bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term survival of subjects in the prostate cancer prevention trial.
Authors: Goodman Phyllis J. , Thompson Ian Murchie , Tangen Catherine M. , Parnes Howard L. , Godley Paul Alphonso , Ford Leslie G. 
Published: February 2017

10 Background: As finasteride could reduce by 25% the number of prostate cancers (PCa) diagnosed in the U.S. annually, the public health benefit of prostate cancer prevention could be enormous. We performed a survival analysis to assess for any evidence of increased risk of death in men randomized to finasteride, a potential indicator of a ‘true’ increased risk of high grade (HG) disease in the PCPT. Methods: A Social Security Death Index search was conducted on all randomized men to ascertain date of death. Cox proportional hazards models adjusting for known risk factors for overall survival and survival from time of diagnosis of PCa overall, low grade (LG) and HG were used to estimate hazard ratios (HR) and construct 95% confidence intervals to determine if survival on finasteride and placebo were equivalent. Results: A total of 5,128 deaths have been reported; 2,584 men on finasteride and 2544 on placebo. 15-year survival rates for all randomized men in each arm is 78%. The HR for overall survival on finasteride compared to placebo is 1.04 (95% CI 0.96, 1.10, p=.19). 10-year survival from diagnosis for men with PCa was slightly higher for men randomized to finasteride (10-year survival 83% vs. 81%) but not statistically significant (HR= 0.87, 95% CI 0.73 - 1.04, p=.14). For the men with HG PCa, there was no evidence of worse survival on finasteride (HR= 1.01; 95% CI 0.73, 1.14, p=.97) while those diagnosed with LG disease finasteride had superior survival (HR= 0.73; 95% CI 0.57, 0.94, p=.01). Conclusions: For men in PCPT with PCa there was no difference in survival from diagnosis date, a slightly-superior 10-year survival with finasteride and a statistically-superior survival among men with LG tumors in the finasteride group. A potential explanation for this phenomenon could be a lead-time bias. Arguing against this bias is the identical survival of HG PCa in both groups. Another potential explanation is that the men with LG PCa on placebo include a greater number with undetected HG disease; HG tumors in men on finasteride were more likely detected due to the improved performance of prostate biopsy. With follow-up of 18 years, finasteride administration for 7-years does not appear to affect mortality but significantly reduces the risk of a PCa diagnosis. Clinical trial information: NCT00288106.
Association of metastasis-free survival (MFS) with overall survival (OS) in men with PSA-recurrent prostate cancer treated with deferred androgen-deprivation therapy.
Authors: Schweizer Michael Thomas , Zhou Xian C. , Wang Hao , Yang Ting , Shaukat Farah , Eisenberger Mario A. , Antonarakis Emmanuel S. 
Published: February 2017

109 Background: To support the hypothesis that metastases are a significant clinical event, we aimed to explore the association between MFS with OS in men with biochemically-recurrent prostate cancer. Methods: This is a retrospective analysis of 450 men treated at a single institution between July 1981 and July 2010 with biochemical recurrence following prostatectomy, of which 140 (31%) developed subsequent metastases. In all patients, androgen deprivation therapy was deferred until after the development of radiographic metastases. Univariate and multivariable Cox regression models were developed to investigate factors influencing OS. Results: The median time from biochemical recurrence to metastasis (i.e. MFS) was 10.2 y (95% CI, 7.6–14.0 y), and the median time from first metastasis to death (i.e. OS) was 6.6 y (95% CI, 5.8–8.4 y). Using multivariable Cox regressions, we identified 4 variables that were independently prognostic for OS (Table): MFS (≤3 vs >3 y; P=0.009), number of metastases (≤3 vs ≥4; P=0.001), painful metastases (present vs absent; P<0.001), and ECOG performance status (0 vs ≥1; P=0.001). The concordance index reflecting the association between MFS and OS was 0.67. Conclusions: After adjusting for other prognostic variables, MFS was independently associated with OS in men with biochemically-recurrent prostate cancer. While this observation requires prospective validation, it suggests that MFS may be a reasonable endpoint in future clinical trials. [Table: see text]
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane.
Authors: Petrylak Daniel Peter , Kantoff Philip W. , Mega Anthony E. , Vogelzang Nicholas J. , Stephenson Joe , Fleming Mark T. , Stambler Nancy , Petrini Michaela , Huang Kathleen , Israel Robert Joseph 
Published: February 2017

119 Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. We have completed a phase 1 dose escalation study of PSMA ADC in subjects with taxane-refractory mCRPC. Methods: Eligibility requirements include progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics (PK), PSA, circulating tumor cells (CTC), clinical disease progression and immunogenicity to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg. Results: 52 subjects with mCRPC were dosed in nine dose levels. All subjects received prior docetaxel, 5 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. Peripheral neuropathy was reported by 7 subjects after repeated doses. Two were grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible liver function tests (LFTs) elevations. Antitumor activity was manifested as reductions either in PSA or CTCs at ≥ 1.8 mg/kg PSMA ADC in approximately 50% of patients. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure and no accumulation was observed. Conclusions: PSMA ADC in this study was generally well tolerated in doses up to 2.8 mg/kg every three weeks in subjects with mCRPC, previously treated with taxane. Antitumor activity was seen at higher dose levels. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose of PSMA ADC was determined to be 2.5 mg/kg. A phase 2 trial in taxane refractory mCRPC has been initiated. Clinical trial information: NCT01414283.
Absence of interaction of cabazitaxel on the pharmacokinetics of midazolam: Results of a drug–drug interaction study in patients with advanced solid tumors.
Authors: Rixe Olivier , Sarantopoulos John , Hsueh Chung-Tsen , Lockhart A. Craig , Ross Sharona , Agarwala Sanjiv S. , Zhang Wendy , Yin Jian Y. , Wack Claudine , Mazuir Florent , Gurtler Jayne S. 
Published: February 2017

126 Background: Cabazitaxel (Cbz) is approved in combination with prednisone/prednisolone for the treatment of men with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen. In vitro studies showed that Cbz is mainly metabolized through CYP3A, resulting in inhibition of this family of enzymes. Midazolam (Mdz) is primarily metabolized by CYP3A4. We aimed to determine the effect of Cbz on CYP3A activity by comparing the pharmacokinetic (PK) properties of Mdz when administered alone and following co-administration with Cbz. Methods: An ongoing safety and PK study of Cbz in patients with metastatic or locally advanced solid tumors and varying degrees of hepatic impairment (NCT01140607) included a cohort with normal hepatic function to assess the effect of a single Cbz dose on the PK profile of a single dose of Mdz. This was an open-label, two-period, fixed-sequence study in patients aged between 45 and 60 years with advanced solid tumors and normal hepatic function. A single dose of Mdz (2 mg) was administered orally alone (Day –1) and at the end of a 1-hour infusion of Cbz (25 mg/m2) (Day 1), with a 24-hour interval between the two administrations of Mdz. Endpoints included AUC and AUClastof Mdz with and without Cbz administration, and safety evaluations. Results: Of the 13 patients enrolled and treated in the cohort, 11 patients were included in the PK analysis. Exposure (AUC and AUClast) and other PK parameters after a single administration of Mdz alone and in combination with Cbz (Day 1) were similar. The AUC ratio for Mdz administered alone or with Cbz was 0.97 (90% CI: 0.76–1.23). The AUClast ratio for Mdz administered alone or with Cbz was 1.04 (90% CI: 0.81–1.34). All 13 patients had ≥1 adverse event (AE), 11 (84.6%) experienced a Grade 3–4 AE, and 4 (30.8%) experienced a serious AE. The majority of Grade 3–4 AEs were haematological and no new or unexpected safety findings were observed. Conclusions: In this study, Cbz did not increase the plasma exposure of Mdz. This indicates that Cbz is not a CYP3A inhibitor in the clinical setting and can be administered in combination with drugs metabolized by CYP3A. Clinical trial information: NCT01140607.
Role for IL2 adjunctive cotherapy for suppression of a solid tumor with designer T cells: Phase I trial data in prostate cancer.
Authors: Junghans Richard Paul 
Published: February 2017

216 Background: We created chimeric antigen receptors (CAR) against prostate specific membrane antigen (PSMA). When expressed in patient T cells, these “designer T cells” (dTc) kill prostate cancer cells in vitro and in vivo in animal models (Ma et al. Prostate2004:61:12-25). A Phase I trial was performed. Methods: Patient T cells are retrovirally transduced and expanded ex vivoto span doses of 10^9 to 10^10 T cells. Patients undergo prior non-myeloablative (NMA) conditioning to create a “hematologic space” into which dTc are infused for stable engraftment and prolonged in vivo efficacy. Continuous infusion low dose IL2 (LDI: 75 kiu/kg/d) is administered. Results: Infused T cells were documented. Safety was shown and partial responses (PR) obtained in 2/5 subjects (40%), with PSA suppressions of 50-70% over 1-2+ mo and PSA progression delay up to 150d. Against expectation, response correlated inversely with engraftment (p=0.06) but directly with plasma IL2 (p=0.03) that was as much as 20-fold lower in non-responders than responders. Low plasma IL2 correlated with high engraftments (p<0.01), prompting an hypothesis that high engrafted numbers of activated T cells absorb out IL2 to a level too low to sustain dTc activation for tumor killing. Conclusions: Encouraging early results were obtained with anti-PSMA dTc in adoptive immune therapy of advanced prostate cancer. It is proposed that adequate higher plasma IL2 will reveal the expected greater potency of higher dTc doses, thereby potentially inducing PSA reductions of 100%, with durable remissions. A study redesign tests moderate dose IL2 (MDI) (300 kiu/kg/8h bolus) versus LDI in a randomized Pilot at the 10^10 cell dose, which is now open to enrolment. To refer patients, please contact the study referral manager by telephone: 401-456-2507 or email: RDavies@rwmc.org. This trial received partial funding from US Army/DOD. Preclinical work was supported by Prostate Cancer Foundation. Clinical trial information: NCT00664196.
A prostate cancer clinical trials consortium trial of disulfiram (D) in men with nonmetastatic recurrent prostate cancer (PCa).
Authors: Schweizer Michael Thomas , Bardia Aditya , Blackford Amanda L. , Lin Jianqing , Armstrong Andrew J. , King Serina , Rudek Michelle A. , Yegnasubramanian Srinivasan Thomas , Carducci Michael Anthony 
Published: February 2017

219 Background: Epigenetic silencing of tumor suppressor genes (TSG) by promoter methylation contributes to carcinogenesis and progression. Targeting these epigenetic changes in PCa has been hindered by a paucity of available agents. D potently inhibits PCa growth in vitro and can cause demethylation and re-expression of known TSGs in PCa cells lines. Methods: To determine if D leads to demethylation changes [i.e. decreased global 5meC DNA content from peripheral blood mononuclear cells (PBMC)] we conducted an open-label, dose escalation trial of D in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating “response” (i.e. >10% decrease in global 5meC content) in <3 patients was observed in cohort 1. Cohort 1 and 2 received D 250 mg and 500 mg daily respectively; 1 cycle equaled 4 weeks. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months (i.e. confirmed >50% rise over baseline and >2 ng/mL above nadir), changes in PSA doubling time (PSADT) and safety/tolerability. Results: Two patients out of 9 (22.2%) in cohort 1 met our primary endpoint. Cohort 2 accrued a total of 10 patients, 3 (30.0%) of which had >10% decrease in global 5meC content. Only 5 subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. Median PSADT change post-treatment was not significantly different between responders and non-responders (266.9 vs -7.8 days, P=0.18) or between cohorts 1 and 2 (22.5 vs -39.7 days, P=0.54). While there were no grade (G) 4 adverse events (AE), the drug was poorly tolerated with 6 patients experiencing G3 AE (3 per cohort). There was a trend toward fewer median number of completed cycles in cohort 2 vs cohort 1 (5 vs 9 cycles, P=0.12). Common AE included: fatigue, GI toxicity, ataxia/dizziness, and constitutional symptoms. Conclusions: A minority of patients had global PBMC demethylation changes, consistent with D acting as a probable demethylating agent in those individuals. Given the toxicities associated with D and no significant clinical benefits, further development of this agent should not be pursued in this population. Clinical trial information: NCT01118741.
Clinical-pathologic stage discrepancy in patients with bladder cancer treated with radical cystectomy: Associations with clinical variables and survival.
Authors: Gray Phillip J. , Fedewa Stacey A. , Shipley William U. , Lin Chun Chieh , Virgo Katherine S. , Kibel Adam Stuart , Kamat Ashish M. , Rosenberg Jonathan E. , Jemal Ahmedin , Zietman Anthony L. , Efstathiou Jason Alexander 
Published: February 2017

248 Background: Radical cystectomy (RC) is the most common treatment for bladder cancer (BC) in the United States. We examined clinical-pathologic stage discrepancy using the National Cancer Data Base. Methods: 16,953 patients with BC treated with RC between 1998 and 2009 were analyzed. Clinical factors associated with stage discrepancy were assessed by multivariable generalized estimating equation models. Survival analysis was conducted for patients treated between 1998 and 2004 (N=7,270) using a Cox proportional hazards model. Results: 41.9% of patients were upstaged at RC while 5.9% were downstaged. Upstaging was more common in females (OR 1.08, p=.04), the elderly (OR 1.26 for age ≥80 vs. 18-59, p=.001), higher tumor grade (OR 2.29 for grade 3-4 vs. grade 1, p<.0001), non-urothelial histology (OR 1.31, p=.002 for squamous and OR 1.26, p=.03 for adenocarcinoma), and with extended lymphadenectomy (OR 1.27 for ≥10 lymph nodes examined vs. 0-9, p<.0001). Downstaging was less common in the elderly (OR 0.50 for age ≥80 vs. 18-59, p<.0001), in Hispanics (OR 0.58, p=.009) and with variant histology (OR 0.55, p=.003 for squamous and OR 0.3, p<.0001 for adenocarcinoma). Receipt of neoadjuvant chemotherapy (CT) was highly associated with downstaging (OR 2.31, p<.0001). 5-year survival by stage is shown in the table. Upstaging was associated with increased 5-year mortality (HR 1.79, p<.0001) as was receipt of CT (HR 1.28, p=.02 for neoadjuvant and HR 1.23, p<.0001 for adjuvant). Extended lymphadenectomy was associated with decreased 5-year mortality (HR 0.82 for ≥10 lymph nodes examined vs. 0-9, p<.0001). Downstaging was not associated with survival (HR 0.88, p=0.17). Conclusions: This study is the largest to date to analyze stage discrepancy and survival in BC patients treated with RC. Upstaging is common and is associated with decreased 5-year survival. These data can be used in pre-operative risk stratification, treatment decision making and comparison with studies of non-operative management. [Table: see text]
Randomized phase III trial of neoadjuvant chemotherapy (NAC) with methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) followed by radical cystectomy (RC) compared with RC alone for invasive bladder cancer (BC): Japan Clinical Oncology Group Study, JCOG0209.
Authors: Kitamura Hiroshi , Tsukamoto Taiji , Masumori Naoya , Shibata Taro , Kunieda Futoshi , Fujimoto Hiroyuki , Hirao Yoshihiko , Kitamura Yasuo , Tomita Yoshihiko , Tobisu Kenichi , Niwakawa Masashi , Naito Seiji , Eto Masatoshi , Kakehi Yoshiyuki ,   Urologic Oncology Study Group of the Japan Clinical Oncology Group
Published: February 2017

249 Background: Cisplatin-based NAC for patients (pts) with invasive BC is considered to provide a 5–8% overall survival (OS) advantage, although several studies failed to prove the survival benefit of NAC. Methods: Eligibility criteria included histologically proven urothelial carcinoma, invasive (T2-4aN0M0) bladder cancer within 8 weeks from TURBT, PS 0-1, age 20 to 75 years old. Patients were randomized to receive either 2 cycles of neoadjuvant MVAC followed by RC (NAC arm) or RC alone (RC arm). MVAC comprised M (30 mg/m2) on days 1, 15, and 22; V (3 mg/m2) on days 2, 15, and 22; A (30 mg/m2) on day 2; C (70 mg/m2) on day 2. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), the surgery-related complication rate, adverse events during NAC, the rate of no residual tumor in the RC specimens (pT0), and quality of life. The sample size was 180 pts in each arm with a one-sided alpha of 5% and a power of 80% to detect a difference in 5-year OS from 45% in the RC arm to 57% in the NAC arm. Results: From March 2003 to March 2009, 130 pts were randomized to the NAC arm (n=64) and RC arm (n=66). The patient registration was terminated early because of slow accrual. At the second interim analysis conducted after the completion of patient accrual, the OS of the NAC arm was better than that of the RC arm (median, 102 and 81 months, respectively), although the difference was not statistically significant (HR, 0.65; multiplicity adjusted 99.99%CI, 0.19 - 2.18; one-sided log-rank p = 0.07). Considering the current situation in which NAC with gemcitabine and cisplatin (GC) is widely used in clinical practice, the Data and Safety Monitoring Committee recommended early publication of the results. The median PFS times in the RC arm and NAC arm were 78 and 99 months, respectively (p=0.04). No differences in perioperative complications, other than lymph leakage, were observed between the groups. pT0 in the NAC arm and RC arm was 34 % vs. 9 %, respectively (p<0.01). Conclusions: Although NAC with GC is widely used for invasive BC, NAC with MVAC can still be considered promising. Clinical trial information: 000000093.
HER2 expression in patients (pts) with surgically resected urothelial cancer at high risk of recurrence screened for the phase II randomized, open-label trial of DN24-02, an autologous cellular immunotherapy targeting HER2.
Authors: Press Michael F. , O'Donnell Peter H. , Plimack Elizabeth R. , Gomella Leonard G. , Quinn David I. , Sharma Padmanee , DeVries Todd , Sims Robert Brownell , Chen Melissa , Bajorin Dean F. 
Published: February 2017

292 Background: HER2 overexpression has been suggested as a poor prognostic factor in pts with high-risk urothelial carcinoma (UC). Published data note a wide range of HER2 overexpression in UC, with some reports showing <10% of cases and others exhibiting >50% of cases with ≥2+ HER2 expression by immunohistochemistry (IHC). NeuACT (N10-1; NCT01353222) is a phase 2 trial to determine whether DN24-02, an autologous cellular immunotherapy targeting HER2 based on the same platform used for sipuleucel-T, given as adjuvant therapy following surgical resection can prolong survival (Bajorin, et al. ASCO 2012). Here we report preliminary data for HER2 expression on primary tumor and positive lymph node samples from this study. Methods: Trial eligibility criteria include surgical resection of a primary UC, with either ≥pT2 or pN+ staging, and HER2 expression ≥1+ IHC. Surgical specimens are screened for HER2 expression by central pathology laboratory review and HER2 positivity is scored using the Dako HercepTest scoring system. Results: As of August 2012, tumor specimens from 61 pts have been screened for HER2 expression. Of these pts, 49 (80%; 95% CI: 68–89%) had a HER2 expression score of ≥1+ in the primary tumor, with 27 (44%) having ≥2+ score and 3 (5%) having a 3+ score. Twenty-three pts (38%) also had HER2 expression levels evaluated in tumor from involved lymph nodes. A total of 20 (87%; 95% CI: 66–97%) of these pts had a HER2 expression score of ≥1+ in the lymph nodes, with 12 (52%) having a ≥2+ score and 3 (15%) having a 3+ score. Two pts had primary tumor samples that expressed HER2 but were negative for HER2 expression in the lymph nodes submitted for analysis. Conclusions: Although preliminary, a high frequency (≥80%) of HER2 expression score of ≥1+ in primary tumor and lymph node samples was observed. These data highlight the prevalence of HER2 protein expression in high-risk UC. Furthermore, the HER2 expression data are consistent with previously published data in pts with invasive UC. Clinical trial information: NCT01353222.