bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel orthotopic murine model of neuroendocrine bladder cancer: Insights into the phenotypic plasticity of small cell bladder cancer (SCBC).
Authors: Balyimez Aysegul , Ganguly Shinjini , Grivas Petros , Ornstein Moshe Chaim , Gupta Shilpa , Garcia Jorge A. , Lee Byron H , Tendulkar Rahul D. , Stephans Kevin L. , Ciezki Jay P. , McKenney Jesse , Klein Eric A. , Mian Omar Y. 
Published: February 2020

571 Background: SCBC is an aggressive subtype of bladder cancer with high metastatic potential and few effective treatment options. We developed an orthotopic mouse model of SCBC to understand the development of this rare bladder cancer variant and identify epigenetic drivers of neuroendocrine differentiation. Methods: Lentiviral particles carrying Cre recombinase were produced using Lenti-sgNeo#2/Cre. The bladders of Rb1fl/fl Trp53fl/fl MycLSL/LSL (RPM) mice was transduced with Cre recombinase expressing lentivirus via transurethral catheterization. Mice were monitored by micro-ultrasound (mUS) and detected tumors were verified by histology. SCBC morphology was confirmed by H&E staining and synaptophysin IHC. Whole transcriptome (RNAseq) analysis was performed to correlate transcriptomic profile of neuroendocrine mouse tumors to a cohort of human SCBC tumors. Results: Transurethral catheterization successfully transduced the bladder urothelium without evidence of exposure of ectopic (non-urothelial) tissues. RPM mice developed SCBC visible on mUS with a latency of 8-10 weeks. As expected in neuroendocrine tumors, mice developed liver and lung metastases. High grade neuroendocrine morphology and NE markers were confirmed on H&E and IHC, respectively, by a GU pathologist. Western blot analysis confirmed cMyc expression and suppression of TP53 and RB1. Synaptophysin expression was confirmed by IHC. Transcriptomic profiling of both mouse and human SCBC demonstrated concordant gene expression. Gene expression profiling of urothelial and non-urothelial neuroendocrine tumors suggested a phenotypic convergence. Conclusions: We developed a novel genetically engineered murine model of SCBC. Ongoing work seeks to identify epigenetic markers playing role in the development of this aggressive variant of bladder cancer. We are assessing the activity of immune checkpoint inhibitors in this immunocompetent background.
Safety and efficacy of immune checkpoint inhibitors (ICI) in metastatic non-clear cell renal cell carcinoma (nccRCC): An institutional experience.
Authors: Schwartzman William , Elias Roy , Patel Viral M. , Bowman Alex Isaac , Chintalapati Suneetha , Kapur Payal , Hammers Hans J. , Brugarolas James 
Published: February 2020

640 Background: ICIs have improved outcomes in clear cell RCC patients (pts), and emerging data suggest that they may be effective against nccRCC. nccRCC comprises ~25% of renal tumors and consist of a diverse group of diseases. Despite recent evidence, data regarding the efficacy of ICIs in nccRCC remain limited, especially among rarer nccRCC subtypes. Methods: We identified all cases of metastatic nccRCC that received at least one dose of ICI therapy at UT Southwestern Medical Center from 2014 – 2018. Baseline characteristics and IMDC criteria were evaluated at the time of ICI initiation. Outcomes included objective response rate (ORR) per RECIST v1.1 criteria, time to next treatment (TNT), and overall survival (OS). Immune-related adverse events (irAE) were graded per CTCAE 4.0 criteria. Survival estimates were evaluated using Kaplan Meier methods. Results: We identified 28 pts with metastatic nccRCC; 12 (42.9%) unclassified RCC (uRCC), 8 (28.6%) papillary RCC (pRCC), 3 (10.7%) chromophobe RCC (chRCC), 3 (10.7%) hereditary leiomyomatosis and renal cell cancer (HLRCC), 1 (3.6%) translocation RCC (tRCC) and 1 (3.6%) acquired cystic disease-associated RCC (ACD-RCC). 23 (82.1%) pts were intermediate or poor risk by IMDC criteria. In total, 13 (46.4%) pts received nivolumab monotherapy, and 15 (53.6%) in combination with ipilimumab. 12 (42.9%) pts received ICI in the first line. The median TNT and OS amongst all nccRCC subtypes was 4.9 (95% CI: 1.7-8.1) and 15.9 (95% CI: 5.9 – 25.9) months respectively. The ORR was 3/28 (10.7%), with 2 complete responses. All responses were restricted to the pRCC and uRCC subtypes. 11 (39.3%) pts experienced any irAE and 5 (17.9%) had a grade 3/4 irAE, including one case of grade 4 myocarditis. The median time to onset of an irAE was 1.9 months (Range: 0.1 to 12.0). At a median follow up of 10.8 months (95% CI: 10.2 – 17.9), 4 pts remain on therapy and 13 pts have died. Conclusions: ICI therapy demonstrated modest efficacy in this cohort with comparable irAE profiles to ccRCC. Objective responses were not seen in pts with HLRCC, ACD-RCC, tRCC, or chRCC in this study.
Surgical learning curve for robotic multiplex partial nephrectomy: The National Cancer Institute Experience.
Authors: Telfer Siobhan , Gurram Sandeep , Gomella Patrick H. , Li Winston , Bratslavsky Gennady , Metwalli Adam R. , Linehan W. Marston , Ball Mark Wayne 
Published: February 2020

660 Background: Multiplex partial nephrectomy (MPN) remains the standard of care for hereditary and bilateral kidney tumors. Our institution is an international referral center for the management of hereditary renal cell carcinoma, and therefore has considerable experience with MPN. The objective of this study was to evaluate surgical learning curve for MPN among multiple surgeons at a single institution over an 11-year period. Methods: Retrospective review of a prospectively maintained registry of patients who underwent MPN from 2007-present. The first 100 consecutive surgeries of 3 NIH fellowship trained Urologic Oncologists were identified and evaluated in quartiles. Surgical outcome measures including operative duration (OD), estimated blood loss (EBL), number of tumors resected, and complication rate were chosen as surrogate markers of learning curve. Differences in individual surgeon outcomes were evaluated and variables including re-do surgery and surgical approach were considered. Significant differences found among quartiles or among surgeon were evaluated with multivariate logistic regression analysis. Results: A total of 300 MPN's were identified. In the quartile analysis, there were no significant differences in OD, EBL, numbers of tumors resected or rates of complication. Among surgeon factors, there were differences in surgical approach and EBL (table). In a multivariate analysis of factors associated with EBL, open approach (95%CI 245-831), p < 0.0001) and number of tumors (95%CI 43-82), p < 0.0001) were independently associated. No factors were associated increased rate of complication. Conclusions: As surgeons progressed through their first 100 operations, no true learning curve was appreciated, with similar outcomes in each quartile. Among surgeon factors, open surgical approach appears to drive difference in EBL.[Table: see text]
Using high-resolution magic angle spinning magnetic resonance spectroscopy to characterize the metabolomic profile of renal cell carcinoma.
Authors: Huynh Melissa Jessica , Gusev Andrew , Palmas Francesco , Vandergrift Lindsey , Wu Chin-Lee , Cheng Leo , Feldman Adam S. 
Published: February 2020

710 Background: Renal cell carcinoma (RCC) is a metabolic disease, with the various subtypes exhibiting aberrations in different metabolic pathways. Metabolomics may offer greater sensitivity for revealing disease biology than evaluation of tissue morphology. In this study, we investigate the metabolomic profile of RCC using high resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS). Methods: Tissue samples were obtained from radical or partial nephrectomy specimens that were fresh frozen & stored at -80ºC. Tissue HRMAS MRS was performed by a Bruker AVANCE spectrometer. Metabolomic profiles of RCC & adjacent benign renal tissue were compared, and false discovery rates (FDR) were used to account for multiple testing. Regions of interest (ROI) with FDR < 0.05 were selected as potential predictors of malignancy. The Wilcoxon rank sum test was used to compare median MRS relative intensities for the candidate predictors. Logistic regression was used to determine odds ratios for risk of malignancy based on abundance of each metabolite. Results: There were 38 RCC (16 clear cell, 11 papillary, 11 chromophobe) & 13 adjacent normal tissue specimens (matched pairs). Metabolic predictors of malignancy based on FDR include histidine, phenylalanine, phosphocholine, serine, phosphocreatine, creatine, glycerophosphocholine, valine, glycine, myo-inositol, scylla-inositol, taurine, glutamine, spermine, acetoacetate & lactate. Higher levels of spermine, histidine & phenylalanine at 3.15-3.13 ppm were associated with a decreased risk of RCC (OR 4x10−5, 95% CI 7.42x10−8, 0.02), while 2.84-2.82 ppm increased the risk of malignant pathology (OR 7158.67, 95% CI 6.3, 8.3x106), and the specific metabolites characterizing this region remain to be identified. Tumor stage did not appear to affect the metabolomics of malignant tumors, suggesting that metabolites are more dependent on histologic subtype. Conclusions: HRMAS-MRS identified many metabolites that may predict RCC. We demonstrated that those in the 3.14-3.13 ppm ROI were present in lower levels in RCC, while higher levels of metabolites in the 2.84-2.82 ppm ROI substantially increased the risk of RCC.
Metastatic renal cell carcinoma (mRCC) in young patients: A comprehensive genomic profiling (CGP) study.
Authors: Bratslavsky Gennady , Necchi Andrea , Grivas Petros , Shapiro Oleg , Jacob Joseph , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Keith , Lin Douglas I. , Williams Erik , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Schrock Alexa Betzig , Chung Jon , McGregor Kimberly , Reddy Prasanth , Alexander Brian Michael , Danziger Natalie , Ross Jeffrey S. 
Published: February 2020

727 Background: We studied the genomic alterations (GA) in patients with mRCC under 40 years of age (<40) and patients 40 years of age or older (>40). Methods: 2,128 mRCC underwent hybrid-capture based CGP. Clear cell (ccRCC), papillary (pRCC), sarcomatoid (sRCC), NOS (nosRCC), chromophobe (chrRCC), medullary (medRCC) and collecting duct (cdRCC) were separately evaluated. 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: Male preponderance in all subsets increased in the >40 patients. The GA/tumor increased significantly in the >40 cohorts except for in medRCC. The relatively low TMB was higher in all >40 and MSI high status was infrequent in all groups. PD-L1 expression was generally low, the 44% high positive PD-L1 in sRCC was noteworthy. Significant differences in GA in <40 vs >40 RCC included increased PBRM1 and SETD2 GA in >40 vs <40 ccRCC; increased C DKN2A/B and TERT and decreased FH GA in >40 vs <40 pRCC; increased TP53, PTEN and TERT GA with decreased NF2 GA in >40 vs <40 sRCC; increased TP53, VHL and TERT in >40 vs <40 nosRCC. Changes in GA in <40 vs >40 chrRCC, medRCC and cdRCC were noted but insufficient cases prevented statistical evaluation. Conclusions: When evaluated by age, CGP of mRCC demonstrates significant differences in the genomic landscapes with >40 cases featuring increasing male preponderance and higher GA/tumor, TMB and increases in TP53, CDKN2A/B and TERT GA. These findings may play important roles in the planning of future clinical trials designed to personalize the treatment of mRCC.[Table: see text]
Safety and outcome of stereotactic body radiation therapy (SBRT) with rectal hydrogel spacer for prostate cancer.
Authors: Chen Lily , Gao Ang , Gannavarapu Bhavani S. , Garant Aurelie , Desai Neil Bipinchandra , Folkert Michael Ryan , Ahn Chul , Roehrborn Claus G. , Lotan Yair , Timmerman Robert D. , Hannan Raquibul 
Published: February 2020

76 Background: Ultra-hypofractionated radiotherapy delivered using stereotactic body radiotherapy (SBRT) is a cost-effective treatment for localized prostate cancer. Optimal dosing remains unclear, as commonly used 30-40Gy/5fx regimens appear to overestimate hypofractionation’s control benefits. Here, we report the largest experience of 45Gy/5Fx of SBRT for prostate cancer patients treated with hydrogel peri-rectal spacer (‘hydrogel’). Methods: An IRB-approved retrospective protocol was used to conduct a registry search identifying all patients with prostate cancer who received 45Gy/5Fx between 2015-2019 with hydrogel. Genitourinary (GU) and gastrointestinal (GI) toxicities were defined using the NCI Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. The ASTRO-Phoenix failure definition of Nadir+2 ng/mL was used for biochemical failure. Results: We analyzed 250 low (9.2%), intermediate (85.2%), and high-risk (5.6%) prostate cancer patients with a median follow-up of 9.9 months (range: 0-45.7 months). Acute GU and GI grade ≥ II toxicities were noted in 15.2% and 7.2% of patients, respectively. Late GU grade II and III toxicities occurred in 24.0% and 1.2% of patients, respectively, while late GI grade II and III toxicities occurred in 4.0% and 0.4% of patients, respectively. In patients (N=44) with follow-up >2 years, late GU and GI grade III toxicities occurred in 4.55% and 2.27% of patients, respectively. A significant correlation was noted for acute GI and GU toxicity predicting the respective late GI and GU toxicity (p-value < 0.001 for both). Physician-reported Grade ≥ II new onset erectile dysfunction was 17.2%. A gradual decline in prostate-specific antigen with a mean nadir of 0.04 (95% CI: [0.018, 0.067]) at 36 months was noted. The actuarial freedom from biochemical failure was 96.33% at 3 years. Overall survival was 94.09% at 3 years with no deaths attributed to prostate cancer. Conclusions: SBRT treatment of 45Gy/5Fx with hydrogel is well tolerated with GU/GI toxicities comparable to those reported for conventional fractionation. Although short, the 3-year biochemical control rate is encouraging. Longer follow-up and prospective evaluation are warranted.
Propensity score matched comparison of docetaxel and androgen receptor axis-targeted (ARAT) agents in castration-resistant prostate cancer patients with intraductal carcinoma of the prostate (IDC-P).
Authors: Yamamoto Akiyuki , Kato Masashi , Tsuzuki Toyonori , Gotoh Momokazu 
Published: February 2020

80 Background: Several studies have reported that intraductal carcinoma of the prostate (IDC-P) is a pathological adverse prognostic factor in patients with prostate cancer. However, the optimal treatment has not been established. The present study aimed to evaluate the efficacy of docetaxel and androgen receptor axis-targeted (ARAT) agents in patients with castration-resistant prostate cancer (CRPC) with IDC-P using a propensity score-matched analysis. Methods: We retrospectively identified 309 patients with CRPC from February 2007 to February 2016. They received initial androgen deprivation therapy (ADT) and after progression to CRPC, they received docetaxel or ARAT (abiraterone or enzalutamide) as the first-line life-prolonging therapy. The primary outcome of interest was OS from the time of CRPC diagnosis. We also investigated PFS from the time of docetaxel or ARAT initiation. Results: Propensity score-matching identified 85 patients in each group. There were no significant differences in patient characteristics between the groups. The median OS in the docetaxel group was 38.2 months versus 58.3 months in the ARAT group (HR 0.57; 95% CI 0.37–0.89; P =.01). Regarding patients with IDC-P, OS was significantly longer in the ARAT group than the docetaxel group (HR 0.48; 95% CI 0.26–0.86; P =.01), and there was no significant difference in each group, as in patients without IDC-P (HR 0.75; 95% CI 0.37–1.52; P =.43). The median PFS in the docetaxel group was 6.7 versus 7.8 months in the ARAT group (HR 0.65; 95% CI 0.45–0.94; P =.02). A multivariate analysis demonstrated that the presence of IDC-P, duration of primary ADT, visceral metastasis, and administration of ARAT as the first treatment for CRPC were independent prognostic factors for OS. Conclusions: Administration of ARAT as the first treatment for CRPC may prolong OS more than that of docetaxel, especially in patients with IDC-P.
Bicalutamide with or without metformin for biochemical recurrence in prostate cancer patients (BIMET-1).
Authors: Bilusic Marijo , Zibelman Matthew R. , Ghatalia Pooja , Wroblewski Susan , Madan Ravi Amrit , Karzai Fatima , Dahut William L. , Gulley James L. , Plimack Elizabeth R. , Geynisman Daniel M. 
Published: February 2020

85 Background: Metformin (MET) may play a role as an anti-proliferative and anti-carcinogenic agent. Epidemiological studies have demonstrated that MET is associated with decreased prostate cancer (PCa) incidence, including decreased PCa specific mortality in diabetic men with PCa. Preclinical studies have shown synergistic effect of MET with bicalutamide, thus prompting this clinical trial evaluating the combination (NCT02614859). Methods: This was an open label, randomized, phase II trial of pts with biochemically recurrent PCa, PSA doubling time 3-9 months, normal testosterone, and BMI > 25. Pts were randomized (2:1) either to MET 1000 mg twice daily orally or observation for initial 8 weeks. Bicalutamide 50 mg orally daily was added to both arms after 8 weeks. Total duration of treatment was 32 weeks. The primary objective was to determine number of pts with undetectable PSA ( < 0.2 ng/mL) at the end of study with key secondary objectives of evaluating PSA declines of ≥ 85%, PSA responses to MET alone and safety. An early stopping rule for futility was set at 39 pts, but due to slow accrual, an unplanned interim analysis was undertaken. Results: 28 patients were randomized between December 2015 and September 2019. Treatment was well tolerated with no dose reductions or treatment discontinuation. No Grade 3 treatment-related adverse events were observed. Conclusions: PSA responses were seen in 50% pts with MET monotherapy after 8 weeks. Although well tolerated, there was no difference in PSA at 32 weeks between the two arms. The trial will be stopped early due to poor accrual and inability to achieve its primary endpoint. Ongoing larger studies of MET in PCa (STAMPEDE) will define it’s utility in prostate cancer. Clinical trial information: NCT02614859. [Table: see text]
Disulfiram (DSF) pharmacokinetics (PK) and copper PET imaging in a phase Ib study of intravenous (IV) copper loading with oral DSF for patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Zhang Tian , Kephart Julie , Bronson Elizabeth , Anand Monika , Daly Christine , Spasojevic Ivan , Berg Hannah , James Olga G. , Healy Patrick , Halabi Susan , Harrison Michael Roger , Armstrong Andrew J. , George Daniel J. 
Published: February 2020

96 Background: In preclinical models of prostate cancer (PC), DSF reduced tumor growth when co-administered with copper (Cu). Further, intracellular Cu uptake is partially regulated by androgen-receptor signaling. Given these data, we conducted a phase Ib clinical trial of mCRPC patients (pts) receiving Cu with DSF. Methods: Pts with mCRPC were assigned to 1 of 3 cohorts: neuroendocrine PC (NEPC) (A), adenocarcinoma (adenoCA) mCRPC with non-liver/peritoneal metastases (B), and adenoCA mCRPC with liver and/or peritoneal metastases (C). IV CuCl2 was given weekly for 3 doses with oral daily DSF. After CuCl2 dosing, daily oral Cu gluconate was started and DSF continued until disease progression as defined by Prostate Cancer Working Group Three (PCWG3). DSF and metabolite MeDDC levels in plasma were sampled at 0, 2, 4, 6 and 8 hours after the first dose and on Cycle 2 Day 1, and measured by HPLC. DSF and MeDDC were evaluated for cytotoxicity in 3 PC cell lines (22Rv1, LnCAP, and PC3) and a prostate epithelial cell line (PWR-1E). mCRPC Cu avidity was measured by 64Cu PET scan at baseline for all pts. Results: We treated 9 pts with mCRPC, 6 on cohort B and 3 on cohort C. No confirmed PSA declines or radiographic responses were observed in either cohort. Common adverse events included fatigue and psychomotor depression; no grade 4/5 AEs were observed. PK analysis: No DSF was detected in plasma (LOQ = 0.032 ng/mL, LOD = 0.01 ng/mL), whereas MeDDC was measurable in all study samples (LOQ = 0.512 ng/mL). MeDDC exhibited no cytotoxicity activity in PC cell lines. On 64Cu PET scans, bone metastases showed differential and heterogeneous Cu uptake. Lymph node and pulmonary metastases were evaluable, but not liver metastases due to significant Cu uptake in the liver. Conclusions: Oral DSF is not an effective treatment for mCRPC because it is quickly metabolized into the non-cytotoxic inactive metabolite, MeDDC. As such, this trial has stopped enrollment. Further work is needed to identify a stable DSF formulation so that the conditional lethality of Cu and DSF may be evaluated for treatment of mCRPC. Clinical trial information: NCT02963051.
Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) versus placebo plus enza for metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-641.
Authors: Graff Julie Nicole , Burgents Joseph , Liang Li Wen , Stenzl Arnulf 
Published: February 2020

TPS258 Background: The mechanisms of action of pembro, a PD-1 inhibitor, and enza, an androgen receptor inhibitor, may be synergistic in the treatment of patients (pts) with mCRPC. The phase 1b/2 KEYNOTE-365 (NCT02861573) study showed antitumor activity with pembro + enza in pts with mCRPC pretreated with abiraterone acetate. A phase 2 study (NCT02312557) of enza-pretreated patients with mCRPC showed that some pts had a profound and durable anticancer response to pembro + enza. Methods: KEYNOTE-641 (NCT03834493) is a randomized, double-blind, phase 3 trial to evaluate efficacy and safety of pembro + enza versus placebo + enza in pts with mCRPC. An estimated 1200 patients will be randomly assigned 1:1 to receive enza 160 mg/day + pembro 200 mg IV Q3W or enza 160 mg/day + placebo. Treatment will be stratified by prior abiraterone acetate treatment (yes/no), metastases location (bone only/liver/other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes/no). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who experienced biochemical or radiographic progression, ECOG PS 0/1, and adequate organ function are eligible. Pts will be required to provide tissue for biomarker analysis. Intolerance to or progression while receiving prior abiraterone acetate therapy is permitted, but not required. Prior chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor is prohibited. Responses will be assessed by CT/MRI and radionuclide bone imaging per PCWG3-modified RECIST v1.1 Q9W during the first year and Q12W thereafter. Treatment will continue until progression, unacceptable toxicity, or consent withdrawal, with up to 2 years of pembro/placebo. Dual primary end points are OS and rPFS by blinded independent central review. Secondary end points are time to subsequent anticancer therapy or death, ORR, DOR, PSA response rate, PSA undetectable rate, time to PSA progression, time to pain progression, time to soft tissue progression, time to symptomatic skeletal-related event, and safety. Accrual began July 28, 2019. Clinical trial information: NCT03834493.