bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subgroup analyses of Japanese patients from the PREVAIL trial of enzalutamide (ENZA) in patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kimura Go , Yonese Junji , Fukagai Takashi , Kamba Tomomi , Nishimura Kazuo , Nozawa Masahiro , Mansbach Harry H. , Phung De , Beer Tomasz M. , Tombal Bertrand F. , Ueda Takeshi 
Published: February 2017

265 Background: In PREVAIL, an international phase 3 randomized trial, treatment with ENZA decreased the risk of radiographic progression or death by 81% and the risk of death by 29% compared with placebo. We evaluated efficacy, safety and pharmacokinetic exposure with ENZA in the Japanese subgroup of patients participating in PREVAIL. Methods: Asymptomatic or mildly symptomatic chemotherapy-naïve patients with mCRPC progressing on androgen deprivation therapies were randomized 1:1 to ENZA 160 mg or placebo until discontinuation upon radiographic progression or initiation of chemotherapy. Continued androgen-deprivation therapy was required. Coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS). Prostate-specific antigen (PSA) response was defined as a confirmed ≥50% reduction from baseline to nadir. Results: A total of 1,717 patients (ENZA: 872, placebo: 845) were randomized in PREVAIL, of which 61 patients were Japanese (ENZA: 28, placebo: 33). The trial was halted after a planned interim analysis at which hazard ratios calculated for OS (0.71; 95%CI: 0.60-0.84) and rPFS (0.19; 95%CI: 0.15-0.23) showed significant benefit of ENZA vs placebo. Hazard ratios for OS and rPFS in Japanese patients were 0.60 (95%CI: 0.20-1.78) and 0.29 (95%CI: 0.030-2.95), respectively. Time to chemotherapy was delayed from a median 10 months on placebo vs not yet reached on ENZA, with a hazard ratio of 0.46 (95%CI: 0.22-0.96). PSA responses were more common in Japanese patients receiving ENZA (61%) vs placebo (21%) (treatment effect = 39.5%; 95%CI: 16.7%-62.3%). Plasma concentration of ENZA was slightly higher in the Japanese subgroup: geometric mean Cmin= 13.8 µg/mL vs 12.3 µg/mL in the non-Japanese cohort at 13 weeks. In the Japanese subgroup adverse events (AEs) ≥ Grade 3 were reported by 9/28 patients (32%) on ENZA vs 13/33 patients (39%) on placebo. Treatment-related AEs ≥ Grade 3 were rare: in the ENZA arm (1/28; 3.6%) and in the placebo arm (2/33; 6.1%). Conclusions: Theefficacy and safety results in the Japanese subgroup were generally consistent with the overall results from the PREVAIL trial. Clinical trial information: NCT01212991.
A phase Ib study of BKM120 combined with abiraterone acetate for castrate-resistant, metastatic prostate cancer.
Authors: Patnaik Akash , Kung Justin , Loda Massimo , Taplin Mary-Ellen , Lis Rosina , Kantoff Philip W. , Balk Steven P. , Bubley Glenn J. 
Published: February 2017

274 Background: There is cross-talk between PI3-kinase (PI3K) pathway and androgen receptor (AR) signaling pathways, respectively, which are both critical for cell survival in castrate-resistant prostate cancer (CRPC). The primary study objective is to determine the safety profile and MTD of BKM120 (B, pan-PI3K inhibitor) in combination with abiraterone/prednisone (A/P) in CRPC patients. The secondary objectives are to assess the impact of PTEN status on duration of response/time to progression in the expansion cohort, and to evaluate the impact of B on a PI3-kinase activation fingerprint in metastatic bone or lymph node tissue samples. An exploratory objective is to assess the effect of B on transcription of a set of AR-regulated genes in metastatic bone biopsy samples. Methods: The trial design involves a 14 day lead-in phase with B alone, to assess single-agent toxicity and perform correlative studies. A/P is combined with B at the end of 14 days using the standard 3+3 dose-escalation design with 3 dose levels of B, and participants are assessed for safety and MTD on the combination therapy. To determine PD impact of single agent B on the PI3K activation signature at a metastatic site, a mandatory CT-guided bone or lymph node biopsy is performed prior to B initiation and at the end of 2 weeks on B single-agent therapy. Immunohistochemical (IHC) stains for three markers (p-AKT, p-S6 and PTEN) are used to obtain a semi-quantitative PI3K activation score, based on the quartile levels of continuous staining scores of each marker. Results: Patient 1 had symptomatic bone pain improvement, marked decline in narcotic pain requirements and a biochemical decline in PSA from 156.5 to a PSA nadir of 9.2 within 4 weeks of combination therapy. Patient 3 had a symptomatic and >90% biochemical improvement and has currently completed 15 cycles on treatment, and remains on study to date. RT-PCR analysis showed that the feedback circuitry between PI3K and AR signaling is heterogeneous in the metastatic prostate cancer-bone microenvironment, and dependent on tumor PTEN status. Conclusions: Preliminary data shows promising anti-tumor activity in CRPC patients from dual targeting of PI3K and AR pathways with B and A/P, respectively. Clinical trial information: NCT01741753.
Effect of selinexor (KPT-330), a novel oral selective inhibitor of nuclear export (SINE), on tumor suppressors and cell cycle proteins in prostate cancer cells and regression of castration-resistant patient-derived xenograft tumor growth.
Authors: Maity Sankar N. , Wu Guanglin , Lu Jing-Fang , Hoang Anh , Landesman Yosef , McCauley Dilara , Carlson Robert , Rashal Tami , Shacham Sharon , Broom Bradley McIntosh , Baggerly Keith A. , Aparicio Ana , Efstathiou Eleni , Araujo John C. , Logothetis Christopher 
Published: February 2017

277 Background: Androgen deprivation, anti-androgen and androgen biosynthesis inhibitor treatment can initially control the metastatic prostate cancer (PCa), but treatment-refractory progression frequently follows, with the loss of tumor suppressors (TSPs) and increased expression of cell cycle proteins. Inhibition of the nuclear export protein, Exportin 1 (XPO1) leads to nuclear accumulation of cargo proteins such as TSPs & cell-cycle regulators implicated in castration-resistant PCa (CRPC) progression. XPO1 and specific cargo genes are overexpressed in metastatic CRPC relative to benign & primary prostate tumors, implicating XPO1 activity as playing a role in disease progression. Selinexor (KPT-330), a novel, oral SINE currently in Phase 1/2 for both hematological and solid tumors, has potent activity against CRPC. We hypothesized this activity is due selinexor induced nuclear expression of TSPs. Methods: To test this hypothesis, we treated selected PCa cell lines and patient-derived xenografts (PDXs, two adenocarcinomas and one small cell carcinonoma) with selinexor to determine the effect on survival and cargo protein localization. Results: Treatment with selinexor markedly inhibited PCa cell proliferation in vitro, activated the tumor suppressor TP53 & inhibited cell-cycle regulators. Also, treatment of the PDXs with selinexor for at least 3 weeks significantly inhibited tumor growth & reduced the prostate-specific antigen level in the adenocarcinomas. Selinexor increased cell death in all three PDX tumors and reduced cell proliferation in the adenocarcinomas, but not in the small-cell tumor. Expression analyses demonstrated that selinexor induced nuclear accumulation of different cargo proteins unique to the PCa model, accounting for PDX-specific regression. Conclusions: These results point to an anti-tumorigenic effect of selinexor treatment across a spectrum of hormone-refractory PCa that may provide insight into the drivers of PCa treatment resistance and heterogeneity.
The basal subtype to predict clinical benefit from neoadjuvant chemotherapy: Final results from a phase II clinical trial of DDMVAC plus bevacizumab.
Authors: Siefker-Radtke Arlene O. , Choi Woonyoung , Porten Sima P. , Shen Yu , Kamat Ashish M. , Matin Surena F. , Dinney Colin P. N. , Czerniak Bogdan , McConkey David James 
Published: February 2017

291 Background: Gene expression profiling (GEP) suggests 3 main subtypes of urothelial cancer: basal, which historically has the worst prognosis with high proliferation and HIF-1 expression; p53-like, with decreased proliferation and increased markers of extracellular matrix (ECM); and luminal which has increased proliferation compared to p53-like tumors. We hypothesized that GEP of transurethral resections (TUR) and cystectomy specimens from patients on a neoadjuvant trial would predict benefit from chemotherapy. Methods: Sixty patients enrolled on a neoadjuvant trial of DDMVAC+B. TUR and cystectomy specimens were available for gene expression profiling in 39 and 33 patients, respectively, with matched specimens in 23 patients. The validation set consisted of 49 patients treated with perioperative MVAC on a previously published clinical trial. Results: Chemotherapy was quite active with pT0N0 and ≤ pT1N0 down-staging rates of 38% and 53%, respectively. Basal tumors had improved survival compared to luminal and p53-like (5-year OS 91%, 73% and 36%, p=0.015). A validation cohort of patients treated with perioperative MVAC confirmed this survival benefit (5-year OS basal, luminal, and p53-like 77%, 57%, and 57%, respectively, p =0.027). The use of bevacizumab in basal tumors did not confirm evidence of significant benefit in these small numbers of patients (5-year OS bevacizumab: 91% vs MVAC: 77%, p=0.68) Bone metastases within 2 years associated exclusively with the p53-like subtype (p53-like: 100%, luminal: 0%, basal 0%, p≤0.001). The p53-like subtype was enriched at cystectomy (basal to p53-like in 3/5 (60%), luminal to p53-like in 5/7 (71%), suggesting chemo-resistance in p53-like tumors. Conclusions: In contrast to historical expectations, the basal subtype was predictive of clinical outcomes from neoadjuvant chemotherapy, reflecting the impact of chemotherapy on highly proliferative tumors. Bone metastases were associated with the p53-like subtype which is enriched for ECM. We can no longer think of urothelial cancer as one disease; subtyping should be considered for all tumors, and may have implications on selecting therapy. Clinical trial information: NCT00506155.
ASCENDE-RT*: A multicenter, randomized trial of dose-escalated external beam radiation therapy (EBRT-B) versus low-dose-rate brachytherapy (LDR-B) for men with unfavorable-risk localized prostate cancer.
Authors: Morris W. James , Tyldesley Scott , Pai Howard H , Halperin Ross , McKenzie Michael R. , Duncan Graeme , Morton Gerard , Murray Nevin , Hamm Jeremy 
Published: February 2017

3 Background: This trial compared the efficacy of DE-EBRT and LDR-B for National Comprehensive Cancer Network (NCCN) high and intermediate-risk disease. Methods: A planned sample size of 400 patients were randomized to one of two treatment arms and stratified by risk group. Both arms received 12 months of androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonist plus a non-steroidal anti-androgen for at least 1 month. After 8 months of neo-adjuvant ADT, both arms received whole pelvis EBRT (46Gy/23#). Patients assigned to DE-EBRT (standard arm) then received a conformal EBRT boost (32Gy/16#). Patients assigned to LDR-B (experimental arm) received an Iodine-125 LDR boost prescribed to a minimum peripheral dose of 115Gy. The primary endpoint was relapse free survival (RFS) defined by biochemical criteria using the nadir+2 ng/mL threshold. Time zero was the date of the first LHRH injection. Results: Between Dec 2002 and Sep 2011, 276 high-risk and 122 intermediate-risk patients were accrued at 6 cancer treatment centers. 200 men were assigned to DE-EBRT and 198 to LDR-B. The treatment arms were well balanced in terms of age and known prognostic factors. Median follow up (FU) is 6.5 years; 65 men have >9 years FU. There were 12 major protocol violations in each arm. By intent-to-treat analysis, the 3-, 5-, 7-, and 9-year Kaplan-Meier RFS estimates are 94% vs 94%, 77% vs 89%, 71% vs 86%, and 63% vs 83% for DE-EBRT and LDR-B respectively (hazard ratio = 0.473; 95% CI 0.292 – 0.765; P = 0.0022). Randomization (p<0.001), percent positive cores (p=0.005), initial PSA (p=0.006) and clinical T-stage (p=0.013) were predictive of RFS in a multivariable Cox model. The median PSA at latest FU for non-relapsing patients assigned to LDR-B is 0.02 vs 0.24 ng/mL for DE-EBRT. Conclusions: In a randomized trial, an Iodine-125 LDR boost was much more effective than an EBRT boost in rendering unfavorable-risk prostate cancer patients biochemically disease free. *ASCENDE-RT- Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy is an NCI registered trial (NCT00175396). Clinical trial information: NCT00175396.
Prognostic significance of perineural invasion in localized prostate cancer.
Authors: Lu Louis , Singhal Udit , Skolarus Ted A. , Palapattu Ganesh S. , Montgomery Jeffrey Scott , Weizer Alon Z. , Hollenbeck Brent K. , Miller David Christopher , McNamara Alyssa , Mehra Rohit , Tomlins Scott A. , Hamstra Daniel A. , Morgan Todd Matthew , Feng Felix Yi-Chung 
Published: February 2017

30 Background: While perineural invasion (PNI) has been associated with poorer clinical outcomes in prostate cancer patients, it is not well defined as a predictor of long-term endpoints in newly diagnosed prostate cancer. Therefore, we evaluated the role of PNI as a prognostic marker in patients with localized prostate cancer who underwent surgery or radiation. Methods: We analyzed a prospectively collected cohort of 5,034 consecutive patients with localized prostate cancer treated with surgery (n = 4,207) or radiation (n = 827) at University of Michigan from 1994-2013. The primary outcome measured was metastasis-free survival, with secondary outcomes of PSA-recurrence free survival and overall survival (OS). Covariates included age, treatment year, race, comorbidity index, pre-treatment PSA, Gleason score, and T-stage. Survival analysis was estimated using the Kaplan-Meir method, and multivariable analysis was performed using a Cox proportional hazards model. Results: 22.6% of surgery patients and 37.5% of radiation patients had PNI. 169 patients developed metastasis a median of 44 months (IQR 21-83 months) after primary therapy. In the combined cohort, PNI was a predictor of metastasis and PSA recurrence, but not OS (Table 1). For surgery, PNI was a predictor of metastasis, PSA recurrence, and OS. For radiation, PNI was a predictor of metastasis and PSA recurrence, but not OS. Conclusions: PNI is an independent predictor of long-term outcomes in newly diagnosed prostate cancer patients regardless of subsequent therapy. These data support the importance of PNI as a key factor denoting potentially aggressive prostate cancer and importing a significant increase in the likelihood of eventual metastatic progression. [Table: see text]
Optimizing chemotherapy in patients with metastatic transitional-cell carcinoma: High rate of complete response with two sequential dose-dense regimens of cisplatin, gemcitabine, paclitaxel, followed by MVAC.
Authors: Passalacqua Rodolfo , Giganti Maria Olga , Brighenti Matteo , Perrucci Bruno , Donini Maddalena , Negri Federica , Tomasello Gianluca , Toppo Laura , Liguigli Wanda , Poli Rossana , Ratti Margherita , Benecchi Luigi , Prati Andrea , Arnaudi Roberto , Potenzoni Michele , Panni Stefano , Lazzarelli Silvia 
Published: February 2017

303 Background: Currently, cisplatin, gemcitabine, paclitaxel (CGP) and MVAC are the most active regimens in transitional-cell carcinoma (TCC). We tested the hypothesis that two sequential non-cross-resistant, dose-dense (DD) regimens may target different cancer cells, avoid drug resistance, and improve response rate. Methods: This is a phase II, single institutional trial, including patients (pts) with bladder, renal pelvis, or ureteral TCC. Primary end point was the rate of complete response (CR) after two sequential DD regimens. Primary analysis was carried out in the intention to treat (ITT) population.Patients with histological diagnosis of TCC, PS 0–2 (ECOG), adequate organ function and no previous systemic regimens were treated with 4 cycles of CGP DD followed by 4 cycles of M-VAC DD. All received peg-filgrastim after chemotherapy. Pts were evaluated with CT scan at the baseline, after 4 cycles, at the end of chemotherapy and then every 3 months for 2 years and 6 months thereafter. Results: 44 consecutive pts followed in the same oncology institution were included. Males were 73%; median age was 66 years; median PS ECOG was 1; Bajorin risk factors was 0 in 36%, 1 in 48%, 2 in 16%. After the first 4 cycles of CGP DD, we observed 6.8% CR, 43.2% PR, 38.6% SD, and 11.4% PD. After the 4 sequential cycles of M-VAC DD, we observed a global 27.3% of CR, 15.9% of PR, 18.2% of SD, and 13.6% of PD. Median TTP was 9.66 months (95% CI, 6.7-13) and median OS was 18.6 months (95% CI, 12-30). Main grade 3–4 toxicity included asthenia (26%), anemia (26%), neutropenia (9.5%), febrile (7%), thrombocytopenia (12%), and neurological toxicity (5%). No toxic deaths were seen. After a median follow up of 50 months, 4 of 12 patients who obtained a complete response are free of disease since more than 3 years. Conclusions: This sequential use of these two DD regimens leads to a 4-fold increase in CR, an increase in survival, and a possible cure for some patients. A phase III trial is warranted.
Incidence and predictors of upgrading and upstaging among 10,000 contemporary patients with low-risk prostate cancer.
Authors: Dinh Kathryn Tindell , Mahal Brandon Arvin Virgil , Ziehr David R. , Muralidhar Vinayak , Chen Yu-Wei , Viswanathan Vidya Bhavani , Nezolosky Michelle Daniel , Beard Clair , Choueiri Toni K. , Martin Neil E. , Orio Peter F. , Sweeney Christopher , Trinh Quoc-Dien , Nguyen Paul Linh 
Published: February 2017

32 Background: To inform decisions about active surveillance, we determined the incidence of upgrading and upstaging for a contemporary cohort of low-risk prostate cancer patients who received radical prostatectomy and identified clinical predictors of advanced disease. Methods: We studied 10,273 patients in the Surveillance, Epidemiology, and End Result (SEER) database diagnosed with low-risk prostate cancer (cT1c-T2a, PSA<10 ng/mL and Gleason 3+3=6) in 2010-2011. Upgrading was defined as pathologic Gleason score 7-10 and upstaging as pathologic T3-T4/N1 disease. Regression coefficients were used to evaluate the predictive value of clinical factors for upgrading or upstaging. Significant factors were used to develop a risk stratification table to evaluate individual patients. Results: At prostatectomy, 44% of patients were upgraded and 9.7% were upstaged. Multivariable analysis showed age, PSA, and percent total cores positive were associated with advanced disease (all p<0.001). When these variables were dichotomized by the median, age >60 (Adjusted Odds Ratio [AOR] 1.39), PSA>5.0 (AOR 1.28), and >25% total cores positive (AOR 1.76) were significantly associated with upgrading (all p<0.001). Similarly, age>60 (AOR 1.42), PSA>5.0 (AOR 1.44), and >25% total cores positive (AOR 2.26) were associated with upstaging (all p<0.001). Sixty percent of low-risk patients with PSA 7.5-9.9 and >25% total cores positive were upgraded. Conclusions: A significant proportion of low-risk patients eligible for active surveillance were harboring more aggressive or locally-advanced prostate cancer. Age, PSA and percent total cores positive should be used to assess risk of upgrading or upstaging and can guide decisions to pursue further evaluation or treatment. [Table: see text]
Predicting survival after radical cystectomy: Validation of the SPARC score.
Authors: Hu Brian Robin , Eisenberg Manuel S , Boorjian Stephen A. , Frank Igor , Dalag Leo , Movassaghi Kamran , Thapa Prabin , Miranda Gus , Daneshmand Siamak 
Published: February 2017

326 Background: The Survival Prediction After Radical Cystectomy (SPARC) score (Eisenberg et al, J Urol 2013) incorporates clinical and pathologic features to predict cancer specific survival (CSS) for urothelial carcinoma of the bladder. Validation of this model would improve its generalizability. Methods: Using the IRB-approved bladder cancer database at the University of Southern California (USC), we identified patients who underwent radical cystectomy (RC) for urothelial carcinoma of the bladder for curative intent from 1971-2009. Clinical factors (Charlson comorbidity index, ECOG performance status, hydronephrosis, adjuvant chemotherapy, smoking status) and pathologic factors (pathologic T stage, nodal status, multifocality, and lymphovascular invasion) included in the SPARC score were obtained. Patients were excluded if there were missing variables or if they underwent neoadjuvant chemotherapy. Associations between clinicopathologic factors and CSS were evaluated using Cox proportional hazards. Calibration plots were generated comparing actuarial CSS with SPARC predicted CSS by deciles. A c-index was generated to determine accuracy of the prediction. Kaplan Meier curves estimated CSS stratified by SPARC score and were compared with the log rank test. Results: A total of 2,045 patients underwent RC and 1,123 (55%) met inclusion criteria with a median follow-up of 4.7 years (IQR 2.0-8.9 years). Of the 1,123 patients, 332 (30%) died of bladder cancer. All the clinical and pathologic variables used in the SPARC scoring model were associated with CSS except for smoking status and tumor multifocality. Calibration plots demonstrated concordance between the SPARC-predicted and actuarial CSS with a c-index of 0.75. Kaplan Meier curves demonstrated significant differences in CSS based upon SPARC score, p<0.001. Conclusions: The SPARC score represents a valid instrument for predicting bladder CSS after RC. The model can be utilized to better tailor adjuvant therapy and surveillance.
Molecular profiling of small cell bladder cancer.
Authors: Wang Jue , Arguello David , Gatalica Zoran , Reddy Sandeep K. 
Published: February 2017

338 Background: Small cell bladder cancer (SCBC), a malignancy indistinguishable from small cell lung cancer (SCLC), is a rare and aggressive subtype of bladder cancer. Response to chemotherapy in SCBC is poor, yet the standard therapy remains cisplatin and etoposide. Novel therapies based on a better understanding of the underlying mechanisms of transformation are needed. The purpose of this study is to identify potential targets and therapeutic options for this disease, using multiplatform tumor profiling. Methods: In total, 19 small cell bladder cancer specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH). Results: Loss of RRM1 (22.2%, 4/18), MGMT (83.3%, 15/18), and TS (26.3%, 5/19) by IHC are associated with potential benefit to traditional chemotherapy. High expression of ERCC1, associated with resistance to platinum-based therapy, was 37.5% (3/8). MRP1, a drug pump associated with resistance to various chemotherapies, was present in 100% (5/5) of specimens. PD-L1 (0%, 0/6) was not expressed. EGFR amplification was detected in 25.0% of patients (1/4). NGS aberrations included TP53 (90.0%), cMET (20.0%, 2/10), RB1 (11.1%), FBXW7 (10%, 1/10), PTEN (10%, 1/10). Sanger sequencing also detected KRAS (100%, 1/1) and PIK3CA (33.3%, 1/3) mutations. Conclusions: Multiplatform tumor profiling identified biomarkers which may clarify treatment dilemmas with this rare cancer. MRP1 overexpression and TP53 loss help explain this cancer’s resistance to traditional chemotherapy and its aggressive course. This approach identified potential therapies, some of which are not typically considered, like temozolomide. Immunotherapy may not be as beneficial in SCBC based on absent PD-L1 expression. NGS and Sanger sequencing identified cell surface receptors and downstream molecules that could be candidates for therapeutic strategies.