bluuebunny/crossref_metadata_2025 huggingface dataset:
Design of phase Ib/II study of oral VERU-111, an α and β-tubulin inhibitor, for the treatment of metastatic castration- and androgen-blocking-agent-resistant prostate cancer.
Authors: Markowski Mark Christopher , Eisenberger Mario A. , Antonarakis Emmanuel S. , Yu Evan Y. , Barnette Gary , Rodriguez Domingo , Getzenberg Robert H. , Steiner Mitchell S.
Published: March 2019

TPS330

Background: VERU-111 is a novel oral small molecule (NCE) that targets α and β-tubulin subunits of microtubules resulting in the inhibition of tubulin polymerization. Agents that target microtubules are among the most effective for the treatment of metastatic cancers. However, these currently available agents target only the β-tubulin subunit and are administered IV. VERU-111 has high oral bioavailability and does not interact with MDR proteins. In nonclinical models, VERU-111 has high activity against many tumor types as well as against prostate cancers that have become resistant to taxanes and novel androgen blocking agents (abiraterone and enzalutamide). In 28-day dog and rat toxicity studies, no neutropenia, myelosuppression, or liver function test changes were observed at oral daily doses in blood concentrations that resulted in antitumor activity in preclinical models. Based on these unique properties, VERU-111 has advanced into a Phase1b/2 clinical trial. Methods: V1011101 is a Phase 1b/2 study, being conducted in at least three sites in the US, evaluating the safety and preliminary efficacy of VERU-111 in men with metastatic castration and androgen blocking agent resistant prostate cancer (mCARPC). The Phase 1b portion of the study consists of 21-day cycles where VERU-111 is taken daily, orally for 7-days followed by a 14-day hiatus (dose cycle). Safety/tolerability of VERU-111 and MTD of VERU-111 will be determined. The Phase 2 will use the selected dose cycle from the Phase 1b and the primary endpoint will be the PSA50 response rate, defined as a decline in PSA to > 50% of baseline level, confirmed with a second measurement at least 3 weeks apart (PCWG3) and determine the pharmacokinetic profile of VERU-111. The secondary endpoints include determining the safety/tolerability of VERU-111 as defined as incidence of CTCAE v5.0 grade ≥3 toxicities; estimating the median PSA progression-free survival (PCWG3); estimating the median progression-free survival (PCWG3); and estimating the objective response rate. It is anticipated that based upon the Phase 1b/2 clinical findings VERU-111 will also be expanded into other cancer types.
Modulation of plasma lipidomic signature in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Mak Blossom , Mahon Kate Lynette , Stockler Martin R. , Joshua Anthony M. , Zhang Alison Yan , Parnis Francis , Meikle Peter , Horvath Lisa
Published: March 2019

TPS331

Background: Altered lipid metabolism and its impact on prostate cancer (PC) is increasingly recognised, in light of the association between obesity and worse PC outcomes. Our exploratory study was the first to identify baseline plasma lipidomic profiles in men with mCRPC commencing docetaxel that were associated with survival. A prognostic three-lipid signature was derived, consisting of ceramide, sphingomyelin and phosphatidylcholine (HR 4.8, 95% CI 2.06-11.1, p = 0.0003). This signature was independently prognostic when modelled with clinicopathological factors and metabolic characteristics. A key question is whether therapeutic modulation of a patient’s lipid profile is possible. Statins significantly reduce the plasma levels of ceramides, sphingomyelin and cholesterol in cardiovascular disease, suggesting that this therapy could change the poor prognostic lipid profile of mCRPC patients. This trial assesses whether addition of simvastatin to docetaxel for mCRPC can reverse the poor prognostic lipid signature with the aim of developing a precision medicine strategy for metabolic targeting. Methods: This investigator-initiated, multi-centre, open-label, single arm, pilot study enrols patients with mCRPC commencing docetaxel for disease progression, not already receiving a lipid-lowering agent. Patients are treated with simvastatin 40mg orally once daily for 12 weeks, commencing on day 1 of the first cycle of docetaxel. Blood is taken at baseline and after 12 weeks of simvastatin and the plasma lipidomic profile is determined using liquid chromatography and electrospray ionisation-tandem mass spectrometry. The lipidomic profile is classified as either good or poor prognostic as per our three-lipid signature model derived by logistic regression. The primary objective is to assess the rates of conversion from a poor prognostic lipid signature to good prognostic after simvastatin. A sample size of 60 men provides over 90% power, with a 1-sided type 1 error of 10%, to detect conversion to the good prognostic signature in 50% of patients, assuming 25% of patients have the poor prognostic signature at baseline as previously detected. To date, 6 patients have been enrolled to the trial. Clinical trial information: ACTRN12617000965303.
Evaluating the clinical, environmental, genetic, and genomic profile of men with early-onset aggressive prostate cancer (PCa).
Authors: Zarzour Ahmad , Morgans Alicia K. , Palmbos Phillip Lee , Jovanovic Borko , Tomlins Scott A. , VanderWeele David James , Yang Ximing J , Schaeffer Edward M. , Sharifi Roohollah , Meeks Joshua J , Abdulkadir Sarki , Hussain Maha H. A.
Published: March 2019

TPS333

Background: Although PCa incidence has stabilized or decreased in most age groups, the incidence of metastatic disease has increased among men 50-69 years old. The incidence of fatal PCa has decreased for most age groups, it has remained unchanged in men under 55 years old. These observations are supported by data from 3 randomized trials. In S9346 in newly diagnosed M1, 18% of men (all-comers N = 3040) were ≤ 60 years. A significant percentage of younger men enrolled in CHAARTED had de-novo metastases at diagnosis; among 575 patients without prior local therapy, the median age was 62 years, and among men < 60 years old (n = 274), 80.3% (n = 220) had de novo metastatic disease. Lastly, in S9921 (N = 983) 15% of men ≤ 60 years had pN1 disease at enrollment. A significant proportion of men with metastatic disease progress to castration -resistance within a short interval of initiating androgen-deprivation therapy (ADT) ± docetaxel or abiraterone for metastatic hormone sensitive PCa. Pivotal studies have described genetic abnormalities in aggressive localized or end stage prostate cancers, but early-onset cases and those with early progression on systemic therapy are not included or are under-represented in these studies. Methods: The primary objective of this multi-institutional trial is to characterize the clinical, environmental, genetic and genomic features of high-risk advanced PCa: Cohort 1: men ≤ 60 years old with N1 or M1 at diagnosis or who develop metastases shortly after local therapy; Cohort 2: men with early progression to castration-resistant PCa in ≤ 1 year on ADT ± docetaxel or ADT ± abiraterone. Clinical and environmental history, peripheral blood for cell free DNA and germline analysis will be collected. Primary/metastatic tumor tissue will be tested via the Tempus platform, which includes DNA sequencing, whole transcriptome expression profiling, copy number analysis, comprehensive fusion gene analysis and calculation of tumor mutational burden. We will also prospectively correlate clinical and molecular characteristics with outcomes. To date, 5 patients have been registered.
ODENZA: A study of patient preference between ODM-201 (darolutamide) and enzalutamide in men with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Martineau Geraldine , Foulon Stéphanie , Baciarello Giulia , Joly Florence , Delva Remy , Barthelemy Philippe , Neuzillet Yann , Priou Franck , Hue Anne Sophie , Fizazi Karim
Published: March 2019

TPS334

Background: In recent years, the treatment of mCRPC has evolved and next-generation androgen receptor (AR)-axis targeting drugs (enzalutamide (ENZ), and abiraterone) have been approved and are routinely used. Darolutamide (DARO) is a new next-generation AR inhibitor which has shown strong activity and minimal toxicity in two phase I-II trials ARADES (Fizazi, Lancet Oncol 2014) and ARAFOR (Massard, Eur Urol 2016) and is currently evaluated in a study in men with non-metastatic CRPC (ARAMIS trial). In contrast to ENZ, DARO does not significantly penetrate the blood-brain barrier in vivo, and this may reduce the risk of fatigue, cognitive impairment, and seizure. Assessing patient preference between DARO and ENZ may contribute further differentiating between these two agents. Methods: ODENZA is a prospective, randomized, open-label, multicenter, cross-over phase II trial assessing patient preference between DARO and ENZ. It was initiated in November 2017. Eligibility criteria include: men with asymptomatic or mildly symptomatic mCRPC, performance status 0-1, no prior next generation AR axis-targeted agent. The randomization is stratified on performance status and prior treatment with a taxane for CSPC. 250 patients will be randomized 1:1 to: 12-week ENZ followed by 12-week DARO or 12-week DARO followed by 12-week ENZ. The primary endpoint is patient preference between DARO and ENZ, assessed after the second treatment period. A two-sided binomial test with a power of 80% and a bilateral α of 0.05 will be used. Secondary endpoints include: reasons for patient preference, dose modifications and time to dose modification, safety, fatigue (BFI), cognitive function as assessed by Cogstate computerized cognitive tests, depression screening (CES-D) test, frequency of falls, PSA declines using Waterfall plots after each treatment period, Progression-Free Survival (PFS), association between 4-weeks PSA value and PFS, incidence of cancer progression or death, and tumor response. The study is recruiting. By October 23, 2018, 75 patients have been screened and 66 have been randomized. Clinical trial information: NCT03314324.
ProSTAR: A phase Ib/II study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Taplin Mary-Ellen , Hussain Arif , Shah Satish , Shore Neal D. , Agrawal Manish , Clark William , Edenfield William Jeffery , Nordquist Luke T. , Sartor Oliver A , Butrynski James E. , Chatta Gurkamal S. , Fleming Mark T. , Oh William K. , Bradley Bill , Piel Jessica , Nash David , Colak Gozde , Li Jian , Lebedinsky Claudia , Antonarakis Emmanuel S.
Published: March 2019

TPS335

Background: EZH2 is frequently mutated and/or overexpressed in numerous cancers. High EZH2 expression is correlated with poor outcomes in prostate cancer patients (Varambally, 2002). EZH2 inhibition combines synergistically with anti-androgen therapies in preclinical models of advanced prostate cancer, suggesting epigenetic reprogramming as a pathophysiologic mechanism to enhance the combination therapy (Ku, 2017; Xiao 2018; Constellation, unpublished). CPI-1205 is a potent, selective, and cofactor-competitive inhibitor of wild type and mutant EZH2 catalytic activity, which demonstrates anti-proliferative effects in prostate and other cancer cell models. Methods: We present a Phase 1b/2 multicenter study of CPI-1205 combined with either E or A/P in patients with mCRPC, which includes phase 1 dose escalation, an expansion cohort in heavily pretreated patients (HPEC), and a randomized phase 2 study. Key eligibility criteria include progressive mCRPC in patients previously treated with a second-generation androgen inhibitor, ECOG 0-1, and measurable or non-measurable disease. During the phase 1b, patients will receive CPI-1205 continuously in 28-day cycles combined with the standard dose of either E (160mg PO once daily) or A/P (1000mg PO once daily/5 mg BID). The primary objective in Phase 1b is to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of CPI-1205 combined with either E or A/P. Secondary objectives include safety, pharmacokinetic and pharmacodynamic profiles, and anti-tumor activity. The HPEC arm, with Simon’s 2-stage design, may begin with the regimen that is deemed safe by the study safety committee. The primary endpoint of the HPEC arm is objective response rate (ORR) per PCWG3, with a requirement ≥ 1 measurable lymph node at baseline. Once RP2D is established, we will start a randomized Phase 2 trial of E or A/P combined with CPI-1205 vs. E or A/P alone. The co-primary endpoint includes PSA50 and composite response rate (either CTC 30% reduction or ORR per PCWG3). Patient accrual in US sites began in December 2017. Clinical trial information: NCT03480646.
A phase II, multicenter, single-arm trial of CV301 plus atezolizumab (Atezo) in locally advanced (unresectable) or metastatic urothelial cancer (UC).
Authors: Sonpavde Guru , Maughan Benjamin Louis , Wei Xiao X. , McGregor Bradley Alexander , Kilbridge Kerry L. , Lee Richard J. , Yu Evan , Schweizer Michael Thomas , Montgomery Robert B. , Cheng Heather H. , Hsieh Andrew Caleb , Birhiray Ruemu E. , Gabrail Nashat Y. , Nemunaitis John J. , Rezazadeh Arash , Van Veldhuizen Peter J. , Vogelzang Nicholas J. , Heery Christopher Ryan , Grivas Petros
Published: March 2019

TPS494

Background: Anti-PD1/PD-L1 can achieve durable responses in advanced UC but most patients (pts) do not respond. Combination strategies with agents that “prime” the immune system may improve outcomes. CV301 comprises two recombinant poxviruses, Modified Vaccinia Ankara (MVA) and Fowlpox (FPV), encoding the human transgenes for CEA, MUC-1, and a Triad of Co-stimulatory Molecules (TRICOM: ICAM-1, LFA-3, and B7-1). MVA-CV301 is used for priming doses and FPV-CV301 is used for booster doses to achieve a heterologous prime boost regimen. In preclinical studies, BN-platform vaccine plus PD1/PD-L1 inhibitors exhibited synergistic anti-tumor efficacy, T-cell infiltration, and PD-L1 upregulation in tumors. CEA and MUC-1 are expressed, in 41-90% and 55-91% of any stage UC, respectively, and in ~100% of metastatic UC. An ongoing Phase Ib trial of CV301 plus anti-PD-1 agent has demonstrated a similar safety profile to anti-PD-1 monotherapy with only mild vaccine-related adverse events (AEs). Methods: This is a Phase 2, single-arm, multi-institutional trial designed to study CV301 plus atezo as 1st-line treatment in pts with advanced UC ineligible for cisplatin-based chemotherapy regardless of PD-L1 (Cohort 1) and as salvage treatment in pts with UC progressing after platinum-based chemotherapy (Cohort 2). MVA-CV301 is given subcutaneously (SC) on Days 1 and 22 and FPV-CV301 SC every 21 days for 4 doses, then every 6 weeks until 6 months, then every 12 weeks until 2 years. Atezo 1200mg is given every 21 days. Primary endpoint is objective response rate (ORR; RECIST 1.1). Secondary endpoints: immune response, OS, PFS, response duration, AEs. Tumor and serial blood samples will be collected for biomarker analyses; 1-sided α is 0.025/cohort in this design. With a 2-stage design, success criteria are based on historic ORR (H0) and alternative ORR (H1) with ≥70% power. For Cohort 1, assuming H0 = 0.23, H1 = 0.43, then Cohort 1 sample size N1= 14, responders required at stage 1 to continue R1≥3, total accrual goal N = 33, total responders to reject H0, R≥13. For Cohort 2, assuming H0 = 0.15, H1 = 0.33, then N1= 13, R1≥2, N = 35, R≥10. Accrual has begun; completion is expected within 1 year. Clinical trial information: NCT03628716.
ATLAS: A phase II open-label study of rucaparib in patients with locally advanced or metastatic urothelial carcinoma (mUC).
Authors: Grivas Petros , Vogelzang Nicholas J. , Alva Ajjai Shivaram , Feyerabend Susan , Loriot Yohann , Necchi Andrea , Gupta Sumati , Josephs Debra Hannah , Rodriguez-Vida Alejo , Srinivas Sandy , Zakharia Yousef , Wride Kenton , Thomas Daleen , Dusek Rachel , Simmons Andrew , Nepert Dale L. , Chowdhury Simon
Published: March 2019

TPS496

Background: There are currently no standard treatment options for patients with mUC that has progressed on or after platinum (cisplatin/carboplatin)–based chemotherapy (PBC) and/or immune checkpoint inhibitors (ICIs), emphasizing the need for new therapies. Analysis of The Cancer Genome Atlas bladder cancer dataset suggests that approximately 60% of bladder cancer tumors have homologous recombination deficiency (HRD), as defined by high genomic loss of heterozygosity (LOH) or a deleterious mutation in a homologous recombination pathway gene. The poly(ADP-ribose) polymerase inhibitor (PARPi) rucaparib has demonstrated activity in tumors with HRD and in homologous recombination proficient tumors in the recurrent ovarian cancer setting. The ATLAS (NCT03397394) trial will evaluate the efficacy and safety of rucaparib in patients with locally advanced/unresectable UC or mUC treated with 1–2 prior anticancer treatments. Methods: Eligible patients must have measurable disease per RECIST v1.1, adequate organ function, and radiographic progression after 1–2 prior regimens (eg, PBC and/or ICI). Confirmation of HRD status before enrollment is not required, but fresh tumor tissue or recently obtained archival tissue is mandatory for HRD profiling. Prior PARPi treatment is exclusionary. All patients will receive oral rucaparib 600 mg BID until disease progression or other reason for discontinuation. The coprimary endpoints are confirmed objective response rate (investigator-assessed per RECIST v1.1) in the intent-to-treat and HRD-positive (signature based on tumor genomic LOH) populations. Secondary endpoints include response duration, progression-free survival, overall survival, safety, and pharmacokinetics. Exploratory endpoints include evaluation of molecular biomarkers associated with response and resistance to rucaparib, including changes in plasma and tumor samples, and circulating tumor DNA. Patients are being enrolled in 6 countries (France, Germany, Italy, Spain, UK, and USA), with a target enrollment of 200 patients. The study has > 90% power to reject the null hypothesis (P = 0.10) at a 5% significance level if the true response rate for rucaparib is 20%. Clinical trial information: NCT03397394.
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

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

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.
Morph- and sex-specific effects of challenging conditions on maintenance parameters in the Gouldian finch
Authors: Fragueira Rita , Verhulst Simon , Beaulieu Michaël
Published: March 2019

Intraspecific discrete polymorphism is associated with the use of alternative life-history strategies, reflected by distinct reproductive or copying strategies in individuals of different morphs. Yet, morph-specific costs and benefits related to different life-history strategies remain unclear. Here, we examined in the polymorphic Gouldian finch (Erythrura gouldiae) whether markers of somatic maintenance (body mass, oxidative status, telomere length) differed between red- and black-headed birds under energetically-demanding conditions (during heatwaves of different intensity, and during moult or breeding following heatwaves). During heatwaves, red-headed birds showed a homogeneous response, as males and females initially tended to gain mass and reduced plasma hydroperoxide levels (a marker of oxidative damage) irrespective of heatwave intensity. In contrast, black-headed birds showed a stronger and more heterogeneous response, as black-headed males gained mass at the beginning of the thermoneutral heatwave and showed stable oxidative status, while black-headed females lost mass and tended to show higher hydroperoxide levels at the end of the thermocritical heatwave. Following heatwaves, we found morph-specific oxidative costs due to moult or reproduction, with oxidative markers varying only in black-headed birds. Again, oxidative markers varied differently in black-headed males and females, as plasma antioxidant capacity decreased in moulting or breeding females, while males showed higher hydroperoxide levels with larger broods. For the first time, our study highlights that within polymorphic species, some individuals appear more vulnerable than others when coping with energetically-demanding conditions. In the context of climate change, such differential effects may ultimately alter the currently-observed balance between morphs and sexes within natural populations.
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

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

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.
Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Burkina Faso: an open label trial
Authors: Birgersson Sofia , Valea Innocent , Tinto Halidou , Traore-Coulibaly Maminata , Toe Laeticia C. , Hoglund Richard M. , Van Geertruyden Jean-Pierre , Ward Stephen A. , D’Alessandro Umberto , Abelö Angela , Tarning Joel
Published: March 2019

Background: Malaria during pregnancy is a major health risk for both the mother and the foetus. Pregnancy has been shown to influence the pharmacokinetics of a number of different antimalarial drugs. This might lead to an under-exposure in these patients which could increase the risk of treatment failure and the development of drug resistance. The study aim was to evaluate the pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant patients using a population modelling approach.

Methods: Twenty-four women in their second and third trimester of pregnancy and twenty-four paired non-pregnant women, all with uncomplicated P. falciparum malaria, were enrolled in this study. Treatment was a fixed-dose combination of oral artesunate and mefloquine once daily for three days. Frequent blood samples were collected and concentration-time data for artesunate and dihydroartemisinin were analysed simultaneously using nonlinear mixed-effects modelling.

Results: Artesunate pharmacokinetics was best described by a transit-compartment absorption model followed by a one-compartment disposition model under the assumption of complete in vivo conversion of artesunate into dihydroartemisinin. Dihydroartemisinin pharmacokinetics was best described by a one-compartment disposition model with first-order elimination. Pregnant women had a 21% higher elimination clearance of dihydroartemisinin, compared to non-pregnant women, resulting in proportionally lower drug exposure. In addition, initial parasitaemia and liver status (alanine aminotransferase) were found to affect the relative bioavailability of artesunate.

Conclusions: Results presented here show a substantially lower drug exposure to the antimalarial drug dihydroartemisinin during pregnancy after standard oral treatment of artesunate and mefloquine. This might result in an increased risk of treatment failure and drug resistance development, especially in low transmission settings where relative immunity is lower.

Trial registration: ClinicalTrials.gov NCT00701961 (19/06/2008)
DfE pledges £6m support fund for RSE and health education
Authors: Henshaw Pete
Published: March 2019

After a three-month consultation, revised statutory guidance sets out content for RSE and health education from September 2020
DESARROLLO DE COMPETENCIAS SOCIOEMOCIONALES EN EDUCACIÓN SUPERIOR: EVALUACIÓN DEL POSGRADO EN EDUCACIÓN EMOCIONAL
Authors: Pérez-Escoda Núria , Berlanga Silvente Vanesa , Alegre Rosselló Albert
Published: March 2019

INTRODUCCIÓN. Los requerimientos para la inserción laboral de los egresados universitarios exigen a las instituciones de educación superior el desarrollo tanto de competencias específicas propias de cada titulación, como de competencias transversales con alto valor en el mercado. Sin embargo, es todavía escasa la introducción de estas competencias en los grados y másteres oficiales. No obstante, en los últimos años se ha producido una creciente demanda de formación en competencias personales que ha propiciado la aparición de diversos posgrados y másteres propios en las universidades españolas. En este trabajo se estudia la eficacia del posgrado en Educación Emocional y Bienestar en el desarrollo de las competencias socioemocionales de sus estudiantes. MÉTODO. Se utilizó un diseño cuasiexperimental con medidas repetidas pretest-postest con grupo control. La muestra es de 503 adultos, 288 del grupo experimental y 215 del grupo control con características semejantes. Se utilizan dos instrumentos: el Cuestionario de Desarrollo Emocional (CDE-A) que evalúa la competencia emocional total y cada una de sus dimensiones, y el test situacional G basado en un caso práctico que mide la comprensión emocional y la respuesta cognitiva y conductual con la que se afronta una situación conflictiva. RESULTADOS. Los resultados del contraste de medias (t-Student) muestran mejoras significativas en la competencia emocional total y en cada una de las dimensiones al final del posgrado. El tamaño del efecto muestra que los cambios son de una magnitud importante en todas las dimensiones. Del estudio cualitativo se desprende que la intervención permite mejorar la precisión en la identificación de las emociones, aumentar el patrón de pensamientos reguladores y las conductas asertivas. DISCUSIÓN. Todo ello permite concluir que el desarrollo de las competencias transversales en educación superior es posible y necesario para la formación de profesionales cualificados.
The politics of rhetoric: Re-membering and re-narrating ‘bodily’ resistances in Rabijita Gogoi’s plays
Authors: Pathak Namrata
Published: March 2019

Orality can be termed as a ‘live experience’ of rhetoric, which enables the listener to engage with what is being said. Within the framework of oral culture, memory can serve as a tool of potent interaction and subversive tendencies to expose exploitative urges and also to produce contrary effects. Memory supplanted with rhetoric, the power of language and arguments, can respond to the situation of the oppressed. The role of rhetoric in motivating action can also take us to a world of verbal and symbolic narratives of politics. In performances like Rongphorpi Rongbe and Gaantha: The First Text, the performative of rhetoric not only offers subversive approach to history/history-making but also provides opportunity for the evocation of the past in an animated language that delivers activism and campaigns for a political reform.
Human Garden Being in Relax Empty Axis/Empty Space with Suprapto Suryodarmo
Authors: Baxter Paul , Suryodarmo Suprapto
Published: March 2019

Following his keynote workshop at the Dance and Somatic Practices Conference at Coventry University in July 2017, Prapto was interviewed a month later during a workshop in Amsterdam, by Paul Baxter and Sandra Reeve. During the interview Prapto reflects upon his experience in Coventry, his concept of Human Garden Being and the meaning of his movement work.