bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma-based exploratory biomarker analysis to evaluate GT0918 in a phase I/II study in mCRPC patients.
Authors: Yu Jianjun , Wang Amy , Zhao Zhixin , Jia Shidong , Zhang Phoebe , Zhou Karl 
Published: March 2019

279 Background: GT0918, a novel potent androgen receptor antagonist, has been evaluated in a ph 1/2 study in mCRPC patients for its safety and efficacy. Here using patient plasma samples, we explored cell-free DNA & RNA-based biomarkers to assess their associations with clinical response of GT0918. Methods: Blood samples were prospectively collected from mCRPC patients at baseline, on- and after study during the trial. PredicinePLUS cfDNA+cfRNA assay, a 180-gene targeted NGS Panel, was used to detect genomic alterations in plasma. Statistical analyses were performed in R 3.5.1. Results: Genomic alterations were detected in all 50 blood samples. Top mutated genes are TP53 (52.5%) and AR (32.5%). When combing variants from genes in a signaling pathway, mutation rates in PI3K axis and homologous recombination pathway are 32.0% and 34.0% respectively. Importantly, AR hotspot mutations (W742C, T878A, and S889G) and amplifications are detected in multiple subjects at baseline, suggesting that it may be the driving events for resistance of prior therapies. AR splicing variants (AR-V3, AR-V7) and TMPRSS2-ERG fusion were also detected by cfRNA profiling. Interestingly, patient 001-001 harboring both AR W742C and T878A mutations detected in cfDNA with high mutation frequency didn’t carry corresponding mutations in cfRNA at the baseline but started to accumulate the mutations in C3D1. Patient 004-002 remained in the study with stable disease for 10 treatment cycles while having continuous increase of PSA. cfDNA profiling indicates frequency of prostate-specific SPOP mutation continued to decrease during the treatment. Conclusions: This is a preliminary analysis to explore potential predictive or pharmacodynamic biomarkers in mCRPC in response to GT0918 treatment. As an non-invasive assay, PredicinePLUS assay was able to detect genomic alterations in blood with a high sensitivity and provided useful molecular insights for treatment monitoring and drug sensitivity & resistance mechanisms. Clinical trial information: NCT02826772.
Clinical risk-based associations of lymph node dissection and detection of metastasis among men treated with radical prostatectomy.
Authors: Abello Alejandro , Kenney Patrick Aloysius , Leapman Michael 
Published: March 2019

284 Background: Pelvic lymph node dissection (PLND) is recommended for most men at risk for lymph node involvement at the time of radical prostatectomy (RP) yet is frequently omitted. We aimed to examine the probability of PLND based on clinical risk status, and evaluate the impact of increasing lymph node yield on cancer detection rate across risk strata. Methods: We queried the National Cancer Database from 2004 to 2014 to identify patients with clinically localized PCa who underwent RP as their primary treatment. We extracted patient clinical and sociodemographic variables. Risk status was assessed using UCSF Cancer of the Prostate Risk Assessment (CAPRA) score. We fit conditional logistic regression models to estimate likelihood of PLND and incremental value of increasing lymph node count by risk strata. Results: We identified 698,728 men with PCa treated with RP including 380.201 (54.41%) whit PLND. Mean age at diagnosis was 62.6. PLND was omitted (Nx) in 56.1% of patients with low CAPRA-risk disease, 31.44% with intermediate and 24.72% high. Proportion of patients with >30 lymph nodes removed decreased from 9.3% on 2004 to 3.64% on 2014. Adjusting for clinical and pathologic factors, treatment in a community versus academic (Odds Ratio, OR=1.62, 95% CI 1.59-1.66; P <0.001) and black race (OR=1.13, 95% CI 1.09-1.17, P: 0.01) was associated with pNx status. Increasing lymph node count was independently associated with greater likelihood of detection of lymph node metastasis in all risk strata (11-20 nodes: OR: 3.13 , 95% CI 2.90-3.37, P<0.001; 20-30 nodes: OR: 5.07 , 95% CI 4.50-5.73, P<0.001; >30 nodes OR: 6.58, 95% CI 5.38-8.05, P<0.001) including patients with CAPRA-0 (11-20 nodes: OR: 3.28 , 95% CI 3.06-3.53, P<0.001; 20-30 nodes: OR: 5.77, 95% CI 5.16-6.45, P<0.001; >30 nodes OR: 7.90, 95% CI 6.56-9.51, P<0.001). Conclusions: PLND continues to be omitted in a substantial proportion of intermediate and high risk patients. Increasing lymph node yield was associated with greater odds of detecting lymph node metastasis in all groups of patients, including those at the lowest level of risk by clinical criteria.
What is the clinical utility of next generation sequencing (NGS) in advanced urologic malignancies?
Authors: Mark James Ryan , Kucherov Victor , Pintauro Michael , Leong Joon Yau , Mann Mark , Trabulsi Edouard John , Lallas Costas D. , Chandrasekar Thenappan , Handley Nathan , Kelly William Kevin , Gomella Leonard G. 
Published: March 2019

285 Background: Widespread availability of NGS and an expanding repertoire of targeted therapies has garnered significant enthusiasm for the concept of NGS directed therapy. FoundationOne (Foundation Medicine, Cambridge, MA) is a validated comprehensive genomic profiling (CGP) assay intended to guide therapy decisions based upon tumor specific genetic variations. We reviewed our experience with FoundationOne testing in advanced genitourinary (GU) cancer and examined whether NGS effected therapy in a meaningful way. Methods: Retrospective review of patients with advanced GU cancer seen between 2/1/2013–8/13/2018 who had FoundationOne CGP testing. We then compared the duration patients were maintained on NGS directed therapy to the duration of each non-NGS therapy. Results: A total of 73 patients were identified with NGS testing for prostate (25, 34%), urothelial (30, 41%), and kidney (18, 25%) cancer. 11 (15%) of these patients had therapy directed against a genetic alteration indicated by NGS. Of the treated patients, 46% (5) had urothelial, 36% (4) had kidney, and 18% (2) had prostate cancer. The average duration that each non-NGS therapy was effective in patients with urothelial, kidney, and prostate cancer was 165, 417, and 382 days respectively. Duration of NGS directed therapy averaged 226, 367, and 278 days for urothelial, kidney, and prostate cancer. The range of the duration of response to NGS directed therapy for urothelial, kidney, and prostate cancer was 66-616 days, 106-467 days, and 28-528 days. Four (36%) patients treated with NGS directed therapy achieved a duration of response greater than the average duration of all other non-NGS directed therapy they had received (Table). Conclusions: A minority of patients received NGS directed therapy following NGS testing. Treated patients demonstrated varying responses with 4 patients experiencing a longer duration of response compared to non-NGS directed therapy. Our experience illustrates that NGS has a limited but evolving role in the management of advanced GU malignancies at this time while also demonstrating a benefit to a subset of patients. Future studies should focus on identifying which patients are most likely to benefit from this technology.
Obesity and metastatic castration resistant prostate cancer: Results from the control arms of ASCENT2, MAINSAL and VENICE trials.
Authors: Martini Alberto , Waingankar Nikhil , Brown Nicholas M , Sfakianos John P. , Tewari Ashutosh , Galsky Matthew 
Published: March 2019

287 Background: Previous findings regarding the correlation between body mass index (BMI) and survival in patients with prostate cancer are conflicting and may be disease-state dependent. We aimed to test whether BMI among patients with metastatic prostate cancer (mCRPC) is associated with overall survival (OS) and cancer-specific mortality (CSM). Methods: We identified 1577 patients with mCRPC from the control arms of 3 randomized trials. The role of BMI was investigated both as a continuous and categorical variable ( < 20 vs. 20-25 vs. 25-30 vs. > 30 km/m2). A BMI > 30 kg/m2 was considered obese. Analyses were adjusted for age, PSA, ECOG, # of metastasis and prior treatment. A Cox semi-proportional hazard model was used to predict OS, whereas the competing risks regression was used for predicting cancer-specific mortality (CSM). Results: The median (IQR) age for the patient population was 69 (63,74) years with a median (IQR) BMI of 28 (25-31) kg/m2. Of the 1577 patients included, 655 had died during follow-up (median follow-up for survivors = 12 months). BMI emerged as a protective factor for OS both as a continuous variable (HR: 0.96; 95% CI: 0.94, 0.99; p = 0.015) and as a categorical variable (obesity: HR: 0.71, 95% CI: 0.53, 0.96; p = 0.027). The effect BMI on CSM was confirmed both as a continuous (SHR: 0.94; 95% CI: 0.91, 0.98; p = 0.002) and as a categorical variable (obesity SHR: 0.65; 95% CI: 0.45, 0.93; p = 0.018). No interaction was detected between the BMI categories and docetaxel dose. Conclusions: Obesity, compared with lower weight categories, is associated with improved CSM and OS in mCRPC treated with docetaxel. The mechanistic basis for this observation warrants further study.
The prognostic value of mid-treatment prostate-specific antigen level in patients receiving salvage radiotherapy.
Authors: Homza Jason , Nawrocki John T. , Brereton Harmar D. , Peters Christopher A. 
Published: March 2019

289 Background: Salvage radiotherapy (SRT) may be employed as a potentially curative intervention for patients experiencing biochemical failure (serum prostate-specific antigen [PSA] ≥ 0.2 ng/mL) after prostatectomy for localized prostate cancer. Patients not showing a favorable response to SRT alone may require additional therapies and may benefit from earlier identification of this need. Methods: 131 consecutive patients received SRT during the timeframe of this study. 76 were deemed eligible based on the following criteria: prostatic adenocarcinoma diagnosis receiving SRT, no clinical evidence of metastasis, no hormone use prior to/during SRT, serum PSA measurement halfway through SRT, and minimum follow-up time of 3 months. Median follow-up time was 51.6 months. Eligible patients were divided into three groups based on PSA response by the midpoint of treatment: no change, decrease, or increase in PSA. The primary endpoint of the study was clinical failure (measured from SRT completion), defined as serum PSA value ≥0.2ng/mL above the post-radiotherapy nadir, initiation of androgen deprivation therapy, development of bone metastasis, or death from prostate cancer. Results: 13.1% experienced no change in PSA halfway through SRT (group 0), 68.4% of patients experienced a decrease (group 1), 18.4% experienced an increase (group 2). Four-year freedom from clinical failure was 60.0% for group 0, 58.3% for group 1, and 41.7% for group 2. Median time to clinical failure was 71.7 months for group 1, 26.8 months for group 2, and was not reached for group 0. Pairwise multiple comparison demonstrated a significant difference in four-year freedom from clinical failure between groups 1 and 2 (p = 0.036). Conclusions: These data strongly suggest that changes in PSA are apparent midway through SRT and are associated with 4-year freedom from clinical failure. Further study is warranted to determine whether mid-treatment PSA during SRT may be used to identify a subset of patients that may benefit from treatment intensification.
Exploratory study of prognostic factors in mCRPC patients who administered enzalutamide focusing on early PSA decline and PSA kinetics at PSA progression: Results of retrospective multicenter study.
Authors: Miyazawa Yoshiyuki , Shimizu Nobuaki , Takezawa Yutaka , Nakamura Toshiyuki , Miyao Takeshi , Nakayama Hiroshi , Kurihara Sota , Syuto Takahiro , Nomura Masashi , Sekine Yoshitaka , Koike Hidekazu , Matsui Hiroshi , Shibata Yasuhiro , Suzuki Kazuhiro 
Published: March 2019

292 Background: Recent studies have shown that an early PSA response to AR-targeting agents in mCRPC is associated with a better prognosis. We analyzed the early PSA response to enzalutamide (ENZ) by measuring the PSA doubling time (PSADT) and PSA Velocity while monitoring oncologic outcomes and survival in Japanese patients. Methods: A total of 241 patients with mCRPC treated with ENZ were analyzed. Patients’ median age is 75±7.9 (range 53-93). The patients pre-docetaxel settings were 171 cases (71 %), post-docetaxel settings were 70 cases (29 %). The PSA-PFS and OS were assessed according to PCWG2 criteria. This study was approved by the institutional review board of Gunma University Hospital (No.1595). Results: A case where PSA did not decline at all was defined as Primary Resistance (PR). A case in which PSA once declined after treatment but then progressed was defined as Acquired Resistance (AR). Those in which PSA remained low after treatment were defined as Good Response (GR). We observed 77 PR cases (31.9 %), 125 AR cases (51.9 %) and 39 GR cases (16.2 %).PSA-PFS and OS pre-docetaxel were significantly increased as compared to patients’ post-docetaxcel (PSA-PFS; 47.0 wks vs. 13.4 wks p < 0.001, OS; Not Yet Reached vs. 80.7 wks p < 0.001). Multivariate analysis of prognostic factors, including the PSA response at 4 weeks, was performed using a Cox regression analysis. The PS (0 or 1-2), Hb (≧11.4 or < 11.4), time to CRPC(≧12 m or < 12 m), docetaxel treatment history (none or done) and a PSA decrease of 50% at 4 weeks were all significant factors for the prediction of OS (all variables, p < 0.05). In cases of acquired resistance (n = 125), a multivariate analysis using PSA kinetics factors such as PSADT and PSA Velocity (ng/mL/month) at PSA progression, Hb, time to CRPC(≧12 m or < 12 m), PSADT (≧2 months or < 2 months) and PSA Velocity ( < 20 ng/mL/month or≧20 ng/mL/month), were all factors predicting OS following PSA progression (p < 0.05). Conclusions: Our study has demonstrated that PSA dynamics after ENZ administration may be a useful prognostication factor for mCRPC patients.
Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: A retrospective study.
Authors: Hamada Kosuke , Iguchi Taro , Tamada Satoshi , Kato Minoru , Yamasaki Takeshi , Takeyama Yuji , Shimizu Yasuomi , Yasuda Sayaka , Nakatani Tatsuya 
Published: March 2019

293 Background: In Asia, including Japan, combined androgen blockade (CAB) therapy with bicalutamide is widely used for metastatic prostate cancer. Alternative anti-androgen therapy (AAT) with flutamide (FLU) after CAB therapy with bicalutamide was common before the androgen receptor-targeted therapy era. The AAT response rate was 20–30%, and there is no evidence of prolonged overall survival (OS), but we have encountered effective clinical cases. Currently, two prospective clinical studies are ongoing, but this is the first retrospective study comparing FLU and enzalutamide (ENZ) for castration-resistant prostate cancer (CRPC). Methods: In our hospital, 55 patients were diagnosed with CRPC after CAB therapy and administered FLU or ENZ between May 2014 and December 2017. Patients with FLU failure then received ENZ. The study evaluation included 1) prostate-specific antigen (PSA) best response with initial therapy, 2) PSA progression-free survival with initial therapy (PSA-PFS), 3) PSA best response with ENZ therapy, 4) PSA-PFS of ENZ therapy (PSA-PFS-ENZ), and 5) OS. Results: As first-line CRPC therapy, patients received ENZ (n=29) or FLU (n=26). In the FLU group, 18 patients showed disease progression and then received ENZ. The PSA best response was statistically higher in the ENZ group. PSA-PFS was significantly statistically longer in the ENZ group (hazard ratio (HR) 1.85, 95% confidence interval (CI) 0.53–0.64, p=0.02). However, there was no significant difference in PSA best response with ENZ therapy and PSA-PFS-ENZ between the ENZ and post-FLU ENZ groups (HR 0.80, 95% CI 0.33–1.94, p=0.62) or in OS between the ENZ and post-FLU ENZ groups (HR 1.85, 95% CI 0.53–6.42, p=0.33). Conclusions: AAT with subsequent FLU after CAB therapy with bicalutamide may be suitable for some CRPC patients. (NCT02346578 and NCT02918968).
The oral α and β tubulin inhibitor, VERU-111, for the treatment of metastatic castration-resistant and androgen blocking agent-resistant prostate cancer in nonclinical toxicity studies.
Authors: Getzenberg Robert H. , Eisenberger Mario A. , Markowski Mark Christopher , Barnette Gary , Patrick Darryl , Steiner Mitchell S. 
Published: March 2019

299 Background: A dose limiting toxicity of taxane chemotherapy, including docetaxel and cabazitaxel, is neutropenia. VERU-111 is a novel, oral aand btubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance mechanisms. Nonclinical toxicity studies were recently performed in order to assess the effects of daily, high-dose administration of orally dosed daily VERU-111. Methods: Toxicity of VERU-111 was evaluated in a 28-day oral dosing toxicity study which was conducted in both rats and dogs. These studies were performed at an independent facility under GLP conditions. Results: In both species evaluated, at oral doses of ≤3 mg/kg/day (rat) and ≤8 mg/kg/day (dog) there were no significant observed findings of neutropenia, myelosuppression, or abnormal liver function. Conclusions: In contrast to cabazitaxel and docetaxel, which are given once every 3 weeks IV, VERU-111 given oral, daily for 28 days in toxicity studies in dog and rat did not result in neutropenia, and myelosuppression. Furthermore, VERU-111 orally each day did not affect liver function tests. These nonclinical toxicity studies provide the basis for progressing VERU-111 into a Phase 1b/2 study which targets men with metastatic castration and androgen blocking agent (abiraterone and enzalutamide) resistant prostate cancer.
Prognostic significance of lactate dehydrogenase-5 expression in patients with prostate cancer treated with androgen deprivation therapy and androgen receptor axis-targeted agents.
Authors: Fukuokaya Wataru , Kimura Takahiro , Honda Mariko , Inaba Hiroyuki , Iwatani Kosuke , Keiichiro Mori , Sato Shun , Takahashi Hiroyuki , Egawa Shin 
Published: March 2019

300 Background: Evidence suggests that hypoxic zones are prevalent in prostate cancer (PC). Recent clinical data showed that the expression of lactate dehydrogenase-5 (LDH5), a tumor hypoxia marker, affected the outcome of PC treated with radiation therapy. However, the impact of its expression on hormone therapy remains unclear. We investigated the predictive value of LDH5 expression in biopsy specimens from patients with PC treated with hormone therapy. Methods: Baseline data were available from 50 patients with PC treated with both androgen deprivation therapy (ADT) and novel androgen receptor axis-targeted agents (ARATs). LDH5 expression in the biopsy specimens was analyzed using immunohistochemical staining. Patients were stratified according to LDH5 expression in needle biopsy specimens. The relationships between LDH5 expression and baseline data at diagnosis, time to emergence of castration resistance, prostate-specific antigen (PSA) progression, and overall survival from induction of ADT and ARATs were examined. Results: Biopsy specimens from 19 patients highly expressed LDH5. High LDH5 expression was significantly associated with high Gleason scores (≥8) (p = 0.03), high clinical T stage (p = 0.008), and the likelihood of having at least one lymph node (p = 0.019) and metastatic lesion (p = 0.024). In a multivariate logistic regression model, LDH5 expression was significantly associated with high clinical T stage (p = 0.038), the presence of lymph node metastasis (p = 0.013), and high neutrophil-to-lymphocyte ratio (p = 0.016). Multivariate Cox regression analysis showed that high LDH5 expression was a significant predictor of time to emergence of castration resistance (hazard ratio [HR] 2.45, 95% confidence interval [CI] 1.12–5.36, p = 0.025) and overall survival (HR 9.3, 95% CI 2.17–39.8, p = 0.003). No significant association was observed between LDH5 expression and time to PSA progression from the induction of ARATs in univariate Cox regression analysis (p = 0.28). Conclusions: The results of this study suggest that LDH5 expression is a predictor of treatment outcomes in patients with PC treated with ADT.
Prostate cancer (PCa) incidence and severity in 821 hypogonadal men with and without testosterone therapy (TTh) in a controlled, observational registry implying more than 7,000 patient-years.
Authors: Haider Ahmad , Haider Karim Sultan 
Published: March 2019

304 Background: Guidelines by AUA and EAU state that there is no evidence for an increased PCa risk for testosterone (T) treatment in hypogonadal men. Methods: In a registry study initiated in 2004 in a urology practice, 428 hypogonadal men (T≤350 ng/dL) received T undecanoate 1000 mg every 3 months following an initial 6-month interval for up to 13 years (T-group). 393 hypogonadal men (age range 51-74) opted against TTh (CTRL). Suspicion of or active PCa was excluded by transrectal ultrasound, digital rectal examination and PSA before treatment/observation initiation. Examinations were repeated between one and four times per year. Biopsies were performed when indicated according to EAU Guidelines. Results: In the T-group, 12 (2.8%) , in CTRL, 42 men (10.9%) were diagnosed with PCa. The mean baseline age of PCa patients was 64.9 years in the T-group and 64 in CTRL.In the T-group, the average time span between day of first injection and positive biopsy was 14.2 months (range: 5-18). No patient was diagnosed with PCa beyond 18 months of TTh. In CTRL, PCa was diagnosed at any time during the observation time. In the T-group, radical prostatectomy (RP) was performed in all men. All but 3 patients had Gleason score (GS) ≤6, and all but 1 had a primary GS of 3. Tumor grade was G2 in all 12 (100%), tumor stage T2a in 7 (58%), T2b in 3 (25%), and T2c in 2 (17%) patients. All but 2 patients are back on TTh after an average time of 25 months. In CTRL, RP was performed in all but 6 patients who received radiation therapy (RT). GS was ≤6 in 2 patients, 7 men had a GS of 7, 21 a GS of 8, and 12 a GS of 9. 4 men had a primary Gleason score of 3, 29 had 4, and 9 had 5. Tumor grade was G2 in 9 (21%) and G3 in 33 (79%) patients, tumor stage T2a in 2 (5%), T2c in 1 (2%), T3b in 15 (36%) and T3c in 24 (57%) patients. In CTRL, biochemical recurrence occurred in 11 (26%) patients. These patients received androgen deprivation therapy (ADT). 12 (34%) patients died of whom 7 were on ADT. In the T-group, no biochemical recurrences or deaths occurred during the observation time. Conclusions: Less PCa occurred and severity was lower in testosterone-treated hypogonadal patients compared to untreated hypogonadal controls.