bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase III, randomized, open-label, multicenter, global study of durvalumab and bacillus calmette-guérin (BCG) versus BCG alone in high-risk, BCG-naïve non-muscle-invasive bladder cancer (NMIBC) patients (POTOMAC).
Authors: De Santis Maria , Abdrashitov Ramil , Hegele Axel , Kolb Margaret , Parker Suzanne , Palou Redorta Juan , Nishiyama Hiroyuki , Xiao Feng , Gupta Ashok Kumar , Shore Neal D. 
Published: March 2019

TPS500 Background: Standard of care (SoC) for high-risk NMIBC patients is transurethral resection of the bladder tumor followed by BCG. Although several randomized clinical studies have demonstrated the efficacy of BCG in NMIBC, recurrence rates are as high as 50% in the first 3 yrs of follow up and can be even higher for aggressive histologic subtypes. Immunotherapy agents active in the programmed cell death (PD) pathway responsible for suppressing anti-tumor immunity present an emerging treatment opportunity. In trials treating patients with metastatic urothelial cancer who progressed after platinum-based chemotherapy, response rates doubling those with traditional chemotherapy have been reported for immunotherapies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1). Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with a manageable safety and tolerability profile. PD-L1 inhibition with durvalumab in combination with other immunotherapies, including SoC BCG, may improve response rate and duration of tumor response. Methods: POTOMAC is an open-label, multicenter, global Phase 3 trial enrolling approximately 1,300 patients ≥18 yrs with histologically confirmed high-risk NMIBC who have undergone complete resection of papillary tumors (patients with residual carcinoma in situ [CIS] are eligible) and are BCG-naïve. Of those, approximately 975 patients will be randomized (1:1:1) to durvalumab (1500 mg every 4 wks for 13 cycles) + BCG induction (6x every 1 wk instillation) and 2 yrs of maintenance (3 doses x every 1 wk at 3, 6, 12, 18, and 24 months), durvalumab + BCG (induction only) or BCG (induction and 2 yrs of maintenance). Randomization will be stratified by high-risk papillary disease (Y/N) and CIS (Y/N). The primary endpoint is disease-free survival. Secondary endpoints include proportion of patients alive and disease free at 24 months, overall survival at 5 yrs, pharmacokinetics, immunogenicity, safety and tolerability, and HRQoL. Clinical trial information: NCT03528694.
Alliance A031501: Phase III randomized adjuvant study of MK-3475 (pembrolizumab) in muscle-invasive and locally advanced urothelial carcinoma (MIBC) (AMBASSADOR) versus observation.
Authors: Apolo Andrea B. , Rosenberg Jonathan E. , Kim William Y. , Chen Ronald C. , Sonpavde Guru , Srinivas Sandy , Mortazavi Amir , Watt Colleen , Mallek Marissa , Graap Katherine , Diaz Carlos , Odegaard Meagan , Ballman Karla V. , Morris Michael J. 
Published: March 2019

TPS504 Background: Patients with high-risk MIBC have a poor prognosis. Radical cystectomy remains the standard treatment. Yet despite substantial improvements in surgical techniques, mortality from metastatic recurrence remains high. A large number of MIBC patients are ineligible for cisplatin-based chemotherapy or have persistent muscle-invasive disease despite neoadjuvant chemotherapy (NAC). Pembrolizumab, a PD-1 inhibitor, has demonstrated significant activity and is FDA-approved for patients with advanced/chemotherapy-refractory metastatic urothelial carcinoma. We hypothesize that pembrolizumab given post-cystectomy will improve overall survival (OS) and disease-free survival (DFS) in patients with high-risk MIBC. Methods: Patients must have histologically confirmed muscle-invasive urothelial carcinoma of the bladder or upper tract, have received NAC and have ≥ pT2 and/or pN+ at surgery or be cisplatin-ineligible and have ≥ pT3 and/or pN+ at surgery or have declined adjuvant cisplatin-based therapy and have ≥ pT3 and/or pN+ at surgery. Surgery could be radical cystectomy, nephrectomy, or ureterectomy. Patients are stratified by pathologic stage, central PD-L1 status, and prior NAC. Patients are randomized to receive pembrolizumab 240 mg every 3 weeks for 1 year, or observation. The dual primary objectives are to determine DFS and OS. Secondary objectives are to determine DFS and OS in PD-L1-positive and -negative patients and assess safety. Correlative objectives are to determine whether 12 immune gene signatures, tumor molecular subtypes, diversity of T-cell receptor (TCR) clonotypes, persistence of TCR clonotypes, tumor and neoantigen burden, HLA subtypes, and plasma HGF and VEGF levels with IL-10 and IL-17 are associated with OS and DFS. Quality of Life Correlative objectives are to compare health-related quality of life as assessed by the EORTC QLQ-C30. Clinical trial information: NCT03244384.
Phase II study of apatinib: A novel VEGFR inhibitor in pretreated patients with metastatic penile cancer.
Authors: Zhang Sheng , Liang Fei 
Published: March 2019

TPS538 Background: Apatinib is an oral, highly potent tyrosine-kinase inhibitor targeting VEGFR2 and has been approved as monotherapy for treatment of metastatic gastric cancer in China. This phase II study aims to evaluate the efficacy and safety of apatinib monotherapy in pretreated patients with metastatic penile cancer in China (all patients have failed cisplatin-based chemotherapy previously). Methods: From October 2016 to May 2018, 9 patients were enrolled, and eight patients were eligible for efficacy analysis. All patients received apatinib 500 mg/day p.o. in a 4-week cycle, with the endpoint progression-free survival (PFS). This trial is ongoing. Longer follow-up and complete enrollment are needed for the final efficacy assessment. Clinical trial information: UMIN000021849.
Phase II trial of ixazomib combined with gemcitabine and doxorubicin in patients with SMARCB1-deficient kidney malignancies.
Authors: Msaouel Pavlos , Slack-Tidwell Rebecca , Genovese Giannicola , Daw Najat C. , Siefker-Radtke Arlene O. , Tannir Nizar M. 
Published: March 2019

TPS678 Background: SMARCB1 (also known as INI-1, hSNF5, or BAF47) is a potent tumor suppressor inactivated in all cases of renal medullary carcinoma (RMC) and renal cell carcinoma unclassified with medullary phenotype (RCCU-MP), as well as the majority of malignant rhabdoid tumors (MRT). These highly aggressive malignancies often occur in young patients (pts) and are associated with poor prognosis. There are currently no approved therapies targeting SMARCB1 defects. We previously showed that SMARCB1 loss induces a synthetically lethal vulnerability to perturbations of the cellular proteostasis machinery by proteasome inhibitors (Genovese et al. Nature, 542:362-366, 2017). The present study was designed to determine whether the addition of the second-generation proteasome inhibitor ixazomib to cytotoxic chemotherapy with gemcitabine and doxorubicin (IGD regimen) can improve outcomes of pts with aggressive SMARCB1-deficient kidney malignancies. Methods: This single-arm trial uses the Bayesian optimal phase II (BOP2) design (Heng et al. Stat Med 2017) to determine if the IGD regimen will improve the two co-primary endpoints of objective response rate (ORR) to 50% and 28-week disease control rate (DCR) to 30% compared with the historical ORR and 28-week DCR of 29% and 14%, respectively, achieved using gemcitabine plus doxorubicin alone as first-line or salvage therapy in pts with SMARCB1-negative RMC, RCCU-MP, and adult-onset kidney MRTs treated at our institution. Up to 30 pts aged ≥ 12 years old will be enrolled and any number of prior therapies is allowed. Ongoing monitoring for safety and futility will be implemented in 10-patient cohorts. If both the ORR and DCR improve to 50% and 30%, respectively, then there is only a 3.5% chance of stopping early and a 93.1% chance of claiming that IGD is efficacious. Secondary endpoints include progression-free survival, and overall survival. Tissue correlative analyses will be performed to determine whether tumors from pts responding to IGD have increased levels of endoplasmic reticulum stress markers involved in protein turnover. At the time of the abstract submission, 5 pts have been enrolled on this study. Clinical trial information: NCT03587662.
Phase II study of sitravatinib in combination with nivolumab in patients undergoing nephrectomy for locally-advanced clear cell renal cell carcinoma (ccRCC).
Authors: Karam Jose A. 
Published: March 2019

TPS686 Background: Sitravatinib is a receptor tyrosine kinase inhibitor (RTKI) that targets multiple closely related RTK pathways including VEGFR, PDGFR, KIT, MET and the TAM receptors (TYRO3, AXL and MERTK) Nivolumab is a monoclonal antibody against PD-1 and releases PD-1-mediated inhibition of T-cell proliferation and cytokine production. Together, sitravatinib and nivolumab may cooperate to elicit greater anti-tumor activity than either agent alone, as sitravatinib is predicted to enhance several steps in the cancer immunity cycle that may augment nivolumab’s efficacy. Mechanisms by which sitravatinib may augment an antitumor immune response include enhanced antigen presentation; depletion of immunosuppressive regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) via inhibition of split kinases VEGFR and KIT; and shifting tumor-associated macrophages from an immunosuppressive M2 to a pro-immunogenic M1 phenotype via inhibition of TAM RTKs. Each of these factors converge on promoting T effector cell expansion, tumor infiltration and an antigen-specific anti-tumor immune response. Methods: This open-label, non-randomized, preoperative window of opportunity Phase 2 study evaluates tolerability and clinical activity of sitravatinib in combination with nivolumab in pts with locally-advanced ccRCC undergoing nephrectomy. Study treatment consists of 2 weeks of sitravatinib monotherapy followed by 4 weeks of the combination. Sitravatinib is administered orally daily at 120 mg; nivolumab intravenously every 2 weeks at 240 mg. The primary objective is to evaluate clinical activity using percentage of pts achieving a presurgical point-in-time objective response. Secondary objectives include evaluation of safety and tolerability, and determination of the immune effects of sitravatinib monotherapy and the combination through serial tissue and blood collections (temporal changes in PD-L1 expression, selected cytokines and immune cell populations including MDSCs, Tregs and ratio of M1:M2 macrophages). The study is open for enrollment and recruitment is ongoing. Clinical trial information: NCT03680521.
Kidney micro-organoids in suspension culture as a scalable source of human pluripotent stem cell-derived kidney cells
Authors: Kumar Santhosh V. , Er Pei X. , Lawlor Kynan T. , Motazedian Ali , Scurr Michelle , Ghobrial Irene , Combes Alexander N. , Zappia Luke , Oshlack Alicia , Stanley Edouard G. , Little Melissa H. 
Published: March 2019

ABSTRACT
Kidney organoids have potential uses in disease modelling, drug screening and regenerative medicine. However, novel cost-effective techniques are needed to enable scaled-up production of kidney cell types in vitro. We describe here a modified suspension culture method for the generation of kidney micro-organoids from human pluripotent stem cells. Optimisation of differentiation conditions allowed the formation of micro-organoids, each containing six to ten nephrons that were surrounded by endothelial and stromal populations. Single cell transcriptional profiling confirmed the presence and transcriptional equivalence of all anticipated renal cell types consistent with a previous organoid culture method. This suspension culture micro-organoid methodology resulted in a three- to fourfold increase in final cell yield compared with static culture, thereby representing an economical approach to the production of kidney cells for various biological applications.
Single cell transcriptomics reveals spatial and temporal dynamics of gene expression in the developing mouse spinal cord
Authors: Delile Julien , Rayon Teresa , Melchionda Manuela , Edwards Amelia , Briscoe James , Sagner Andreas 
Published: March 2019

ABSTRACT
The coordinated spatial and temporal regulation of gene expression in the vertebrate neural tube determines the identity of neural progenitors and the function and physiology of the neurons they generate. Progress has been made deciphering the gene regulatory programmes that are responsible for this process; however, the complexity of the tissue has hampered the systematic analysis of the network and the underlying mechanisms. To address this, we used single cell mRNA sequencing to profile cervical and thoracic regions of the developing mouse neural tube between embryonic days 9.5-13.5. We confirmed that the data accurately recapitulates neural tube development, allowing us to identify new markers for specific progenitor and neuronal populations. In addition, the analysis highlighted a previously underappreciated temporal component to the mechanisms that generate neuronal diversity, and revealed common features in the sequence of transcriptional events that lead to the differentiation of specific neuronal subtypes. Together, the data offer insight into the mechanisms that are responsible for neuronal specification and provide a compendium of gene expression for classifying spinal cord cell types that will support future studies of neural tube development, function and disease.
Sports Contribute to Total Moderate to Vigorous Physical Activity in School Children
Authors: SPRENGELER OLE , BUCK CHRISTOPH , HEBESTREIT ANTJE , WIRSIK NORMAN , AHRENS WOLFGANG 
Published: March 2019

ABSTRACT

Introduction
A third of all children spend at least 60 min·d−1 in moderate to vigorous physical activity (MVPA) as recommended by the World Health Organization. We investigated the distribution of objectively measured physical activity (PA) intensities achieved by schoolchildren during physical education (PE) and organized youth sports (OYS) and the contribution of PE and OYS to the achievement of the PA recommendations.

Methods
In two surveys, PA of 396 children was measured using accelerometry during typical school weeks. Proportions (%) of sedentary behavior, light PA, and MVPA per day and particularly during sports were assessed in children 6–17 yr old. Adjusted odds ratios (AOR) were calculated to analyze the association between frequency (d·wk−1) and duration (min·wk−1) of PE and OYS and meeting the PA recommendations.

Results
Average proportions of MVPA during PE and OYS ranged between 15% and 31%. Between 68% and 74% of children (6–10 yr) and between 27% and 37% of adolescents (11–17 yr) met the PA recommendations. In both age-groups, PE and OYS on at least 2 d·wk−1 were both significantly associated with meeting the PA recommendations (AOR for PE = 3.60, 95% confidence interval [CI] = 2.05–6.31; AOR for OYS = 3.83, 95% CI = 2.09–6.99), compared with no PE or no OYS in that week. Likewise, significant AOR values were found for >90 min of PE per week (AOR = 3.48, 95% CI = 2.03–5.98) and >120 min of OYS per week (AOR = 3.72, 95% CI = 2.01–6.89), compared with no PE or no OYS in that week, respectively.

Conclusion
Schoolchildren spent less than one-third of PE and OYS in MVPA. PE and OYS were found to support children and adolescents to engage sufficiently in MVPA as recommended by the World Health Organization.
Persistent Impairment in Cardiopulmonary Fitness after Breast Cancer Chemotherapy
Authors: FOULKES STEPHEN J. , HOWDEN ERIN J. , BIGARAN ASHLEY , JANSSENS KRISTEL , ANTILL YOLAND , LOI SHERENE , CLAUS PIET , HAYKOWSKY MARK J. , DALY ROBIN M. , FRASER STEVE F. , LA GERCHE ANDRE 
Published: March 2019

ABSTRACT

Purpose
Anthracycline chemotherapy (AC) is associated with acute reductions in cardiopulmonary fitness (V˙O2peak). We sought to determine whether changes in V˙O2peak and cardiac function persisted at 12 months post-AC completion, and whether changes in cardiac function explain the heightened long-term heart failure risk.

Methods
Women with breast cancer scheduled for AC (n = 28) who participated in a nonrandomized trial of exercise training (ET; n = 14) or usual care (UC; n = 14) during AC completed a follow-up evaluation 12 months post-AC completion (16 months from baseline). At baseline, 4 months, and 16 months, participants underwent a resting echocardiogram (left ventricular ejection fraction; global longitudinal strain), a blood sample (troponin; B-type natriuretic peptide), a cardiopulmonary exercise test, and cardiac MRI measures of stroke volume (SV), heart rate, and cardiac output (Qc) at rest and during intense exercise.

Results
Seventeen women (UC, n = 8; ET, n = 9) completed evaluation at baseline, 4 months, and 16 months. At 4 months, AC was associated with 18% and 6% reductions in V˙O2peak in the UC and ET groups, respectively, which persisted at 16 months (UC, −16%; ET, −7%) and was not attenuated by ET (interaction, P = 0.10). Exercise Qc was lower at 16 months compared with baseline and 4 months (P < 0.001), which was due to a blunted augmentation of SV during exercise (P = 0.032; a 14% reduction in peak SV), with no changes in heart rate response. There was a small reduction in resting left ventricular ejection fraction (baseline to 4 months) and global longitudinal strain (between 4 and 16 months) and an increase in troponin (baseline to 4 months), but only exercise Qc was associated with V˙O2peak (R
2 = 0.47, P < 0.01).

Conclusion
Marked reductions in V˙O2peak persisted 12 months after anthracycline-based chemotherapy, which was associated with impaired exercise cardiac function.

Clinical Trial Registration: ACTRN12616001602415.
The prevalence and impacts heavy menstrual bleeding on anemia, fatigue and quality of life in women of reproductive age
Authors: Kocaoz Semra , Cirpan Rabiye , Degirmencioglu Arife Zuhal 
Published: March 2019

Objectives: To investigate the prevalence and impacts of heavy menstrual bleeding (HMB) on anemia, fatigue, and the quality of life (QoL) in women of reproductive age.
Methods: This study was conducted among 306 women of reproductive age who presented at the internal medicine outpatient departments of the training and research hospital of a university. The data of the study were collected by the “Data collection form”, “SF-36 Quality of Life Scale (SF-36 QoLS)” and “Brief Fatigue Inventory (BFI)”.
Results: The prevalence of HMB in women of reproductive age was 37.9%. The ferritin level and physical functions were found to decrease significantly as the duration of menstruation increased (p<0.05). Besides, a positive but very weak relationship was found between the menstruation duration and the subdimensions of the global BFI and the general health perception subscale of the SF-36 QoLS (p<0.05).
Conclusion: It was determined that HMB is common and has negative effects on anemia, fatigue and some subdimensions of the QoL. Regular screening for HMB that may not be expressed by many women may therefore be useful in preventing and resolving the health problems that it will cause.
How to cite this:Kocaoz S, Cirpan R, Degirmencioglu AZ. The prevalence and impacts heavy menstrual bleeding on anemia, fatigue and quality of life in women of reproductive age. Pak J Med Sci. 2019;35(2):365-370. doi: https://doi.org/10.12669/pjms.35.2.644
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Investigating gateway effects using the PATH study
Authors: Lee Peter , Fry John 
Published: March 2019

Background: A recent meta-analysis of nine cohort studies in youths reported that baseline ever e-cigarette use strongly predicted cigarette smoking initiation in the next 6-18 months, with an adjusted odds ratio of 3.62 (95% confidence interval 2.42-5.41). A recent review of e-cigarettes agreed there was substantial evidence for this “gateway effect”. However, the number of confounders considered in the studies was limited, so we investigated whether the effect might have resulted from inadequate adjustment, using Waves 1 and 2 of the Population Assessment of Tobacco and Health study. Methods: Our main analyses considered Wave 1 never cigarette smokers who, at Wave 2, had information available on smoking initiation. We constructed a propensity score for ever e-cigarette use from Wave 1 variables, using this to predict ever cigarette smoking. Sensitivity analyses accounted for use of other tobacco products, linked current e-cigarette use to subsequent current smoking, or used propensity scores for ever smoking or ever tobacco product use as predictors. We also considered predictors using data from both waves to attempt to control for residual confounding from misclassified responses. Results: Adjustment for propensity dramatically reduced the unadjusted odds ratio (OR) of 5.70 (4.33-7.50) to 2.48 (1.85-3.31), 2.47 (1.79-3.42) or 1.85 (1.35-2.53), whether adjustment was made as quintiles, as a continuous variable or for the individual variables. Additional adjustment for other tobacco products reduced this last OR to 1.59 (1.14-2.20). Sensitivity analyses confirmed adjustment removed most of the gateway effect. Control for residual confounding also reduced the association. Conclusions: We found that confounding is a major factor, explaining most of the observed gateway effect. However, our analyses are limited by small numbers of new smokers considered and the possibility of over-adjustment if taking up e-cigarettes affects some predictor variables. Further analyses are intended using Wave 3 data which should avoid these problems.