Dana Farber Brigham and Womens Cancer Center

Brigham City, United States

Dana Farber Brigham and Womens Cancer Center

Brigham City, United States
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Ravandi F.,University of Texas M. D. Anderson Cancer Center | Stone R.,Dana Farber Brigham and Womens Cancer Center
Clinical Lymphoma, Myeloma and Leukemia | Year: 2017

Treatment of patients with acute promyelocytic leukemia has significantly improved with the introduction of target specific agents all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) with long term survival a reality for the majority of patients. This can serve as a paradigm for cancer therapy where with the introduction of more potent target-specific drugs our reliance on the traditional cytotoxic agents is likely to diminish and less toxic and more effective regimens are likely to replace the current intensive chemotherapy regimens. © 2017 Elsevier Inc.

Milbury C.A.,Dana Farber Brigham and Womens Cancer Center | Li J.,Dana Farber Brigham and Womens Cancer Center | Makrigiorgos G.M.,Dana Farber Brigham and Womens Cancer Center
Nucleic Acids Research | Year: 2011

Identifying low-abundance mutations within wild-type DNA is important in several fields of medicine, including cancer, prenatal diagnosis and infectious diseases. However, utilizing the clinical and diagnostic potential of rare mutations is limited by sensitivity of the molecular techniques employed, especially when the type and position of mutations are unknown. We have developed a novel platform that incorporates a synthetic reference sequence within a polymerase chain reaction (PCR) reaction, designed to enhance amplification of unknown mutant sequences during COLD-PCR (CO-amplification at Lower Denaturation temperature). This new platform enables an Improved and Complete Enrichment (ice-COLD-PCR) for all mutation types and eliminates shortcomings of previous formats of COLD-PCR. We evaluated ice-COLD-PCR enrichment in regions of TP53 in serially diluted mutant and wild-type DNA mixtures. Conventional-PCR, COLD-PCR and ice-COLD-PCR amplicons were run in parallel and sequenced to determine final mutation abundance for a range of mutations representing all possible single base changes. Amplification by ice-COLD-PCR enriched all mutation types and allowed identification of mutation abundances down to 1, and 0.1 by Sanger sequencing or pyrosequencing, respectively, surpassing the capabilities of other forms of PCR. Ice-COLD-PCR will help elucidate the clinical significance of low-abundance mutations and our understanding of cancer origin, evolution, recurrence-risk and treatment diagnostics. © 2010 The Author(s).

Watanabe R.,Harvard University | Gehad A.,Harvard University | Yang C.,Harvard University | Scott L.L.,Harvard University | And 10 more authors.
Science Translational Medicine | Year: 2015

The skin of an adult human contains about 20 billion memory T cells. Epithelial barrier tissues are infiltrated by a combination of resident and recirculating T cells in mice, but the relative proportions and functional activities of resident versus recirculating T cells have not been evaluated in human skin. We discriminated resident from recirculating T cells in human-engrafted mice and lymphoma patients using alemtuzumab, a medication that depletes recirculating T cells from skin, and then analyzed these T cell populations in healthy human skin. All nonrecirculating resident memory T cells (TRM) expressed CD69, but most were CD4+, CD103-, and located in the dermis, in contrast to studies in mice. Both CD4+ and CD8+ CD103+ TRM were enriched in the epidermis, had potent effector functions, and had a limited proliferative capacity compared to CD103- TRM. TRM of both types had more potent effector functions than recirculating T cells. We observed two distinct populations of recirculating T cells, CCR7+/L-selectin+ central memory T cells (TCM) and CCR7+/L-selectin- T cells, which we term migratory memory T cells (TMM). Circulating skin-tropic TMM were intermediate in cytokine production between TCM and effector memory T cells. In patients with cutaneous T cell lymphoma, malignant TCM and TMM induced distinct inflammatory skin lesions, and TMM were depleted more slowly from skin after alemtuzumab, suggesting that TMM may recirculate more slowly. In summary, human skin is protected by four functionally distinct populations of T cells, two resident and two recirculating, with differing territories of migration and distinct functional activities. © 2015, American Association for the Advancement of Science. All rights reserved.

Wilder R.B.,Moffitt Cancer Center | Buyyounouski M.K.,Fox Chase Cancer Center | Efstathiou J.A.,Massachusetts General Hospital | Beard C.J.,Dana Farber Brigham and Womens Cancer Center
International Journal of Radiation Oncology Biology Physics | Year: 2012

Virtually all patients with Stage I testicular seminoma are cured regardless of postorchiectomy management. For patients treated with adjuvant radiotherapy, late toxicity is a major concern. However, toxicity may be limited by radiotherapy techniques that minimize radiation exposure of healthy normal tissues. This article is an evidence-based review that provides radiotherapy treatment planning recommendations for testicular seminoma. The minority of Stage I patients who choose adjuvant treatment over surveillance may be considered for (1) para-aortic irradiation to 20 Gy in 10 fractions, or (2) carboplatin chemotherapy consisting of area under the curve, AUC = 7 × 1-2 cycles. Two-dimensional radiotherapy based on bony anatomy is a simple and effective treatment for Stage IIA or IIB testicular seminoma. Centers with expertise in vascular and nodal anatomy may consider use of anteroposterior- posteroanterior fields based on three-dimensional conformal radiotherapy instead. For modified dog-leg fields delivering 20 Gy in 10 fractions, clinical studies support placement of the inferior border at the top of the acetabulum. Clinical and nodal mapping studies support placement of the superior border of all radiotherapy fields at the top of the T12 vertebral body. For Stage IIA and IIB patients, an anteroposterior-posteroanterior boost is then delivered to the adenopathy with a 2-cm margin to the block edge. The boost dose consists of 10 Gy in 5 fractions for Stage IIA and 16 Gy in 8 fractions for Stage IIB. Alternatively, bleomycin, etoposide, and cisplatin chemotherapy for 3 cycles or etoposide and cisplatin chemotherapy for 4 cycles may be delivered to Stage IIA or IIB patients (e.g., if they have a horseshoe kidney, inflammatory bowel disease, or a history of radiotherapy). © 2012 Elsevier Inc.

Alexander B.M.,Dana Farber Brigham and Womens Cancer Center | Ligon K.L.,Dana Farber Brigham and Womens Cancer Center | Wen P.Y.,Center for Neuro Oncology
Expert Review of Anticancer Therapy | Year: 2013

Radiation therapy has been the foundation of therapy following maximal surgical resection in patients with newly diagnosed glioblastoma for decades and the primary therapy for unresected tumors. Using the standard approach with radiation and temozolomide, however, outcomes are poor, and glioblastoma remains an incurable disease with the majority of recurrences and progression within the radiation treatment field. As such, there is much interest in elucidating the mechanisms of resistance to radiation therapy and in developing novel approaches to overcoming this treatment resistance. © 2013 2013 Expert Reviews Ltd.

Arvold N.D.,Dana Farber Brigham and Womens Cancer Center | Reardon D.A.,Center for Neuro Oncology
Clinical Interventions in Aging | Year: 2014

Age remains the most powerful prognostic factor among glioblastoma (GBM) patients. Half of all patients with GBM are aged 65 years or older at the time of diagnosis, and the incidence rate of GBM in patients aged over 65 years is increasing rapidly. Median survival for elderly GBM patients is less than 6 months and reflects less favorable tumor biologic factors, receipt of less aggressive care, and comorbid disease. The standard of care for elderly GBM patients remains controversial. Based on limited data, extensive resection appears to be more beneficial than biopsy. For patients with favorable Karnofsky performance status (KPS), adjuvant radiotherapy (RT) has a demonstrated survival benefit with no observed decrement in quality of life. Concurrent and adjuvant temozolomide (TMZ) along with RT to 60 Gy have not been prospectively studied among patients aged over 70 years but should be considered for patients aged 65-70 years with excellent KPS. Based on the recent NOA-08 and Nordic randomized trials, testing for O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation should be performed routinely immediately after surgery to aid in adjuvant treatment decisions. Patients aged over 70 years with favorable KPS, or patients aged 60-70 years with borderline KPS, should be considered for monotherapy utilizing standard TMZ dosing for patients with MGMT-methylated tumors, and hypofractionated RT (34 Gy in ten fractions or 40 Gy in 15 fractions) for patients with MGMT-unmethylated tumors. The ongoing European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial will help clarify the role for concurrent TMZ with hypofractionated RT. For elderly patients with poor KPS, reasonable options include best supportive care, TMZ alone, hypofractionated RT alone, or whole brain RT for symptomatic patients needing to start treatment urgently. Given the balance between short survival and quality of life in this patient population, optimal management of elderly GBM patients must be made individually according to patient age, MGMT methylation status, performance score, and patient preferences. © 2014 Arvold and Reardon.

Yakoumakis N.,Dana Farber Brigham and Womens Cancer Center
Journal of applied clinical medical physics / American College of Medical Physics | Year: 2012

In this work we used 4D dose calculations, which include the effects of shape deformations, to investigate an alternative approach to creating the ITV. We hypothesized that instead of needing images from all the breathing phases in the 4D CT dataset to create the outer envelope used for treatment planning, it is possible to exclude images from the phases closest to the inhale phase. We used 4D CT images from 10 patients with lung cancer. For each patient, we drew a gross tumor volume on the exhale-phase image and propagated this to the images from other phases in the 4D CT dataset using commercial image registration software. We created four different ITVs using the N phases closest to the exhale phase (where N = 10, 8, 7, 6). For each ITV contour, we created a volume-modulated arc therapy plan on the exhale-phase CT and normalized it so that the prescribed dose covered at least 95% of the ITV. Each plan was applied to CT images from each CT phase (phases 1-10), and the calculated doses were then mapped to the exhale phase using deformable registration. The effect of the motion was quantified using the dose to 95% of the target on the exhale phase (D95) and tumor control probability. For the three-dimensional and 4D dose calculations of the plan where N = 10, differences in the D95 value varied from 3% to 14%, with an average difference of 7%. For 9 of the 10 patients, the reduction in D95 was less than 5% if eight phases were used to create the ITV. For three of the 10 patients, the reduction in the D95 was less than 5% if seven phases were used to create the ITV. We were unsuccessful in creating a general rule that could be used to create the ITV. Some reduction (8/10 phases) was possible for most, but not all, of the patients, and the ITV reduction was small.

Alexander B.M.,Dana Farber Brigham and Womens Cancer Center | Mehta M.P.,Northwestern University
Expert Review of Neurotherapeutics | Year: 2011

Recently, the isocitrate dehydrogenase (IDH) enzymes have become a focal point for research aimed at understanding the biology of glioma and identifying novel targets for therapy. Following the publication of a landmark genetic sequencing study in 2008, which identified IDH1 as a frequently mutated gene in glioblastoma, much work has been carried out to further characterize the frequency, associations and clinical implications of IDH1/2 mutations. Mutations in IDH genes are thought to occur early in tumorigenesis and define a subgroup of glioma that are characterized by specific metabolic changes and improved prognosis. At present, assays identifying tumors with IDH1 mutations are clinically useful as prognostic markers. While the mechanisms linking IDH1/2 mutations to tumor development are still under investigation, the cellular milieu created by these mutations offers potential targets for the development of novel therapeutics. © 2011 Expert Reviews Ltd.

Kulke M.H.,Dana Farber Brigham and Womens Cancer Center
Seminars in Oncology | Year: 2013

Neuroendocrine tumors (NETs) occur throughout the body, and share similar histologic characteristics. However, it has become increasingly evident that pancreatic NETs tend to respond differently to therapeutic agents than do other NET subtypes. In most cases, systemic therapy has been more effective in NETs of pancreatic origin than in NETs arising from other locations. Traditional systemic treatment options for pancreatic NETs include somatostatin analogs or cytotoxic chemotherapy. Recently, the biologically targeted agents everolimus and sunitinib were approved for use in patients with metastatic disease. Novel agents, as well as novel drug combinations, are currently under investigation. © 2013 Elsevier Inc.

Martin N.E.,Dana Farber Brigham and Womens Cancer Center
Current Opinion in Oncology | Year: 2016

PURPOSE OF REVIEW: The initial management of localized prostate cancer is increasingly complex with the identification of a growing number of prognostic subgroups. Molecular and genetic biomarkers have been proposed to help clinicians and patients navigate treatment decisions. RECENT FINDINGS: Three commercially available tests, the Genomic Prostate score, Cell Cycle Progression score, and Genomic Classifier appear to currently have the most supporting data for their use in localized prostate cancer. All three have been shown to identify men at higher risk for poor outcome following radical prostatectomy in retrospective studies whereas the first two have also shown promise in addressing which men might be appropriate for active surveillance. Only the Genomic Classifier has data supporting its use as a predictive marker in addition to a prognostic marker. SUMMARY: Over the past several years, the management of localized prostate cancer has seen the development of several novel biomarkers aimed at improving decision making. Although a lack of prospective validation makes it challenging to know how best to change management based on the results from any of the tests, the growing body of retrospective data suggests significant promise in this arena. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

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