bluuebunny/crossref_metadata_2025_split huggingface dataset:
Periprostatic venous androgen levels in a subset of patients with prostate cancer: An investigation into a novel role of testosterone in localized prostate cancer.
Authors: Thomas Lewis , Alyamani Mohammad , Li Jianbo , Purysko Andrei , Klein Eric A. , Sharifi Nima 
Published: February 2020

341 Background: While androgens drive prostate cancer (PCa), studies of systemic levels in eugonadal patients have not shown a relationship with development or progression of PCa. This study characterizes the relationship between systemic, local venous, and tissue androgen levels to understand the regulation and influence of androgens on localized PCa. Methods: Peripheral & periprostatic venous blood & prostate tissue were collected from patients undergoing radical prostatectomy (RP). Androgen levels (testosterone (T) and dihydrotestosterone (DHT)) were assessed by mass spectrometry. PCa grade and stage, PSA, prostate volume, and periprostatic vein diameter (PPVD) on MRI were recorded. A second cohort of patients undergoing just prostate MRI (non-surgical) was assessed to investigate the relationship between PPVD and disease severity. Results: Samples were collected from 176 patients. Analysis identified a subset of patients with elevated periprostatic T (ppT) relative to systemic T (sT) including 25% with ppT/sT > 2, 14% with ppT/sT > 4, and 7% with ppT/sT > 10. Patients with ppT/sT > 4 had supraphysiologic T levels in the periprostatic venous blood (mean 4223ng/mL). These patients also had higher than predicted levels of tissue T and DHT (tT/sT of 0.48 vs 0.24 (p = 0.004) and tDHT/sT of 7.31 vs 4.72 (p = 0.011)). In the surgical cohort, PPVD was increased in patients with elevated ppT/sT levels (5.8mm vs 3.7mm, p = 0.013). In the biopsy cohort (n = 200), increased PPVD was associated with an increased risk of diagnosis of PCa (4.39mm vs 3.43mm p = 0.006) and clinically significant PCa (4.35mm vs 3.43mm p = 0.01). Conclusions: In a subset of patients with PCa, periprostatic venous T levels were highly elevated compared to peripheral levels. Tissue T and DHT were also increased, and MRI demonstrated increased PPVD. We hypothesize that collateralization of venous drainage from the gonadal vein leads to both high local T and dilated veins. In a biopsy cohort, increased PPVD was associated with an increased risk of diagnosis of any and clinically significant PCa, suggesting that high periprostatic androgen levels may play a role in development of PCa.
Multiple primary prostate tumors with differential drug sensitivity.
Authors: Wilkinson Scott C. , Ye Huihui , Terrigino Nicholas , Carrabba Nicole , Atway Rayann , Trostel Shana Y. , Bright John , Hennigan S. Thomas , Lis Rosina , Lake Ross , Harmon Stephanie , Turkbey Baris , Pinto Peter A. , Choyke Peter L. , Karzai Fatima , VanderWeele David James , Kelly Kathleen , Dahut William L. , Sowalsky Adam G. 
Published: February 2020

342 Background: The differential aggressiveness of potentially independent prostate cancer clones remains largely unknown. Appropriate prostate cancer staging using mpMRI and biopsy tissue can be confounded by sampling error. To date, there has been no understanding of whether clonal variability influences management decisions for localized prostate tumors. We sought to identify the sensitivity and genomic profile of distinct localized tumors from a patient following systemic intense neoadjuvant androgen deprivation therapy (ADT). Methods: A 66-year-old man with high risk prostate cancer enrolled in a Phase 2 study of intense neoadjuvant ADT (goserelin + enzalutamide; inADT). Baseline mpMRI showed a single semi-contiguous lesion encompassing the right apical-mid PZ extending into the left distal apical PZ. MR/US-fusion targeted biopsy was performed before 6 months of inADT. A second mpMRI was performed before radical prostatectomy. Whole exome sequencing on microdissected tumor foci identified somatic mutations and copy number alterations, which were further used with immunohistochemistry to assess tumor clonal architecture and genomic/phenotypic evolution of treatment resistant tumor. Results: We found two clonally independent tumors exhibited intrinsic heterogeneity at baseline which correlated with response or resistance. Biopsies of distinct left- and right-sided tumors showed differing histologies. mpMRI and pathology showed near complete response of the left-sided tumor and substantial resistance of the right-sided tumor, which exhibited a large intraductal component. Histology and whole exome data highlighted a divergence in the status of PTEN and TP53, tumor suppressor genes implicated in prostate cancer progression. Conclusions: These data highlight that even nascent prostate cancer is heterogenous and neoadjuvant therapeutic strategies will need to consider this for clinical optimization. Evolutionary trajectories that resulted in tumor heterogeneity in this case likely contributed to our observation that two independent prostate tumor nodules with distinct genetic alterations responded differently to neoadjuvant intense ADT. Clinical trial information: NCT02430480.
Immunosuppressive milieu of high-risk localized prostate cancer.
Authors: Adorno Febles Victor Ricardo , Adeegbe Dennis , Ahsan Aarif , Wu Jiansheng , Khodadad-Jamayran Alireza , Lepor Herbert , Wysock James , Taneja Samir , Huang William C. , Balar Arjun Vasant , Melamed Jonathan , Deng Fang-Ming , Ren Qinghu , Tsirigos Aristotelis , Kufe Donald W. , Heguy Adriana , Wong Kwok-Kin , Wise David R. 
Published: February 2020

344 Background: The immune factors that modulate the aggressiveness of localized treatment-naïve prostate cancer remain poorly understood. Methods: Fresh tumor and peripheral blood were collected at the time of radical prostatectomy in patients with localized prostate cancer. We evaluated the immune cell composition of 22 patient samples employing multi-parametric flow cytometry. Samples were grouped by histological grade into intermediate (INTPCA) and high-grade (HIGHPCA) prostate cancers based on standard NCCN criteria and immune cell abundances were quantified by mean +/- SEM. Statistical significance was assessed using the Mann-Whitney test. Results: INTPCA and HIGHPCA tumors harbored a similar increase in CD8+ T cells ( p < 0.0005 and p < 0.05, respectively) and CD11b+CD68-CD16+ myeloid-derived cells (p < 0.05) relative to the peripheral blood. Other cell types were similarly decreased in both INTPCA and HIGHPCA, including CD11b+CD68+CD14+ ( p < 0.005 and p < 0.05, respectively). By contrast, regulatory T cells were the only cell type in our analysis to be uniquely enriched in HIGHPCA rather than INTPCA ( p < 0.05). The most unique feature found in phenotypic profiling of the immune repertoire of HIGHPCA relative to INTPCA was an increase in the immune inhibitory receptor ligand, PD-L1, in the tumor associated macrophages (CD11b+CD68+CD14+) compared to the periphery (p < 0.05). Conclusions: Collectively, our findings reveal that HIGHPCA harbors a distinct immunological landscape. Although effector CD8+ T cells are preferentially expressed in the tumor, these are met with an increased proportion of regulatory T cells as well as PD-L1 expressing macrophages that contribute to the inert tumor microenvironment. These are key features of aggressive prostate cancer that may serve as potential biomarkers and therapeutic targets.
Racial/ethnicity differences when endorsing influential factors for prostate cancer treatment choice: An analysis of data from the personal patient profile-prostate (P3P) I and II trials.
Authors: Berry Donna Lynn , Hong Fangxin , Halpenny Barbara , Epstein Matthew , Trinh Quoc-Dien 
Published: February 2020

351 Background: Race and ethnicity impact the type of treatment received for localized prostate cancer in American men. We hypothesized that there may be differences in men’s influential values and preferences related to treatment decisions. Methods: We analyzed samples from two multicenter, randomized trials of the Patient Profile-Prostate (P3P) decision aid, first comparing the trial groups on demographic and decisional variables using Chi-square tests. Stratified (P3P I vs II) logistic regression was then used to assess the univariate association between race/ethnicity and endorsement of moderate-or-strong influence of 14 lifestyle factors, current or future symptoms, or important others on the decision. A multivariable stratified logistic regression with backward variable selection was used to further estimate the association between influential factors and race/ethnicity. Results: Data from 494 and 392 participants in P3PI and P3PII, respectively, were analyzed for 40 Hispanic, 168 non-Hispanic black, 637 non-Hispanic white, 19 others and 6 missing. Age (p=.0001), education (p<.0001), marital status (p<.0001), income (p<.0001), Internet use for information (p<.0001) and decisional control preference were significantly different across racial/ethnic groups. In adjusted analyses, racial/ethnic differences existed for influence of age (Non Hispanic Black (NHB) vs. Non Hispanic White (NHW) OR: 0.56 95%CI 0.38-0.85p=.002), religion/spirituality (NHB vs. NHW OR: 3.2095%CI1.95-5.26, p<.0001), future bladder function (NHB vs. NHW OR: 0.5795%CI0.35-0.90, p=.04), future ability to engage in recreation (NHB vs. NHW OR: 0.5495%CI 0.34-0.86, p=0.02), and a story of a famous person with prostate cancer (NHB vs. NHW OR: 2,11 95%CI1.30-3.43, p=.007). Conclusions: Our results suggest racial/ethnic differences for influences underlying treatment choice. Better understanding these influences may help us present salient information about treatment options to patients and address disparities.
Edmonton Prostate Interdisciplinary Cancer Clinic (EPICC): Real-world efficacy outcomes of a multidisciplinary clinic for metastatic castration-resistant prostate cancer.
Authors: Follett Graeme , Tilley Derek , Basappa Naveen S. , Danielson Brita Lavender , Chetner Michael , Kolinsky Michael Paul , North Scott A. , Rayner-Myers Sarah , Todd Gerry , Fairey Adrian S. 
Published: February 2020

36 Background: Multidisciplinary management improves complex treatment decision making in cancer care but its impact for metastatic castration resistant prostate cancer (M1 CRPC) has not been documented. The Edmonton Prostate Interdisciplinary Cancer Clinic (EPICC) is a multidisciplinary specialized clinic focused on the delivery of novel therapeutics (Androgen Receptor Axis Therapy; ARAT) to men with chemotherapy-naïve M1 CRPC. The objective of the current study was to assess the efficacy of ARAT in the EPICC. Methods: The study was a retrospective quality assurance analysis. Eligible patients had a new diagnosis of chemotherapy-naïve M1 CRPC with minimal symptoms. EPICC patients were assessed and treated by a multidisciplinary cancer control team that included nursing oncology, pharmacy oncology and physician oncology (urologic, medical and radiation). Patients were treated in first line with an ARAT (abiraterone (AA) or enzalutamide (EZ)) from October 2017 to March 2018. The main efficacy outcome was overall survival (OS). The Kaplan-Meier method and Cox regression model were used to analyze survival data. Statistical tests were two-sided (p≤0.05). Results: From October 2017 to March 2018, 160 chemotherapy-naïve M1 CRPC patients were assessed in the EPICC. Median age at EPICC admission was 77 years (range, 54-92 years). Median PSA level at EPICC admission was 26.6 ng/mL (range, 0.1-5000 ng/mL). 84 out of 160 (53%) patients had received prior radical local therapy (RLT) with curative intent. 83 (57%) patients were treated with EZ and 64 (43%) patients were treated AA. Median OS for the entire cohort was 23 months. In multivariable analysis, absence of prior RLT (HR 3.6, 95% CI 1.9 to 6.6, p < 0.001), PSA > 20 ng/mL (HR 3.2, 95% CI 1.4 to 7.2, p = 0.004), and higher ECOG performance status (1 vs 0: HR 2.4, 95% CI 1.3 to 4.4, p = 0.005; 2 versus 0: HR 3.5, 95% CI 1.5 to 8.0, p = 0.003; and 3 versus 0: HR 12.7, 95% CI 2.5 to 63.8, p = 0.002) were independently associated with poorer OS. Conclusions: Multidisciplinary management of chemotherapy-naïve M1 CRPC with ARAT is feasible. Real world efficacy of ARAT in EPICC are similar to data reported in phase 3 trials.
5-alpha reductase inhibitors (5-ARI) and prostate cancer mortality among men with regular access to screening and health care.
Authors: Mucci Lorelei A. , Pernar Claire Hampton , Rencsok Emily , Stopsack Konrad H. , Grob Sydney , Giovannucci Edward L. , Olumi Aria F , Kibel Adam S. , Preston Mark A. , Wilson Kathryn M. 
Published: February 2020

39 Background: The excess risk of high-grade prostate cancer in the Prostate Cancer Prevention Trial (PCPT) among men randomized to finasteride raised concerns that a chemoprevention benefit would be offset by increased mortality. Two 2019 publications had contrasting results whether 5-ARIs increased prostate cancer mortality. In PCPT, there was no excess prostate cancer mortality. In a VA study, 5-ARI use was associated with later stage at diagnosis and 39% higher prostate cancer mortality risk. We studied men with regular access to health care and screening to address this conflicting evidence. Methods: We performed two parallel analyses in the Health Professionals Follow-up Study. 5-ARI use was reported on biennial questionnaires starting in 1996. In line with PCPT, we studied 38,047 men for cancer incidence and mortality through 2016. In line with the VA study, we undertook a case-only study of 4,225 patients with localized/locally advanced cancers followed similarly. We estimated hazard ratios (HR) and 95% confidence intervals accounting for screening patterns, lifestyle factors, and concomitant medications. Results: 5-ARI ever-users (n = 4,101; 10.7%) were more likely to have had regular PSA screening (74% vs. 57% nonusers) and a negative prostate biopsy before diagnosis. Neither ever 5-ARI use (HR 1.08, 0.73-1.60, 445 events) nor long-term use ( > 4 years, HR 1.03, 1.03-2.02) were associated with lethal prostate cancer. There was no difference in stage. Diagnostic PSA levels were lower in 5-ARIs users (10.0 vs. 16.0 ng/ml in never-users). Among nonmetastatic cases, 278 men died of prostate cancer; there was no association between 5-ARIs and prostate cancer survival (HR 0.85, 0.51-1.43). Conclusions: Our results align with PCPT and show no excess risk of lethal prostate cancer, no higher stage at diagnosis, and no excess mortality after diagnosis associated with 5-ARI. Men on 5-ARIs had more interactions with health care, which may have led to higher quality care. This contrasts with the VA study where men on 5-ARIs were diagnosed later due to suppressed PSA and had worse survival. These results show the importance of real-world data in framing the benefits and risks associated with 5-ARIs.
Comprehensive genomic profiling (CGP) of histologic subtypes of urethral carcinomas (UrthCa).
Authors: Jacob Joseph , Shapiro Oleg , Necchi Andrea , Grivas Petros , Sokol Ethan , Vergilio Jo-Anne , Killian Keith , Lin Douglas I. , Williams Erik , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Chung Jon , Alexander Brian Michael , McGregor Kimberly , Elvin Julia Andrea , Schrock Alexa Betzig , Danziger Natalie , Ross Jeffrey S. , Bratslavsky Gennady 
Published: February 2020

426 Background: UrthCa is an uncommon GU malignancy that can progress to advanced metastatic disease. Methods: 126 metastatic UrthCa underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 49 (39%) urothelial (UrthUC), 31 (24%) squamous (UrthSCC), 34 (27%) adenocarcinomas (UrthAC) and 12 (9%) clear cell (UrthCC) were evaluated. UrthUC and UrthSCC were more common in men; UrthAC and UrthCC more common in women. Ages were similar in all groups. GA in PIK3CA were the most frequent potentially targetable GA; mTOR pathway GA in PTEN also identified. GA in other potentially targetable genes were also identified including ERBB2 (6% in UrthUC, 3% in UrthSCC and 12% in UrthAC), FGFR1-3 (3% in UrthSCC), BRAF (3% in UrthAC), PTCH1 (8% in UrthCC) and MET (8% in UrthCC). Possibly reflecting their higher GA/tumor status, potential for immunotherapy benefit associated with higher TMB and PD-L1 staining levels were seen in UrthUC and UrthSCC compared to UrthAC and UrthCC. MSI high status was absent throughout. Conclusions: CGP reveals GA that may be predictive of both targeted and immunotherapy benefit in patients with advanced UrthCa and that could potentially be used in future adjuvant, neoadjuvant and metastatic disease trials.[Table: see text]
The emerging target KRAS G12C in genitourinary malignancies.
Authors: Grivas Petros , Necchi Andrea , Bratslavsky Gennady , Shapiro Oleg , Jacob Joseph , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Keith , Williams Erik , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Schrock Alexa Betzig , Chung Jon , McGregor Kimberly , Reddy Prasanth , Alexander Brian Michael , Sokol Ethan , Danziger Natalie , Ross Jeffrey S. 
Published: February 2020

434 Background: KRAS has recently emerged as a druggable driver with novel agents targeting G12C genomic alteration (GA). Methods: FFPE tissue from 1453 renal clear cell carcinomas (RCCC), 3879 urothelial bladder carcinomas (UBC) and 8322 prostate acinar adenocarcinomas (PAAC) underwent comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on 0.8 to 1.2 Mbp of sequenced DNA and MSI was determined on 114 loci. PD-L1 expression (Dako 22C3) was measured by IHC. Results: KRAS GA were identified in 7 RCCC (<1%), 202 UBC (5.2%), and 158 PAAC (1.9%). KRAS G12C mutations were observed in 0 RCCC, 24 (2%) of UBC, and 1 (<1%) PAAC. Age/gender distributions were similar. VHL, SETD2, and PBRM1 mutations were the most frequent concurrent GA in the 7 RCCC with KRAS G12C GA. In KRAS G12C mutated UBC, co-mutations in TERT were significantly reduced and in KDM6A were significantly increased (both p<0.05) in cases with KRAS G12C GA versus KRAS G12C negative tumors. Conclusions: KRAS G12C mutations are extremely rare in the major genitourinary malignancies. However, given the emerging interest in identifying KRAS G12C for potential basket-type clinical trials using novel anti-KRAS G12C targeted therapies, further study of these alterations in genitourinary malignancies, especially bladder and prostatic carcinomas, appears warranted.[Table: see text]
Randomized phase III trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC) as perioperative chemotherapy for muscle invasive urothelial bladder cancer (MIUBC): Preliminary results of the GETUG/AFU V05 VESPER trial on toxicity and pathological responses.
Authors: Culine Stephane , Gravis Gwenaelle , Flechon Aude , Soulie Michel , Guy Laurent , Laguerre Brigitte , Mottet Nicolas , Joly Florence , Allory Yves , Harter Valentin , Pfister Christian 
Published: February 2020

437 Background: The optimal perioperative chemotherapy regimen for patients (pts) with MIUBC is not defined. Methods: Between February 2013 and February 2018, 494 pts were randomized in 28 French centres and received either 4 cycles of GC every 3 weeks or 6 cycles of dd-MVAC every 2 weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). The primary endpoint was the progression-free survival at 3 years. Secondary endpoints included toxicity, pathological responses and overall survival. Results: In the neoadjuvant group, 218 pts received dd-MVAC and 219 pts GC. The median number of cycles was 6 (0-6) and 4 (1-4), respectively. 60% of pts received 6 cycles in the dd-MVAC arm, 84% received 4 cycles in the GC arm. 199 pts (91%) and 198 (90%) pts underwent surgery, respectively. Complete pathologic responses (ypT0pN0) were observed in 84 (42%) and 71 (36%) pts, respectively (p=0.02). An organ-confined status (<ypT3pN0) was obtained in 154 (77%) and 124 (63%) pts, respectively (p=0.002). In the adjuvant group (57 pts), the median number of cycles was 5 (1-6) and 4 (1-4), respectively. 40% of pts received 6 cycles in the dd-MVAC arm, 60% received 4 cycles in the GC arm. Most of CTCAE grade ≥ 3 toxicities concerned hematological toxicities. At least one of these where reported for 125 (50%) pts in the dd-MVAC group and 134 (54%) pts in the GC group (p=NS). Gastrointestinal (GI) grade ≥ 3 disorders were more frequently observed in the dd-MVAC arm (p<0.0001) as well as grade ≥ 3 asthenia (p<0.00001). Four deaths (3 in the dd-MVAC) occurred during chemotherapy. Conclusions: Complete pathological responses and organ-confined status were more frequently observed in the dd-MVAC arm. Toxicity was manageable with more severe asthenia and GI side effects in the dd-MVAC arm. Clinical trial information: 2012-000563-25.
Trends in management and outcomes in patients with upper tract urothelial carcinoma following radical nephrouretectomy at Memorial Sloan Kettering Cancer Center.
Authors: Wong Nathan Colin , Assel Melissa , Tracey Andrew , Alvim Ricardo , Almassi Nima , Singla Nirmish , Clinton Timothy Nguyen , Chesnut Gregory Thomas , Sjoberg Daniel D. , Bajorin Dean F. , Coleman Jonathan 
Published: February 2020

469 Background: Although there have been changes in the treatment paradigm of patients with upper tract urothelial carcinoma (UTUC) over the past 2 decades, there is limited data on the particular management strategies and associated outcomes. We evaluated surgical trends, perioperative management, and oncologic outcomes of patients who underwent radical nephroureterectomy (RNU) for UTUC at Memorial Sloan Kettering Cancer Center over a 24-year period. Methods: Between 1995 and 2018, we identified 760 patients with UTUC who underwent RNU. 15 had multiple RNU and we kept only the first procedure for analysis. Generalized additive models were fitted to examine the association between date of surgery and continuous while generalized additive models with a logit link were used to estimate categorical variables. As surgical approach was defined using three different categories (open, laparoscopic and robotic) a generalized additive multinomial model was used. Generalized additive cox proportional hazards models were used to estimate the association between surgery date and estimate 2-year cancer-specific survival. Results: The use of pre-operative diagnostic endoscopic biopsies also increased from 12% to 72% which coincides with an increased proportion high grade disease on final pathology from 55% to 91%. The rate of open RNU declined from 100% to 54% with a coinciding rise in the utilization of minimally invasive approaches. Laparoscopy peaked in 2008 and then was subsequently replaced by the robotic approach. Mean lymph node yield increased over the study interval with more retroperitoneal lymph node dissections performed. Utilization of neoadjuvant chemotherapy also increased over time with a current rate of 31%, coinciding with an increase in pT0 rate from only 2% to 9%.The 2-year cancer specific survival probability has improved from 76% to 87% over the study period. Conclusions: Several changes in treatment patterns for patients with UTUC over the past 2 decades appear to correspond with an improvement of oncologic outcomes. How these changes directly relate to each other requires further investigation.