Dana-Farber Cancer Institute | Wright F.A.,University of North Carolina at Chapel Hill
Biostatistics | Year: 2013

Resampling-based expression pathway analysis techniques have been shown to preserve type I error rates, in contrast to simple gene-list approaches that implicitly assume the independence of genes in ranked lists. However, resampling is intensive in computation time and memory requirements. We describe accurate analytic approximations to permutations of score statistics, including novel approaches for Pearson's correlation, and summed score statistics, that have good performance for even relatively small sample sizes. Our approach preserves the essence of permutation pathway analysis, but with greatly reduced computation. Extensions for inclusion of covariates and censored data are described, and we test the performance of our procedures using simulations based on real datasets. These approaches have been implemented in the new R package safeExpress. © 2013 The Author. Published by Oxford University Press. All rights reserved.

Seo J.H.,Dana-Farber Cancer Institute
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

Breast cancer genome-wide association studies have pinpointed dozens of variants associated with breast cancer pathogenesis. The majority of risk variants, however, are located outside of known protein-coding regions. Therefore, identifying which genes the risk variants are acting through presents an important challenge. Variants that are associated with mRNA transcript levels are referred to as expression quantitative trait loci (eQTLs). Many studies have demonstrated that eQTL-based strategies provide a direct way to connect a trait-associated locus with its candidate target gene. Performing eQTL-based analyses in human samples is complicated because of the heterogeneous nature of human tissue. We addressed this issue by devising a method to computationally infer the fraction of cell types in normal human breast tissues. We then applied this method to 13 known breast cancer risk loci, which we hypothesized were eQTLs. For each risk locus, we took all known transcripts within a 2 Mb interval and performed an eQTL analysis in 100 reduction mammoplasty cases. A total of 18 significant associations were discovered (eight in the epithelial compartment and 10 in the stromal compartment). This study highlights the ability to perform large-scale eQTL studies in heterogeneous tissues.

Fecher L.A.,University of Pennsylvania | Agarwala S.S.,St Lukes Cancer Center | Stephen Hodi F.,Dana-Farber Cancer Institute | Weber J.S.,H. Lee Moffitt Cancer Center and Research Institute
Oncologist | Year: 2013

The treatment for metastatic melanoma has evolved significantly in the past few years. Ipilimumab, an immunotherapy, is now in mainstream oncology practice given that it has shown improved overall survival in randomized clinical trials. Other immune modulating agents, such as programmed death receptor-1 and programmed death receptor ligand-1 antibodies, are showing promise in early clinical trials. This manuscript will review ipilimumab and its most common side effects. Immune-related adverse events (irAEs) are important to recognize early,andtheir presentation, timing of onset,and general recommendations for workup and management will be reviewed. Assembling a multidisciplinary team, as well as thorough education of the patient, is recommended to optimize patient care. ©AlphaMed Press 2013.

Wang Y.,U.S. National Institutes of Health | Godec J.,Dana-Farber Cancer Institute | Ben-Aissa K.,U.S. National Institutes of Health | Cui K.,U.S. National Institutes of Health | And 7 more authors.
Immunity | Year: 2014

T helper 17 (Th17) cells can give rise to interleukin-17A (IL-17A)- and interferon (IFN)-γ-double-producing cells that are implicated in development ofautoimmune diseases. However, the molecular mechanisms that govern generation of IFN-γ-producing Th17 cells are unclear. We found that coexpression of the Th1 and Th17 cell master transcription factors, T-bet and retinoid-related orphan receptor gamma-t (RORγt), respectively, did not generate Th cells with robust IL-17 and IFN-γ expression. Instead, development of IFN-γ-producing Th17 cells required T-bet and Runx1 or Runx3. IL-12-stimulated Th17 cells upregulated Runx1, which bound to the Ifng locus in a T-bet-dependent manner. Reciprocally, T-bet or Runx1 deficiency or inhibition of Runx transcriptional activity impaired the development ofIFN-γ-producing Th17 cells during experimental autoimmune encephalomyelitis, which correlated with substantially ameliorated disease course. Thus, our studies identify a critical role for T-bet andRunx transcription factors in the generation of pathogenic IFN-γ-producing Th17 cells. © 2014 Elsevier Inc.

D'Andrea A.D.,Dana-Farber Cancer Institute
Cancer Discovery | Year: 2013

Domchek and colleagues provide a case report of a 28-year-old woman with congenital abnormalities, inherited ovarian cancer, and carboplatin hypersensitivity. Interestingly, the woman had validated germline mutations in both BRCA1 alleles. These findings further implicate BRCA1 in the Fanconi anemia/BRCA pathway and have important implications for BRCA1 genetic testing. © 2013 American Association for Cancer Research.

Dutchak P.A.,University of Texas Southwestern Medical Center | Katafuchi T.,University of Texas Southwestern Medical Center | Bookout A.L.,University of Texas Southwestern Medical Center | Choi J.H.,Dana-Farber Cancer Institute | And 4 more authors.
Cell | Year: 2012

Fibroblast growth factor-21 (FGF21) is a circulating hepatokine that beneficially affects carbohydrate and lipid metabolism. Here, we report that FGF21 is also an inducible, fed-state autocrine factor in adipose tissue that functions in a feed-forward loop to regulate the activity of peroxisome proliferator-activated receptor γ (PPARγ), a master transcriptional regulator of adipogenesis. FGF21 knockout (KO) mice display defects in PPARγ signaling including decreased body fat and attenuation of PPARγ-dependent gene expression. Moreover, FGF21-KO mice are refractory to both the beneficial insulin-sensitizing effects and the detrimental weight gain and edema side effects of the PPARγ agonist rosiglitazone. This loss of function in FGF21-KO mice is coincident with a marked increase in the sumoylation of PPARγ, which reduces its transcriptional activity. Adding back FGF21 prevents sumoylation and restores PPARγ activity. Collectively, these results reveal FGF21 as a key mediator of the physiologic and pharmacologic actions of PPARγ. © 2012 Elsevier Inc.

Reardon D.A.,Dana-Farber Cancer Institute | Cheresh D.,University of California at San Diego
Genes and Cancer | Year: 2011

Integrins are critical intermediaries in a wide spectrum of cancer cell activities and thus represent a highly attractive target in oncology therapy. Nonetheless, successful exploitation of anti-integrin therapeutics has proven challenging to date for cancer patients. In this review, we will focus on cilengitide, an RGD pentapeptide inhibitor of α V integrins. Although several integrin inhibitors are under clinical evaluation, cilengitide is the most clinically advanced and is emerging as a prototype for this class of anticancer therapy. A foundation of encouraging preclinical studies led to a well-designed clinical development plan that culminated in a pivotal phase III study of cilengitide in combination with radiation therapy and temozolomide chemotherapy for newly diagnosed glioblastoma patients. Accrual to this study recently completed, while phase II studies of cilengitide are ongoing for head and neck cancer as well as lung cancer. Important future considerations for cilengitide and other integrin-targeting agents will likely include the identification of optimal combinatorial regimens and the delineation of biomarkers associated with efficacy. © The Author(s) 2011.

Kimmelman A.C.,Dana-Farber Cancer Institute
Genes and Development | Year: 2011

Macroautophagy (referred to hereafter as autophagy) is a highly regulated cellular process that serves to remove damaged proteins and organelles from the cell. Autophagy contributes to an array of normal and pathological processes, and has recently emerged as a key regulator of multiple aspects of cancer biology. The role of autophagy in cancer is complex and is likely dependent on tumor type, stage, and genetic context. This complexity is illustrated by the identification of settings where autophagy acts potently to either promote or inhibit tumorigenesis. In this review, I discuss the underlying basis for these opposing functions and propose a model suggesting a dynamic role for autophagy in malignancy. Collectively, the data point to autophagy as serving as a barrier to limit tumor initiation. Once neoplastic lesions are established, it appears that adaptive changes occur that now result in positive roles for autophagy in malignant progression and in subsequent tumor maintenance. Remarkably, constitutive activation of autophagy is critical for continued growth of some tumors, serving to both reduce oxidative stress and provide key intermediates to sustain cell metabolism. Autophagy is also induced in response to cancer therapies where it can function as a survival mechanism that limits drug efficacy. These findings have inspired significant interest in applying anti-autophagy therapies as an entirely new approach to cancer treatment. It is now apparent that aberrant control of autophagy is among the key hallmarks of cancer. While much needs to be learned about the regulation and context-dependent biological functions of autophagy, it seems clear that modulation of this process will be an attractive avenue for future cancer therapeutic approaches. © 2011 by Cold Spring Harbor Laboratory Press.

MacConaill L.E.,Dana-Farber Cancer Institute
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Ongoing global genome characterization efforts are revolutionizing our knowledge of cancer genomics and tumor biology. In parallel, information gleaned from these studies on driver cancer gene alterations--mutations, copy number alterations, translocations, and/or chromosomal rearrangements--an be leveraged, in principle, to develop a cohesive framework for individualized cancer treatment. These possibilities have been enabled, to a large degree, by revolutionary advances in genomic technologies that facilitate systematic profiling for hallmark cancer genetic alterations at increasingly fine resolutions. Ongoing innovations in existing genomics technologies, as well as the many emerging technologies, will likely continue to advance translational cancer genomics and precision cancer medicine.

Van Allen E.M.,Dana-Farber Cancer Institute
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

The scale of tumor genomic profiling is rapidly outpacing human cognitive capacity to make clinical decisions without the aid of tools. New frameworks are needed to help researchers and clinicians process the information emerging from the explosive growth in both the number of tumor genetic variants routinely tested and the respective knowledge to interpret their clinical significance. We review the current state, limitations, and future trends in methods to support the clinical analysis and interpretation of cancer genomes. This includes the processes of genome-scale variant identification, including tools for sequence alignment, tumor-germline comparison, and molecular annotation of variants. The process of clinical interpretation of tumor variants includes classification of the effect of the variant, reporting the results to clinicians, and enabling the clinician to make a clinical decision based on the genomic information integrated with other clinical features. We describe existing knowledge bases, databases, algorithms, and tools for identification and visualization of tumor variants and their actionable subsets. With the decreasing cost of tumor gene mutation testing and the increasing number of actionable therapeutics, we expect the methods for analysis and interpretation of cancer genomes to continue to evolve to meet the needs of patient-centered clinical decision making. The science of computational cancer medicine is still in its infancy; however, there is a clear need to continue the development of knowledge bases, best practices, tools, and validation experiments for successful clinical implementation in oncology.

Garraway L.A.,Dana-Farber Cancer Institute
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

A majority of cancers are driven by genomic alterations that dysregulate key oncogenic pathways influencing cell growth and survival. However, the ability to harness tumor genetic information for its full clinical potential has only recently become manifest. Over the past several years, the convergence of discovery, technology, and therapeutic development has created an unparalleled opportunity to test the hypothesis that systematic knowledge of genomic information from individual tumors can improve clinical outcomes for many patients with cancer. Rigorous evaluation of this genomics-driven cancer medicine hypothesis will require many logistic innovations that are guided by overarching conceptual advances in tumor genomic profiling, data interpretation, clinical trial design, and the ethical return of genetic results to oncologists and their patients. The results of these efforts and the rigor with which they are implemented will determine whether and how comprehensive tumor genomic information may become incorporated into the routine care of patients with cancer.

Daniel C.,Dana-Farber Cancer Institute
Methods in molecular biology (Clifton, N.J.) | Year: 2011

The peripheral induction of Foxp3-expressing regulatory T cells outside the thymus is required in order to maintain local homeostasis in distinct microenvironments such as the gut. Extrathymic induction of Treg may also be exploited to prevent unwanted immune responses. Here, we discuss the methodology allowing for the stable de novo generation of Tregs specific for foreign antigens in peripheral lymphoid tissue via subimmunogenic peptide delivery using either peptide contained in fusion antibodies directed against the DEC205 endocytotic receptor on steady-state dendritic cells or the implantation of peptide-delivering osmotic mini-pumps. Furthermore, we also address methods in order to achieve TGFβ-dependent Treg conversion in vitro, thereby mainly focusing on the role of retinoic acid (RA) to enhance TGFβ-dependent conversion into Tregs.

Tirumani S.H.,Dana-Farber Cancer Institute | Shanbhogue A.K.P.,Beth Israel Deaconess Medical Center | Prasad S.R.,University of Houston
Radiologic Clinics of North America | Year: 2013

Cross-sectional imaging modalities play a pivotal role in the diagnosis and multidisciplinary management of patients with endometrial and cervical carcinomas. Ultrasonography, including sonohysterography, permits evaluation of endometrial abnormalities and characterization of adnexal masses. Computed tomography, particularly in conjunction with 18F-fluorodeoxyglucose positron emission tomography, is increasingly used to stage the cancers and to detect disease recurrence. Magnetic resonance imaging plays a major role in accurate locoregional staging of these cancers, and significantly influences treatment decisions and outcomes. This article discusses the role of imaging modalities in the diagnosis, management, and surveillance of these cancers. © 2013 Elsevier Inc.

Kim J.,University of Texas at Austin | Orkin S.H.,Dana-Farber Cancer Institute
Genome Medicine | Year: 2011

Embryonic stem (ES) cells are of great interest as a model system for studying early developmental processes and because of their potential therapeutic applications in regenerative medicine. Obtaining a systematic understanding of the mechanisms that control the 'stemness' - self-renewal and pluripotency - of ES cells relies on high-throughput tools to define gene expression and regulatory networks at the genome level. Such recently developed systems biology approaches have revealed highly interconnected networks in which multiple regulatory factors act in combination. Interestingly, stem cells and cancer cells share some properties, notably self-renewal and a block in differentiation. Recently, several groups reported that expression signatures that are specific to ES cells are also found in many human cancers and in mouse cancer models, suggesting that these shared features might inform new approaches for cancer therapy. Here, we briefly summarize the key transcriptional regulators that contribute to the pluripotency of ES cells, the factors that account for the common gene expression patterns of ES and cancer cells, and the implications of these observations for future clinical applications. © 2011 BioMed Central Ltd.

Nombela-Arrieta C.,Joint Program in Transfusion Medicine | Ritz J.,Dana-Farber Cancer Institute | Ritz J.,Cellular One | Silberstein L.E.,Joint Program in Transfusion Medicine | Silberstein L.E.,Cellular One
Nature Reviews Molecular Cell Biology | Year: 2011

Mesenchymal stem cells (MSCs) are a diverse subset of multipotent precursors present in the stromal fraction of many adult tissues and have drawn intense interest from translational and basic investigators. MSCs have been operationally defined by their ability to differentiate into osteoblasts, adipocytes and chondrocytes after in vitro expansion. Nevertheless, their identity in vivo, heterogeneity, anatomical localization and functional roles in adult tissue homeostasis have remained enigmatic and are only just starting to be uncovered. © 2011 Macmillan Publishers Limited. All rights reserved.

Marcus K.J.,Childrens Hospital Boston | Tishler R.B.,Dana-Farber Cancer Institute
Seminars in Radiation Oncology | Year: 2010

Carcinomas of the head and neck occur in both children and adults, but notable differences exist in their relative frequency, pathologic subtypes, etiologies, presenting symptoms, and late effects. In contrast, treatment strategies are similar depending on the disease type and distribution at the time of diagnosis. Thus, in adult patients, squamous cell carcinomas or one of its variants are the most common malignancies in the head and neck. However, in children, cancers of the head/neck are most commonly rhabdomyosarcomas, lymphomas, including Hodgkin's lymphoma, lymphoblastic lymphomas, and Burkitt's lymphoma or neuroblastoma. Epithelial cancers are unusual in the pediatric population, with the exception of nasopharyngeal carcinoma. Although nasopharyngeal carcinoma is a rare disease in children, representing less than 1% of childhood cancers, it does constitute 20%-50% of pediatric malignancies of the nasopharynx. This is one of the few malignant tumors in children that arise from the epithelium. Despite the differences between the diseases in children from that in adults, the management strategy has been based largely on the experience in adults. This review will describe the epidemiology, etiology, management, and late effects in children and adults, and offer explanations for both the similarities and differences. © 2010 Elsevier Inc. All rights reserved.

Winner M.,Columbia University | Goff S.L.,Dana-Farber Cancer Institute
Seminars in Oncology | Year: 2015

Treatment of pancreatic cancer is increasingly multimodal, with patients receiving chemotherapy, radiation, and surgical extirpation in hope of long-term cure. There is ongoing debate over the timing, sequence, and necessity of these treatments as they pertain to the spectrum of local-regional disease. Current guidelines support a neoadjuvant strategy in patients with locally advanced and borderline resectable disease. Although there is currently no high-level evidence to recommend neoadjuvant therapy for all patients, there are data to suggest that wider application of neoadjuvant therapy may be beneficial. Random-assignment prospective trials are ongoing. In this review we examine the literature addressing a neoadjuvant approach to potentially resectable, borderline resectable, and locally advanced pancreatic cancer and highlight the outcomes of preoperative emergence of latent metastatic disease, attempted resection rates, margin negative resection rates, and pathologic response to treatment. © 2015 Elsevier Inc. All rights reserved.

Huang Q.,City of Hope National Medical Center | Hair A.,University of Glasgow | Holyoake T.L.,University of Glasgow | Huettner C.,Dana-Farber Cancer Institute
Cancer Cell | Year: 2012

We characterized leukemia stem cells (LSC) in chronic phase chronic myelogenous leukemia (CML) using a transgenic mouse model. LSC were restricted to cells with long-term hematopoietic stem cell (LTHSC) phenotype. CML LTHSC demonstrated reduced homing and retention in the bone marrow (BM), related to decreased CXCL12 expression in CML BM, resulting from increased G-CSF production by leukemia cells. Altered cytokine expression in CML BM was associated with selective impairment of normal LTHSC growth and a growth advantage to CML LTHSC. Imatinib (IM) treatment partially corrected abnormalities in cytokine levels and LTHSC growth. These results were validated using human CML samples and provide improved understanding of microenvironmental regulation of normal and leukemic LTHSC and their response to IM in CML. © 2012 Elsevier Inc.

Di Lorenzo G.,University of Naples Federico II | Buonerba C.,University of Naples Federico II | Kantoff P.W.,Dana-Farber Cancer Institute
Nature Reviews Clinical Oncology | Year: 2011

Failure of immune surveillance has a prominent role in tumorigenesis. Cancerous cells can evade T-cell responses to tumor-associated antigens by multiple mechanisms. Active immunotherapy aims to stimulate the immune response against cancer cells. Unlike normal prostate tissue, prostate cancer is not ignored by the immune system, as shown by the presence of tumor infiltrating lymphocytes. This characteristic renders prostate cancer particularly suitable for immunotherapy. The existence of well-defined antigens, largely limited to prostate tissue, allows prostate cancer cells to be targeted without the risk of systemic autoimmune reactions, as autoimmunity specifically directed at the prostate is the goal of prostate cancer immunotherapy. Active immunotherapy directed towards prostate cancer can be conducted using multiple strategies, involving dendritic cells, whole-cell vaccines, viral vectors, DNA-based and peptide-based agents, as well as immunostimulatory agents. The only FDA-approved immunotherapy for prostate cancer is the dendritic-cell-based agent Sipuleucel-T, which yielded an advantage in overall survival, but not in progression-free survival in a phase III trial. We present the clinical developments in the field of immunotherapy and critically analyze methodological issues related to the evaluation of tumor responses to immunotherapy, trial design, and surrogate end points. © 2011 Macmillan Publishers Limited. All rights reserved.

Letai A.,Dana-Farber Cancer Institute
Advances in Experimental Medicine and Biology | Year: 2010

Abstract Apoptosis, a form of cellular suicide is a key mechanism involved in the clearance of cells that are dysfunctional, superfluous or infected. For this reason, the cell needs mechanisms to sense death cues and relay death signals to the apoptotic machinery involved in cellular execution. In the intrinsic apoptotic pathway, a subclass of BCL-2 family proteins called the BH3-only proteins are responsible for triggering apoptosis in response to varied cellular stress cues. The mechanisms by which they are regulated are tied to the type of cellular stress they sense. Once triggered, they interact with other BCL-2 family proteins to cause mitochondrial outer membrane permeabilization which in turn results in the activation of serine proteases necessary for cell killing. Failure to properly sense death cues and relay the death signal can have a major impact on cancer. This chapter will discuss our current models of how BH3-only proteins function as well as their impact on carcinogenesis and cancer treatment. © 2010 Landes Bioscience and Springer Science+Business Media.

Buchbinder E.I.,Dana-Farber Cancer Institute | McDermott D.F.,Beth Israel Deaconess Medical Center
Clinical Therapeutics | Year: 2015

Purpose Melanoma is an aggressive malignancy that has a complex relationship with the host immune system. Immunotherapies have long been a mainstay of melanoma therapy, and advanced therapies continue to be effective in treating this disease. Immune checkpoint blockade has proven to be a novel target in melanoma, with the approval of cytotoxic T-lymphocyte antigen-4 (CTLA-4)-targeted therapy. This review evaluates the role of CTLA-4-targeted therapies in the treatment of metastatic melanoma, with a focus on mechanisms, efficacy, toxicity, and future directions of this therapy. Methods A search was performed in PubMed to identify relevant clinical studies that explored the clinical experience with CTLA-4-targeted therapy in melanoma. Findings Signaling through CTLA-4 causes deactivation of T cells after the initial stimulatory signals. Therapies that block CTLA-4 lead to increased T-cell function and an antitumor response in patients with metastatic melanoma. The adverse event profile of these agents is different from that seen with more traditional cancer therapies and consists of dermatitis, colitis, and other autoimmune toxicities. In addition, the pattern of response is different from that seen with traditional cytotoxic therapies, with some patients experiencing initial progression followed by response and some patients having long-term durable responses. Implications Extensive clinical evidence supports the use of CTLA-4-targeted agents in the treatment of metastatic melanoma. The durability of response seen in patients receiving these agents has changed the landscape for patients with melanoma. Combination therapies and other agents with similar mechanisms warrant further exploration for the treatment of metastatic melanoma. © 2015 Elsevier HS Journals, Inc.

Galectin-1 (Gal1) is a member of a highly conserved family of carbohydrate-binding proteins. It modulates innate and adaptive immune responses and fosters tumor-immune escape. Hodgkin lymphoma (HL) Reed-Sternberg cells overexpress and secrete Gal1, which selectively kills T helper (Th)1 and Th17 cells and cytotoxic T cells and promotes the immunosuppressive Th2/regulatory T-cell-predominant HL microenvironment. We developed a sandwich enzyme-linked immunosorbent assay and assessed serum Gal1 levels in 293 newly diagnosed, previously untreated patients with classical HL (cHL) enrolled in 3 risk-adapted clinical trials. Serum Gal1 levels were significantly higher in patients with cHL than in normal controls (P < .0001). Gal1 serum levels also increased with Ann Arbor stage (P = .012), areas of nodal involvement (P < .0001), and the International Prognostic Score (2-7, P = .019). We conclude that Gal1 serum levels are significantly associated with tumor burden and related clinical features in newly diagnosed cHL patients.

Nathan D.G.,Dana-Farber Cancer Institute
Annals of the New York Academy of Sciences | Year: 2016

To assess the future of a clinical science one must first assess the rate of accrual of understanding in the past century. From the time of Cooley's description (1925) to 1964, the year of the first Symposium, progress was glacial because the molecular biology revolution in medicine was in its infancy and therapy other than transfusion was impossible. But between 1964 and 2015, progress has been huge on every front. Our patients ushered in the molecular biology revolution in medicine. They have benefited from far better understanding of molecular pathophysiology, substantial improvements in transfusion and chelation, more effective stem cell transplantation, the beginnings of gene therapy, and now major advances in our capacity to reinduce fetal hemoglobin. We have only lagged in the application of prevention technology in the less developed world that suffers the most from thalassemia and sickle cell disease. We must redouble our efforts to spare patients from these cruel diseases. © 2016 The New York Academy of Sciences.

Burstein H.J.,Dana-Farber Cancer Institute
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting | Year: 2014

Breast cancer treatment has evolved dramatically in the past 50 years. In addition to innovations in medical therapy-including widespread use of endocrine treatments, chemotherapy, and anti-HER2 agents-medical advances in genetic testing, imaging, and screening have revolutionized care. As profound as these changes in medical treatment have been, however, they are matched by a cultural transformation in the way society understands, discusses, and cares about breast cancer. Breast cancer has evolved from an unnamed affliction to a disease that is regularly featured on the front page of the newspapers, and is discussed in countless forums in traditional and social media. Clinical specialization in breast cancer among oncologists has given patients access to dedicated specialists around the country. These transformations will be highlighted through the analysis of a patient, Rachel Carson, who died 50 years ago from breast cancer.

Lim E.,Dana-Farber Cancer Institute
Oncology (Williston Park, N.Y.) | Year: 2012

Abstract: Approximately 70% of human breast tumors express hormone receptors (HRs), comprising the estrogen receptor (ER) and/or progesterone receptor (PR).The ER is the primary transcription factor driving oncogenesis in HR-positive (HR+) breast cancers; it is both a target of, and predictor of response to, antiestrogen therapy. Unlike in other breast cancer subtypes, more than half of all disease recurrences in HR+ breast cancer occur 6 years or more after diagnosis, particularly following 5 years of adjuvant anti-estrogen therapy. Late relapses in HR+ breast cancer thus represent a significant clinical challenge. There is considerable molecular and clinical heterogeneity underlying HR+ breast cancers, and a limited understanding of the mechanisms underlying treatment resistance and late relapse. In this review, we describe the long natural history of HR+ breast cancer and discuss relapse patterns in relation to their clinicopathological and molecular characteristics. We highlight the relationship between tumor relapse and anti-estrogen therapy resistance, and we describe the concept of tumor dormancy. Finally, we review novel translational research strategies utilizing preclinical models and patient tumor samples, and current clinical strategies that address this increasingly common challenge in breast cancer.

Yonesaka K.,Dana-Farber Cancer Institute
Science translational medicine | Year: 2011

Cetuximab, an antibody directed against the epidermal growth factor receptor, is an effective clinical therapy for patients with colorectal, head and neck, and non-small cell lung cancer, particularly for those with KRAS and BRAF wild-type cancers. Treatment in all patients is limited eventually by the development of acquired resistance, but little is known about the underlying mechanism. Here, we show that activation of ERBB2 signaling in cell lines, either through ERBB2 amplification or through heregulin up-regulation, leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance. Inhibition of ERBB2 or disruption of ERBB2/ERBB3 heterodimerization restores cetuximab sensitivity in vitro and in vivo. A subset of colorectal cancer patients who exhibit either de novo or acquired resistance to cetuximab-based therapy has ERBB2 amplification or high levels of circulating heregulin. Collectively, these findings identify two distinct resistance mechanisms, both of which promote aberrant ERBB2 signaling, that mediate cetuximab resistance. Moreover, these results suggest that ERBB2 inhibitors, in combination with cetuximab, represent a rational therapeutic strategy that should be assessed in patients with cetuximab-resistant cancers.

Spiegelman B.M.,Dana-Farber Cancer Institute
Diabetes | Year: 2013

The Banting Medal for Scientific Achievement Award is the American Diabetes Association's highest scientific award and honors an individual who has made significant, long-term contributions to the understanding of diabetes, its treatment, and/or prevention. The award is named after Nobel Prize winner Sir Frederick Banting, who codiscovered insulin treatment for diabetes. Bruce M. Spiegelman, PhD, of Harvard Medical School and the Dana-Farber Cancer Institute in Boston, received the American Diabetes Association's Banting Medal for Scientific Achievement at the Association's 72nd Scientific Sessions, 8-12 June 2012, Philadelphia, Pennsylvania. He presented the Banting Lecture, " Transcriptional Control of Adipogenesis - Toward a New Generation of Therapeutics for Metabolic Disease," on Sunday, 10 June 2012. In his lecture, Dr. Spiegelman described the discovery of several transcriptional components that control adipose cell development: PPAR-γ, PGC1-α, and PRDM16. He also described the cloning and characterization of beige fat cells, the thermogenic "brown-like" cells that can develop in white fat depots. Lastly, Dr. Spiegelman discussed irisin, a newly discovered regulatory hormone that converts white fat into the more thermogenic beige fat. Dr. Spiegelman's research has found that irisin, which is induced by exercise, appears to activate some of the same health benefits as exercise, including improvement of glycemic control. Understanding the regulation of adipose tissue, white, brown, and beige, can potentially lead to the development of a new generation of therapeutics for diabetes prevention and treatment. © 2013 by the American Diabetes Association.

Myers A.P.,Dana-Farber Cancer Institute | Myers A.P.,Beth Israel Deaconess Medical Center
Clinical Cancer Research | Year: 2013

Endometrial cancer is the most common gynecologic malignancy in the developed world and affects approximately 40,000 women in the United States each year. The phosphoinositide 3-kinase (PI3K) signaling pathway regulates key aspects of cancer biology including glucose uptake and metabolism, cellular growth, and survival. Endometrial cancers harbor the highest rates of PI3K pathway alterations reported to date. The PI3K pathway is highly druggable and several classes of agents are in clinical development including rapalogs, pan-PI3K inhibitors, PI3K isoform-specific inhibitors, dual PI3K/mTOR catalytic inhibitors, mTOR-specific catalytic inhibitors, and AKT inhibitors. It has been 10 years since the initiation of the first studies of rapalogs as anticancer agents. There are more than 20 registered clinical trials of PI3K/mTOR inhibitors as single agents or in therapeutic combinations for the treatment of endometrial cancers. What have we learned from the completed studies? What can we expect to learn from ongoing studies? What should we anticipate moving forward? © 2013 American Association for Cancer Research.

Senerchia A.A.,Institute of Pediatric Oncology IOP GRAACC UNIFESP EPM | Rodriguez-Galindo C.,Dana-Farber Cancer Institute
Pediatric Blood and Cancer | Year: 2014

Background: Skin cancer incidence among young adults is rising; however, the epidemiological characteristics of primary cutaneous lymphomas and cutaneous soft tissue sarcomas (CSTS) in individuals <30 years old has not been investigated. We analyzed the incidence and time-trends of primary cutaneous malignancies in children and adolescents/young adults (AYA). Procedure: SEER-17 and -13 data were used to assess the descriptive epidemiology and time-trends in incidence of primary cutaneous malignancies in children and AYA. SEERStat and Joinpoint softwares were utilized to estimate annual percent changes (APC) in incidence. Results: In total, 7,814 cases (ASR=25.66/1,000,000 habitants) of primary skin cancers in <30 years old were diagnosed in 2000-2008. Females had a higher incidence of melanoma (risk ratio (RR)=1.95; P<0.001) and a lower risk of developing CSTS (RR=0.64, P<0.001). Compared to whites, blacks have a lower incidence of melanoma (RR=0.03, P<0.001), and higher risk of CSTS (RR=2.28, P<0.001). Melanoma increased in females over a 15-year period (1992-2006) (APC=2.5, 95%CI=1.8; 3.2), and the incidence of cutaneous T-cell lymphomas increased over the period 1992-2008 (APC=9.5, 95% CI=6.7; 12.4). CSTS incidence decreased among males over the period 1992-1999 (APC=-21.4, 95% CI -27.2; -15.1), particularly due to a decrease in Kaposi sarcoma incidence (AAPC 1992-2008=-13.6, 95% CI=-22.4;-3.8), although with a notable racial disparity (whites, AAPC=-15.2, 95% CI=-23.2;-6.4; blacks, AAPC=-10.6, 95% CI=-13.2;-7.9). Conclusions: Non-melanoma skin cancer is very rare in children and AYA. We have shown variation in time-trends in incidence as well as in incidence patterns by race, sex, age, and histologic type, highlighting the importance of descriptive epidemiology to better understand the characteristics of these malignancies. © 2013 Wiley Periodicals, Inc.

Star K.V.,Brigham and Womens Hospital | Ho V.T.,Dana-Farber Cancer Institute | Wang H.H.,Beth Israel Deaconess Medical Center | Odze R.D.,Brigham and Womens Hospital
American Journal of Surgical Pathology | Year: 2013

Mycophenolate mofetil (MMF) is a T-cell inhibitor frequently used in the treatment of acute allograft rejection. MMF may cause colitis that clinically and histologically resembles graft-versus-host disease (GVHD). The aim of this study was to evaluate a wide range of histologic features that may help differentiate MMF from GVHD-induced colitis and to validate significant features on a cohort of bone marrow transplant patients who were also taking MMF as part of their immunosuppressive regimen and developed a diarrheal illness due to colitis. Routinely processed colonic biopsies from 17 patients with MMF colitis and 40 patients with GVHD-induced colitis were evaluated for the overall grade of colitis (grades 1 to 4) and histologically for a wide range of inflammatory, epithelial, and architectural changes in a blinded manner. Statistically significant features were then tested in a cohort of 20 bone marrow transplant patients who also received MMF, and later developed a diarrheal illness. Both univariate and multivariate analyses (including receiver operating characteristic analysis) were performed. Morphologic features shown to be independently associated with MMF include the presence and quantity of lamina propria eosinophils and endocrine cell aggregates and the presence and quantity of apoptotic microabscesses, hypereosinophilic (degenerated) crypts, and crypt distortion. Eosinophils were present in all MMF patients, but apoptotic microabscesses were present in none and endocrine cell aggregates in only 1 case. When a grade-by-grade comparison was made between MMF and GVHD, grade 1 or 2 MMF also showed an increased prevalence rate and quantity of lamina propria neutrophils in comparison with grade 1 or 2 GVHD. By receiver operating characteristic analysis, a combination of lamina propria eosinophils >15 per 10 HPF, combined with a lack of endocrine cell aggregates and apoptotic microabscesses, revealed sensitivity, specificity, and positive and negative predictive values of 76%, 93%, 81%, and 90%, respectively, for identification of MMF colitis. On the basis of these data, we conclude that a variety of histologic features, in particular, eosinophils >15 per 10 HPF, lack of endocrine cell aggregates in the lamina propria, and lack of apoptotic microabscesses, can be used by pathologists to help separate MMF from GVHD-induced colitis in routine clinical practice. Copyright © 2013 by Lippincott Williams & Wilkins.

Sackstein R.,Dana-Farber Cancer Institute
Annals of the New York Academy of Sciences | Year: 2012

The proximate hurdle for cell trafficking to any anatomic site is the initial attachment of circulating cells to target tissue endothelium with sufficient strength to overcome prevailing forces of blood flow. E-selectin, an endothelial molecule that is inducibly expressed at all sites of inflammation, is a potent effector of this primary braking process. This molecule is a member of a family of C-type lectins known as selectins that bind sialofucosylated glycans displayed on either a protein (i.e., glycoprotein) or lipid (i.e., glycolipid) scaffold. On human cells, the predominant E-selectin ligand is a specialized glycoform of CD44 known as hematopoietic cell E-/L-selectin ligand (HCELL). This review focuses on the biology of HCELL/E-selectin interactions in cell migration, and discusses the utility and applicability of glycosyltransferase-programmed stereosubstitution (GPS) for glycoengineering HCELL expression. Without compromising cell viability or native phenotype, this exoglycosylation technology literally "sweetens" CD44, licensing E-selectin-dependent vascular delivery for all cell-based therapeutics. © 2012 New York Academy of Sciences.

Castillo J.J.,Dana-Farber Cancer Institute | Bibas M.,Lazzaro Spallanzani National Institute for Infectious Diseases | Miranda R.N.,University of Houston
Blood | Year: 2015

Plasmablastic lymphoma (PBL) is an aggressive lymphoma commonly associated with HIV infection. However, PBL can also be seen in patients with other immunodeficiencies as well as in immunocompetent individuals. Because of its distinct clinical and pathological features, such as lack of expression of CD20, plasmablastic morphology, and clinical course characterized by early relapses and subsequent chemotherapy resistance, PBL can represent a diagnostic and therapeutic challenge for pathologists and clinicians alike. Despite the recent advances in the therapy of HIV-associated and aggressive lymphomas, patients with PBL for the most part have poor outcomes. The objectives of this review are to summarize the current knowledge on the epidemiology, biology, clinical and pathological characteristics, differential diagnosis, therapy, prognostic factors, outcomes, and potential novel therapeutic approaches in patients with PBL and also to increase the awareness toward PBL in the medical community. © 2015 by The American Society of Hematology.

Greulich H.,Dana-Farber Cancer Institute | Greulich H.,Cambridge Broad Institute
Genes and Cancer | Year: 2010

Standard cytotoxic chemotherapy is effective for some cancers, but for many others, available treatments offer only a limited survival benefit. Lung adenocarcinoma is one such cancer, responsible for approximately half of lung cancer deaths each year. Development of targeted therapies is thought to hold the most promise for successfully treating this disease, but a targeted approach is dependent on understanding the genomic state of the tumor cells. Exon-directed sequencing of large numbers of lung adenocarcinoma tumor samples has provided an initial low-resolution image of the somatic mutation profile of these tumors. Such cancer sequencing studies have confirmed the high frequency of TP53 and KRAS mutations in lung adenocarcinoma, have found inactivating mutations in known tumor suppressor genes not previously associated with lung adenocarcinoma, and have identified oncogenic mutations of EGFR upon which the first targeted therapy for lung adenocarcinoma patients was based. Additional candidate oncogenes await functional validation. It is anticipated that upcoming whole-exome and whole-genome lung adenocarcinoma sequencing experiments will reveal a more detailed landscape of somatic mutations that can be exploited for therapeutic purposes. © The Author(s) 2011.

Armand P.,Dana-Farber Cancer Institute
Blood | Year: 2015

Therapeutic blockade of immune checkpoint pathways, in particular cytotoxic T-lymphocyte associated protein 4 and programmed-death 1 (PD-1), has become a paradigm-shifting treatment in solid tumor oncology. Hematologic malignancies (HMs), many of which are known to have clinically exploitable immune sensitivity, are a natural target for this type of treatment. Several clinical trials of checkpoint blockade have been conducted in HM, with preliminary results suggesting the therapeutic usefulness of this approach across several tumor types. In particular, the results of PD-1 blockade in Hodgkin lymphoma (HL) are remarkable, and raise hope that it may alter the treatment landscape in this disease. However, numerous questions remain about the optimal role of checkpoint blockade both in HL and beyond. Those questions are the focus of this review, in the hope that, if we are at the dawn of a new day in HM immunotherapy, wemaybegin to envision its morning. © 2015 by The American Society of Hematology.

Burstein H.J.,Dana-Farber Cancer Institute
Breast | Year: 2011

Summary: Treatment of HER2 positive breast cancer is one of the great successes in recent breast oncology. This article will review recent information on patient and tumor selection for anti-HER2 therapy, and new data on optimal use of trastuzumab-based treatments in the adjuvant setting. © 2011 Elsevier Ltd.

Ghobrial I.M.,Dana-Farber Cancer Institute
Blood | Year: 2012

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of multiple myelomatous "omas" throughout the skeleton, indicating that there is continuous trafficking of tumor cells to multiple areas in the bone marrow niches. MM may therefore represent one of the best models to study cell trafficking or cell metastasis. The process of cell metastasis is described as a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood vessels, passage into the circulation, followed by homing into predetermined distant tissues, the formation of new foci of micrometastases, and finally the growth of micrometastasis into macroscopic tumors. This review discusses the significant advances that have been discovered in the complex process of invasion-metastasis in epithelial carcinomas and cell trafficking in hematopoietic stem cells and how this process relates to progression in MM. This progression is mediated by clonal intrinsic factors that mediate tumor invasiveness as well as factors present in the tumor microenvironment that are permissive to oncogenic proliferation. Therapeutic agents that target the different steps of cell dissemination and progression are discussed. Despite the significant advances in the treatment of MM, better therapeutic agents that target this metastatic cascade are urgently needed. © 2012 by The American Society of Hematology.

Bass A.J.,Dana-Farber Cancer Institute
Oncogene | Year: 2016

Esophageal cancer is a deadly disease, ranking sixth among all cancers in mortality. Despite incremental advances in diagnostics and therapeutics, esophageal cancer still carries a poor prognosis, and thus, there remains a need to elucidate the molecular mechanisms underlying this disease. There is accumulating evidence that a comprehensive understanding of the molecular composition of esophageal cancer requires attention to not only tumor cells but also the tumor microenvironment (TME), which contains diverse cell populations, signaling factors and structural molecules that interact with tumor cells and support all stages of tumorigenesis. In esophageal cancer, environmental exposures can trigger chronic inflammation, which leads to constitutive activation of pro-inflammatory signaling pathways that promote survival and proliferation. Antitumor immunity is attenuated by cell populations such as myeloid-derived suppressor cells and regulatory T cells, as well as immune checkpoints like programmed death-1. Other immune cells such as tumor-associated macrophages can have other pro-tumorigenic functions, including the induction of angiogenesis and tumor cell invasion. Cancer-associated fibroblasts secrete growth factors and alter the extracellular matrix to create a tumor niche and enhance tumor cell migration and metastasis. Further study of how these TME components relate to the different stages of tumor progression in each esophageal cancer subtype will lead to development of novel and specific TME-targeting therapeutic strategies, which offer considerable potential especially in the setting of combination therapy.Oncogene advance online publication, 29 February 2016; doi:10.1038/onc.2016.34. © 2016 Macmillan Publishers Limited

Steensma D.P.,Dana-Farber Cancer Institute
Hematology/Oncology Clinics of North America | Year: 2010

Preliminary therapeutic successes have prompted a new wave of clinical trials enrolling patients with myelodysplastic syndromes (MDS), using compounds with a broad range of potential mechanisms of action. This article discusses several of the agents currently in development for MDS, reviewing clinical trial data related to five classes of novel therapeutics: clofarabine, a halogenated purine nucleoside analog; ezatiostat (TLK199), a glutathione analog that indirectly activates c-Jun kinase; tipifarnib, a farnesyltransferase inhibitor; laromustine (cloretazine), an alkylating agent with a metabolite that inhibits one mechanism of DNA damage repair; and eight drugs that inhibit histone deacetylase. Although MDS are still difficult clinical problems, and most patients with MDS still succumb to disease-related complications within 3 to 5 years of diagnosis, ongoing development of novel agents promises that there will be new treatment options for patients within the next 5 to 10 years. © 2010 Elsevier Inc.

Iwasa Y.,Kyushu University | Michor F.,Dana-Farber Cancer Institute
PLoS ONE | Year: 2011

Intraneoplastic diversity in human tumors is a widespread phenomenon of critical importance for tumor progression and the response to therapeutic intervention. Insights into the evolutionary events that control tumor heterogeneity would be a major breakthrough in our comprehension of cancer development and could lead to more effective prevention methods and therapies. In this paper, we design an evolutionary mathematical framework to study the dynamics of heterogeneity over time. We consider specific situations arising during tumorigenesis, such as the emergence of positively selected mutations ("drivers") and the accumulation of neutral variation ("passengers"). We perform exact computer simulations of the emergence of diverse tumor cell clones over time, and derive analytical estimates for the extent of heterogeneity within a population of cancer cells. Our methods contribute to a quantitative understanding of tumor heterogeneity and the impact of heritable alterations on this tumor trait. © 2011 Iwasa, Michor.

Meyerhardt J.A.,Dana-Farber Cancer Institute
Seminars in Oncology | Year: 2011

Epidemiologic and scientific research indicates that diet and other lifestyle factors have a significant influence on the risk of developing colorectal cancer. Obesity, consumption of red meat, a Western pattern diet, alcohol, and smoking influence one's risk of developing colorectal cancer while physical activity, vitamin D, postmenopausal estrogen use, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs) decrease one's risk. Until recently, it was largely unknown if any of these modifiable factors influence the outcomes of patients already diagnosed with colorectal cancer. However, data are emerging of factors that may influence disease recurrences and mortality for colorectal cancer survivors. Prospective observational studies have shown that increased exercise after diagnosis and avoidance of a Western pattern diet are associated with reduced risk of cancer recurrence and improved overall survival in early-stage colorectal cancer after standard therapy. Patients with class II and III obesity (body mass index [BMI] <35 kg/m 2) have a modestly increased risk of recurrence. Regular use of aspirin or cyclooxygenase (COX)-2 inhibitors decrease recurrence rates and increase serum vitamin D levels. In contrast, change of weight after diagnosis or smoking status (never, past, or current) are not associated with outcomes after diagnosis. The data supporting these observations will be reviewed, potential mechanisms of actions will be discussed, and the next steps forward will be proposed. © 2011 Elsevier Inc. All rights reserved.

Michelson A.D.,Dana-Farber Cancer Institute
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2011

Because of the central role of platelets in cardiovascular atherothrombosis, there is a well-established therapeutic role for antiplatelet therapy that includes aspirin (a cyclooxygenase 1 [COX1] inhibitor), clopidogrel (an antagonist of the ADP P2Y(12) receptor), and the GPIIb-GPIIIa (αIIbβ3) antagonists. However, there remains a significant incidence of arterial thrombosis in patients treated with currently available antiplatelet therapy. Novel P2Y(12) antagonists such as the recently US Food and Drug Administration (FDA)-approved prasugrel, along with ticagrelor, cangrelor, and elinogrel, have advantages over clopidogrel, including more rapid, less variable, and more complete inhibition of platelet function. Currently ongoing phase 3 studies will determine whether these new P2Y(12) antagonists will result in better and/or more rapid antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic or other side effects, as has been recently reported in some clinical settings for prasugrel and ticagrelor. Antagonists of the thrombin receptor protease-activated receptor 1 (PAR1) are also undergoing phase 3 trials, and many other novel antiplatelet agents are under investigation as antithrombotic agents.

Tichy J.R.,University of North Carolina at Chapel Hill | Lim E.,Dana-Farber Cancer Institute | Anders C.K.,University of North Carolina at Chapel Hill
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2013

Breast cancer is a substantial contributor to adolescent and young adult (AYA) malignancies, defined as a diagnosis of cancer between the ages of 15 and 39. In the United States, 6.6% of breast cancer cases are diagnosed among women younger than 40 years. When breast cancer occurs in AYAs, it typically has a worse prognosis and more-Aggressive phenotype; higher proportions of high-grade and later-stage tumors; lower estrogen receptor positivity; and, in some studies, higher expression of HER2. Age-specific differences in the biology of AYA breast cancer have been explored in large-scale genomic studies with mixed results. Although some studies suggest that AYA breast cancer has a unique biology, others have shown that its aggressive nature is the result of higher frequencies of aggressive breast cancer subtypes among younger patients. More recently, stromal-related gene signatures have shown prognostic significance in AYA breast cancer, suggesting that differences in microenvironment may account for age-specific differences in breast cancer behavior. Although general principles for selecting cytotoxic and targeted agents are similar between AYAs and the general breast cancer population, endocrine therapy choices in the adjuvant and metastatic settings vary by pre-And postmenopausal status. The role of ovarian suppression remains controversial and is reviewed. The AYA population is a unique group of patients who need individualized care, including considerations of hereditary breast cancer predispositions, future fertility, and the effect of therapy on immediate and long-term quality of life, all of which require coordinated multidisciplinary care. This article addresses the epidemiology, genetics, and management of breast cancer in AYA women and highlights unique medical issues important to this population. © JNCCN-Journal of the National Comprehensive Cancer Network.

Storer N.Y.,Dana-Farber Cancer Institute
Cold Spring Harbor perspectives in biology | Year: 2010

Zebrafish models have significantly contributed to our understanding of vertebrate development and, more recently, human disease. The growing number of genetic tools available in zebrafish research has resulted in the identification of many genes involved in developmental and disease processes. In particular, studies in the zebrafish have clarified roles of the p53 tumor suppressor in the formation of specific tumor types, as well as roles of p53 family members during embryonic development. The zebrafish has also been instrumental in identifying novel mechanisms of p53 regulation and highlighting the importance of these mechanisms in vivo. This article will summarize how zebrafish models have been used to reveal numerous, important aspects of p53 function.

Kantoff P.,Dana-Farber Cancer Institute
Urologic oncology | Year: 2012

Until recently, the only therapy shown to improve survival in men with metastatic castration-resistant prostate cancer (mCRPC) had been chemotherapy, usually reserved for symptomatic patients. However, sipuleucel-T, a cellular product directed toward a specific antigen, prostatic acid phosphatase, was Food and Drug Administration (FDA) approved in 2010 in the United States, based on phase 3 data showing improved overall survival in men with minimal or no symptoms due to mCRPC compared with placebo. Subsequently, several other promising immunotherapeutic approaches have advanced to study in the phase 3 setting, including ipilimumab and PROSTVAC. The demonstration of efficacy of immunotherapy in prostate cancer provides a new treatment option for men with no or few symptoms early in the course of mCRPC. Since sipuleucel-T was approved, several drugs that favorably impact survival have also been approved or are close to approval in the United States. These agents include cabazitaxel, abiraterone, radium-223, and MDV3100. There are many unresolved issues about sipuleucel-T, such as best timing in the course of mCRPC, the role for booster therapy, and the role of combinations with other active drugs, including other immune-modulating approaches. There are also many questions regarding sequencing of these new agents and, given the number of other promising agents in phase 3 trials, these questions will become more complicated, underscoring the need for better predictors of benefit for the individual patient. Copyright © 2012 Elsevier Inc. All rights reserved.

Stanton A.L.,University of California at San Diego | Petrie K.J.,University of Auckland | Partridge A.H.,Dana-Farber Cancer Institute
Breast Cancer Research and Treatment | Year: 2014

Rates of adherence and persistence with endocrine therapy regimens (i.e., tamoxifen, aromatase inhibitors) by breast cancer survivors are suboptimal, with negative implications for prognosis. This study identified potential contributors to nonadherence and nonpersistence. From an online breast cancer research registry (Army of Women) including approximately 51,000 breast cancer survivors, we recruited 1,371 women who currently were taking endocrine therapy and 94 nonpersisters (i.e., diagnosed during the prior 5 years and on endocrine therapy within the prior 12 months, but no longer taking it). Participants completed an online questionnaire assessing demographic/medical characteristics, general and cancer-related psychosocial variables (i.e., depressive symptoms, anxiety, patient-oncologist relationship quality, cancer recurrence worry, general symptoms), and endocrine therapy-specific variables (i.e., endocrine therapy-related symptoms, perceived endocrine therapy necessity, long-term therapy use concern, endocrine therapy-related emotions). Two weeks later, current users were re-contacted to complete an endocrine therapy adherence measure. In a final regression model, patient-reported nonadherence among current users was significantly associated with lower financial status, a prior switch in endocrine therapies, a poorer relationship with the oncologist, and lower perceived need for and more negative emotions regarding endocrine therapy (adjusted R 2 = 0.15, P < 0.001). In a final logistic regression model, endocrine therapy nonpersisters were significantly more likely than current users to report depressive symptoms, as well as more negative emotions and lower positive emotions related to endocrine therapy (adjusted R 2 = 0.10, P < 0.001). In addition to demographic/medical variables, several potentially modifiable psychosocial characteristics are likely to contribute to endocrine therapy nonadherence and nonpersistence. © 2014 Springer Science+Business Media New York.

Horowitz N.S.,Dana-Farber Cancer Institute
Clinical Obstetrics and Gynecology | Year: 2011

The identification of a pelvic mass during pregnancy can often change a time of happiness and exciting anticipation to 1 of anxiety and fearful unknown. Although diagnosed more commonly with the implementation of ultrasonography as part of routine prenatal care, discovering an adnexal mass during pregnancy remains a rare event. Fortunately, the majority of masses are benign and rarely negatively impact pregnancy outcomes; however, no specific protocols exist for the appropriate management of these women. This study will review the most current incidence, management, and outcomes for women diagnosed with an adnexal mass during pregnancy. © 2011 Lippincott Williams & Wilkins.

Ohno H.,University of California at San Francisco | Shinoda K.,University of California at San Francisco | Spiegelman B.M.,Dana-Farber Cancer Institute | Kajimura S.,University of California at San Francisco
Cell Metabolism | Year: 2012

Brown adipose tissue dissipates energy through heat and functions as a defense against cold and obesity. PPARγ ligands have been shown to induce the browning of white adipocytes; however, the underlying mechanisms remain unclear. Here, we show that PPARγ ligands require full agonism to induce a brown fat gene program preferentially in subcutaneous white adipose. These effects require expression of PRDM16, a factor that controls the development of classical brown fat. Depletion of PRDM16 blunts the effects of the PPARγ agonist rosiglitazone on the induced brown fat gene program. Conversely, PRDM16 and rosiglitazone synergistically activate the brown fat gene program in vivo. This synergy is tightly associated with an increased accumulation of PRDM16 protein, due in large measure to an increase in the half-life of the protein in agonist treated cells. Identifying compounds that stabilize PRDM16 protein may represent a plausible therapeutic pathway for the treatment of obesity and diabetes. © 2012 Elsevier Inc.

Davies J.K.,Dana-Farber Cancer Institute
International journal of hematology | Year: 2011

Alloreactive donor T cells are central to the pathogenesis of Graft-versus-Host Disease (GvHD). Non-specific T cell depletion of donor grafts reduces GvHD, but increases infection and disease relapse. Several strategies are, therefore, in development to selectively remove alloreactive donor T cells prior to transplant while retaining beneficial donor T cells. An alternative approach is ex vivo alloanergization of donor T cells via allostimulation and blockade of costimulatory signals with fusion proteins or monoclonal antibodies. This strategy, which selectively inactivates alloreactive donor T cells, has been tested with some success in previous clinical trials of HLA-mismatched bone marrow transplantation. To build on the findings of these early trials, the strategy is now being tested in a multi-center clinical study of alloanergized donor lymphocyte infusion after HLA-mismatched stem cell transplantation. Recent advances in the understanding of alloanergization include the recognition of the central role played by CD4(+) regulatory T cells and new applications include the combination of alloanergization with T cell redirection to maximize anti-tumor activity. This mini-review will give an overview of the immunological basis for alloanergization, the previous and current clinical applications, and how new pre-clinical data have helped to create exciting new avenues of translational research in this area.

Steensma D.P.,Dana-Farber Cancer Institute
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2011

The appropriate role of iron chelation therapy in the management of patients with myelodysplastic syndromes (MDS) is currently controversial. Some investigators interpret data to indicate that careful attention to iron parameters, with early initiation of iron chelation in patients with evidence suggesting transfusion-associated iron overload, is an important component of high-quality MDS patient care. Other physicians are more skeptical, noting that chelation can be cumbersome or costly, has associated risks, and has not yet been shown to reduce morbidity or mortality in the MDS setting. This article reviews the extent to which iron chelation therapy might be either an important clinical intervention in MDS or a distraction from more pressing clinical concerns. © JNCCN-Journal of the National Comprehensive Cancer Network.

Wucherpfennig K.W.,Dana-Farber Cancer Institute
Cold Spring Harbor perspectives in biology | Year: 2010

The T-cell receptor (TCR)-CD3 complex serves as a central paradigm for general principles of receptor assembly, ligand recognition, and signaling in the immune system. There is no other receptor system that matches the diversity of both receptor and ligand components. The recent expansion of the immunological structural database is beginning to identify key principles of MHC and peptide recognition. The multicomponent assembly of the TCR complex i