bluuebunny/crossref_metadata_2025 huggingface dataset:
Moderately hypofractionated radiotherapy for localized prostate cancer: Long-term outcomes for 854 consecutive patients treated over 10 years (70 Gy in 2.5 Gy/fraction).
Authors: Mian Omar Y. , Abu-Gheida Ibrahim , Kotecha Rupesh , Weller Michael A. , Reddy Chandana A. , Kupelian Patrick , Ornstein Moshe Chaim , Gilligan Timothy D. , Garcia Jorge A. , Rini Brian I. , Stephenson Andrew J. , Klein Eric A. , Shah Chirag , Ciezki Jay P. , Stephans Kevin L. , Tendulkar Rahul D.
Published: March 2019

78

Background: Moderately hypofractionated radiotherapy has been increasingly adopted in the management of localized prostate cancer (PCa). We report 10-year outcomes for patients treated with intensity modulation radiation therapy (IMRT) for localized PCa with 70 Gy in 28 fractions at 2.5 Gy/fraction. Methods: This retrospective study included 854 consecutive patients with localized PCa treated with image-guided moderately hypofractionated IMRT at a single institution between 1998 and 2012. Patients with a single intermediate-risk factor were considered to have favorable intermediate-risk (FIR) disease; multiple intermediate-risk factors were considered unfavorable (UIR). Biochemical relapse free survival (bRFS), clinical relapse free survival (cRFS), overall survival (OS) and PCa specific mortality (PCSM) were analyzed used Kaplan-Meier analysis. Grade ≥3 genitourinary (GU) and gastrointestinal (GI) toxicities were recorded (CTCAE v4.03). Results: The median follow-up was 11.3 years (Max. 19 years). For patients with low-risk (LR, 31%), FIR (28%), UIR (12.5%), and high-risk (HR, 28.5%) disease the 10 year bRFS rates were 88%, 78%, 71% and 42%, respectively (p < 0.0001). The number of patients receiving no ADT, 1-6 months, or > 6 months of ADT were 39%, 50%, and 11%, respectively, reflecting practice patterns during this treatment period. The 10-year cRFS were 95%, 91%, 85% and 72% for patients with LR, FIR, UIR, and HR, respectively (p < 0.0001). The 10-year actuarial OS rate was 69% (95% CI 66-73%) and the 10-year PCSM was 6.8% (95% CI 5.1-8.6%) overall. For patients with LR, FIR, UIR and HR disease, the 10 year PCSM rates were 2%, 5%, 5% and 15%. 10-year cumulative incidence of grade ≥3 GU and GI toxicity was 2% and 1%, respectively. Multivariate analysis identified associations between clinical variables (ADT use, PSA nadir < 0.5ng/ml, and ISUP Grade Group) and bRFS, cRFS, and PCSM. Conclusions: Moderately hypofractionated IMRT with daily image guidance for localized PCa demonstrates favorable 10-year oncologic outcomes with a low incidence of toxicity for patients across all risk groups.
The molecular hallmarks and clinical consequences of tumor hypoxia in prostate cancer.
Authors: Vinayak Bhandari , Liu Lydia , Espirritu Shadrielle , Lalonde Emilie , Yamaguchi Takafumi , Heisler Lawrence , Livingstone Julie , Huang Vincent , Shiah Yu-Jia , Sabelnykova Veronica , Yousif Fouad , Fraser Michael , Chua Melvin , Van Der Kwast Theodorus , Liu Stanley K. , Boutros Paul Christopher , Bristow Robert G.
Published: March 2019

81

Background: Localised prostate cancers are classified into risk-groups using clinical measurements like grade and stage to inform treatment decisions. However, these groupings are imprecise: ~30% of intermediate-risk patients suffer relapse of their disease despite precision image-guided radiotherapy or radical prostatectomy. One reason for this variability in response to treatment is the underlying cellular and molecular heterogeneity of tumours. Prostate tumour cells exist within a microenvironment characterized by gradients of oxygen levels and prostate tumours with low levels of oxygen (hypoxia) have poor clinical outcomes. Methods: Hypoxia was measured using multiple mRNA-based signatures. We examined 548 patients with localised prostate cancer and statistically assessed the association of hypoxia with copy-number alterations (CNAs), single-nucleotide variants (SNVs), genomic rearrangements, focal genomic events ( i.e. kataegis, chromothripsis), telomere length, clinical indices ( i.e. grade, stage) and subclonal architecture. Results: Elevated hypoxia was associated with allelic loss of PTEN, higher rates of chromothripsis and intraductal and cribriform carcinoma (IDC-CA). To translate these findings into a biomarker for prostate cancer precision medicine, we integrated tumour microenvironmental data with genomic and pathological information to stratify patients into distinct prognostic groups. Patients with localized prostate cancer that have polyclonal tumours with elevated hypoxia, allelic loss of PTEN and IDC-CA were at the highest risk of rapid biochemical failure (P = 3.48 x10-3, Logrank test) and metastasis (P = 4.61 x 10-3, Logrank test), even after controlling for T-category, Gleason score and pre-treatment PSA. Conclusions: These data suggest that the aggressiveness of prostate cancers is driven by the interplay of the tumour microenvironment, tumour evolutionary trajectories and its genomic mutational profile.
Concordance of systematic and fusion biopsy with surgical pathology.
Authors: Yu Alice , Yamany Tammer , Hanna Nawar , Nicaise Eduoard , Mojtahed Amirkasra , Harisinghani Mukesh , Wu Chin-Lee , Dahl Douglas M. , Wszolek Matthew , Blute Michael L. , Feldman Adam S.
Published: March 2019

93

Background: Multiparametric MRI is increasingly used in prostate cancer detection. Previous studies have shown that detection rate of clinically significant cancer is higher in MRI targeted biopsy than systematic biopsy. However, the concordance between the Gleason score on fusion biopsy and radical prostatectomy is less well known. The objective of this study is to look for predictors of histopathologic concordance between biopsy (fusion and systematic) and radical prostatectomy. Methods: We used an institutional database of men who underwent mpMRI-ultrasound fusion targeted and systematic biopsy followed by radical prostatectomy. Gleason score on targeted, systematic and combination (targeted + systematic) biopsy were compared with Gleason score on radical prostatectomy, and concordance was recorded. The McNemar test was used to compare concordance and upgrade rates. Predictors of concordance and upgrade such as age, prostate volume, PSA, PSA density, Gleason score on biopsy, number of targets reported on mpMRI, and PI-RADS score were evaluated with Fisher’s exact test and logistic regression. Results: Surgical pathology was concordant with 47.4% of systematic biopsies, 52.0% of targeted biopsies and 58.4% of combination biopsies. There was no significant difference in concordance rates between systematic and targeted biopsy (P = 0.37). However, combination biopsy was superior to both systematic (RR 1.23, 95% CI 1.08-1.40, P = 0.03) and targeted biopsy (RR 1.12, 95% CI 1.02 – 1.24, P = 0.03) in predicting concordance with surgical pathology. Risk of upgrade to a higher Gleason score on surgical pathology was significantly lower with combination biopsy compared to systematic (RR 0.57, 95% CI 0.46-0.69, P < 0.001) or targeted biopsy alone (RR 0.72, 95% CI 0.61-0.84, P = 0.001). Upgrade rates were 43.9% for systematic biopsy, 34.7% for targeted, and 24.9% for combination. Lastly, we found no significant predictors of concordance or upgrade. Conclusions: Combination biopsy is associated with the highest concordance rate between biopsy and radical prostatectomy when compared with systematic or targeted biopsy alone. Performing targeted biopsy alone will underestimate tumour aggressiveness on surgical pathology.
Validation of a two-gene mRNA urine test for detection of high-grade prostate cancer in German men.
Authors: Tilki Derya , Hessels Daphne , Trooskens Geert , Mulders Susan , Brawer Michael , Van Criekinge Wim , Groskopf Jack , Haese Alexander
Published: March 2019

96

Background: There is an unmet need for non-invasive methods that can accurately identify patients at increased risk for clinically significant prostate cancer (PCa). SelectMDx is a urine-based molecular test that has been clinically validated for the detection of high-grade PCa. We evaluated SelectMDx clinical performance in a cohort of German men undergoing initial prostate biopsy. Methods: The study population consisted of 443 men sequentially enrolled men who underwent initial prostate biopsy between July 2009 and December 2014 due to suspected PCa. Post-DRE urine was collected from all subjects prior to biopsy, and samples stored at -70C. Urinary HOXC6 and DLX-1 mRNAs were quantified by PCR in May 2018, and RNA results combined with clinical risk factors to determine the likelihood that biopsy would identify ISUP grade group (GG) ≥ 2 (Gleason Score ≥ 7) PCa. We assessed SelectMDx performance for detection of GG ≥ 2 PCa, compared to the PCPT Risk Calculator Version 2.0 (PCPTRC, http://myprostatecancerrisk.com , accessed Oct 7, 2018). Results: For the 443 subjects enrolled, average age was 66 years (median 66, interquartile range 61 to 71), and average serum PSA level 8.8 ng/mL (6.4, 4.8 to 9.7). Cancer was detected in 243/443 (55%) men biopsied (43% GG1, 36% GG2, 9% GG3 and 12% GG4-5). The prevalence of GG2-5 PCa in this population was 31.4% (139/443). For detection of GG2 or higher PCa versus GG1 or no PCa at biopsy, SelectMDx AUC was 0.82 (95% C.I. 0.78-0.86) and the PCPTRC yielded AUC 0.75 (0.70-0.80), P < 0.001. SelectMDx sensitivity was 94% (89-98%), specificity 46% (40-52%), positive predictive value 45% (42-47%) and negative predictive value (NPV) 95% (90-97%). If the initial biopsy had been performed based on SelectMDx results alone, 46% of potentially unnecessary biopsies and 34% of all biopsies would have been avoided, while 5.8% of men with biopsy-detectable high-grade PCa (seven GG2, one GG3) may have had their diagnosis delayed. Conclusions: In this first validation study of SelectMDx in German men, the test’s clinical performance was comparable to the published EU validation study, showing a high NPV for detection of GG2 or higher PCa. These results provide further evidence for the clinical validity of SelectMDx.
Preoperative trial of neoadjuvant abiraterone plus or minus cabazitaxel: Early results.
Authors: Herrera-Caceres Jaime Omar , Goldberg Hanan , Hansen Aaron Richard , Sridhar Srikala S. , Hamilton Robert James , Finelli Antonio , Zlotta Alexandre , Joshua Anthony M. , Fleshner Neil Eric
Published: March 2019

98

Background: High-risk prostate cancer (PC) has a significant risk of recurrence when treated with unimodal therapy. The utility of neoadjuvant therapy, prior to RP has yet to be defined. The Princess Margaret Cancer Centres’ ACDC study investigates the application of agents used for castration resistant PC in the neoadjuvant setting by comparing the use of abiraterone (AA) + prednisone (P) + leuprolide (LHRH) with or without cabazitaxel (CA) prior to RP in 76 high-risk patients. Herein, we report early results and protocol modifications. Methods: This phase II trial will randomize patients to two treatment arms: Arm A (AA/P + LHRH + CA 25 mg/m2 with peg-filgrastim 6 cycles) or Arm B (AA/P + LHRH) for 6 months prior to RP. The primary objective is to compare the pathological complete response (CR) between the treatment arms. We present the RP outcomes and safety data for the first 13 participants. Results: Out of 13 randomized participants, 10 completed study procedures and underwent RP. One participant (Arm B) completed study drug treatment, but opted for radiation therapy, while 2 participants (both in Arm B) were discontinued due to hepatoxicity. At RP, 2 participants exhibited CR (1 in each group) and an additional 3 patients exhibited near CR (less than 5% tumor volume). The Table demonstrates patient characteristics, pathologic results and Grade 3 adverse events rates. Of note, 2 patients (both in CA arm) developed post-operative thrombo-embolic events post RP and two experienced febrile neutropenia. Conclusions: Early findings indicate significant tumor response with 50% of patients exhibiting CR or near CR. Reduction in dosage of Cabazitaxel to 20 mg/m2 as well as need for extended post-operative thromboembolic prophylaxis have been implemented. ACDC early outcomes. [Table: see text]
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.
Financial Toxicity in Advanced and Metastatic Cancer: Overburdened and Underprepared
Authors: Rotter Jason , Spencer Jennifer C. , Wheeler Stephanie B.
Published: March 2019

Patients with metastatic or advanced cancer are likely to be particularly susceptible to financial hardship for reasons related both to the characteristics of metastatic disease and to the characteristics of the population living with metastatic disease. First, metastatic cancer is a resource-intensive condition with expensive treatment and consistent, high-intensity monitoring. Second, patients diagnosed with metastatic disease are disproportionately uninsured and low income and from racial or ethnic minority groups. These vulnerable subpopulations have higher cancer related financial burden even in earlier stages of illness, potentially resulting from fewer asset reserves, nonexisting or less generous health insurance benefits, and employment in jobs with less flexibility and fewer employment protections. This combination of high financial need and high financial vulnerability makes those with advanced cancer an important population for additional study. In this article, we summarize why financial toxicity is burdensome for patients with advanced disease; review prior work in the metastatic or advanced settings specifically; and close with implications and recommendations for research, practice, and policy.
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.
Becoming a middle leader
Authors: Stephenson Dave
Published: March 2019

Becoming a middle leader can be a daunting prospect, especially if you are still a relatively young teacher or new to the school. Dave Stephenson has recently made this step up and offers some basic advice
Performing ethnocultural nationalism: Choreographies of Hindu nationalism in theatre performances
Authors: Kishore Sushant
Published: March 2019

This article attempts to explore the thespian performances of Hindutva-based ethnocultural nationalism in India using a selection of three plays. A conventional proscenium play, a postmodern proscenium play and a street play are analysed for their various perspectives and strategies of reproducing experiences – of both the victims and the perpetrators – of Hindu nationalism in India. This selection allows to discuss the varied experiences of Hindu nationalism based on class, caste and religion. The trans generic selection, in this particular order also allows to demonstrate an opening up of performance and performativity from conventional thespian spaces to the streets where the plebeian quotidian life plays. It allows the opening up of an ontological space for further deliberations on the ubiquitous quotidian rituals and performances of Hindu nationalism in India.
This level of crust
Authors: Kramer Paula
Published: March 2019

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

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.
Francisco de Vitoria on Prudence and the Nature of Practical Reasoning
Authors: Spindler Anselm
Published: March 2019

The history of prudence is often depicted as a history of loss. According to one version, the scientification of moral knowledge in medieval philosophy calls into question the role of prudence in moral action (Nussbaum 1978). And while Thomas Aquinas (1225–1274) still tries to integrate prudence into a scientific framework of moral knowledge, the Salmantine theologian Francisco de Vitoria (1483–1546) eventually abandons this approach and excludes prudence from moral knowledge altogether (Fidora 2013). I would like to argue, however, that Vitoria plays a different role in this development: He does not exclude prudence from scientific moral knowledge but gives an integrated account that Aquinas lacks. But this integration comes at a price because he is eventually unable to explain how prudence allows an agent to deal with the problem of contingency in action.
Geometric difference of six-dimensional Riesz almost lacunary rough
statistical convergence in probabilistic space of 𝜒𝑓 3
Authors: Indumathi A. , Subramanian Nagarajan , Esi Ayhan
Published: March 2019

In this paper we study the concept of generalized geometric difference
of six-dimensional rough almost lacunary statistical Cesáro of

{\chi^{3}}

over probabilistic space P
is defined by Musielak–Orlicz function. Since the study of convergence in
Probabilistic space P is fundamental to
probabilistic functional analysis, we feel that the concept of generalized
geometric difference of six-dimensional rough almost lacunary statistical
Cesáro of

{\chi^{3}}

over probabilistic space P
defined by Musielak in a probabilistic space P
would provide a more general framework for the subject.
Polygenic Inheritance of Bracts Number in Sunflower
Authors: Soroka A. I. , Lyakh V. A.
Published: March 2019

Two inbreds of mutant origin, differing in the number of bracts, were crossed to obtain the F1 hybrid. One mutant line had 24.5 ± 1.01 bracts, while the other, 78.6 ± 1.69 bracts. The F1 hybrid had an average value between parents, which practically did not differ from the mean value in the F2 population. The variability of the trait under study in the F2 population was continuous, varying from 20 to 84 bracts. This indicated the probable participation of several genes with an additive effect in the control of the number of bracts. Assuming that the differences between the parental lines are due to two pairs of genes, the F2 plant population, grown in 2016, was divided into 5 classes. In that population the observed classes ratio turned out to be close to the theoretically expected ratio of 1 : 4 : 6 : 4 : 1. Over the next two years F2 populations were tested in a similar way. In all the cases, the calculated chi-square value did not exceed the critical value for 4 degrees of freedom and 5 % significance level. This gave reason to talk about the two-loci control of a such quantitative trait as the number of bracts. The participation of two non-allelic genes in the control of this trait is also proved by matching the actual number of plants in the parental classes to the theoretically expected number of plants. Thus, the number of bracts depends on the number of dominant alleles of two different genes in the genotype.
Erythropoietin in perinatal hypoxic-ischemic encephalopathy: a systematic review and meta-analysis
Authors: Razak Abdul , Hussain Asif
Published: March 2019

Background

Erythropoietin (EPO) appears to confer neuroprotection to the injured brain. Randomized clinical trials (RCTs) have demonstrated its safety in neonates with hypoxic-ischemic encephalopathy (HIE); however, the evidence is unclear. The objective of this study was to examine the role of EPO in perinatal HIE by a systematic review and meta-analysis.

Methods

Database search included Embase, MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Central Register of Controlled Trials (CENTRAL). RCTs reporting a death, neurodevelopmental outcomes or brain injury were included. Two authors extracted the data independently from included studies and assessed the level of evidence (LOE).

Results

Six RCTs (EPO=5 and darbepoetin α=1) involving 454 neonates were included. A trend toward a lower risk of death was identified in infants treated with EPO [EPO with or without hypothermia: five RCTs, 368 participants, relative risk (RR) 0.74, 95% confidence interval (CI) 0.47–1.19, LOE−low; EPO without hypothermia: four RCTs, 318 participants, RR 0.89, 95% CI 0.49–1.32, LOE−low]. EPO treatment without hypothermia compared to placebo resulted in a reduced risk of cerebral palsy (two RCTs, 230 participants, RR 0.47, 95% CI 0.27–0.80, LOE−moderate) and moderate to severe cognitive impairment (two RCTs, 226 participants, RR 0.49, 95% CI 0.28–0.85, LOE−moderate). A reduced risk of brain injury was identified in EPO treated infants (EPO with or without hypothermia, two RCTs, 148 participants, RR 0.70, 95% CI 0.53–0.92, LOE−moderate).

Conclusion

EPO administration in neonates with perinatal HIE reduces the risk of brain injury, cerebral palsy and cognitive impairment. The evidence is limited to suggest its role as an adjuvant to hypothermia. Larger powered trials are underway to overcome this limitation.
Effects of 6-Month Military Deployment on Physical Fitness, Body Composition, and Selected Health-Related Biomarkers
Authors: Sedliak Milan , Sedliak Peter , Vaara Jani P.
Published: March 2019

Sedliak, M, Sedliak, P, and Vaara, JP. Effects of 6-month military deployment on physical fitness, body composition, and selected health-related biomarkers. J Strength Cond Res 35(4): 1074–1081, 2021—The purpose was to study the effects of 6-month deployment to Afghanistan on physical performance, anthropometrical, and health-related biochemical parameters in soldiers with sedentary to light physical workload shifts. Twenty-five male soldiers (30 ± 4 years) volunteered and were measured before and after the 6-month deployment. Another 25 home-land–based male soldiers (30 ± 6 years) served as controls. Total body fat percentage decreased in deployed soldiers (Pre: 23.2 ± 5.3 vs. Post: 20.8 ± 5.5%, p < 0.05), whereas no change was observed in control (20.2 ± 6.9 vs. 20.5 ± 7.0%). Physical performance improved in deployed soldiers in 4 × 10-m shuttle run (10.86 ± 0.90 vs. 10.49 ± 0.63 seconds) and pull-up test to failure (4.7 ± 3.7 vs. 7.5 ± 6.7 rep.) (p < 0.05) but not in the controls for the respective tests (10.28 ± 0.74 vs. 10.40 ± 0.76 seconds and 10.2 ± 7.8 vs. 10.2 ± 7.5 rep.). Deployed soldiers also improved 5-km run with a simulated combat gear time (29.2 ± 3.1 vs. 27.4 ± 3.0 minutes), whereas in control the time increased (26.4 ± 2.9 vs. 27.8 ± 2.6 minutes, p < 0.05). Load at maximum power output in bench press was improved in deployed soldiers (51.6 ± 11.3 vs. 56.2 ± 12.6 kg, p < 0.05). Serum glucose and creatinine decreased (5.46 ± 0.53 vs. 4.87 ± 0.74 mmol·L−1 and 87.4 ± 10.7 vs. 80.9 ± 10.2 μmmol·L−1, respectively), and hemoglobin and hematocrite increased (15.13 ± 0.82 vs. 16.75 ± 0.85 g·dl−1 and 45.3 ± 1.5 vs. 48.1 ± 2.4%, respectively, p < 0.05) in the deployment group. In conclusion, after 6-month deployment consisting of sedentary and low physical occupational load, soldiers were able to increase their physical fitness and decrease their body fat content and improve selected health-related biochemical parameters. Therefore, the adoption and promotion of leisure-time physical activity in soldiers during deployments is essential to maintain combat readiness.
Similar Anaerobic and Aerobic Adaptations After 2 High-Intensity Interval Training Configurations: 10:5 s vs. 20:10 s Work-to-Rest Ratio
Authors: Moghaddam Masoud , Estrada Carlos A. , Muddle Tyler W.D. , Magrini Mitchel A. , Jenkins Nathaniel D.M. , Jacobson Bert H.
Published: March 2019

Moghaddam, M, Estrada, CA, Muddle, TWD, Magrini, MA, Jenkins, NDM, and Jacobson, BH. Similar anaerobic and aerobic adaptations after 2 high-intensity interval training configurations: 10:5 s vs. 20:10 s work-to-rest ratio. J Strength Cond Res 35(6): 1685–1692, 2021—This study compares the effects of 2 high-intensity interval training (HIIT) configurations, a 10-5 vs. a 20-10 second work-to-rest ratio, on anaerobic and aerobic performance. Thirty-four individuals were randomly assigned to 10-5-HIIT (n = 17) and 20-10-HIIT (n = 17) groups to complete 6 cycles of 6 exercises, 3 days a week for 4 weeks. The 10-5-HIIT was performed with 10 s:5 s work-to-rest ratio with 1-minute recovery between cycles, while the 20-10-HIIT was performed with 20 s:10 s work-to-rest ratio followed by a 2-minute recovery. Anaerobic (i.e., peak power [PP], anaerobic capacity [AC], anaerobic power [AP], and total work [TW]) and aerobic fitness (i.e., time to exhaustion [TE], absolute V̇o
2max [A-V̇o
2max], relative V̇o
2max [R-V̇o
2max]) were measured with pre-training and post-training intervention. A significant main effect time was observed for both 10-5-HIIT and 20-10-HIIT (p < 0.05) in PP (9.2%, 5.7%); AC (14.9%, 8.6%); AP (9.0%, 6.2%); TW (15.1%, 8.5%); TE (4.3%, 5.5%); A-V̇o
2max (9.4%, 8.9%); R-V̇o
2max (8.5%, 8.2%), respectively. In conclusion, individuals may be able to achieve similar health benefits as 20-10-HIIT by performing 10-5-HIIT, despite exercising for 50% less total time. High-intensity interval training has been suggested as a “time-efficient” mode of exercise that can mitigate the most significant barrier to physical activity, “lack of time.” Both 10-5-HIIT and 20-10-HIIT can induce performance adaptations to a similar extent. However, because of shorter time commitment, performing 10-5-HIIT at 10 s:5 s work-to-rest ratio may offer a shorter and equally efficient interval. Functional fitness training during HIIT protocols seems to be as beneficial as ergometer-based HIIT to improve anaerobic and aerobic performance.