bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor response and adaptation to CYP17 inhibition in prostate cancer: Induction of steroidogenesis and androgen receptor splice variants.
Authors: Mostaghel E. A. , Marck B. , Matsumoto A. M. , Nelson P. , Vessella R. , Plymate S. R. , Montgomery R. B. 
Published: February 2017

18 Background: Abiraterone is a novel inhibitor of the steroidogenic enzyme CYP17 and suppresses tumor growth in patients with castration-resistant prostate cancer (CRPC). The efficacy of abiraterone in suppressing tumor androgens or mechanisms of resistance to abiraterone are not known. Methods: Human CRPC xenografts LuCaP 23 and LuCaP 35 grown in castrated male mice were treated with abiraterone to determine effects on tumor growth and tumor androgen levels. Tumor gene expression measurements were obtained to delineate mechanisms of abiraterone resistance. Results: Abiraterone i.p. for 21 days improved survival (time to tumor size 750 mm3) vs vehicle control (VC) in LuCaP 35 (HR 3.8 [95% CI 3.1-53.7] median survival 39 vs 18 days) and LuCap 23 (HR 2.4 [1.43-10.24] median survival 24 vs. 14 days). Greater anti-tumor activity correlated with superior tumor androgen suppression. Tumor testosterone was strongly suppressed in both LuCaP35 (0.20 + 0.24 vs VC 0.69 + 0.36 pg/mg) and LuCaP 23 (0.07 + 0.11 vs VC 0.49 + 0.22 pg/mg). DHT levels were also markedly suppressed in LuCaP35 (1.17 + 1.46 vs VC 3.49 + 1.81pg/mg). In contrast, DHT levels in LuCap23 were unchanged early (day 7-21) and only partially suppressed at longer time points (VC 5.73 + 1.88; early 5.31 + 2.69; late 2.82 + 2.27 pg/mg). Expression of the abiraterone target CYP17 was upregulated in both xenografts (LuCaP23 2.5 fold, p<0.0001; LuCap35 2.9 fold, p=0.028). Overall, LuCap23 appeared resistant to suppression of tumor androgens due to induction of steroidogenic transcripts (including STAR, CYP11, HSD3B1 and AKR1C3) without statistically significant increases in androgen receptor (AR). In contrast, LuCap35 demonstrated strong induction of transcripts for AR and AR splice variants (AR 3.8 fold, p<0.0001, V7 AR splice variant 3.7 fold, p<0.0001), with induction of steroidogenic transcripts only at late time points. Conclusions: Abiraterone treatment suppressed intratumoral androgen levels and reduced growth of CRPC xenografts. Abiraterone resistance may occur through upregulation of the abiraterone target CYP17, and/or the induction of AR and AR splice variants that confer ligand-independent AR trans-activation. [Table: see text]
Diabetes mellitus, race, and the odds of high-grade prostate cancer in men diagnosed with prostate cancer in the United States.
Authors: Mitin T. , Chen M. , Moran B. J. , Dosoretz D. E. , Katin M. J. , Braccioforte M. H. , Salenius S. , D'Amico A. V. 
Published: February 2017

180 Background: African American (AA) men present more frequently with high-grade prostate cancer (PCa) and are also more likely to have diabetes mellitus (DM). We evaluated whether there is an independent association between DM and the risk of high-grade PCa in men diagnosed with PCa, adjusting for the known predictors of high-grade PCa including AA race. Methods: Between 1991 and 2009 15,377 men newly diagnosed with PCa and treated at 1 of 26 centers, were analyzed in 2 cohorts. Multivariable logistic regression was performed to evaluate whether a diagnosis of DM was associated with the odds of Gleason 7 or 8 to 10 PCa, adjusting for AA race, advancing age, PSA level, and DRE findings. Results: AA men (AOR, 1.87; 95% CI, 1.04-3.37, P=0.04) and non-AA men (AOR, 1.61; 95% CI, 1.34-1.93; P<0.001) with diabetes were more likely to have GS 8 to 10 versus GS 6 or less PCa, compared to non-diabetic men. AA as compared to non-AA race was not significantly associated with the odds of having GS 8 to 10 as compared to 6 or less PCa, both in men with a diagnosis of DM (AOR, 1.47; 95% CI, 0.87-2.50; P=0.15) and without DM (AOR, 1.27; 95% CI, 0.92-1.74, P=0.14). AA race, however (AOR, 1.37; 95% CI, 1.17-1.60, P<0.001), but not DM (AOR 1.09; 95% CI, 0.97-1.22, P=0.16), was associated with GS 7 versus 6 or less PCa. Conclusions: A diagnosis of DM is a risk factor for presenting with Gleason 8 to 10 PCa independent of race. [Table: see text] No significant financial relationships to disclose.
Diabetes and cancer risk in the REDUCE trial.
Authors: Wu C. , Moreira D. M. , Gerber L. , Rittmaster R. S. , Andriole G. L. , Freedland S. J. 
Published: February 2017

194 Background: Men with diabetes mellitus (DM) are less likely to be diagnosed with prostate cancer (PC). As diabetic men have lower PSA values, it is unclear if this is due to reduced PC incidence or lower biopsy rates from the lower PSA. To account for differential biopsy rates, we explored the link between DM and risk of PC and high-grade PC in the REDUCE trial. We also explored if these associations differed by body mass index (BMI) as a prior study suggested BMI may modify the effect of DM on PC aggressiveness. Methods: The 4-year REDUCE study tested the effect of dutasteride 0.5 mg daily on PC risk reduction in men with PSA of 2.5-10.0 ng/mL and a negative prostate biopsy. Men underwent study-mandated biopsies at 2 and 4 years regardless of PSA. DM was determined by self report at baseline. BMI (kg/m2) was calculated from height and weight measured at baseline. The risk of PC and high-grade PC (Gleason 7-10) was determined using multivariate logistic regression adjusting for age, race, BMI, PSA, and treatment arm. Effect modification by BMI (<25, 25-29.9, and >30 kg/m2) was tested via interactions. Results: Of 8,122 men in the REDUCE trial, 499 (6.1%) had DM. Diabetic men were older (63.8 vs. 62.7 yrs, p=0.001) with a higher BMI (median BMI 27.8 vs. 26.8, p<0.0001). After adjusting for age and BMI, diabetic men had lower PSA values (p=0.04). On multivariate analysis, DM was not associated with PC risk (OR 0.96, 95% CI 0.75-1.22, p=0.74). When stratified by BMI, DM was not associated with PC risk in any group (all p>0.23) and the results did not vary by BMI category (p-interaction=0.13). DM was not associated with high-grade PC on multivariate analysis (OR 0.88, 95% CI 0.58-1.33, p=0.55). When stratified by BMI, though DM was not associated with high-grade PC risk in any single group (all p>0.14), there was a suggestion of effect modification by BMI (p-interaction=0.056) with a positive association between DM and high-grade PC in obese men (OR 1.32) and an inverse association in normal weight men (OR 0.35). Conclusions: In the REDUCE trial, when all men undergo biopsy regardless of PSA, DM is not associated with lower PC risk, but rather equal PC risk and equal risk of high-grade PC. These results suggest the lower rate of PC among diabetic men in prior studies may be driven by lower biopsy rates from lower PSA. [Table: see text]
Clinical recurrence post-biochemical failure of prostate cancer.
Authors: Reddy C. A. , Ciezki J. P. , Klein E. A. 
Published: February 2017

195 Background: The purpose of this study is to evaluate the role of salvage therapy (STx) after biochemical failure (bF) for prostate cancer (CaP) and to determine what factors are associated with the development of clinical recurrence (cR). Methods: From 1996-2009, 7,585 patients (pts) with CaP were treated with prostatectomy (RP), brachytherapy (PI), or external beam radiotherapy (RT). For RP patients (pts), bF was defined as a postoperative PSA >0.3 and for PI and RT pts the Phoenix definition was used. bF was documented in 927 pts. cR was defined as any image-based or pathological diagnosis of disease recurrence after bF. Cox proportional hazards regression was used to examine if the use of STx after bF, the time of bF, along with disease characteristics were associated with cR after bF. Results: The median follow-up after bF was 31months (mo; range: 0-131). Thirty percent of pts had a cR after bF, and the 5-year rate of cR free survival was 58%. STx within 1 year after bF (early) was given to 46% of pts, STx more than 1 year after bF (late) was given to 11% of pts, and 43% of pts did not receive STx. On univariate analysis, factors found to be significantly associated (p-value <0.05) with cR were a short interval between initial treatment and bF (bFTime), no use of STx, early initiation of STx, biopsy Gleason Score (bGS), clinical stage, older age at bF, the use of PI or RT, and increased frequency of PSA follow-up after bF (PSAfreq). In multivariable analysis, bFTime, no use of STx, early initiation of STx, bGS, the use of PI or RT, and PSAfreq remained significant. To better evaluate the effect the timing of initiation of STx had on the development of cR, a second analysis was preformed, limited to the 529 pts who did receive STx after bF. In multivariable analysis, early use of STx remained significant for cR (HR=2.09, 95%CI=1.24- 3.51). As a continuous variable, in a second multivariable analysis, delayed use of STx resulted in a reduced risk of developing cR (HR=0.98, 95%CI=0.96-1.00). Conclusions: This study suggests that while the use of STx after bF reduces the risk of subsequently developing cR, early use of STx after bF is not beneficial. Other factors such as the time interval between initial treatment and bF need to be evaluated when determining when to initiate STx after bF. No significant financial relationships to disclose.
Racial disparities in stage IV prostate cancer outcomes in the Veterans Affairs hospital system.
Authors: Al-Howaidi I. , Shatat L. , Tashi T. , Gonsalves W. , Silberstein P. T. , Subbiah S. 
Published: February 2017

199 Background: Epidemiological studies have demonstrated that African-American (AA) men with prostate cancer have lower overall survival and cancer-specific survival rates than Caucasian (CA) men with prostate cancer. We aim to assess whether racial disparities exist for prostate cancer within an equal access health care system like the Veterans Affairs (VA) hospitals. Methods: A retrospective analysis of AA and CA with metastatic prostate adenocarcinoma diagnosed between 1995 to 2007 via the Veterans Affairs Central Cancer Registry was conducted. Age, Race and type of treatment received were studied with respect to overall survival by using log-rank and Kaplan-Meier analysis. Results: A total of 8,195 patients with advanced prostate cancer were analyzed, majority of them where CA (66.32%), 30.8% were AA and 2.8% belonged to other races. The median survival for AA was 2.71 years, 2.88 years in CA and 4.02 years in other races (P value <0.0001). Subgroup analysis based on treatment modality used showed the following median survival rates in years: No treatment (CA: 1.73, AA: 1.39, other races: 3.79, P<0.816), Hormonal therapy alone (CA: 2.51,AA: 2.45, Others:3.72, P<0.022), Radiation therapy alone (CA: 2.2, AA: 2.7, Others: 2.26, P<0.832), combined hormone and radiation therapy (CA: 2.71, AA: 2.31, Others: 6.64, P<0.029). However when CA and AA survival were compared excluding other races there was no statistically significant difference in survival irrespective of type of therapy received. Conclusions: In advanced prostate cancer, AA and CA have uniformly poor prognosis. Type of therapy received did not influence the survival of both races. The numbers for other races is too small to make a definitive conclusion regarding their prognosis. No significant financial relationships to disclose.
Influence of body mass index (BMI) on PSA kinetics in castrate-resistant prostate cancer (CRPC).
Authors: Teo M. , Mayer N. J. , Khan N. , Sweeney J. P. , O'Reilly S. , Power D. G. 
Published: February 2017

209 Background: Understanding of the role of host energetics in cancer outcomes has been increasing in recent years. In early stage prostate cancer trials obesity is associated with worse outcome. Its effect on treatment response and survival in advanced disease is largely unexplored. We sought to explore the relationship between BMI, the most validated measure of obesity, and biochemical response as well as overall survival in patients receiving first-line chemotherapy. Methods: We reviewed a prospectively-maintained institutional database identifying patients who received docetaxel (D) for CRPC. Demographics and PSA levels during treatment were extracted. Pts were divided into 2 BMI groups (> and < 30 kg/m2). We calculated biochemical responses as per historically validated surrogates: PSA decrease > 30% at 3months; overall decrease > 50%; time to PSA nadir and PSA half-life after 4 cycles, for each group. Results were compared with unpaired t-test and chi-square test. Results: 33 pts were identified between June ‘04 and Sept ‘10, 16 pts with BMI > 30 (hBMI) (range 30.1-34.2) and 17 with BMI < 30 (nBMI) (21.5-29.6). Median age for the entire cohort was 67.9 yrs (47.7-79.8), median Gleason score 8, median cycles of D received was 6 (3-20) with median duration of 3.7 months (1.4-8.7), p>0.05. Baseline PSA was 89.1 ng/ml (0.34-417) and 259.2 (16.1-1,589) for hBMI and nBMI respectively, p = 0.023. For hBMI group, only 56.3% (9/16) of patients demonstrated biochemical response, compared with 88.2% (15/17) in nBMI group(p = 0.039). Of the biochemical responders, 6/16 (38%) of hBMI and 9/7 (53%) of nBMI achieved >50% fall in PSA (p = 0.743) while 8/16 (50%) patients in hBMI group and 10/17 (59%) in nBMI group had a PSA drop >30% at 3 months (p = 0.61); Median time to PSA nadir was 3.4 months (0.7-4.9) and 2.7 (0.7-7.5), and median PSA half life was 56.4 days (16-138) and 46.1 days (16-302) for hBMI and nBMI groups, respectively, p > 0.05. Conclusions: Obese patients with CRPC have lower pre-D PSA levels. However, they also experience a lower rate of biochemical response to therapy. PSA kinetics in biochemical responders do not appear to be influenced by BMI. Survival data will be presented. No significant financial relationships to disclose.
Clinicopathologic findings in Jamaican men with prostate cancer.
Authors: Kampel L. J. , Tse K. , Joseph M. 
Published: February 2017

214 Background: Jamaican men appear to have higher age adjusted incidence rates (302/100K) than African Americans (250/100K) and Caucasians (182/100K). The purpose of this study is to examine the clinicopathologic findings in Jamaican born men presenting to Memorial Sloan-Kettering Cancer Center over a five-year period. Methods: We reviewed the records of 150 Jamaican-born men seen at MSKCC for prostate cancer between 2003 and 2008. Age at diagnosis, highest pretreatment PSA levels, Gleason scores, and clinical stage were tabulated. Pathologic T and N stage was included for patients undergoing prostatectomy. Results: 23 patients were excluded because the diagnosis of prostate cancer was not confirmed. The mean age at diagnosis was 59 years (37-77). The median PSA was 8 ng/mL (1-7,400 ng/mL). The distribution of Gleason scores was Gleason 6: 51 patients (40%), Gleason 7: 57 patients (45%), and Gleason 8-10: 19 patients (15%). 92% (75/81) of the men had organ confined disease by (cT1-2) by DRE. Of 46 men who had prostatectomy, 31 (67%) had organ confined disease (p T2) and 84% (37/44) were node negative. Conclusions: Without a comparison cohort, no firm conclusions can be drawn. But, Jamaican born men presenting to MSKCC for treatment of prostate cancer do not seem to have unusually adverse pretreatment characteristics or more advanced pathological findings at prostatectomy. Our results may be affected by referral bias in favor of patients with lower risk disease. Further research is needed to determine if Jamaican men with prostate cancer present with more advanced stage or higher grade disease than men in the general population. No significant financial relationships to disclose.
EGFR, TS, and ERCC1 expression in penile squamous cancer (PSC).
Authors: Dorff T. B. , Schwartz R. , Ma Y. , Cai J. , Bulbul A. , Skinner E. C. , Quinn D. I. , Danenberg K. , Schuckman A. 
Published: February 2017

219 Background: PSC is an aggressive disease with devastating consequences. While near-universal EGFR overexpression has been documented, little is known about its clinical implications, and the potential role of KRAS mutations has not been described. In other tumor types, ERCC1 and TS expression are associated with response to platinum and 5FU chemotherapy, but have not yet been evaluated in PSC. Methods: After IRB approval, 28 PSC patients treated at LAC-USC were identified with tumor specimens available. Testing for EGFR, TS, and ERCC1 expression relative to internal standard gene was performed by real-time RT-PCR and correlated with clinical features. Results: The median age was 45 (30-78). There were 2 Black, 1 Asian, 1 White, and 15 Hispanic men; 9 had unspecified race. T stages included 4 Tis, 6 T1, 17 T2, and 9 T3; 11 men had lymph node (LN) involvement. No KRAS mutations were identified. EGFR had the highest relative expression (median 4.65, range 1.6-44.2), followed by TS (median 1.69, range 0.49-4.69); ERCC1 overexpression was rare (median 0.54, range 0.21-1.29). Higher EGFR expression was significantly associated with poor differentiation (median 12.5 compared to 3.6 for moderate/well differentiated tumors) on continuous (p=0.03 by Mann Whitney) and cut-point analysis using >7 (two- sided p=0.03 by Fisher's exact test) but did not correlate with stage. Stage > T2 showed a trend toward higher risk of LN involvement (p=0.06 by chi square). There was no correlation between differentiation and stage, and no significant correlation for ERCC1 or TS with grade or stage. Conclusions: EGFR overexpression is common in PSC and correlates with tumor grade but not stage, suggesting it may be important for disease progression. The absence of KRAS mutations may portend responsiveness to EGFR- targeted therapy based on experience in other tumors. Low ERCC1 as an association with platinum response will be explored in an expanded cohort. No significant financial relationships to disclose.
Utilizing metformin to enhance the efficacy of androgen-deprivation therapy in the treatment of prostate cancer.
Authors: Klotz L. , Venier N. , Vandersluis A. , Besla R. , Fleshner N. , Pollak M. N. , Venkateswaran V. , Colquhoun A. J. 
Published: February 2017

22 Background: Prostate cancer (PCa) incidence varies by geographic location, with developed countries exhibiting higher levels of disease. Some attribute this to the “Westernized lifestyle” of high energy diets and limited physical activity with consequent obesity. Obesity and related diseases like diabetes, cause hyperinsulinemia, which upregulates pro-survival insulin/insulin-like growth factor signalling. Previous work shows diet-induced hyperinsulinemia enhances PCa tumor growth in vivo. Metformin, a diabetic treatment, reduces hyperinsulinemia, and also exhibits anti-neoplastic properties. We assessed the potential benefit of combining a standard PCa treatment (bicalutamide) with metformin in vitro and in vivo. Methods: The effect of bicalutamide and/or metformin on colony formation rates was assessed in LNCaP, PC3, DU145 and PC3AR2 PCa cell lines using clonogenic assay. Western blot and cell cycle analyses were used to elucidate mechanisms of interaction between the drugs. The combination treatment regimen was assessed in vivo using a murine xenograft model. Results: Micromolar bicalutamide or millimolar metformin caused significant dose-dependent reduction in colony formation rates (p<0.001). Combination treatment further significantly reduced colony formation rates (p<0.005). Differing mechanisms of interaction occurred in AR positive and negative cell lines. Following combination treatment LNCaP cells exhibited altered cell proliferation (decreased PCNA) and perturbed cell cycle kinetics (G1/S arrest). PC3 cells showed evidence of enhanced apoptosis (increased BAX, decreased caspase 3, phospho-Akt). Preliminary in vivo results show significantly diminished tumor growth following combination treatment (p<0.0001). Conclusions: Combining bicalutamide and metformin significantly reduces PCa cell colony formation rates further than either monotherapy. In AR positive cells this effect is mediated by reducing cell proliferation rates, whereas in AR negative cells combination treatment promotes apoptosis. This combination drug regimen may potentially improve prostate-cancer specific survival via the direct anti-neoplastic properties outlined. [Table: see text]
Chemotherapy for squamous cell carcinoma of the penis: An 8-year, single-institution experience.
Authors: Kularatne B. Y. , Ayres B. E. , Mukherji D. , Watkin N. , Lam W. , Perry M. , Pickering L. M. 
Published: February 2017

222 Background: Penile cancer is a rare malignancy affecting approximately 400 men per year in the United Kingdom. There are relatively limited data regarding the role of chemotherapy, although it may be considered in the adjuvant setting for high-risk disease and for palliation of metastatic disease. Methods: Patients treated with chemotherapy between June 2002 and March 2010 were identified from our prospectively maintained institutional database. Regimens were recorded and toxicity documented according to the Common Toxicity Criteria version 4.0. Response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 until 2009 and then version 1.1. Results: Twenty patients received chemotherapy either for adjuvant treatment (n=6) or for metastatic disease (n=14). Median age was 59 (range 33-80). Different regimens were used over the time period. In the adjuvant setting 4-6 cycles of chemotherapy were planned and all patients received cisplatin in combination with 5-FU or capecitabine. Five (83%) completed planned treatment with no grade 3 or 4 toxicities. One patient stopped after 2 cycles due to deteriorating renal function. Patients remained disease free at up to 22 months follow-up. In the metastatic setting, 10 patients received cisplatin and capecitabine, 1 cisplatin and 5-FU and 1 carboplatin and capecitabine. Of these 12 patients, 2 (17%) had partial response as their best response, 4 (33%) had stable disease (SD) and 6 (50%) had progressive disease (PD). Three patients (25%) experienced pulmonary embolism, 1 of whom died. Two (17%) developed grade 3 neutropenia. One patient received carboplatin, methotrexate and bleomycin with PD after 3 cycles and developed grade 3 neutropenia, stomatitis, and diarrhea. One patient received 3 cycles of paclitaxel, ifosfamide, and cisplatin with SD and no grade 3 or 4 toxicities. Conclusions: Combination chemotherapy can be delivered with acceptable toxicity in the adjuvant setting. In the metastatic setting response rates were disappointing and treatments were associated with greater toxicity. New treatments are urgently required to improve outcomes in this difficult malignancy. [Table: see text]