Evaluating the association of multiple single nucleotide polymorphisms with response to gemcitabine and platinum combination chemotherapy in urothelial carcinoma of the bladder
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OBJECTIVE: To examine germline single nucleotide polymorphisms (SNPs) as markers of response to gemcitabine platinum (GP) combination chemotherapy in urothelial carcinoma (UC). METHODS: Saliva or blood was prospectively collected from 216 patients treated with GP for UC of the bladder between 1991 and 2011. Based on reported associations with gemcitabine and cisplatin response or putative mechanisms of gemcitabine or cisplatin/carboplatin activity, we selected SNPs of interest and were able to genotype 59 SNPs (using the SequenomMass ARRAYiPLEX platform) in 261 patients randomly split 2/3 into a training set (n = 174) and 1/3 into a test set (n = 87). Logistic regression was used to test the association between response to GP and SNPs. RESULTS: The median age at diagnosis was 64 years (range: 28 - 85) for the discovery set and 67 years (range: 30 - 84) for the validation set. Males composed 76% and 69%, and white non-Hispanics composed 88% and 91% of the training and test validation sets, respectively. Three SNPs on GALNTL4 (rs7937567, rs12278731, and rs9988868) and one intergenic SNP (rs1321391) were significantly associated with response to GP in the training set and were used to build a SNP score. However, when assessed in the test set, the SNP score was not significantly associated with response. CONCLUSION: Multiple SNPs selected from previous studies failed to predict response to GP in this cohort. Larger studies capable of accounting for population-based allele frequency heterogeneity may be required for replication of genetic alterations important to pharmacogenomics.
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A1 Adenosine Receptor-Mediated Inhibition of Parasympathetic Neuromuscular Transmission in Human and Murine Urinary Bladder.

The potential role of A1 adenosine receptors in modulating neuromuscular transmission in the detrusor muscle of the urinary bladder has been tested in human and murine preparations with the intent to determine the viability of using adenosine receptor agonists as adjuncts to treat overactive bladder. In human detrusor muscle preparations, contractile responses to electrical field stimulation were inhibited by the selective A1 adenosine receptor agonists 2-chloro-N(6)-cyclopentyladenosine, N(6)-cyclopentyladenosine (CPA), and adenosine (rank order of potency: 2-chloro-N(6)-cyclopentyladenosine > CPA > adenosine). Pretreatment with 8-cyclopentyl-3-[3-[[4(fluorosulphonyl)benzoyl]oxy]propyl]-1-propylxanthine, an irreversible A1 antagonist, blocked the effects of CPA, thus confirming the role of A1 receptors in human detrusor preparations. In murine detrusor muscle preparations, contractions evoked by electrical field stimulation were reduced by CPA or adenosine. Amplitudes of the P2X purinoceptor-mediated excitatory junctional potentials (EJPs) recorded with intracellular microelectrodes were reduced in amplitude by CPA and adenosine with no effect on the spontaneous EJP amplitudes, confirming the prejunctional action of these agents. 8-Cyclopentyltheophylline, a selective A1 receptor antagonist, reversed the effects of CPA on EJP amplitudes with no effect of spontaneous EJPs, confirming the role of A1 receptors in mediating these effects.

Impact of county rurality and urologist density on urological cancer mortality in illinois.

PURPOSE: The urology work force is contracting at a time when service demand is increasing due to demographic changes, especially in rural areas. We investigated the impact of rural status and urologist density on kidney and renal pelvis, bladder and prostate cancer mortality at the county level in Illinois. MATERIALS AND METHODS: We stratified the 102 Illinois counties by 2003 RUCCs as urban (36, RUCCs 1 to 3) and rural (66, RUCCs 4 to 9). Area Health Resource Files were used for county demographic data and urologist density. County level age adjusted mortality rates from 1990 to 2010 were derived from National Center for Health Statistics data using SEER*Stat. We examined the associations of urological cancer mortality rates with rural status and urologist density. RESULTS: Average urologist density significantly differed between rural and urban counties (1.9 vs 3.4/100,000 population, p < 0.01). The kidney and renal pelvis cancer mortality rate in rural counties was higher than in urban counties while that of prostate cancer was lower (4.9 vs 4.3 and 28.7 vs 32.2/100,000 population, respectively, each p < 0.01). Urologist density correlated with the mortality rate of kidney and renal pelvis cancer (Pearson coefficient -0.33, p < 0.01) but not with the bladder or prostate cancer mortality rate. Multiple regression analysis revealed that rurality and lower urologist density (p = 0.01 and < 0.05) were significantly associated with higher kidney and renal pelvis cancer mortality. CONCLUSIONS: Rural residence and low urologist density were associated with increased kidney and renal pelvis cancer mortality on the county level in Illinois. Further expansion and testing of evidence-based telemedicine is warranted because remote technical consultation is now technologically feasible, effective, inexpensive and satisfactory to patients.

Three-dimensional external beam radiotherapy for prostate cancer increases the risk of hip fracture.

BACKGROUND: Hip fracture is associated with high morbidity and mortality. Pelvic external beam radiotherapy (EBRT) is known to increase the risk of hip fractures in women, but the effect in men is unknown. METHODS: From the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, 45,662 men who were aged ≥66 years and diagnosed with prostate cancer in 1992-2004 were identified. By using Kaplan-Meier methods and Cox proportional hazards models, the primary outcome of hip fracture risk was compared among men who received radical prostatectomy (RP), EBRT, EBRT plus androgen suppression therapy (AST), or AST alone. Age, osteoporosis, race, and other comorbidities were statistically controlled. A secondary outcome was distal forearm fracture as an indicator of the risk of fall-related fracture outside the radiation field. RESULTS: After covariates were statistically controlled, the findings showed that EBRT increased the risk of hip fractures by 76% (hazards ratio [HR], 1.76; 95% confidence interval [CI], 1.38-2.40) without increasing the risk of distal forearm fractures (HR, 0.80; 95% CI, 0.56-1.14). Combination therapy with EBRT plus AST increased the risk of hip fracture 145% relative to RP alone (HR, 2.45; 95% CI, 1.88-3.19) and by 40% relative to EBRT alone (HR, 1.40; 95% CI, 1.17-1.68). EBRT plus AST increased the risk of distal forearm fracture by 43% relative to RP alone (HR, 1.43; 95% CI, 0.97-2.10). The number needed to treat to result in 1 hip fracture during a 10-year period was 51 patients (95% CI, 31-103). CONCLUSIONS: In men with prostate cancer, pelvic 3-D conformal EBRT was associated with a 76% increased risk of hip fracture. This risk was slightly increased further by the addition of short-course AST to EBRT. This risk associated with EBRT must be site-specific as there was no increase in the risk of fall-related fractures in bones that were outside the radiation field.

Renal cell tumors convert natural killer cells to a proangiogenic phenotype.

Natural killer (NK) cells are classically associated with immune surveillance and destruction of tumor cells. Inconsistent with this function, NK cells are found in advanced human tumors including renal cell carcinoma (RCC). NK cells with non-classical phenotypes (CD56+CD16dim/neg; termed decidua NK (dNK) cells) accumulate at the maternal-fetal interface during embryo implantation. These dNK cells are poorly cytotoxic, proangiogenic, and facilitate placenta development. As similarities between embryo implantation and tumor growth exist, we tested the hypothesis that an analogous shift in NK cell phenotype and function occurs in RCC tumors. Our results show that peripheral NK (pNK) cells of RCC patients were uniformly CD56+CD16bright, but lacked full cytotoxic ability. By comparison, RCC tumor-infiltrated NK (TiNK) cells were significantly enriched for CD56+CD16dim-neg cells, a phenotype of dNK cells. Gene expression analysis revealed that angiogenic and inflammatory genes were significantly increased for RCC TiNK versus RCC pNK populations, with enrichment of genes in the hypoxia inducible factor (HIF) 1α pathway. Consistent with this finding, NK cells cultured under hypoxia demonstrated limited cytotoxicity capacity, but augmented production of vascular endothelial growth factor (VEGF). Finally, comparison of gene expression data for RCC TiNK and dNK cells revealed a shared transcriptional signature of genes with known roles in angiogenesis and immunosuppression. These studies confirm conversion of pNK cells to a dNK-like phenotype in RCC tumors. These characteristics are conceivably beneficial for placentation, but likely exploited to support early tumor growth and promote metastasis.

30-day all-cause hospital readmission after cystectomy: no worse for rural Medicare residents.

OBJECTIVE: To evaluate rural/urban disparities in 30-day all-cause hospital admission after cystectomy. MATERIALS AND METHODS: We used the SEER-Medicare database to identify all Medicare beneficiaries who underwent radical cystectomy (ICD-9 codes 57.7, 57.71, 57.79, and 68.8) between the years 1991 and 2009, yielding a total sample size of 15,572. Our primary outcome was 30-day hospital readmission rate. Rural Urban Continuum Codes were used to designate county-level rural status based on patient residence. Location of surgery was not a variable considered in this analysis. A multivariable regression model was constructed with demographic and clinical variables as covariates. RESULTS: A total of 2,003 rural and 2,904 urban patients (31.1% vs. 31.8%, P = 0.33) were readmitted within 30 days of discharge. In the multivariable model, older age, unmarried status, lower socioeconomic status, higher Charlson comorbidity score, shorter index admission hospital stay, and discharge to a skilled nursing facility were associated with higher odds of readmission. The variables for gender, race, cancer stage, tumor grade, and type of urinary diversion were not significant. The odds ratio for readmission was not significant for patients from rural counties in the final model. CONCLUSIONS: Rural Medicare residents were not at higher risk for 30-day all-cause hospital readmission after cystectomy after accounting for various demographic and clinical variables.

Pelvic Lymph Node Dissection in Patients Treated for Testis Cancer: The Memorial Sloan Kettering Cancer Center Experience.

OBJECTIVE: To describe the pathologic findings and clinical outcome data for patients undergoing pelvic lymph node dissection (PLND) in the course of management of testicular germ cell tumors at Memorial Sloan Kettering Cancer Center (MSKCC). PATIENTS AND METHODS: Following institutional review board approval, data on 2186 patients who underwent retroperitoneal lymph node dissection (RPLND) at MSKCC between 1989 and 2011 were retrospectively reviewed. Of these 2186 patients, we analyzed data for 44 patients (2%) who underwent PLND at the time of RPLND. RESULTS: PLND was performed in 14/44 (31%) patients at time of primary RPLND (P-RPLND), and in 21/44(48%) patients at time of postchemotherapy RPLND (PC-RPLND), usually for suspicious radiologic or intraoperative findings, whereas 9/44 (21%) underwent PLND for treatment of relapse. Positive pelvic findings on imaging included pelvic disease ≤5 cm in 17/44 (39%) patients and >5 cm in 11/44 (25%) patients (median size = 4 cm). At the time of PC-RPLND, alpha-fetoprotein and beta human chorionic gonadotropin were elevated in 6/21 (29%) and 4/21 (19%) patients, respectively. Histology revealed teratoma in 15/44 (34%) and viable tumor in 5/44 (11%) patients. At a median follow-up of 46 months, 40/44 (91%) patients were living without disease, 3/44 (7%) were living with disease (1 after PC-RPLND and 2 after relapse), and 1/44 (2%) died of other causes. CONCLUSION: PLND was performed infrequently in our series of patients who underwent RPLND for testis cancer. Teratoma was the dominant tumor histology in the resected tissue.

Kidney Cancer in Rural Illinois: Lower Incidence Yet Higher Mortality Rates.

OBJECTIVE: To determine if rural status was associated with kidney and renal pelvis cancer (KCa) incidence and mortality in Illinois while controlling for known KCa risk factors and access to care variables. MATERIALS AND METHODS: Age-adjusted KCa incidence rates from 1991 to 2010 were calculated from Illinois State Cancer Registry data. Age-adjusted KCa mortality rates were obtained from health statistics embedded within SEER*Stat. Rural Urban Continuum Codes designated Illinois' 102 counties as urban, rural adjacent to, and rural non-adjacent to a metropolitan area. County-level demographics and physician density were obtained from the Area Health Resource File. Behavioral Risk Factor Surveillance System data were used for smoking, obesity, and hypertension prevalence. Analysis of variance, correlation, and regression analyses were used. RESULTS: The incidence of KCa was found to be higher among urban compared to rural counties after controlling for known risk factors (P < .01). A larger proportion of cases were diagnosed at a localized stage in urban counties (<0.01). Mortality rates were significantly higher in rural counties (P = .02). The final regression model found rural status, higher incidence rate, fewer with localized stage at diagnosis, and lower urologist density to be variables significantly associated with higher KCa mortality. CONCLUSION: KCa incidence was higher in urban counties whereas mortality was higher in rural counties. The higher number of KCa cases diagnosed at a localized stage in urban counties and lower urologist density in rural counties suggest that poorer access to care may contribute to higher KCa mortality in rural Illinois. Telemedicine may be an opportunity to improve this disparity.

Long-term mortality in patients with germ cell tumors: effect of primary cancer site on cause of death.

OBJECTIVES: To examine the effect of extragonadal tumor site on the risk for cardiovascular, hematopoietic malignancies, and solid cancer-related causes of death. PATIENTS AND METHODS: Male patients diagnosed with germ cell tumors (GCTs) between 1973 and 2008 were identified from the Surveillance, Epidemiology and End Results database, and stratified by the site of primary cancer (mediastinal and nonmediastinal extragonadal vs. gonadal). Using competing risk analysis restricted to events that happened at least 5 years after diagnosis, we examined the possible effect of primary tumor site on the risk for death related to hematopoietic malignancies, cardiovascular disorders, and solid cancers in the study cohort. RESULTS: Of 37,283 patients included in our analysis, 17,715 were diagnosed with nonseminomas and 19,568 with seminomas. Eight hundred and twenty four patients (2%) were diagnosed with primary mediastinal GCTs and 1,469 (4%) with nonmediastinal extragonadal tumors. Patients with mediastinal GCTs had an increased risk for death related to hematopoietic malignancies (hazard ratio [HR] = 8.84; 95% confidence interval [CI]: 3.16-24; P<0.0001) and cardiovascular disorders (HR = 4.45; 95% CI: 2.52-8.0; P<0.0001), but no significant difference in risk of dying of solid cancers (HR = 1.46; 95% CI: 0.36-5.9; P = 0.59) compared to patients with gonadal GCTs. Patients with nonmediastinal extragonadal GCTs had a significantly increased risk for dying of cardiovascular disorders (HR = 2.75; 95% CI: 1.67-4.51; P<0.0001), but not a significantly different risk for dying of hematopoietic malignancies (HR = 0.93; 95% CI: 0.13-6.84; P = 0.94) or solid cancers (HR = 1.45; 95% CI: 0.68-5.0; P = 0.23) compared with patients with gonadal GCTs. CONCLUSIONS: Patients with GCTs and extragonadal primary sites have an increased risk for death from cardiovascular disease and hematopoietic malignancies compared to those with gonadal GCTs, and could benefit from more intense preventive measures to decrease the risk of death related to these disorders.

Clinical features and management of BRCA1 and BRCA2-associated prostate cancer.

It is thought that over forty percent of an individual's risk of developing prostate cancer (PCa) is related to familial and genetic factors. Although multiple genes have been implicated in the development of PCa, few confer as high a risk as mutations in the genes associated with early-onset breast cancer (BRCA1 and BRCA2). Not only do mutations in BRCA genes increase the risk of PCa, but they have also been related to adverse disease characteristics and outcomes. Therefore, a better understanding of the association between BRCA gene mutations and PCa may provide the backdrop for individualized management of patients with PCa who are carriers of a gene mutation. Such management may include an individualized approach to screening and treatment including chemotherapeutic regimens targeted to the underlying genetic mechanism of disease. In this paper, we review the evidence relating BRCA gene mutations to the risk of PCa, as well as outcomes and response to therapy, and suggest an approach to the management of such patients.