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Antonarakis E.S.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Hormones and Cancer | Year: 2014

The FDA approvals of enzalutamide and abiraterone have rapidly changed the clinical landscape of prostate cancer treatment. Both drugs were designed to further suppress androgen receptor (AR) signaling, which is restored following first-line androgen deprivation therapies. Resistance to enzalutamide and abiraterone, however, is again marked by a return of AR signaling, indicating a remarkable “addiction” of prostate cancer cells to the AR pathway. Several mechanisms of castration resistance have been uncovered in the past decades, featuring a wide spectrum of molecular alterations that may explain sustained AR signaling in castration-resistant prostate cancers (CRPC). Among these, the androgen receptor splice variants (AR-Vs), particularly variant 7 (AR-V7), have been implicated in resistance to enzalutamide and abiraterone in preclinical studies, and they cannot be targeted by currently available AR-directed drugs. Drug development for AR-V-associated CRPC may therefore be necessary to augment the preexisting treatment repertoire. In this mini-review, we will discuss general mechanisms of resistance to AR-directed therapies, with a focus on the role of androgen receptor splice variants in the new era of treating advanced prostate cancer with enzalutamide and abiraterone. © 2014, Springer Science+Business Media New York.

Sartor O.,Tulane Cancer Center | Eisenberger M.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Kattan M.W.,Cleveland Clinic | Tombal B.,Catholic University of Louvain | Lecouvet F.,Catholic University of Louvain
Oncologist | Year: 2013

The therapeutic landscape for the treatment of advanced prostate cancer is rapidly evolving, especially for those patients with metastatic castration-resistant prostate cancer (CPRC). Despite advances in therapy options, the diagnostic landscape has remained relatively static, with few guidelines or reviews addressing the optimal timing or methodology for the radiographic detectionofmetastaticdisease.Givenrecentreportsindicatinga substantial proportion of patients with CRPC thought to be nonmetastatic (M0) are in fact metastatic (M1), there is now a clear opportunity and need for improvement in detection practices. Herein, we discuss the current status of predicting the presence of metastatic disease, with a particular emphasis on the detection of the M0 to M1 transition. In addition, we review current data on newer imaging technologies that are changing the way metastases are detected. Whether earlier detection of metastatic disease will ultimately improve patient outcomes is unknown, but given that the therapeutic options for those with metastatic and nonmetastaticCPRCvary, there are considerable implications ofhowand when metastases are detected. ©AlphaMed Press 2013.

Cohen K.J.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Current Treatment Options in Oncology | Year: 2014

Approximately 70 % of newly diagnosed children with medulloblastoma (MB) will be classified as “standard risk”: their tumor is localized to the posterior fossa, they undergo a near or gross total resection, the tumor does not meet the criteria for large cell/anaplastic histology, and there is no evidence of neuroaxis dissemination by brain/spine MRI and lumbar puncture for cytopathology. Following surgical recovery, they are treated with craniospinal radiation therapy with a boost to the posterior fossa or tumor bed. Adjuvant therapy for approximately 1 year follows anchored by the use of alkylators, platinators, and microtubule inhibitors. This approach to standard risk MB works; greater than 80 % of patients will be cured, and such approaches are arguably the standard of care worldwide for such children. Despite this success, some children with standard risk features will relapse and die of recurrent disease despite aggressive salvage therapy. Moreover, current treatment, even when curative causes life-long morbidity in those who survive, and the consequences are age dependent. For the 20-year-old patient, damage to the cerebellum from surgery conveys greater risk than craniospinal radiation; however, for the 3-year-old patient, the opposite is true. The challenge for the neuro-oncologist today is how to identify accurately patients who need less therapy as well as those for whom current therapy is inadequate. As molecular diagnostics comes of age in brain tumors, the question becomes how to best implement novel methods of risk stratification. Are we able to obtain specific information about the tumor’s biology in an increasingly rapid and reliable way, and utilize these findings in the upfront management of these tumors? Precision medicine should allow us to tailor therapy to the specific drivers of each patient’s tumor. Regardless of how new approaches are implemented, it is likely that we will no longer be able to have a single standard approach to standard risk medulloblastoma in the near future. © 2014, Springer Science+Business Media New York.

Shelton B.K.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Critical Care Clinics | Year: 2010

Critical care for patients with cancer was once considered inappropriate because of a perceived poor prognosis for their long-term survival. Three decades of research has yielded evidence to support the use of critical care resources for many patients with cancer. A methodical approach to triage and evaluation of critically ill patients regardless of baseline medical diagnosis, coupled with an appreciation for the likely prognosis of their current cancer, is most likely to yield the fairest and most accurate appropriation of care. No clinical scoring system has emerged that accurately defines the severity of illness and likelihood for survival in patients with cancer. This article reviews the studies that have attempted to apply mortality prediction scales or scoring systems to these patients. Clinical judgment with incorporation of consensus opinions from the literature should be used to develop admission or restriction criteria for intensive care of patients with cancer. © 2010 Elsevier Inc. All rights reserved.

Fecher L.A.,Indiana University | Fecher L.A.,University of Michigan | Sharfman W.H.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Biologics: Targets and Therapy | Year: 2015

Cutaneous basal cell carcinoma (BCC) is the most common human cancer and its incidence is rising worldwide. Ultraviolet radiation exposure, including tanning bed use, as well as host factors play a role in its development. The majority of cases are treated and cured with local therapies including surgery. Yet, the health care costs of diagnosis and treatment of BCCs in the US is substantial. In the United States, the cost of nonmelanoma skin cancer care in the Medicare population is estimated to be US$426 million per year. While rare, locally advanced BCCs that can no longer be controlled with surgery and/or radiation, and metastatic BCCs do occur and can be associated with significant morbidity and mortality. Vismodegib (GDC-0449), a smoothened inhibitor targeted at the hedgehog pathway, is the first US Food and Drug Association (FDA)-approved agent in the treatment of locally advanced, unresectable, and metastatic BCCs. This class of agents appears to be changing the survival rates in advanced BCC patients, but appropriate patient selection and monitoring are important. Multidisciplinary assessments are essential for the optimal care and management of these patients. For some patients with locally advanced BCC, treatment with a hedgehog inhibitor may eliminate the need for an excessively disfiguring or morbid surgery. © 2015 Fecher and Sharfman.

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