bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of the USPSTF recommendations on prostate cancer stage migration and de-novo metastatic prostate cancer.
Authors: Chen Yu-Wei , Gupta Ruby , Ornstein Moshe Chaim , Rini Brian I. , Gilligan Timothy D. , Garcia Jorge A. 
Published: March 2019

166 Background: The US Preventive Services Task Force (USPSTF) recommended against prostate specific antigen (PSA) screening for men aged≥75 in 2008 and all men in 2012 in an effort to reduce overdiagnosis and overtreatment of men with prostate cancer (PCa). This recommendation may delay diagnosis of clinically significant PCa. Methods: The Surveillance, Epidemiology and End Results Program (SEER) was used to identify men diagnosed with PCa between 2004-2015. PCa stage was categorized as localized (N0M0), nodal (N1M0) and metastatic (NxM1). Trend analysis was stratified on age group (PSA screening eligible was defined as age 55-69 according to the 2018 updated USPSTF recommendation). Multivariable logistic regression was used to identify predictors for nodal and metastatic disease. Results: Between 2004-2015, there were 603,323 men with PCa identified. Metastatic disease accounted for 2.8% of PCa in 2004-2008, 3.7% in 2009-2012, and 6.1% in 2013-2015. In men eligible for PCa screening, metastatic disease increased from 1.9% in 2004-2008, to 2.6% in 2009-2012, to 4.2% in 2013-2015; nodal disease increased from 1.4% to 1.6% to 2.6%, respectively (both p-value for trend< 0.0001). This stage migration was also observed in non-screening eligible groups (age >70 and <55). Compared with PCa diagnosed in 2009-2012, PCa diagnosed in 2013-2015 had higher odds of metastatic disease (AOR: 1.70, p-value<0.0001) or nodal disease (AOR: 1.71, p-value<0.0001). Conclusions: Men diagnosed with PCa in 2013-2015 were more likely to have metastatic or nodal disease, suggesting PCa stage migration since PSA screening was recommended to be discontinued in 2012. Although the impact of PSA screening on PCa mortality remains debatable, the reduced quality of life with advanced Pca should not be overlooked. Future population studies are warranted to investigate the influence of the updated 2018 USPSTF recommendation. [Table: see text]
Genomic determinants of sensitivity to bipolar androgen therapy (BAT) in castrate-resistant prostate cancer (CRPC).
Authors: Schweizer Michael Thomas , Antonarakis Emmanuel S. , Eisenberger Mario A. , Nelson Peter , Luo Jun , Pritchard Colin , Denmeade Samuel R. 
Published: March 2019

200 Background: BAT is a promising treatment for CRPC and preclinical work has shown that its effects may be mediated by inducing DNA damage or cell cycle arrest. We sought to evaluate if mutations in DNA damage repair (DDR) genes or cell cycle regulators were associated with improved outcomes. Methods: Biospecimens from CRPC patients enrolled to studies testing BAT underwent germline or somatic next-generation sequencing (NGS). Samples tested included plasma (i.e. cell-free DNA) (N = 79), tumor tissue (N = 21) and saliva (N = 10). A variety of clinical grade NGS platforms were generally used. Given the concern for false negatives, we excluded cases if plasma NGS did not reveal a somatic alteration. Absence of a germline alteration was not assumed to indicate absence of somatic alterations. Comparative analyses to assess candidate biomarkers of BAT efficacy were performed. Results: Most patients received BAT following one or more next generation hormonal therapy, while 6 received BAT as first-line CRPC therapy. Of 65 cases where a germline or somatic pathogenic alteration in any gene was detected, 30 (46%) had evidence of homologous recombination deficiency (HRD), with mutations found in BRCA2 (N = 10), ATM (N = 8), CHEK2 (N = 5), PALB2 (N = 4), CDK12 (N = 3), CHD1 (N = 2), FANCA (N = 1), FANCD2 (N = 1) and BRCA1 (N = 1). TP53 alterations were also common (27/65; 42%). HRD mutations associated with increased PSA50 responses, with a trend toward improved PSA50 responses in TP53 mutated cases too (Table). In a combined analysis, men with HRD and/or TP53 mutations had improved PSA50 responses and near-significant improvement in progression free survival (PFS). Conclusions: These preliminary data suggest that BAT may be most efficacious in cancers harboring mutations in genes involved in DDR and/or cell cycle regulation. These results require prospective confirmation. [Table: see text]
Impact of new systemic therapies on outcomes of patients with non-metastatic castration resistant prostate cancer (nmCRPC).
Authors: Vicier Cecile , Xie Wanling , Hamid Anis , Evan Carolyn , Sweeney Christopher 
Published: March 2019

244 Background: Treatments and outcomes of men with nmCRPC in routine care are poorly described. We assessed the cumulative impact of new therapies in men who transition through nmCRPC using a single-institution database. Methods: We conducted a retrospective study of consecutive nmCRPC pts enrolled into a hospital-based registry at Dana-Farber Cancer Institute. Pts were analyzed by era of diagnosis of nmCRPC: 2000-2009 (when docetaxel was the only life prolonging metastatic CRPC therapy) (cohort A) and 2010-2018 (when new systemic therapies were approved for mCRPC or in trials for nmCRPC) (cohort B). We collected pt, treatment, metastasis-free survival (MFS) and overall survival (OS) data. Results: 230 men were included: 148 in cohort A and 62 in cohort B. Despite only 39% of cohort B pts receiving new hormonal therapies for nmCRPC, there was no difference in median MFS between both eras: 2.7 yrs (2.1-3.2) in cohort A and 2.2 yrs (1.4-3.3) in cohort B. 30% of pts in cohort A and 53% of pts in cohort B had two or more life prolonging mCRPC therapies at any time (Table). No difference in 3-year OS was seen but 4-year OS was numerically higher in cohort B, with a trend towards improved OS in the new era. Conclusions: In an era with access to more than one life prolonging therapy for mCRPC, greater use of these agents in pts who transition through nmCRPC to mCRPC did not improve 3-year OS but may impact longer term OS. [Table: see text]
Neutrophil-to-lymphocyte ratio as a prognostic biomarker for overall survival in men with advanced prostate cancer treated with platinum chemotherapy.
Authors: Vlachostergios Panagiotis J. , Lee Aileen , Thomas Charlene , Hackett Amy , Molina Ana M. , Nanus David M. , Beltran Himisha , Tagawa Scott T. 
Published: March 2019

266 Background: Platinum compounds are active in pts with metNEPC/CRPC. The neutrophil-to-lymphocyte ratio (NLR) is a simple clinical metric of systemic inflammation with prognostic and predictive value in advanced PC treated with FDA-approved therapies (doc, abi, enza, cabaz, mitox). We hypothesized that pretreatment NLR may be associated with clinical outcomes of platinum-treated pts. Methods: Records were reviewed from NEPC/CRPC platinum-treated pts with available information to enable pretreatment NLR calculation. Kaplan Meier curves, Cox regression analyses were used to predict PSA-PFS, radiographic PFS and OS after platinum initiation. For NLR, a cutoff of ≤5 was used as previously described (Leibowitz-Amit et al. 2014). Results: 108 men, median age 64 yrs (range 46-80), were studied. 28 pts (26%) were NEPC based on histological features. 54 had visceral mets (39 liver, 31 lung, 8 brain). 100 received carboplatin, 17 received cisplatin (9 received both sequentially, with initial platinum used for this analysis). Most received platinum in combination with other drugs, most commonly paclitaxel (N = 71) and etoposide (N = 20). 51 (47.2%) had low NLR ≤5 and 57 (52.7%) had high NLR > 5. Median PSA-PFS was 5 months in the low NLR group versus 3 months in the high NLR group (log-rank P = 0.07). Median rPFS did not differ between the two NLR groups (log-rank P = 0.36). Median OS of pts with NLR ≤5 was 15 months vs only 9 months in the high NLR ( > 5) subgroup (log-rank P = 0.06). There was no significant difference in NLR or OS status between NEPC and CRPC pts. On multivariate analysis (adjusted for age at platinum, Gleason, PSA, ALP, LDH, Hb, measurable disease, visceral mets, ECOG PS, use of opioids), NLR emerged as an independent prognostic factor for OS (HR 5.39, 95% CI 1.25-23.33, P = 0.02), together with PSA (P = 0.03) and visceral mets (P = 0.02). Conclusions: NLR is associated with shorter OS in men with advanced PC who receive platinum-based chemotherapy. It may serve as a useful clinical indicator of systemic inflammatory response and is more prognostic than standard NEPC vs adenocarcinoma histology. Prospective validation studies in such pts are needed to confirm these findings.
Racial disparities in radium-223 treatment in a large real-world population.
Authors: Zhao Hanson Hanqing , Howard Lauren , de Hoedt Amanda , Terris Martha K , Amling Christopher L. , Kane Christopher J. , Cooperberg Matthew R. , Aronson William J. , Polascik Thomas , Freedland Stephen J. 
Published: March 2019

268 Background: Black men with prostate cancer are more likely to have unfavorable tumor characteristics and are at greater risk of prostate cancer mortality. Radium-223 is a FDA approved treatment for metastatic castration-resistant prostate cancer (mCRPC) that showed a survival benefit in the ALSYMPCA trial, where 94% of the participants were Caucasian. We aim to examine treatment patterns and outcomes of radium-223 in a large, heterogeneous population in the real world. Methods: We reviewed charts of all men with diagnosed with mCRPC in the entire Veterans Affairs (VA) system alive as of January 1st, 2013 who received radium-223. We compared common treatment patterns and characteristics between black and nonblack men. We analyzed predictors of time from radium-223 start to overall survival and time to skeletal related event (SRE) with Cox models. Results: 318 patients with bone mCRPC who received radium-223 were identified. 27% (87/318) were black. Black men were younger (67 vs 70 years, p = 0.001) and had higher PSA and alkaline phosphatase (ALP) levels at radium start (p = 0.014 and 0.017, respectively). There were no significant differences in biopsy Gleason, number of bone metastasis, primary localized treatment (yes/no), PSA doubling time, bone pain, or number of radium injections. Black men had lower mortality risk (HR 0.75; 95% CI 0.57 to 0.98; P = 0.038) on multivariable analysis. Comparison of common treatment patterns between black and nonblack men revealed that black men were more likely to receive other therapies prior to radium, including chemotherapy. Conclusions: Using a large, heterogeneous, real world cohort, we describe differences in treatment patterns and outcomes with radium-223 between black and nonblack men with mCRPC. While black men had a lower risk of mortality in this cohort, they had higher PSA and ALP levels when receiving radium-223. They were also more likely to receive other therapies prior to radium-223, indicating a possible delay in radium use in black men.
SelectMDx versus Prostate Health Index in the identification of high-grade prostate cancer.
Authors: Hoyer Gretchen , Crawford E. David , Arangua Paul , Stanton Whitney , La Rosa Francisco G. , Poage Wendy , Lucia M. Scott , van Bokhoven Adrie , Werahera Priya N. 
Published: March 2019

30 Background: A major clinical challenge is to identify patients at increased risk of high-grade prostate cancer (PCa) (Gleason scores ≥ 7) before biopsy. Thus, we evaluated the clinical utility of SelectMDx and Prostate Health Index (phi) tests for diagnosis of high-grade PCa as compared with transperineal mapping biopsy (TMB) results, where an average of 80 prostate needle biopsies are taken every 5 mm for a diagnostic accuracy of 98%. Methods: 70 patients were selected who had TMB. They were evaluated with both SelectMDx and phi tests from before or after TMB; all had serum and post-digital rectal examination urine samples collected prior to treatment, stored in our biorepository. phi was evaluated using proPSA, free PSA and total PSA in serum. SelectMDx test measured mRNA levels of the HOXC6 and DLX1 in post-DRE urine. Published data shows that phi <27 and SelectMDx score = 0% correlate with patients free of HG PCa. Test results were compared against TMB histopathology data. Multivariate logistic regression (MLS) analyses and receiver operating characteristic (ROC) curves were used to determine diagnostic accuracy. DeLong test was used to determine statistical significance of ROC curves. All analyses were done for diagnosis of any PCa and high-grade PCa. Results: TMB histopathology showed 17/70 patients with no PCa and 22/53 with high-grade PCa. The sensitivity, specificity, positive (PPV) and negative (NPV) predictive values of each test are shown in the table below. Pairwise ROC comparison showed no statistically significant difference in the area under the curve of diagnosing PCa (0.75 vs 0.65) and high-grade PCa (0.71 vs 0.81) by phi and SelectMDx tests respectively. MLS analyses showed phi was significantly better than SelectMDx for diagnosing PCa (β = 0.054; p=0.005) and SelectMDx was significantly better than phi for diagnosing high-grade PCa (β = 8.45; p=0.0002). Conclusions: With high sensitivity and NPV, SelectMDx test is more useful than phi for screening patients at risk of high-grade PCa prior to biopsy. [Table: see text]
Impact of compliance on outcomes for patients on active surveillance for prostate cancer.
Authors: Detsky Jay , Fotouhi Ghiam Alireza , Mamedov Alexandre , Commisso Kristina , Commisso Angela , Klotz Laurence , Liu Stanley K. , Loblaw Andrew , Vesprini Danny 
Published: March 2019

36 Background: Active surveillance (AS) is the standard of care for low-risk prostate cancer to reduce the risk of overtreatment. However, the impact of compliance to AS on outcomes has not been well described. We hypothesized that compliance to an AS protocol and to the recommendation for active treatment would affect subsequent treatment failure. Methods: A prospective, single-arm cohort study was initiated in 1995 to assess an AS program. Triggers for intervention included a PSA doubling time of less than three years and histologic upgrade. The AS protocol was defined as PSA measurements every three months for two years and then twice annually, as well as a confirmatory biopsy within 12 months and then every three years. Compliance to the AS protocol was defined as four PSA tests and a confirmatory biopsy by 1.5 years after enrollment. Compliance to treatment was defined as the initiation of any active therapy within 12 months from the time of any trigger described above. Treatment failure was defined as a PSA > 0.2 after surgery, PSA > nadir + 2 for other treatments, or the development of metastases. Statistics were performed using logistic regression analysis and the Fisher exact test. Results: A total of 1282 patients were included in the final analysis, of which 460 received treatment. Median follow up was 7.1 years. The actuarial rate of biochemical control at five and 10 years amongst treated patients was 78% and 59% respectively. The rates of compliance to biopsy at years one, four and seven were 71%, 36% and 13%. The treatment failure rate was lower for patients compliant to the AS protocol (crude rate 28%) than those non-compliant (crude rate 38%) with an odds ratio of 0.64 (95% CI 0.43-0.94, p = 0.03). Patients compliant to the protocol were also less likely to develop metastases (OR 0.42, 95% CI 0.21-0.88, p = 0.02). There was no impact on treatment failure by adherence to active therapy within 12 months (p = 0.25) after reaching a trigger to come off AS. Conclusions: Non-compliance to an AS protocol leads to a higher risk of subsequent treatment failure and development of metastases. Physicians and patients need to work together diligently to ensure enrollment on an AS program is followed by adherence to regular PSA checks and repeat biopsies.
The role of adjuvant chemotherapy for pT2-4 upper urinary tract urothelial cancer: Exploratory analysis of large multi-institutional study (JCOG1110A).
Authors: Inokuchi Junichi , Kuroiwa Kentaro , Nishiyama Hiroyuki , Kojima Takahiro , Kakehi Yoshiyuki , Sugimoto Mikio , Tanikawa Toshiki , Fujimoto Hiroyuki , Gotoh Momokazu , Masumori Naoya , Ogawa Osamu , Eto Masatoshi , Ohyama Chikara , Yamaguchi Akito , Matsuyama Hideyasu , Ichikawa Tomohiko , Ito Keiichi , Mizusawa Junki , Eba Junko , Naito Seiji ,   The Urologic Oncology Study Group of Japan Clinical Oncology Group (JCOG)
Published: March 2019

374 Background: Recently, it was presented that adjuvant chemotherapy (AC) after radical nephroureterectomy (RNU) improved metastasis-free survival in pT2-4 upper urinary tract urothelial cancer (UTUC) with a median follow-up of 17.6 months (POUT study). However, the impact of AC on other outcomes remains unclear, especially for pT2 disease. Methods: The large case-series study, JCOG1110A, included 2,744 patients with non-metastatic UTUC who underwent RNU in 30 institutions in Japan between 1995 and 2009. In this analysis, patients with prior history or synchronous bladder cancer, patients who received neoadjuvant chemotherapy were excluded. Patients who received AC except for GC (gemcitabine, cisplatin) or MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) were also excluded. We extracted pT2-4 patients as study subjects from remaining patients, and identified 950 patients. The impact of AC on overall survival (OS) and extravesical recurrence-free survival (RFS) were examined by the multivariable Cox regression model in all patient and pT2, pT3-4 subgroups. Results: Of 244 pT2 and 706 pT3-4 patients with a median follow-up of 41.1 months, AC were performed in 34 (13.9%) and 183 (25.9%). In AC (+) group, high frequency of pT3-4 disease, high grade tumor, pathological node metastasis, lymphovascular invasion, and younger age were seen compared to AC (-) group. The 5-year survival of the AC (+) and AC (-) were 66.0% and 67.4% for OS, 58.0% and 57.8% for RFS, respectively. Multivariable analysis showed the improved outcome in AC (+) group on both OS and RFS in all patients (OS: HR 0.60, 95% CI 0.41-0.89, RFS: HR 0.71, 95% CI 0.51-1.00). Although AC had a great impact on OS in pT3-4 patients (HR 0.56, 95% CI 0.36-0.87), there was no clear impact on either OS or RFS in pT2 patients (OS: HR 0.81, 95% CI 0.32-2.07, RFS: HR 0.69, 95% CI 0.29-1.62). Conclusions: AC after RNU had the significant impacts on OS and RFS in pT2-4 UTUC patients. This tendency was seen strongly in pT3-4 patients, but not in only pT2 patients. The randomized trial is necessary to determine the utility of AC in UTUC patients, especially in pT2 patients. Clinical trial information: NCT01993979.
Effect of concurrent beta-blocker (BB) use in patients receiving immune checkpoint inhibitors for metastatic urothelial (mUC) and renal cell carcinomas (mRCC).
Authors: Patel Vaibhav G. , Oh William K. , Galsky Matt D. , Liaw Bobby Chi-Hung , Tsao Che-Kai 
Published: March 2019

467 Background: Stress-induced adrenergic signaling suppresses the immune system. A pre-clinical mouse model has shown that pharmacologic beta-blockade can stimulate CD8+ T-cell activity, and as a result improve efficacy of checkpoint inhibitors (CPI) to inhibit growth in solid tumors. Herein, we investigate the effect of BB on outcomes of patients receiving immunotherapy in mUC and mRCC. Methods: Using the Mount Sinai Genitourinary (GU) Cancer Biorepository, an IRB approved database containing all consented GU cancer patients seen between 2010-2018, we identified patients with either UC or RCC that have received CTLA-4 and/or PD-1/PD-L1 blockade. Patients who received only 1 dose of CPI were excluded from this analysis. A descriptive analysis was performed to assess clinical characteristics and treatment response. Overall Survival (OS) was calculated with Kaplan-Meier curves and cox proportional hazard models. Results: We identified 34 evaluable patients with mUC and 14 with mRCC that received CPI (Table). The median age at initiation was 69 years (39–91 years) and 81.2% (39/48) received prior chemotherapy and/or molecular targeted therapies. The mean duration of therapy was longer in the BB group compared to non-BB group (10.6 vs. 4.0 mo). For patients with mUC, the overall response rate (ORR) was 62.5% vs. 12.5% in favor of the BB group. For the patients with mRCC, the ORR was 40.0% vs. 10.0% in favor of the BB group. There were more outstanding responders (>1 year) in the BB group when compared with the non-BB group (41.2% vs. 6.5%). Patients with BB use had significantly improved median OS (NR vs. 11.6 mo, p = 0.004) when compared to those who did not receive BB. Conclusions: In this single-center cohort, the concurrent use of BB receiving CPI therapy is associated with an improved ORR, duration of therapy, and OS. Although this is hypothesis generating, the addition of BB is a promising strategy to improve response of immunotherapy, and prospective validation of this approach will be needed. [Table: see text]
CB-839, a glutaminase inhibitor, in combination with cabozantinib in patients with clear cell and papillary metastatic renal cell cancer (mRCC): Results of a phase I study.
Authors: Meric-Bernstam Funda , Lee Richard J. , Carthon Bradley Curtis , Iliopoulos Othon , Mier James Walter , Patel Manish R. , Tannir Nizar M. , Owonikoko Taofeek Kunle , Haas Naomi B. , Voss Martin Henner , Harding James J. , Srinivasan Ramaprasad , Shapiro Geoffrey , Telli Melinda L. , Munster Pamela N. , Carvajal Richard D. , Jenkins Yonchu , Whiting Sam H. , Bendell Johanna C. , Bauer Todd Michael 
Published: March 2019

549 Background: Glutaminase (GLS) is a key enzyme that controls glutamine utilization, a metabolic pathway upregulated in RCC and important for tumor proliferation and survival. CB-839 is a first-in-clinic, small molecule, reversible, oral GLS inhibitor that synergizes with cabozantinib (Cabo), a VEGFR2/MET/AXL inhibitor, in preclinical RCC models to inhibit metabolic pathways and enhance anti-tumor activity. Cabo monotherapy is associated with a 17% overall response rate (ORR) for clear cell (cc) mRCC (Choueiri et al. Lancet Oncol. 2016). Here we present findings from a Phase 1 study cohort evaluating the safety, efficacy, and recommended Phase 2 dose (RP2D) of CB-839 + Cabo in patients (pts) with mRCC as 2L+ therapy. Methods: Eligible pts had mRCC with cc or papillary histology, ECOG 0-1, RECIST measurable disease, and, for cc pts, treatment with ≥1 prior anti-VEGF therapy. Escalating doses of CB-839 (600-800 mg PO BID) plus Cabo (60 mg PO QD) were evaluated using a 3+3 design. Tumor response was assessed per RECIST 1.1 every 8 wks. Results: The CB-Cabo cohort enrolled 13 pts with a median 3 (range, 0-7) prior lines of therapy. No maximum tolerated dose was reached; 800 mg was selected as the CB-839 RP2D. The most common treatment-related AEs (occurring in >25% of pts) were diarrhea (62%), decreased appetite (46%), ALT increased (39%), fatigue (39%), AST increased (31%), nausea (31%), and rash (31%); Gr ≥3 treatment-related AEs included diarrhea, hypertension, platelet count decreased, and hallucination (n=1 each). Among 12 evaluable pts, ORR was 42% and disease control rate (DCR = complete response + partial response [PR] + stable disease [SD]) was 100%: 42% (5/12) PR, 58% (7/12) SD. Among 10 evaluable cc mRCC pts, 50% (5/10) had PRs, 50% (5/10) SDs. As of Sept 24, 2018, 5 pts received >12 months treatment; 4 remain on study. Conclusions: CB-839 plus Cabo showed encouraging clinical activity and tolerability in heavily pretreated mRCC pts, with response rates for cc mRCC (50% ORR, 100% DCR) comparing favorably to historical Cabo monotherapy. A randomized Phase 2 study of CB-839 + Cabo vs. Cabo + placebo in cc mRCC is ongoing. (CANTATA; NCT0342821) Clinical trial information: NCT02071862.