bluuebunny/crossref_metadata_2025_split huggingface dataset:
TALAPRO-2: A two-part, placebo-controlled phase III study of talazoparib (TALA) with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Agarwal Neeraj , Shore Neal D. , Dunshee Curtis , Karsh Lawrence Ivan , Sullivan Beth , Di Santo Nicola , Elmeliegy Mohamed , Casey Michelle , Quek Ruben G.W. , Czibere Akos , Fizazi Karim 
Published: March 2019

TPS337 Background: ENZA is approved to treat men with CRPC. TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/PARP2 and traps PARP on DNA, preventing DNA damage repair (DDR), and causing cell death in BRCA1/2-mutated cells. TALA is approved in the US to treat germline BRCA1/2-mutated HER2- locally advanced/metastatic breast cancer. A combination of TALA with ENZA in mCRPC may improve clinical outcomes. Methods: Eligible patients (pts) in parts (P) 1 and 2 of this study are aged ≥18 years; have asymptomatic/mildly symptomatic mCRPC, ECOG PS ≤1, and no brain metastases; and have not received taxanes/novel hormonal therapy (NHT). P1 is an open label study to confirm the starting dose of TALA to be given in combination with ENZA. P2 is a randomized double-blind study that will evaluate the safety, efficacy and pt reported outcomes of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA in 2 cohorts (C). C1: pts with mCRPC (all comers) (N = 560); C2: pts with DDR gene mutations likely to sensitize to PARP inhibition (DDR deficient) (N = 300). Randomization will be stratified by prior treatment with NHT for castration sensitive prostate cancer (CSPC) or prior treatment with taxane-based chemotherapy for CSPC (yes/no), and DDR mutation status (deficient vs. nondeficient/unknown). For P1, the primary endpoint is safety; the secondary endpoint is pharmacokinetics of TALA and ENZA. For P2, the primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v1.1 or in bone per PCWG3 criteria or death and evaluated separately in all comers (C1) and DDR-deficient (DDR-deficient pts from C1 and C2 combined, N = 380 pts) populations. The key secondary endpoint is overall survival. Efficacy will be assessed by radiography every 8 weeks up to week 25 and every 8-12 weeks thereafter. P2 analysis for rPFS is powered at 90% and 85% using a 2-sided log-rank test with alpha of 0.025, respectively, in the all comers and DDR deficient populations. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03395197.
A phase II study of nivolumab in patients with high-risk biochemically recurrent (BCR) prostate cancer (PCa).
Authors: Einstein David Johnson , Wei Xiao X. , Werner Lillian , Ye Huihui , Calagua Carla , Bubley Glenn , Balk Steven P. 
Published: March 2019

TPS341 Background: Although androgen deprivation therapy (ADT) may be used for high-risk BCR PCa prior to radiographic metastases, evidence is lacking and toxicities are clear. Recent data show higher prevalence of programmed death-ligand 1 (PD-L1) expression in primary PCa than previously seen. Tumor PD-L1 expression also significantly correlates with risk of BCR, suggesting that inhibition of innate immune function could be associated with recurrence. Finally, immune-suppressive immune cells may increase after castration resistance, so the early-stage tumor microenvironment may differ from the castration-resistant setting in which prior studies were conducted. These data justify a novel trial investigating PD-1 inhibition in the setting of BCR. We hypothesize that PD-L1 expression in primary PCa is a marker of immunogenicity and therefore may predict for response to PD-1 inhibition. Methods: We designed a single-arm phase 2 clinical trial of nivolumab 480 mg every 28 days for men experiencing high-risk BCR. The primary endpoint is the proportion of patients experiencing PSA decline or stabilization (without symptomatic/radiographic progression) after 12 weeks of nivolumab; secondary endpoints are best PSA response, change in PSA doubling time, time to ADT initiation and to metastatic disease, and safety. The study will include one cohort with PD-L1 expression on tumor cells >5% (“PD-L1-positive”), the other, PD-L1-negative, thus enriched for but not limited to PD-L1-expressing primary PCa. We are conducting correlative studies using tumor tissue and blood samples collected during treatment. We will perform next-generation sequencing on tissue to identify genomic biomarkers correlated with PD-L1 expression and with response to nivolumab. Using neoantigen prediction models, we will examine whether there are peripheral T cells present in nivolumab responders that recognize tumor-associated neoantigens and are expanded by PD-1 inhibition. We will evaluate subsets of tumor-infiltrating lymphocytes, including “exhausted” phenotypes, and other infiltrating immune cells. Finally, we will assess changes in peripheral immune cells and plasma cytokines as potential biomarkers. Clinical trial information: NCT03637543.
Personalized use of metronomic cyclophosphamide for DNA repair deficient castration-resistant prostate cancer: A phase II trial.
Authors: Phillips Cameron , Francia Giulio , Kerbel Robert S. , Emmenegger Urban 
Published: March 2019

TPS346 Background: There is a continued need to identify novel targets for the treatment of metastatic, castration-resistant prostate cancer (mCRPC). DNA damage repair (DDR) aberrations are emerging as such a target: 20%-30% of mCRPCs harbor DDR gene aberrations, rendering tumors particularly sensitive to DNA damaging agents and poly ADP-ribose polymerase inhibitor (PARPi) therapy. 88% of men with DDR deficient mCRPC responded to the PARPi olaparib in a phase II trial, whereas in unselected mCRPC patients the metronomic use of the DNA damaging agent cyclophosphamide (CPA) resulted in response rates of 25-60%. Intriguingly, in randomized phase II trials of unselected ovarian and triple-negative breast cancer (ie tumor types enriched for DDR defects), metronomic CPA alone was as active as metronomic CPA plus the PARPi veliparib. Based on this we hypothesize that DDR deficient mCRPC is particularly sensitive to metronomic CPA. To the best of our knowledge this is the first attempt to utilize metronomic CPA in a personalized manner. Our study has the potential to define metronomic CPA as an affordable and well-tolerated alternative to PARPi therapy in men with DDR deficient mCRPC. Methods: To study if metronomic CPA achieves a similar response rate (ie ≥85%) in DDR deficient mCRPC as seen with olaparib, men with mCRPC progressing after 1-2 lines of systemic therapy will undergo circulating tumor DNA based testing for BRCA1/2 or ATM aberrations. Patients with such aberrations will proceed with metronomic CPA (50 mg po daily). Primary endpoint: RECIST 1.1 and/or ≥50% PSA response rate at 12 weeks. Secondary endpoints include biochemical, radiological and clinical progression-free survival. Applying the Optimal Simon's Two-Stage design, and using a type I error rate of 0.05 and a power of 0.8, in the first stage we plan to enroll 14 patients. If there are ≤10 or fewer responses, the study will be stopped. Otherwise, another 19 patients will be accrued as part of the second stage.
TROPHY-u-01: A phase II open-label study of sacituzumab govitecan (IMMU-132) in patients with advanced urothelial cancer after progression on platinum-based chemotherapy and/or anti-PD-1/PD-L1 checkpoint inhibitor therapy.
Authors: Tagawa Scott T. , Petrylak Daniel Peter , Grivas Petros , Agarwal Neeraj , Sternberg Cora N. , Siemon-Hryczyk Peggy , Goswam Trishna , Loriot Yohann 
Published: March 2019

TPS495 Background: Patients (pts) with unresectable locally advanced or metastatic urothelial cancer (mUC) who progress after platinum-based chemotherapy and checkpoint inhibitor (CPI) therapy and pts ineligible for platinum-based chemotherapy who progress after CPI have limited treatment options and poor outcomes. Trop-2 is an epithelial cell surface antigen that is overexpressed in UC. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate that targets Trop-2 and delivers the active metabolite (SN38) of the topoisomerase I inhibitor irinotecan to tumor cells. In a phase 1/2 single-arm trial, pts with advanced cancers received SG 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle; preliminary results in the cohort of 41 evaluable pts with mUC and a median of 3 (range 1–6) prior therapies showed an objective response rate (ORR) of 34%. Adverse events (AE) were mostly low grade, including diarrhea (63%), nausea (56%), and fatigue (49%). Neutropenia (all grades) occurred in 49% of pts (≥ grade 3/4, 39%; treatment-related serious AE of febrile neutropenia, 5%). Median overall survival was 16.1 months, and median progression-free survival was 7.1 months. These results warrant further investigation in a dedicated phase 2 trial. Methods: TROPHY-U-01 is a single-arm, open-label, global phase 2 trial evaluating the antitumor activity and safety of SG in 140 pts with advanced UC. The primary cohort (progression after platinum chemotherapy and CPI) will enroll 100 pts in a Simon 2-stage design with > 90% power accounting for dropouts to exclude the null hypothesis or ORR < 12%, while a second cohort (40 pts) will comprise cisplatin-ineligible pts who received prior CPI. The primary objective is ORR per RECIST 1.1, assessed by central review. Secondary objectives include response duration, PFS, OS, and safety/tolerability. Enrollment began in August 2018. Clinical trial information: NCT03547973.
Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer: NEODURVARIB Trial.
Authors: Rodriguez-Moreno Juan Francisco , Sevillano Elena , Fenor MD , Collado Martín Ricardo , Esteban Emilio , Fernandez Ricardo , Font Pous Albert , Gajate Pablo , Muñoz-Langa José , Vazquez-Estevez Sergio , de Velasco Guillermo , Virizuela Juan Antonio , Navarro Paloma , Ruiz-LLorente S , Beltran Luis , Rodríguez-Antona Cristina , GarcÃa-Donas JesÃºs 
Published: March 2019

TPS503 Background: Perioperative treatment of muscle-invasive bladder carcinoma (MIBC) remains cisplatin-based chemotherapy, but recent evidences suggest that immune checkpoint inhibitors could be incorporated in this setting. Durvalumab is a PD-L1 blocking antibody active in advanced urothelial carcinoma pretreated with platinum-containing chemotherapy and currently under evaluation in first-line, both as monotherapy and in combination with tremelimumab. Olaparib is a PARP inhibitor especially important in tumors with deficiencies in DNA repair mechanisms. Preliminary results from combination trials suggest that these drugs could have synergistic effect dependent on an immunogenic modulation related with STING pathway, and an increase of neoantigens. Unexpected toxicities have not been described. Methods: Design: Open label phase II single arm clinical trial. Primary Objective: To assess the impact of neoadjuvant treatment with durvalumab plus olaparib in the molecular profile of MIBC. Secondary Objectives: Efficacy (Radiological and pathological responses); Safety. Exploratory objective: To identify predictive and prognostic biomarkers. Key correlative studies: Independent central pathologist for histological review and assessment of immunohistochemistry for PD1, PD-L1 and PD-L2; Genomic characterization (WES) and Expression assessment (RNAseq) of the tumors pre and post treatment; Assessment of soluble biomarkers and their evolution during the treatment: flow cytometry for immune cells; immunoassays for cytokines; HLA genotyping. Treatment: Durvalumab 1500 mg iv Q4W & Olaparib 150 mg bid orally during 6 to a maximum of 8 weeks pre-cystectomy. Recruitment: 29 patients. Collaborating institutions: 10 (members of Spanish Oncology Genitourinary Group). Key Inclusion Criteria: Subjects with histological confirmation of T2-T4a MIBC aimed for cystectomy without neoadjuvant chemotherapy; Available samples for correlative studies; Adequate medullary, renal and hepatic function. Key Exclusion Criteria: Use of immunosuppressive medication; Documented autoimmune disorders. Clinical trial information: NCT03534492.
Randomized phase II trial of intravenous ascorbic acid (AA) as an adjunct to pazopanib for metastatic and unresectable clear cell renal cell carcinoma (ccRCC): A study of Academic and Community Cancer Research United (ACCRU) GU1703.
Authors: Shenoy Niraj Konchady , Ou Fang-Shu , Cheville John C. , Bhagat Tushar , Gartrell Benjamin Adam , Verma Amit , Levine Mark , Pagliaro Lance C. 
Published: March 2019

TPS679 Background: AA has re-emerged as a promising anti-cancer agent based on recent knowledge of pharmacokinetics, discovery of unexpected mechanisms of action, and early phase trials with IV AA.(Shenoy et al, Cancer Cell 34: 2018, in press) We hypothesized that ccRCC would be particularly susceptible to anti-cancer effects of IV AA due to: a. TET dependent demethylation of the hypermethylated genome of ccRCC causing re-expression of tumor suppressors (Shenoy et al, AACR 2018 Targeting DNA methylation conf. A11; Hu et al, Clin Cancer Res 20:4349-60, 2014) b. H2O2 production causing intra-tumoral oxidative damage, hypothesized to be enhanced by high iron content in RCC microenvironment c. Intracellular accumulation of dehydroascorbic acid secondary to high HIF activity in ccRCC. Animal data and case reports support the hypothesis. Methods: Trial design: Patients (pts) with newly diagnosed metastatic/ unresectable ccRCC are randomized 1:1 to arm A (pazopanib 800 mg/d plus IV AA 1g/kg 3 times/week) or arm B (pazopanib 800 mg/d). Protocol treatment is for 10 cycles (unless PD, unacceptable AE, alternative therapy, or pt refusal), each cycle being 28 days. Primary endpoint is Treatment Failure-Free rate at 40 weeks (TFF40). Treatment Failure is defined as: Radiographic disease progression, off-protocol treatment due to AE, alternative therapy initiation (except metastasectomy post clinical benefit), or death. Secondary endpoints include OS, PFS, ORR and AE. Statistical methods: 82 eligible pts (41 in each in arm) will provide 81% power to detect a 19% increase of TFF40 from 45% in arm B to 64% in arm A assuming a one-sided type I error rate of 0.19 (EAST 6.4). Correlatives: Epigenetic mechanism: 5mC, 5hmC and H3K27me3 IHC, MeDIP/ hMeDIP seq, RNA seq. H2O2 mechanism: tumor microenvironment iron, tumor catalase IHC. Dehydroascorbic acid mechanism: HIF-1 alpha, HIF-2 alpha, GLUT-1 IHC. Key exclusion criteria: G6PD deficiency, renal disease (Cockcroft Gault CrCl < 55 ml/min). ClinicalTrials.gov Identifier: NCT03334409 Status: Open for accrual in 9/10 planned sites. Funding Source: Foundation. Clinical trial information: NCT03334409.
Does evidence support the high expectations placed in precision medicine? A bibliographic review
Authors: Cortés Jordi , González José Antonio , Medina María Nuncia , Vogler Markus , Vilaró Marta , Elmore Matt , Senn Stephen John , Campbell Michael , Cobo Erik 
Published: March 2019

Background: Precision medicine is the Holy Grail of interventions that are tailored to a patient’s individual characteristics. However, conventional clinical trials are designed to find differences in averages, and interpreting these differences depends on untestable assumptions. Although ideal, a constant effect would facilitate individual management. Another consequence of a constant effect is that the outcome variance would be the same in treated and control arms. We reviewed the literature to explore the similarity of these variances as a foundation for examining whether and how often precision medicine is definitively needed. Methods: We reviewed parallel trials with quantitative outcomes published in 2004, 2007, 2010 and 2013. We collected baseline and final standard deviations of the main outcome. We assessed homoscedasticity by comparing the variance of the primary endpoint between arms through the outcome variance ratio (treated to control group). Results: The review provided 208 articles with enough information to conduct the analysis. One out of seven studies (n = 30, 14.4%) had statistically different variances between groups, leading a non-constant-effect. The adjusted point estimate of the mean outcome variance ratio (treated to control group) is 0.89 (95% CI 0.81 to 0.97). Conclusions: We found that the outcome variance was more often smaller in the intervention group, suggesting that treated patients may end up pertaining more often to reference values. This observed reduction in variance might also imply that there could be a subgroup of less ill patients who derive no benefit, which would require studying whether the effect merits enduring the side effects as well as the economic costs. We have shown that the comparison of variances is a useful but not definitive tool for assessing whether or not the assumption of a constant effect holds.
The impact of the open-access status on journal indices: a review of medical journals
Authors: AlRyalat Saif Aldeen , Saleh Mohammad , Alaqraa Mohammad , Alfukaha Alaa , Alkayed Yara , Abaza Maryann , Abu Saa Hadeel , Alshamiry Mohamed 
Published: March 2019

Background: Over the past few decades, there has been an increase in the number of open access (OA) journals in almost all disciplines. This increase in OA journals was accompanied an increase in funding to support such movements. Medical fields are among the highest funded fields, which further promoted its journals to move toward OA publishing. Here, we aim to compare OA and non-OA journals in terms of citation metrics and other indices. Methods: We collected data on the included journals from Scopus Source List on 1st November 2018. We filtered the list for medical journals only. For each journal, we extracted data regarding citation metrics, scholarly output, and wither the journal is OA or non-OA. Results: On the 2017 Scopus list of journals, there was 5835 medical journals. Upon analyzing the difference between medical OA and non-OA journals, we found that OA journals had a significantly higher CiteScore (p< 0.001), percent cited (p< 0.001), and source normalized impact per paper (SNIP) (p< 0.001), whereas non-OA journals had higher scholarly output (p< 0.001). Among the five largest journal publishers, Springer Nature published the highest frequency of OA articles (31.5%), while Wiley-Blackwell had the lowest frequency among its medical journals (4.4%). Conclusion: Among medical journals, although non-OA journals still have higher output in terms of articles per year, OA journals have higher citation metrics.
Assessing the development and implementation of the Global Trigger Tool method across a large health system in Sicily
Authors: Parrinello Vincenzo , Grasso Elena , Saglimbeni Giuseppe , Patanè Gabriella , Scalia Alma , Murolo Giuseppe , Lachman Peter 
Published: March 2019

Background: The Institute for Healthcare Improvement (IHI) has proposed a new method, the Global Trigger Tool (IHI GTT), to detect and monitor adverse events (AEs) and provide information to implement improvement. In 2015, the Sicilian Health System adopted IHI GTT to assess the number, types and severity levels of AEs. The GTT was implemented in 44 of 73 Sicilian public hospitals and 18,008 clinical records (CRs) were examined. Here we present the standardized application of the GTT and the preliminary results of 14,706 reviews of CRs. Methods: IHI GTT was adapted to the local context, and developed and implemented. Reviews of CRs were conducted by 199 professionals divided into 71 review teams consisting of three individuals: two of whom had clinical knowledge and expertise, and a physician to authenticate the AE. The reviewers entered data into a dedicated IT-platform. All 44 of the public hospitals were included, with approximately 300,000 inpatient yearly admission out of a population of approximately 5 million. In total, 14,706 CRs of inpatients from medicine, surgery, obstetric and ICU wards, from June 2015 to June 2018 were reviewed. Results: In 975 (6.6%) CRs at least one AE was found. Approximately 20,000 patients of the 300,000 discharged each year in Sicily have at least one AE. In 5,574 (37.9%) CRs at least one trigger was found. A total of 1,542 AEs were found. The analysis of ROC curve shows that the presence of two triggers in a CR indicates an AE with a high probability. The most frequent type of AE was in-hospital related infection. Conclusions: The GTT is an efficient method to identify AEs and to track improvement of care. The analysis and monitoring of some triggers is important to prevent AEs. However, it is a labor-intensive method, particularly if the CRs are paper based.
This level of crust
Authors: Kramer Paula 
Published: March 2019

Abstract
These pages reflect on a short, intensive collaboration that took place during the fourth Dance and Somatic Practices Conference (2017) – a methodology lab I initiated to discuss and elaborate on working among and across material constellations of various orders. Three people with diverse backgrounds spent time co-investigating material agency, earthly matters, atmospheric impacts, geoastrological time scales and emplacement: Nigel Clark (NZ/UK) – social geography/geological agency/anthropocene/fire; Simo Kellokumpu (FI) – choreographic thinking/atmosphere/scale/reading; and Paula Kramer (DE/FI) – intermateriality/movement/body/site-specificity. The lab took place in the studio and outdoors, where together and alone we tested, moved, read, talked, discussed. In the end we shared an indoor installation and outdoor performance practice. This text is written by Paula, a third of the trio, from a partial and particular perspective.
Somatic/embodiment/technology as an evolutive strategy: The ontological shift of the performative body in contact with technologies
Authors: Choinière Isabelle 
Published: March 2019

Abstract
This article examines the new and multiple relationships of the senses and related perceptual and cognitive processes that characterize contemporary performance integrating new technologies. Focusing on the corresponding effects on embodiment, corporeality and performativity, it considers the sensori-perceptual ‘re-creation’, reorganization, deconstruction and reconstruction involved when the body interacts with, is ‘touched’ by, and ‘incorporates’ the effects of technology. While taking into consideration a current context of research-creation and its conceptual prerogatives, the article centres on the question of technological intervention from the perspective of its encounter(s) with the sensate, somatic body. Based on the premise of the body as a living perceptual entity, adaptive biological phenomenon and indeed, technology in its own right, the author redefines a contemporary status of the body while analysing the artistic strategies employed to inscribe the mediated body and its manifestations within a contemporary artistic production. The article concludes by suggesting that the phenomenological mediation of the performative body is an evolutive form of the sensate, somatic body that could have the potential to bring about the emergence of another form of embodiment and intercorporeality, or even, another form of dance specific to the twenty-first century. Possibly an alternative to the concept of the post-human.