bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of immune-related adverse events (irAEs) in a phase 3 trial of ipilimumab (Ipi) versus placebo (Pbo) in post-docetaxel mCRPC.
Authors: Beer Tomasz M. , Logothetis Christopher , Gerritsen Winald R. , Kwon Eugene D. , Scher Howard I. , Bossi Alberto , van den Eertwegh Alfons JM , Drake Charles G. , McHenry Brent , Liu David , Fizazi Karim 
Published: February 2017

52 Background: Ipi enhances antitumor immunity by blocking cytotoxic T-lymphocyte antigen-4. We recently reported the results of CA184-043, a phase 3 study of post-docetaxel mCRPC with Ipi vs Pbo, following single-dose radiotherapy (RT). While the study did not meet the primary endpoint of improving overall survival (HR=0.85, p=0.053), Ipi demonstrated antitumor activity in other efficacy endpoints, including progression-free survival. The present analyses further characterize the safety profile of Ipi in this study. Methods: Safety was evaluated for all treated patients (pts; N=393 for Ipi 10 mg/kg, N=396 for Pbo) starting from first study dose and ending 70 days after the last study dose, including maintenance dosing. Results: Any grade (Gr) irAEs occurred in 63.4% and 21.7% of pts in the Ipi and Pbo arms, respectively. Most common Gr 3/4 irAEs were gastrointestinal (GI) (18.1%; mostly diarrhea and colitis). Gr 3/4 liver irAEs (4.6%) were mostly elevations in AST or ALT. Other Gr 3/4 irAEs were uncommon: endocrine (2.0%), skin (1.0%), and neurological (0.3%). Among Ipi-treated pts, there were no meaningful differences in the frequency or severity of GI AEs between those who received baseline pelvic RT and those who did not (n=141 vs 252; any Gr 77.3% vs 69.8%; Gr 3/4 25.5% vs 21.8%, respectively). There were 5 GI perforations in the Ipi arm (3 within 70 days of last dose [2 related, 1 unrelated], 2 after 70 days of last dose, both related), and none in the Pbo arm. Deaths due to study drug toxicity, as per the investigators, occurred in 4 pts (4, Ipi and 0, Pbo). Conclusions: In this study of Ipi in mCRPC, the most frequent severe irAEs were diarrhea and colitis. Most irAEs were manageable using established treatment algorithms. Clinical trial information: NCT00861614. [Table: see text]
Interest of percutaneous renal biopsy for small renal masses.
Authors: Ingels Alexandre , Barret Eric , Audenet Francois , Lunelli Luca , Prada Costa Guilherme , Validire Pierre , Lenoir Stephane , Rozet Francois , Galiano Marc , Sanchez-Salas Rafael , Cathelineau Xavier 
Published: February 2017

539 Background: Assess CT-scan guided renal biopsies relevance in the management of small renal masses. Methods: Retrospective analysis from 01/2007 to 12/2012 of percutaneous CT-scan guided renal biopsies performed at our institution for patients harboring renal tumors. Exclusion criteria were presence of metastasis and/or >4cm tumors. Data analyzed were pathological outcomes, management of the tumors and complications from the procedure during the 30 days post-biopsies. Results: 119 patients underwent a renal biopsy during this period. 79 presented the selection criteria. Renal biopsies lead to a diagnosis in 70 cases (88.6%) and were non contributive in 9 cases (11.4%). Among contributive biopsies, there were 46 (66%) cases of cancer and 24 cases (34%) of benign tumors. During follow-up, 2 (2.5%) patients presented Clavien-Dindo grade I-II complications: 1 acute urinary retention and 1 subfebrile lumbar pain. Conclusions: The yield of CT-scan guided renal biopsies to define pathological features of small renal masses was of 88.6%. Morbidity of the technique is low. We consider renal biopsy as a relevant strategy to diagnose a small renal mass, to define the best treatment and to prevent morbidity from useless invasive surgical procedures. [Table: see text]
ABO blood group and risk of lethal prostate cancer.
Authors: Urun Yuksel , Wilson Kathryn M , Shui Irene M. , Giovannucci Edward L. , Wolpin Brian M. , Nguyen Paul Linh , Mucci Lorelei A. , Choueiri Toni K. 
Published: February 2017

69 Background: An individual’s blood group is defined by variability in glycotransferases expressed on red blood cell surface; these ABO antigens are also highly expressed on epithelial cells. Previous studies have suggested associations between ABO blood group and increased risk of epithelial cancers including gastric, pancreatic, and ovarian; however, its relationship with risk of prostate carcinoma, and its aggressiveness remains unclear. Methods: We prospectively evaluated the association between ABO blood group and risk of lethal prostate cancer in the Health Professionals Follow-up Study (HPFS) from 1996 to 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models with adjustment for other risk factors and prostate-specific antigen testing. Results: During 12 years of follow-up of 26,602 men, 2,703 cases of incident prostate cancer were documented, including 289 lethal cases (prostate cancer death or distant metastases). The frequency of ABO blood type was similar between men who developed prostate cancer (37% A, 7% AB, 13% B, and 43% O) and other participants (37% A, 8% AB, 12% B, and 43% O). On multivariate analysis, blood type was not associated with overall prostate cancer incidence. However, compared to men with blood group O, those with blood group AB were significantly less likely to develop lethal prostate cancer (multivariate-adjusted HR = 0.39 [95% confidence interval {CI} = 0.18-0.85]). There was no association between type B or A compared to O with lethal disease. ABO blood type was not significantly associated with the risk of advanced stage or high-grade cancers (Gleason score 8 to 10). Conclusions: Blood group AB was associated with a lower risk of lethal prostate cancer compared to blood group O. Further studies are needed to replicate these findings and to clarify possible biological mechanisms underlying this association.
Results from a phase 3, randomized, double-blind, multicenter, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy (ELM-PC 5 trial).
Authors: Dreicer Robert , Jones Robert , Oudard Stephane , Efstathiou Eleni , Saad Fred , De Wit Ronald , De Bono Johann Sebastian , Shi Yuanjun , Tejura Bindu , Agus David B. , Borgstein Niels Geert , Bellmunt Joaquim , Fizazi Karim 
Published: February 2017

7^ Background: Orteronel is an investigational, non-steroidal selective inhibitor of 17,20-lyase; a key enzyme in the production of steroidal hormones. Methods: Eligible men with metastatic castration-resistant prostate cancer (mCRPC) had progressive disease (PD; radiographic or prostate-specific antigen), castrate levels of testosterone, and had received more than or equal to 360 mg/m2docetaxel within the prior 6 months. Prior orteronel, abiraterone, or ketoconazole was not permitted. Patients were randomized 2:1 to continuous 28-day cycles of oral orteronel 400 mg BID + prednisone 5 mg BID, or placebo + prednisone without regard to food. Primary endpoint: overall survival (OS); other key endpoints: radiographical progression-free survival (rPFS), 50% or more PSA decrease at 12 weeks, pain response at 12 weeks and safety (NCT01193257). Results: One thousand ninety nine patients were randomized.The study was terminated for failing to meet its primary endpoint: median overall survival (OS) was 17.0 months (95% CI 15.2, 19.9) in patients receiving orteronel versus 15.2 months (95% CI 13.5, 16.9) in those receiving placebo (HR: 0.886 [95% CI: 0.739, 1.062]; P=0.1898). Substantial regional differences were seen in OS benefit: median OS (orteronel vs. placebo) was 20.9 vs. 16.9 mo (HR: 0.889) in North America (n=112), 18.3 vs. 17.8 mo (HR: 1.048) in Europe (n=590), and 15.3 vs 10.1 mo (HR: 0.709) in the rest of the world (n=397). In the overall population, rPFS was significantly improved in the orteronel arm, with a median of 8.3 months vs. 5.7 months in the placebo arm (HR: 0.76 [95% CI: 0.653, 0.885]; P=0.00038). Drug-related adverse events (AEs; any grade) included (orteronel/placebo) nausea (30/16%), vomiting (23/8%), fatigue (17/11%), and diarrhea (16/9%); grade 3 or higher drug-related AEs included increased lipase (12/less than 1%), increased amylase (8/less than 1%), and fatigue (3/3%). Additional sub-analyses looking at potential factors that affected OS will also be reported. Conclusions: Whileorteronel + prednisone did not show a statistically significant overall OS improvement versus placebo + prednisone, rPFS findings and striking regional OS differences suggest that orteronel has clinically meaningful activity. Clinical trial information: NCT01193257.
The molecular and pathway characterization of patients with metastatic castration resistant prostate cancer (mCRPC) refractory to therapy with abiraterone acetate or enzalutamide: Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT).
Authors: Small Eric Jay , Youngren Jack , Beer Tomasz M. , Ryan Charles J. , Thomas George , Pourmand Nader , Reiter Robert Evan , Alumkal Joshi J. , Stuart Joshua M. , Evans Christopher P. , Gleave Martin Edwin , Chi Kim N. , Toschi Alex , Foye Adam , Lara Primo , Witte Owen ,   SU2C/PCF/AACR West Coast Prostate Cancer Dream Team
Published: February 2017

79 Background: Progressive metastatic castration resistant prostate cancer (mCRPC) has historically been challenging to biopsy and characterize on a molecular basis because of its bone tropism. Since mechanisms of resistance to androgen signaling inhibitors such as enzalutamide or abiraterone are not fully understood, both an unbiased and a targeted assessment of the molecular landscape of these patients is required. Methods: Patients (pts) with mCRPC undergo biopsy at one of five West Coast Prostate Cancer Dream Team (WCDT) clinical sites, using a uniform biopsy protocol, following central radiologic review. Tissue is both frozen, and formalin fixed/paraffin embedded (FFPE). Frozen tissue undergoes laser capture microdissection (LCM) for RNA seq, DNA seq, and array comparative genomic hybridization (aCGH). An RNA seq process was developed that allows using extremely small quantities of RNA (approximately 1 ng). FFPE tissue undergoes a CLIA-certified assessment of a 37-gene mutational panel, FISH for AR, and IHC for PTEN. Peripheral blood is collected for miRNA, immune responses, and CTC analysis including aCGH. Pathway assessment integrating clinical, RNA seq, DNA seq, aCGH data is undertaken using PARADIGM analysis. Results: Thirty six of 300 planned mCRPC pts have undergone a metastasis biopsy: 17 from bone, eight from liver, one from lung, and 10 from distant lymph nodes. Tumor is present in around 75% of the frozen specimens. To date, LCM has been undertaken in 11 samples, with RNA seq done in six, DNA whole exome seq in one, aCGH in four. FFPE tissue has been evaluated by mutational panel sequencing (n=9), FISH for AR (n=11), and IHC for PTEN (n=13). CTC have been isolated in 33 pts. aCGH has been successfully undertaken in paired CTC and biopsy specimens. Expression data from patients with full RNA sequencing have been analyzed by PARADIGM, with top disrupted pathways identified. Conclusions: Biopsies of mCRPC, including from bony sites, can be undertaken and used for molecular and pathway analysis. Sufficient tissue for unbiased and targeted assessment can be obtained. Linkage of results from these studies to the clinical characteristics of these patients will reveal important insights into mechanisms of resistance.
Predictors of choice of treatment in men with localized prostate cancer.
Authors: Konijeti Ramdev , Blonquist Traci M. , Halpenny Barbara , Hong Fangxin , Chang Steven L. , Trinh Quoc-Dien , Kibel Adam S. , Berry Donna Lynn 
Published: February 2017

82 Background: The Personal Patient Profile-Prostate (P3P) is an Internet-based decision support program for men with newly diagnosed prostate cancer (CaP), which significantly reduced decisional conflict in treatment selection in a multicenter trial (2007 to 2009). We performed an ad hoc analysis of data from the trial (including five sites in Washington, Pennsylvania, Georgia, and Texas) to determine factors associated with initial treatment selection (watchful waiting [WW], external radiation [XRT], brachytherapy, or surgery [RP]) in men with localized CaP. Methods: Baseline patient characteristics measured for 462 patients included age, income (less than $35,000 vs. more than $35,000), employment (working vs. not ), relationship status (married/partnered vs. not), state and trait anxiety, amount of confidence in a particular physician (a lot vs. less), and whether the patient was seen by a urologist only or both a urologist and radiation oncologist. Univariate and multivariable logistic regression were used to identify predictors of initial treatment choice within 6 months of diagnosis. Results: Common treatment choices were RP (48%), XRT (21%), and WW (15%). In both univariate and multivariable analyses, men seen by a urologist only were more likely to choose WW (p=0.03 and p=0.02, respectively); employed men were less likely to choose WW (p=0.01 and p=0.02, respectively). In multivariable analysis, married/partnered men were more likely to choose surgery (p=0.03); anxiety was not statistically significantly associated with any treatment choice. Conclusions: Our findings suggest that treatment choice is related to social infrastructure and type of specialist seen. These findings should guide counseling of patients with newly diagnosed localized CaP. Further studies related to the role of sociodemographic characteristics and access to specialty care in initial treatment choice are warranted.
A phase II trial of prostate-specific membrane antigen antibody drug conjugate (PSMA ADC) in taxane-refractory metastatic castration-resistant prostate cancer (mCRPC).
Authors: Petrylak Daniel Peter , Smith David C. , Appleman Leonard Joseph , Fleming Mark T. , Hussain Arif , Dreicer Robert , Sartor A. Oliver , Shore Neal D. , Vogelzang Nicholas J. , Youssoufian Hagop , Olson William C. , Stambler Nancy , Huang Kathleen , Israel Robert Joseph 
Published: February 2017

83 Background: The abundant expression of prostate-specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA antibody drug conjugate (ADC) is a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE). It binds PSMA and is internalized and cleaved by lysosomal enzymes releasing free MMAE causing cell cycle arrest and apoptosis. We enrolled 70 patients (pts) in a phase II trial of PSMA ADC in taxane-refractory metastatic castration-resistant prostate cancer (mCRPC). Methods: Pts with progressive mCRPC following taxane and ECOG PS 0 or 1 were eligible. PSMA ADC was administered Q3 week IV for up to eight cycles. Safety, tumor response by prostate-specific antigen (PSA), circulating tumor cells (CTC), imaging, biomarkers and clinical progression were assessed. Dosing was initiated at 2.5 mg/kg and adjustment for tolerability was allowed. Results: Thirty five pts began treatment at 2.5 mg/kg. Due to neutropenia, the remaining 35 pts began at 2.3 mg/kg. All pts received prior docetaxel and abiraterone and/or enzalutamide. Forty one percent also received cabazitaxel. Adverse events (AEs) were consistent with what was seen in phase I; most common significant AEs were neutropenia (grade 4, 6.7% and 11.4% at 2.3 and 2.5 mg/kg, respectively) and peripheral neuropathy (grade 3 or higher, 6.7% (2.3) and 5.7% (2.5)). Two pts at 2.5 mg/kg died of sepsis. 43% of pts at 2.3 and 37% of pts at 2.5 had declines in CTC from 5 or more to less than 5 cells/7.5 ml blood and 57.1% (2.3) and 74.1% (2.5) had 50% or more CTC declines; 26.1% (2.3) and 16.1% (2.5) had PSA declines of 30% or more thus far. PSA and CTC responses were associated with higher PSMA expression on CTC and lower neuroendocrine (NE) markers. The CTC conversion rate (5 or more to less than 5) was approximately 80% in pts with low NE markers. Prior cabazitaxel or abiraterone and/or enzalutamide did not appear to affect response. Centralized assessments of images by RECIST of all pts are currently planned and will be presented. Conclusions: PSMA ADC at 2.3 mg/kg was generally well tolerated in pts with progressive mCRPC previously treated with taxane. Anti-tumor activity, CTC and PSA reductions were observed at 2.3 and 2.5 mg/kg. Updated safety, tumor response and radiographic assessments from the full cohorts of 2.3 and 2.5 mg/kg will be presented. Testing in taxane naïve pts is also ongoing. Clinical trial information: NCT01695044.
PD-1 blockade in tumors with mismatch repair deficiency.
Authors: Le Dung T. , Uram Jennifer N. , Wang Hao , Bartlett Bjarne , Kemberling Holly , Eyring Aleksandra , Skora Andrew , Azad Nilofer Saba , Laheru Daniel A. , Donehower Ross C. , Luber Brandon , Crocenzi Todd S. , Fisher George A. , Duffy Steve M , Lee James J. , Koshiji Minori , Eshleman James R. , Anders Robert A , Vogelstein Bert , Diaz Luis A. 
Published: February 2017

LBA100 Background: Somatic mutations have the potential to be recognized as “non-self” immunogenic antigens. Tumors with genetic defects in mismatch repair (MMR) harbor many more mutations than tumors of the same type without such repair defects. We hypothesized that tumors with mismatch repair defects would therefore be particularly susceptible to immune checkpoint blockade. Methods: We conducted a phase II study to evaluate the clinical activity of anti-PD-1, pembrolizumab, in 41 patients with previously-treated, progressive metastatic disease with and without MMR-deficiency. Pembrolizumab was administered at 10 mg/kg intravenously every 14 days to three cohorts of patients: those with MMR-deficient colorectal cancers (CRCs) (N = 11); those with MMR-proficient CRCs (N = 21), and those with MMR-deficient cancers of types other than colorectal (N = 9). The co-primary endpoints were immune-related objective response rate (irORR) and immune-related progression-free survival (irPFS) at 20 weeks. Results: The study met its primary endpoints for both MMR-deficient cohorts. The irORR and irPFS at 20 weeks for MMR-deficient CRC were 40% and 78%, respectively, and for MMR-deficient other cancers were 71% and 67%, respectively. In MMR-proficient CRC, irORR and irPFS at 20 weeks were 0% and 11%, respectively. Response rates and Disease Control Rates (CR+PR+SD) by RECIST criteria were 40% and 90% in MMR-deficient CRC, 0% and 11% in MMR-proficient CRC, and 71% and 71% in MMR-deficient other cancers, respectively. Median PFS and overall survival (OS) were not reached in the MMR-deficient CRC group but was 2.2 and 5.0 months in the MMR-proficient CRC cohort (HR for PFS = 0.103; 95% CI, 0.029 to 0.373; p < 0.001 and HR for OS = 0.216; 95% CI, 0.047 to 1.000; p = 0.05). Whole exome sequencing revealed an average of 1,782 somatic mutations per tumor in MMR-deficient compared to 73 in MMR-proficient tumors (p = 0.0015), and high total somatic mutation loads were associated with PFS (p = 0.02). Conclusions: MMR status predicts clinical benefit of immune checkpoint blockade with pembrolizumab. Clinical trial information: NCT01876511.
Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI).
Authors: Schöffski Patrick , Maki Robert G. , Italiano Antoine , Gelderblom Hans , Grignani Giovanni , Camargo Veridiana Pires De , Bauer Sebastian , Rha Sun Young , Chawla Sant P. , Blay Jean-Yves , Hohenberger Peter , D'Adamo David R. , Wang Benjamin , Chmielowski Bartosz , Le Cesne Axel , Demetri George D. , Patel Shreyaskumar 
Published: February 2017

LBA10502 Background: In a phase II study of pts with advanced soft tissue sarcoma, 32% and 47% of pts with LMS and ADI respectively, treated with the microtubule dynamics inhibitor eribulin achieved progression-free survival (PFS) at the 12 wk timepoint (Schöffski et al. Lancet Oncol. 2011; NCT00413192). Based on these findings, this phase III study (NCT01327885) compared overall survival (OS) in pts with advanced LMS and ADI treated with eribulin or dacarbazine. Methods: Pts aged ≥ 18 yrs with advanced high/intermediate grade LMS or dedifferentiated, myxoid, round cell or pleomorphic variants of ADI incurable by surgery and/or radiotherapy were enrolled. Pts had ECOG status ≤ 2 and had received ≥ 2 standard systemic treatment regimens including an anthracycline. Pts were randomized 1:1 to eribulin (1.4 mg/m2, IV on D1 and D8) or dacarbazine (850–1200 mg/m2, IV on D1) every 21 days until disease progression. Primary endpoint was OS. Secondary endpoints included PFS, PFS rate at Wk 12 and safety. Results: Overall, 452 pts (67% female; 79% < 65 yrs) were randomized (228 eribulin; 224 dacarbazine). Median OS for eribulin and dacarbazine was 13.5 and 11.5 months, respectively (HR = 0.768, 95% CI 0.618–0.954; P= 0.017). PFS was 2.6 months in both arms (HR = 0.877, 95% CI 0.710–1.085; P= 0.229). PFS rate at Wk 12 was 33% and 29% for eribulin and dacarbazine, respectively. In eribulin and dacarbazine arms, respectively, 26% and 14% of pts required dose reductions and 8% and 5% discontinued due to treatment-emergent adverse events (TEAEs). TEAEs were more frequent in eribulin than dacarbazine arm, including neutropenia (44% vs 24%), pyrexia (28% vs 14%), peripheral sensory neuropathy (20% vs 4%) and alopecia (35% vs. 3%); as were TEAEs of grade 3 (63% vs 53%), grade 4 (26% vs 20%), and fatal TEAEs (4% vs 1%). Thrombocytopenia was more frequent in dacarbazine than eribulin arm (28% vs 6%). Conclusions: This phase III trial of eribulin trial met its primary objective of OS benefit in pretreated pts with advanced LMS or ADI. Eribulin had a toxicity profile consistent with prior experience, with no unexpected or new safety findings. Funding Source: Eisai Inc. Clinical trial information: NCT01327885.
NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases.
Authors: Brown Paul D. , Asher Anthony L. , Ballman Karla V. , Farace Elana , Cerhan Jane H , Anderson S. Keith , Carrero Xiomara W. , Barker Frederick G. , Deming Richard L. , Burri Stuart , Menard Cynthia , Chung Caroline , Stieber Volker W. , Pollock Bruce E. , Galanis Evanthia , Buckner Jan C. , Jaeckle Kurt A. 
Published: February 2017

LBA4 Background: WBRT significantly improves tumor control in the brain after SRS, yet the role of adjuvant WBRT remains undefined due to concerns regarding neurocognitive risks. Methods: Patients with 1-3 brain metastases, each < 3 cm by contrast MRI, were randomized to SRS alone or SRS + WBRT and underwent cognitive testing before and after treatment. The primary endpoint was cognitive progression (CP) defined as decline > 1 SD from baseline in any of the 6 cognitive tests at 3 months. Time to CP was estimated using cumulative incidence adjusting for survival as a competing risk. Results: 213 patients were enrolled with 2 ineligible and 3 cancels prior to receiving treatment. Baseline characteristics were well-balanced between study arms. The median age was 60 and lung primary the most common (68%). CP at 3 months was more frequent after WBRT + SRS vs. SRS alone (88.0% vs. 61.9% respectively, p = 0.002). There was more deterioration in the WBRT + SRS arm in immediate recall (31% vs. 8%, p = 0.007), delayed recall (51% vs. 20%, p = 0.002), and verbal fluency (19% vs. 2%, p = 0.02). Intracranial tumor control at 6 and 12 months were 66.1% and 50.5% with SRS alone vs. 88.3% and 84.9% with SRS+WBRT (p < 0.001). Median OS was 10.7 for SRS alone vs. 7.5 months for SRS+WBRT respectively (HR = 1.02, p = 0.93). Conclusions: Decline in cognitive function, specifically immediate recall, memory and verbal fluency, was more frequent with the addition of WBRT to SRS. Adjuvant WBRT did not improve OS despite better brain control. Initial treatment with SRS and close monitoring is recommended to better preserve cognitive function in patients with newly diagnosed brain metastases that are amenable to SRS. Clinical trial information: NCT00377156.