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Background: The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single-arm, open-label phase 2 study.Methods: Eligible patients with platinum-treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28-day cycles in a 3-stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate.Results: Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent-to-treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose-normalized maximum serum concentration [Cmax ] after TIW dosing of 0.2 ng/mL/mg).Conclusions: To the authors' knowledge, the current study represents the first clinical trial using genomic-based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting. [ABSTRACT FROM AUTHOR]

Neoadjuvant cisplatin‐based chemotherapy (NAC; 70 mg/m2) is standard of care for muscle‐invasive bladder carcinoma (MIBC). Many patients (pts) cannot receive cisplatin because of renal impairment, and administration of cisplatin 35 mg/m2 on day 1 + 8 or 1 + 2 (i.e., split schedule) is a commonly used alternative. In this retrospective analysis, we compared complete (pT0) and partial (

Background: Platinum (Pt)-based chemotherapy is the standard of care for muscle-invasive bladder cancer (MIBC). However, resistance is a major limitation. Reduced intratumoral drug accumulation is an important mechanism of platinum resistance. Our group previously demonstrated a significant correlation between tissue Pt concentration and tumor response to Pt-based neoadjuvant chemotherapy (NAC) in lung cancer. We hypothesized that increased Pt concentration in radical cystectomy (RC) specimens would correlate with improved pathologic response to Pt-based NAC in MIBC. Methods: A cohort of 19 clinically annotated, archived, fresh frozen RC specimens from patients with MIBC treated with Pt-based NAC was identified [ypT0 (pathologic complete response, pCR), N = 4; ≤ypT1N0M0 (pathologic partial response, pPR), N = 6; ≥ypT2 (minimal pathologic response/progression), N = 9)]. RC specimens from 2 patients with MIBC who did not receive NAC and 1 treated with a non-Pt containing NAC regimen were used as negative controls. Total Pt concentration in normal adjacent urothelial tissue and bladder tumors from RC specimens was measured by flameless atomic absorption spectrophotometry. Results: Total Pt concentration in normal urothelium differed by tumor pathologic response (P = 0.011). Specimens with pCR had the highest Pt concentrations compared to those with pPR (P = 0.0095) or no response/progression (P = 0.020). There was no significant difference in Pt levels in normal urothelium and tumor between pPR and no response/progression groups (P = 0.37; P = 0.25, respectively). Conclusions: Our finding of increased intracellular Pt in RC specimens with pCR following NAC for MIBC compared to those with residual disease suggests that enhanced Pt accumulation may be an important determinant of Pt sensitivity. Factors that modulate intracellular Pt concentration, such as expression of Pt transporters, warrant further investigation as predictive biomarkers of response to Pt-based NAC in MIBC. [ABSTRACT FROM AUTHOR]

We evaluated primary tumors from two cohorts, Spain (N = 111) and Greece (N = 102), for patients who were treated with platinum-based chemotherapy. Patients were tested for HER2 status (IHC score of 3+ or FISH ratio of ⩾2.2) by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), DNA copy number, mRNA expression, and mutation status in patients with metastatic urothelial carcinoma (UC), and its impact on survival. ERBB2 mutation was determined by hotspot sequencing. mRNA expression was assessed using NanoString counting. Association of overall survival (OS) and HER2 status was assessed by a Cox regression model. NIH-3T3 cells containing HER2 V777L were assessed for growth, invasion, and HER2 kinase activation. In all, 22% of Spanish and 4% of Greek cohorts had 3+ HER2 staining by IHC. FISH amplification was identified in 20% of Spanish and 4% of Greek cohorts. Kappa coefficient between FISH and IHC was 0.47. HER2 status was not associated with OS in univariate (Spanish P = 0.34; Greek P = 0.11) or multivariate (Spanish P = 0.49; Greek P = 0.12) analysis. HER2-positive tumors expressed higher levels of HER2 mRNA than HER2-negative tumors (P < 0.001). HER2 mutations (V777L and L755S) were identified in two (2%) patients. In vitro analysis of V777L results in transformation of NIH-3T3 cells, leading to increased growth, invasion on soft agar, and HER2 kinase constitutive activation. In summary, HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. HER2 positivity rates can differ between different populations. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC. [ABSTRACT FROM AUTHOR]

Bladder cancer (BC) is an age-associated malignancy with increased prevalence in the elderly population. Elderly patients are a vulnerable population at increased risk for treatment-related toxicity secondary to medical comorbidities and geriatric syndromes. As a result, this population has been historically undertreated and suffers worse disease-specific outcomes than younger patients with BC. Recognition of this disparity has led to efforts to individualize treatment decisions based on functional status rather than chronologic age in an effort to optimize the use of curative therapies for the fit elderly and modify treatments to reduce the risk of toxicity and disease-related morbidity in vulnerable or frail patients. The comprehensive geriatric assessment is a decision framework that helps to balance underlying health considerations and risks of therapy with aggressiveness of the cancer. Development of systemic therapies with increased efficacy against BC and reduced toxicity are eagerly awaited, as are techniques and interventions to reduce the morbidity from surgery and radiation for patients with BC. [ABSTRACT FROM AUTHOR]

Purpose The impact of bladder cancer diagnosis on health related quality of life is poorly understood. We compared health related quality of life measures in patients before and after bladder cancer diagnosis. Materials and Methods We performed a cross-sectional study in 1,476 patients 65 years old or older with bladder cancer in the SEER-MHOS linkage database between 1998 and 2007 to assess differences in physical and mental component summary scores in 620 and 856 who completed a survey before and after bladder cancer diagnosis, respectively. To determine differences in physical and mental scores in the prediagnosis and post-diagnosis cohorts, we used ANOVA adjusting for baseline covariates. Results There were statistically significant differences in physical and mental component summary scores between the prediagnosis and post-diagnosis groups (-2.7, 95% CI -3.8, -1.7 vs -1.4, 95% CI -2.6, -0.3). In patients with nonmuscle invasive bladder cancer the physical and mental score differences were -1.9 (p <0.01) and -1.4 (p = 0.01), respectively. In those with muscle invasive bladder cancer there was a statistically and clinically significant difference in the physical but not the mental score (-5.3, p <0.01 vs -2.7, p = 0.07). This difference in the physical domain persisted up to 10 years after the diagnosis of muscle invasive bladder cancer. Patients with bladder cancer who had 4 or more comorbid medical conditions and 1 or more deficits in daily living activity were most at risk for low physical component summary scores. Conclusions Future research into interventions to improve health related quality of life and methods to incorporate health related quality of life into decision making models are critical to improve outcomes in older patients with bladder cancer. [ABSTRACT FROM AUTHOR]

While fibroblast growth factor receptor 3 ( FGFR3) is frequently mutated or overexpressed in nonmuscle-invasive urothelial carcinoma ( UC), the prevalence of FGFR3 protein expression and mutation remains unknown in muscle-invasive disease. FGFR3 protein and mRNA expression, mutational status, and copy number variation were retrospectively analyzed in 231 patients with formalin-fixed paraffin-embedded primary UCs, 33 metastases, and 14 paired primary and metastatic tumors using the following methods: immunohistochemistry, NanoString nCounterTM, OncoMap or Affymetrix OncoScanTM array, and Gain and Loss of Analysis of DNA and Genomic Identification of Significant Targets in Cancer software. FGFR3 immunohistochemistry staining was present in 29% of primary UCs and 49% of metastases and did not impact overall survival ( P = 0.89, primary tumors; P = 0.78, metastases). FGFR3 mutations were observed in 2% of primary tumors and 9% of metastases. Mutant tumors expressed higher levels of FGFR3 mRNA than wild-type tumors ( P < 0.001). FGFR3 copy number gain and loss were rare events in primary and metastatic tumors (0.8% each; 3.0% and 12.3%, respectively). FGFR3 immunohistochemistry staining is present in one third of primary muscle-invasive UCs and half of metastases, while FGFR3 mutations and copy number changes are relatively uncommon. [ABSTRACT FROM AUTHOR]

BACKGROUND There have been no improvements in the treatment of metastatic urothelial cancer in the past several decades. A census of contemporary clinical research in this disease was performed to identify potential barriers and opportunities. METHODS These authors performed a search for clinical trials exploring interventions in muscle-invasive and metastatic urothelial cancer, using the ClinicalTrials.gov registry. Data extracted from the registry included title, recruitment status, interventions, sponsor, phase, enrollment, study design, and study sites. RESULTS Among 120 eligible trials exploring interventions in muscle-invasive and metastatic urothelial cancer, 73% were phase 2 and 73% were nonrandomized. The majority (63%) involved treatment in the metastatic disease state. The median planned enrollment size per trial was 45 patients (interquartile range, 47 patients). The majority of trials (55%) involved ≤ 3 study sites. Trials most commonly explored interventions in the first-line metastatic (30%) or second-line metastatic (37%) settings. Targeted therapeutics were studied in 58% of the trials. Among 56 trials that completed enrollment, the median time to complete accrual was 50 months (range, 10-109 months), and these trials enrolled a median of 40 patients per trial (interquartile range, 44 patients). CONCLUSIONS The majority of contemporary clinical trials in muscle-invasive and metastatic urothelial cancer are small, nonrandomized, phase 2 trials involving 1 to 3 study sites. Enhanced communication and collaboration among the urothelial cancer community, and other stakeholders, is needed to facilitate the design and conduct of trials capable of expediting progress in this disease. Cancer 2013;119:1994-1998. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Participation of women in the medical profession has increased during the past four decades, but issues of concern persist regarding disparities between the sexes in academic medicine. Advancement is largely driven by peer-reviewed original research, so we sought to determine the representation of female physician-investigators among the authors of selected publications during the past 35 years. Methods: Original articles from six prominent medical journals — the New England Journal of Medicine (NEJM), the Journal of the American Medical Association (JAMA), the Annals of Internal Medicine (Ann Intern Med), the Annals of Surgery (Ann Surg), Obstetrics & Gynecology (Obstet Gynecol), and the Journal of Pediatrics (J Pediatr) — were categorized according to the sex of both the first and the senior (last listed) author. Sex was also determined for the authors of guest editorials in NEJM and JAMA. Data were collected for the years 1970, 1980, 1990, 2000, and 2004. The analysis was restricted to authors from U.S. institutions holding M.D. degrees. Results: The sex was determined for 98.5 percent of the 7249 U.S. authors of original research with M.D. degrees. The proportion of first authors who were women increased from 5.9 percent in 1970 to 29.3 percent in 2004 (P<0.001), and the proportion of senior authors who were women increased from 3.7 percent to 19.3 percent (P<0.001) during the same period. The proportion of authors who were women increased most sharply in Obstet Gynecol (from 6.7 percent of first authors and 6.8 percent of senior authors in 1970 to 40.7 percent of first authors and 28.0 percent of senior authors in 2004) and J Pediatr (from 15.0 percent of first authors and 4.3 percent of senior authors in 1970 to 38.9 percent of first authors and 38.0 percent of senior authors in 2004) and remained low in Ann Surg (from 2.3 percent of first authors and 0.7 percent of senior authors in 1970 to 16.7 percent of first authors and 6.7 percent of senior authors in 2004). In 2004, 11.4 percent of the authors of guest editorials in NEJM and 18.8 percent of the authors of guest editorials in JAMA were women. Conclusions: Over the past four decades, the proportion of women among both first and senior physician-authors of original research in the United States has significantly increased. Nevertheless, women still compose a minority of the authors of original research and guest editorials in the journals studied. N Engl J Med 2006;355:281-7. [ABSTRACT FROM AUTHOR]

Objective: Understanding socioeconomic disparities in the care of patients with incurable cancer is a high priority. We hypothesized that patients without a high school education are more likely to believe that they could be cured and we explored the role of fatalism.Methods: We studied 977 patients with advanced, incurable cancer. Two logistic regression analyses were conducted. Model One examined the effect of education on beliefs about curability. Model Two added fatalism.Results: The significant association between having less than a high school education and the belief that advanced cancer can be cured (OR=2.55; 95% CI: 1.09-5.96) in Model One was attenuated by 39% and rendered nonsignificant in Model Two. Fatalism was associated with the belief that advanced cancer can be cured. Whites were less likely to believe they could be cured than Blacks and Asians/Pacific Islanders. Beliefs about curability were not associated with income or insurance status.Conclusions: People who do not complete high school are more likely to believe that their advanced cancer is curable, in part because they are more likely to hold fatalistic worldviews.Practice Implications: Interventions to help oncologists care for patients with fatalistic beliefs could mitigate socioeconomic disparities in end-of-life care. [ABSTRACT FROM AUTHOR]