Filson C.P.,University of California at Los Angeles |
Marks L.S.,University of California at Los Angeles |
Litwin M.S.,Urologic |
Litwin M.S.,University of California at Los Angeles
CA Cancer Journal for Clinicians | Year: 2015
Answer questions and earn CME/CNE Since the dissemination of prostate-specific antigen screening, most men with prostate cancer are now diagnosed with localized, low-risk prostate cancer that is unlikely to be lethal. Nevertheless, nearly all of these men undergo primary treatment with surgery or radiation, placing them at risk for longstanding side effects, including erectile dysfunction and impaired urinary function. Active surveillance and other observational strategies (ie, expectant management) have produced excellent long-term disease-specific survival and minimal morbidity for men with prostate cancer. Despite this, expectant management remains underused for men with localized prostate cancer. In this review, various approaches to the expectant management of men with prostate cancer are summarized, including watchful waiting and active surveillance strategies. Contemporary cancer-specific and health care quality-of-life outcomes are described for each of these approaches. Finally, contemporary patterns of use, potential disparities in care, and ongoing research and controversies surrounding expectant management of men with localized prostate cancer are discussed. CA Cancer J Clin 2015;65:264-282. © 2015 American Cancer Society.
Neckers L.,Urologic |
Workman P.,Institute of Cancer Research
Clinical Cancer Research | Year: 2012
Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone that is exploited by malignant cells to support activated oncoproteins, including many cancer-associated kinases and transcription factors, and it is essential for oncogenic transformation. Originally viewed with skepticism, Hsp90 inhibitors are now being actively pursued by the pharmaceutical industry, with 17 agents having entered clinical trials. Investigators established Hsp90's druggability using the natural products geldanamycin and radicicol, which mimic the unusual ATP structure adopted in the chaperone's N-terminal nucleotide-binding pocket and cause potent and selective blockade of ATP binding/hydrolysis, inhibit chaperone function, deplete oncogenic clients, and show antitumor activity. Preclinical data obtained with these natural products have heightened interest in Hsp90 as a drug target, and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has shown clinical activity (as defined by Response Evaluation Criteria in Solid Tumors) in HER2+ breast cancer. Many optimized synthetic, small-molecule Hsp90 inhibitors from diverse chemotypes are now in clinical trials. Here, we review the discovery and development of Hsp90 inhibitors and assess their potential. There has been significant learning from studies of the basic biology of Hsp90, as well as translational drug development involving this chaperone, enhanced by the use of Hsp90 inhibitors as chemical probes. Success will likely lie in treating cancers that are addicted to particular driver oncogene products (e.g., HER2, ALK, EGFR, and BRAF) that are sensitive Hsp90 clients, as well as malignancies (especially multiple myeloma) in which buffering of proteotoxic stress is critical for survival. We discuss approaches for enhancing the effectiveness of Hsp90 inhibitors and highlight new chaperone and stress-response pathway targets, including HSF1 and Hsp70. ©2012 AACR.
Clinical Journal of the American Society of Nephrology | Year: 2014
The National Institute of Diabetes and Digestive and Kidney Diseases–supported Kidney Research National Dialogue asked the scientific community to formulate and prioritize research objectives aimed at improved understanding of kidney function and disease progression. Over the past 2 years, 1600 participants posted almost 300 ideas covering all areas of kidney disease. An overriding theme that evolved through these discussions is the need to move beyond pathology to take advantage of basic science and clinical research opportunities to improve diagnostic classification and therapeutic options for people with primary glomerular disease. High-priority research areas included focus on therapeutic targets in glomerular endothelium and podocytes, regenerating podocytes through developmental pathways, use of longitudinal phenotypically defined disease cohorts to improve classification schemes, identifying biomarkers, disease-specific therapeutics, autoantibody triggers, and changing the clinical research culture to promote participation in clinical trials. Together, these objectives provide a path forward for improving clinical outcomes of glomerular disease. © 2014 by the American Society of Nephrology
Mollapour M.,Urologic |
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2012
Molecular chaperones, as the name suggests, are involved in folding, maintenance, intracellular transport, and degradation of proteins as well as in facilitating cell signaling. Heat shock protein 90 (Hsp90) is an essential eukaryotic molecular chaperone that carries out these processes in normal and cancer cells. Hsp90 function in vivo is coupled to its ability to hydrolyze ATP and this can be regulated by co-chaperones and post-translational modifications. In this review, we explore the varied roles of known post-translational modifications of cytosolic and nuclear Hsp90 (phosphorylation, acetylation, S-nitrosylation, oxidation and ubiquitination) in fine-tuning chaperone function in eukaryotes. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90). © 2011.
Genome Research | Year: 2012
Kidney cancer is not a single disease; it is made up of a number of different types of cancer, including clear cell, type 1 papillary, type 2 papillary, chromophobe, TFE3, TFEB, and oncocytoma. Sporadic, nonfamilial kidney cancer includes clear cell kidney cancer (75%), type 1 papillary kidney cancer (10%), papillary type 2 kidney cancer (including collecting duct and medullary RCC) (5%), the microphalmia-associated transcription (MiT) family translocation kidney cancers (TFE3, TFEB, and MITF), chromophobe kidney cancer (5%), and oncocytoma (5%). Each has a distinct histology, a different clinical course, responds differently to therapy, and is caused by mutation in a different gene. Genomic studies identifying the genes for kidney cancer, including the VHL, MET, FLCN, fumarate hydratase, succinate dehydrogenase, TSC1, TSC2, and TFE3 genes, have significantly altered the ways in which patients with kidney cancer are managed. While seven FDA-approved agents that target the VHL pathway have been approved for the treatment of patients with advanced kidney cancer, further genomic studies, such as whole genome sequencing, gene expression patterns, and gene copy number, will be required to gain a complete understanding of the genetic basis of kidney cancer and of the kidney cancer gene pathways and, most importantly, to provide the foundation for the development of effective forms of therapy for patients with this disease. © 2012, Published by Cold Spring Harbor Laboratory Press.
The oncologist | Year: 2011
In the past 15 years, there has been an increased understanding of the tumor biology of renal cell carcinoma (RCC). The identification of vascular endothelial growth factor (VEGF), its related receptor (VEGFR), and the mammalian target of rapamycin as dysregulated signaling pathways in the development and progression of RCC has resulted in the rational development of pharmaceutical agents capable of specifically targeting key steps in these pathways. Clinical trials have demonstrated survival benefit with these agents, particularly in clear cell RCC patients. However, metastatic RCC will progress in all patients, resulting in a critical need to determine patient risk and optimize treatment. The goal of this article is to highlight the significant breakthroughs made in understanding the critical genetic alterations and signaling pathways underlying the pathogenesis of RCC. The discovery of prognostic factors and development of comprehensive nomograms to stratify patient risk and predictive biomarkers to facilitate individualized treatment selection and predict patient response to therapy also are reviewed.
Advances in Anatomic Pathology | Year: 2013
TMPRSS2:ERG gene fusions, the most common molecular subtype of ETS family gene fusions occur in ∼50% of prostate carcinomas (PCas) and ∼20% of high-grade prostatic intraepithelial neoplasia (HGPIN) intermingled with adjacent PCa demonstrating identical gene fusions. ERG gene fusions have not yet been demonstrated in isolated benign prostate tissue, isolated high-grade prostatic intraepithelial neoplasia, or benign cancer mimics. Taken together, ERG gene fusions are the most prostate cancer-specific biomarker yet identified and define a specific molecular subtype of PCa with important clinical and biological implications. ERG gene fusions result in the overexpression of a chimeric fusion transcript that encodes a truncated ERG protein product. Recently, N-terminal epitope-targeted mouse (9FY) and C-terminal-targeted rabbit monoclonal (EPR 3864) ERG antibodies are commercially available and are increasingly utilized as a surrogate for TMPRSS2:ERG gene fusions. Until recently, because of lack of availability of reliable ERG antibody, the most commonly utilized methods for studying ERG aberrations in PCa specimens included fluorescence in situ hybridization or reverse transcriptase polymerase chain reaction. The knowledge gleaned from these studies has significantly improved our understanding of molecular biology of ERG gene fusions. With availability of highly specific anti-ERG monoclonal antibodies, there are now unprecedented opportunities to explore and validate clinical applications of ERG antibody in routine pathology practice, which has just started. This review provides a brief background of molecular biology of ERG gene fusions in PCa and focuses on characterizing the current state of ERG oncoprotein and determining the role of ERG immunohistochemistry in the diagnosis and biological stratification of prostate cancer. Copyright © 2013 by Lippincott Williams & Wilkins.
Linehan W.M.,Urologic |
Rouault T.A.,U.S. National Institutes of Health
Clinical Cancer Research | Year: 2013
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for development of cutaneous and uterine leiomyomas and an aggressive form of type II papillary kidney cancer. HLRCC is characterized by germline mutation of the tricarboxylic acid (TCA) cycle enzyme, fumarate hydratase (FH). FH-deficient kidney cancer is characterized by impaired oxidative phosphorylation and a metabolic shift to aerobic glycolysis, a form of metabolic reprogramming referred to as the Warburg effect. Increased glycolysis generates ATP needed for increased cell proliferation. In FH-deficient kidney cancer, levels of AMP-activated protein kinase (AMPK), a cellular energy sensor, are decreased resulting in diminished p53 levels, decreased expression of the iron importer, DMT1, leading to low cellular iron levels, and to enhanced fatty acid synthesis by diminishing phosphorylation of acetyl CoA carboxylase, a rate-limiting step for fatty acid synthesis. Increased fumarate and decreased iron levels in FH-deficient kidney cancer cells inactivate prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor (HIF)-1a and increased expression of genes such as VEGF and glucose transporter 1 (GLUT1) to provide fuel needed for rapid growth demands. Several therapeutic approaches for targeting the metabolic basis of FH-deficient kidney cancer are under development or are being evaluated in clinical trials, including the use of agents such as metformin, which would reverse the inactivation of AMPK, approaches to inhibit glucose transport, lactate dehydrogenase A (LDHA), the antioxidant response pathway, the heme oxygenase pathway, and approaches to target the tumor vasculature and glucose transport with agents such as bevacizumab and erlotinib. These same types of metabolic shifts, to aerobic glycolysis with decreased oxidative phosphorylation, have been found in a wide variety of other cancer types. Targeting the metabolic basis of a rare cancer such as FH-deficient kidney cancer will hopefully provide insights into the development of effective forms of therapies for other, more common forms of cancer. ©2013 AACR.
Urologic | Date: 2014-05-27
The invention is a simple surgical drape system for female urology procedures that provides sealed isolation of top versus bottom sides of the drape and only exposes the female urethral meatus area for the procedure. It is achieved by a combination of a drape with a fenestration, a labia spreader where the drape fenestration is attached to provide a seal, and local illumination of the meatus area integrated in the drape system for safer and easier instrument insertion. The labia spreader also frees up one of the operators hands and provides protection for false catherization. The labia spreader can have a vaginal inserted portion for precise position fixation of the drape fenestration to the female. The drape system also provides improved liquid management made possible by the unique combination of drape and labia spreader acting as seal between the two sides of the drape.
Urologic | Date: 2015-11-12
Device and method for correcting urinary incontinence and urinary retention, by implanting a urinary flow control device for elective user control of urinary function in male and female patients. The device is a mechanical valve to a natural or artificial bladder, and includes a to reach the abdominal wall of the patient. Preferably a bladder anti-prolapse skirt is attached between the bladder and control valve. The device provides a urine flow channel that passes through the valve from one side to the other of a valve seat where an actuator with a mating stopper is controlled to open and close the valve at the election of the user with an external controller. The valve is an occlusion type (seat with stopper), or a pinch type. The flow channel may be an artificial urethra passing through a pinch valve.