bluuebunny/crossref_metadata_2025 huggingface dataset:
The contribution of germline DNA damage response mutations on prostate cancer risk and prognosis: A UK Biobank whole-exome analysis.
Authors: Camacho Niedzica , Matakidou Athena
Published: March 2021

67

Background: Germline mutations in DNA Damage Response (DDR) genes such as BRCA2 and ATM have been associated with prostate cancer risk and aggressiveness. These associations are largely based on studies that ascertain for cancer diagnosis and family history and provide risk estimates with limited population-level accuracy. Here we evaluate the clinical significance of germline pathogenic variants in 20 DDR genes and a high-risk susceptibility coding variant in HOXB13 using whole exome sequences from (1) the UK Biobank (UKBB), a population-based cohort (300,000 participants) and (2) patients recruited in AZ clinical trials. Methods: Whole exomes from 6,987 prostate cancer patients (5,921 UKBB and 1,066 AZ) and 88,499 cancer-free males were analysed. Known and novel pathogenic variants were identified and associations with disease risk, age of onset, family history, response to hormonal therapy and overall survival were estimated (multiplicity corrected P value < 0.005). Results: HOXB13 G48E (1.36%), ATM (1.03%) and BRCA2 (0.99%) were the largest contributors to prostate cancer risk, each conferring an increase of ~4-fold, followed by CHEK2 with a moderate contribution (0.46%). No significant contributions to prostate cancer risk were observed for any of the other genes analysed. Family history of prostate cancer was not significantly enriched in any of the gene subpopulations of prostate cancer carriers and compared with non-carriers, there was no significant difference in the median age of disease onset. Analysis of clinical outcomes showed that BRCA2 carriers had a 4-fold increased risk of death (Cox PH HR p = 4.11E-12) and poorer overall survival (Log-Rank p = 4.60E-14), with 88% dying from prostate cancer compared to 49% of non- BRCA2 carriers (UKBB analysis). BRCA2 pathogenic mutations were also associated with early failure to hormonal therapy (Cox PH HR 2.38; p = 9.48E-04; AZ cohort analysis). HOXB13, ATM and CHEK2 mutations were not significantly associated with clinical outcomes. Conclusions: This is the largest study to date providing population-based estimates of prostate cancer risk and prognosis, highlighting BRCA2 carriers as a population in clinical need of early identification and targeted intervention. Updated analyses with data from the full 450,000 UKBB participants (9,000 prostate cancers) will be presented.
Adiposity and response to androgen signaling inhibition (ASI) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hahn Andrew Warren , Tidwell Rebecca , Surasi Devaki Shilpa , Pilie Patrick Glen , Frigo Daniel , Subudhi Sumit Kumar , Efstathiou Eleni , Zurita Amado J. , Tu Shi-Ming , Chapin Brian Francis , Fogelman David R. , Starbuck Michael W , Corn Paul G. , Aparicio Ana , McQuade Jennifer Leigh , Logothetis Christopher
Published: March 2021

72

Background: Improved understanding of how host factors influence the efficacy and toxicity of ASI could improve outcomes. Adiposity increases the risk for recurrence and lethal disease in men with localized prostate cancer. Few studies have evaluated the influence of adiposity in metastatic prostate cancer, and in these studies, adiposity was associated with improved outcomes, a potential “obesity paradox”. Herein, we assess whether adiposity is associated with response to maximal ASI in mCRPC and assess how individual body composition measurements interact to influence outcomes. Methods: Men with mCRPC uniformly treated on a prospective clinical trial with abiraterone acetate plus apalutamide were included in this post-hoc analysis (NCT02703623). Responders were defined as those with a decrease in PSA of > 50% after 8 weeks of therapy. Body composition was assessed at the level of L3 on baseline CT scan at trial registration using Slice-O-Matic version 5.0. Body composition indices were normalized for height (m2). Non-parametric Kruskal-Wallis test was used to evaluate associations between continuous baseline measures. A multivariable CART model was used to determine if baseline measures could divide patients into distinct risk groups. Results: In 186 men with mCRPC, responders to maximal ASI (n = 128) had higher subcutaneous adiposity (SATi, 79.3 vs. 67.6, p = 0.02), visceral adiposity (VATi, 76.4 vs. 61.5, p = 0.03), and body mass index (BMI, 30.3 vs. 29.2, p = 0.04). There was a strong correlation between BMI and SAT (r = 0.81). In exploratory multivariable modeling, BMI and VATi had the strongest associations with response to ASI. Specifically, men with a BMI ≥ 26.73 had a higher response rate (75% vs. 46%). For men with a BMI < 26.73, a VATi ≥ 24.7 enriched for response to therapy (86% vs. 26%). Conclusions: Elevated subcutaneous and visceral adiposity is associated with improved response to maximal ASI in men with mCRPC. In hypothesis-generating models, visceral adiposity had the strongest association with response to ASI in men with lower BMI. Further studies need to assess how and when adiposity becomes favorable for outcomes in advanced prostate cancer.
The effects of bright white light therapy on obese frailty in older men with prostate cancer on hormonal therapy: A pilot randomized control trial.
Authors: Bergerot Cristiane Decat , Razavi Marianne , Celis Ashley , Clark Karen L. , Dorff Tanya B. , Pal Sumanta K. , Loscalzo Matthew J. , Dale William
Published: March 2021

75

Background: Exposure to bright white light (BWL) has been shown to improve outcomes including fatigue, depression, and sleep disturbances among the general older population but the benefit has not been demonstrated as yet in prostate cancer. Older men with prostate cancer on androgen deprivation therapy (ADT) are at risk for obese frailty (components: fatigue, weakness, poor mood, slowness and obesity). In this pilot study, we aimed to determine if BWL, compared to dim white wight (DWL), reduces obese frailty in older prostate cancer patients starting anti-androgens. Methods: Men age ≥ 65 with prostate cancer initiating ADT were randomly assigned to either the BWL (exposure to full spectrum light, 500-1500 lux) or DWL cohort (exposure to low dose white light (<50 lux)) and were blinded to assignment. Men received daily 30-minute morning light session from special glasses (Luminette) for 3 months. Participants were assessed at the beginning of treatment and 3 months later with the Short Physical Performance Battery (SPPB) - including timed 4m walk, tandem balance, and timed chair stands (range: 0 to 12) - energy levels (self-reported 5-point Likert scale), waist circumference (measured via tape (mm)), and muscle strength (handgrip: assessed via dynamometer (kg)). Pre-post outcomes (means differences) were evaluated using paired t-tests with a p-value of 0.05 considered significant. Results: 18 patients (9 per cohort) were recruited. Patients in the BWL arm showed a statistically significant improvement in muscle strength (BWL p=0.012 versus in DWL p=0.22). Compared with DWL, BWL arm showed no decline in energy levels, (BWL p=0.28 vs. DWL p=0.035) nor gain in waist circumference (BWL p=0.51, DWL p=0.046). There were no statistically significant differences in either arm on the SPPB (BWL p=0.44, and in DWL p=0.09). Conclusions: BWL may offset negative effects of ADT for older men with prostate cancer, through improved muscle strength, maintained energy levels, and no waist circumference gain. While a small pilot study, the intervention warrants further research in a larger sample.
A phase II study to evaluate the effects of docetaxel plus lycopene in advanced castrate-resistant prostate cancer.
Authors: Zhuang Eric , Uchio Edward M. , Lilly Michael B. , Fruehauf John P.
Published: March 2021

77

Background: Lycopene, the carotenoid responsible for the red colors seen in tomatoes, grapefruit, and other foods, has demonstrated synergism with docetaxel in prostate cancer cell culture and tumor xenograft models. This phase II study investigated the clinical activity and safety profile of docetaxel plus lycopene in advanced castrate resistant prostate cancer. Methods: Eligible patients had histologically confirmed adenocarcinoma of the prostate, two rising pre-study prostate specific antigen (PSA) values ≥ 1 ng/ml, and no prior treatment with any chemotherapy, biological therapy, or investigational drug. All patients initially received docetaxel 75mg/m2 every 21 days in combination with lycopene 30 mg orally once daily. The primary endpoint was PSA response rate, defined as the proportion of subjects achieving a ≥ 50% reduction in PSA at any point after starting therapy. Secondary endpoints included median time to PSA progression, duration of response (DOR), and overall survival (OS). Results: Fourteen patients were screened, and thirteen patients were initiated on protocol therapy. Median age was 77 years (range 55-90). Twelve patients (92%) had bone metastases. Four patients (30%) had bone and visceral metastases. The PSA response rate was 76.9% [95% confidence interval (CI), 46.2-94.9], comprising of ten PSA responses. Two patients had a best response of stable disease, yielding a disease control rate of 92% [95% CI, 57.2-98.2]. Median time to PSA progression was 8 months [95% CI, 3.5-8.7]. Median duration of response was 7.3 months [95% CI, 4.8-13.2]. On 5-year follow-up, median overall survival was 35.1 months [95% CI, 25.7-57.7]. The most frequently reported ( > 15%) non-hematologic adverse events included diarrhea, nausea, vomiting, peripheral neuropathy, weight loss, fatigue, onycholysis, and alopecia. One patient (7%) experienced febrile neutropenia. No patients experienced grade 3 or above anemia. Conclusions: The combination of docetaxel with lycopene led to improved PSA response rate and tolerability in patients with advanced castrate resistant prostate cancer. Docetaxel plus lycopene merits further research in this patient population. Clinical trial information: NCT01882985.
Outcomes of older men receiving docetaxel for metastatic hormone-sensitive prostate cancer.
Authors: Lage Daniel E , Michaelson M Dror , Lee Richard J. , Greer Joseph A. , Temel Jennifer S. , Sweeney Christopher
Published: March 2021

82

Background: Most men who die of prostate cancer are older than 70 years, and the impact of therapy in this population is poorly defined. The ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) randomized men of all ages with metastatic hormone-sensitive prostate cancer (mHSPC) to receive androgen deprivation therapy (ADT) with or without docetaxel. Methods: The results of CHAARTED showed an overall survival (OS) benefit for the addition of docetaxel to ADT in men with mHSPC. In a secondary analysis of this trial, we assessed patient characteristics and OS in patients ≥70 years (“older men”) versus <70 years (“younger men”) with Cox proportional hazards models. Additionally, we compared adverse events, therapy completion rate, and subsequent treatment patterns between these two groups using Chi-squared tests. Results: Of the 790 patients enrolled, 177 (22.4%) were ≥70 years. A greater proportion of older men had an impaired performance status (Eastern Cooperative Oncology Group 1-2: 36.7% vs. 28.6%, p=0.038) and prior local therapy (31.7% vs. 25.9%, p<0.001) compared to younger men. Docetaxel + ADT resulted in improved OS in both older and younger men (Hazard Ratio [HR] 0.45, 95%CI: 0.25-0.80 for older men; HR 0.71, 95%CI: 0.53-0.95 for younger men). This treatment benefit was seen for subgroups of older men with high volume disease (HR 0.43, 95%CI 0.23-0.79) and de novo metastatic disease (HR 0.36, 95%CI 0.19-0.69). A similar proportion of older and younger men completed all six cycles of docetaxel (82.6% vs. 87.1%, p=0.28). Rates of grade 3-5 adverse events were similar between older and younger men (36.8% of older men vs. 26.8% of younger men, p=0.69). The rate of any Grade 4-5 adverse events did not differ significantly between older and younger men (14.9% vs. 11.9%, respectively, p=0.46). In the control arm, a smaller proportion of older men received subsequent cancer treatments (34.4% vs. 51.5%, p=0.017) or subsequent docetaxel (25.6% vs. 37.6%, p=0.035) compared to younger men. Conclusions: In summary, older men with mHSPC who were eligible to participate in a clinical trial had similar OS benefit and clinical outcomes compared to younger men when receiving docetaxel chemotherapy + ADT. Oncologists should consider docetaxel chemotherapy as a favorable treatment option for older men with mHSPC who are fit for chemotherapy. Clinical trial information: NCT00309985.
Impact of treatment sequence on survival outcome in patients with a second treatment line for metastatic castration-resistant prostate cancer: A new user design in the French nationwide claims database.
Authors: Gross-Goupil Marine , Thurin Nicolas H. , Rouyer Magali , Haaser Thibaud , Rebillard Xavier , Soulie Michel , de Pouvourville Gérard , Messaoudi Fatiha , Capone Camille , Bignon Emmanuelle , Jové Jérémy , Lamarque Stéphanie , Droz-Perroteau Cécile , Moore Nicholas , Blin Patrick
Published: March 2021

91

Background: Abiraterone acetate in association with prednisone/prednisolone and docetaxel can both be used as first or second line treatments for metastatic castration-resistant prostate cancer (mCRPC). As a result, one may wonder if it is better to start with an abiraterone acetate first line followed by a docetaxel second line (ABI–DOCE sequence) or to use the inverse sequence DOCE-ABI. Methods: A new user cohort study design with a 3-year follow-up: patients initiating a first-line treatment for mCRPC in 2014 followed by a second treatment line were identified from the French nationwide claims database (SNDS), which covers about 86% of the population at the time of the study. Patients with sequence ABI–DOCE and those with DOCE-ABI were 1:1 matched on prostate cancer stage before mCRPC status, duration from prostate cancer diagnosis, and a high-dimensional propensity score. The 36-month overall survival and the 36-month survival time until treatment switch or death (proxy of progression-free survival) were compared using Cox proportional hazards risk model. Results: Out of the 3 949 mCRPC patients that initiated a first-line treatment in 2014, 1 162 died during this first line, and 2 283 had a second-line treatment. Among them, 693 received the sequence ABI–DOCE and 354 DOCE–ABI. A total of 159 patients per group were 1:1 matched. The median duration of the first treatment line was 8.4 months in the ABI–DOCE sequence and 6.6 months in the DOCE–ABI sequence. The median duration of the second line was 6.3 months and 6.5 months in the ABI–DOCE and DOCE–ABI sequences, respectively. Results are presented in the table below. Median survivals were similar in both groups with no significant differences observed in the 36-month survival probabilities. Around 60% of the patients received a third-line treatment in both groups. Conclusions: In real life settings, treatment sequences (ABI–DOCE versus DOCE–ABI) seem to have no differential impact on survival outcome in mCRPC patients sharing same characteristics. [Table: see text]
A multicenter, randomized, controlled phase II study: Efficacy and safety of PSMA-targeted radioligand therapy I-131-1095 (1095) plus enzalutamide (enza) in 18F-DCFPyL PSMA scan avid, metastatic castration-resistant prostate cancer (mCRPC) patients post-abiraterone (abi) progression (ARROW).
Authors: Sartor A. Oliver , Laidley David , Pouliot Frederic , Probst Stephan , Sabbagh Robert , Esposito Giuseppe , Saad Fred , Stambler Nancy , Yu Evan Y.
Published: March 2021

TPS187

Background: PSMA is a transmembrane glycoprotein overexpressed in prostate cancer (PC) and further upregulated in castrate resistant disease. 1095 is a novel PSMA-targeted small molecule radioligand therapeutic that binds to the extracellular domain of PSMA selectively with high affinity, internalized, and delivers a targeted lethal radiation dose to PC cells. 18F-DCFPyL is a novel PSMA-targeted PET imaging agent that has shown robust diagnostic performance for detecting recurrent and metastatic PC. In the ARROW study, pts must demonstrate 18F-DCFPyL avidity prior to 1095 treatment. Methods: ARROW is an open-label, randomized (2:1) trial of enza plus 1095 or enza alone in pts with progressive mCRPC who previously received abi. ~120 pts (80: 1095 + enza; 40: enza alone) will be treated at multiple sites in the US and Canada. Eligible male pts must have metastatic disease documented by bone scan or soft tissue lesions measurable per RECIST 1.1 on CT/MRI, be PSMA-avid as determined by 18F-DCFPyL PET/CT, have evidence of biochemical or radiographic progression on abi, and be ineligible for or refuse to receive chemotherapy. Pts will receive enza (prescribed per approved labeling) with or without 1095 (100 mCi dose, followed by up to 3 additional doses administered at least 8 weeks apart, as determined by dosimetry evaluation and occurrence of dose-limiting events). The primary objective is to determine the efficacy of 1095 plus enza compared to enza alone, based on PSA response (confirmed PSA decline ≥50%) rate according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Additional objectives include objective response rate based on PCWG3-modified RECIST 1.1, progression-free survival (PFS) defined as the first occurrence of radiographic progression (PCWG3-modified RECIST 1.1), unequivocal clinical progression, or death from any cause, duration of response, overall survival, and the safety and tolerability of 1095 radioligand therapy. Due to the COVID-19 pandemic, enrollment was halted in April 2020 but is reopening in October 2020. Clinical trial information: NCT03939689.
PLANETTE: A modular phase IIa multicenter open-label study evaluating the ATR inhibitor ceralasertib (AZD6738) in ATM mutant advanced solid tumors.
Authors: Abida Wassim , Sanay Elkhan , Lukashchuk Natalia , Pierce Andrew , de Graaf Wessel , Lau Alan , Rocher Ros Vidalba , Kurian Nisha , Parr Graeme , LoembE Bienvenu , Dean Emma , Aggarwal Rahul Raj
Published: March 2021

TPS189

Background: Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) are kinases that orchestrate cellular responses to DNA damage. ATM is primarily activated by DNA double strand breaks, and ATR is recruited to regions of single stranded DNA that arise due to collapsed or stalled replication forks. Although ATM and ATR are activated by distinct pathways, their downstream targets and effects partially overlap to activate cell cycle checkpoints and DNA damage repair. Ceralasertib is a potent, oral, selective inhibitor of ATR. Pre-clinical studies have consistently demonstrated synthetic lethality of ATR inhibitors, including ceralasertib, in ATM-deficient models across multiple tumor types (Kwok et al 2017, Min et al 2017, Lloyd et al 2020, Hustedt et al 2019). Early clinical evidence of efficacy is from a phase I study of ceralasertib in combination with olaparib in relapsed, refractory cancer (NCT02576444). Amongst 5 participants with a range of solid tumors harboring deleterious ATM mutations, there was 1 complete response, 3 stable diseases (1 with minor response 20-30%) and 1 patient with disease progression. Two participants had clinical benefit ongoing for more than 12 months (Eder et al 2019). ATM deficiency may be detected through genomic testing for loss-of-function alterations in the gene, or through immunohistochemical methods to detect loss of protein expression. Genomic alterations in ATM occur across multiple solid tumor types, including approximately 4% of advanced prostate cancers. Methods: PLANETTE (clinicaltrials.gov identifier (NCT 04564027) is a modular phase 2a multicenter open-label study investigating DNA-damage response agents in patients with advanced cancers that harbor molecular alterations. Module 1 will study the ATR inhibitor ceralasertib in tumors with deleterious or suspected deleterious mutations in ATM. Patients will be identified at cancer centers which routinely perform molecular profiling to detect ATM mutations. Central confirmation of ATM mutation by NGS and ATM IHC testing will be conducted retrospectively. Cohort A will enroll ~25 patients with advanced solid tumors (except NSCLC and prostate cancer), cohort B will include ~27 patients with metastatic CRPC who have previously progressed on a novel hormonal agent. The primary endpoints are investigator assessed ORR in Cohort A and composite response that includes radiographic, PSA, and CTC response per PCWG criteria in Cohort B. Secondary endpoints include duration of response, and progression free survival. Pharmacodynamic and other biomarkers will be explored. Enrolment is planned to start in November 2020. Clinical trial information: 04564027.
A phase III, randomized, open-label, study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy (NHT) in patients (pts) with metastatic, castration-resistant prostate cancer (mCRPC).
Authors: Agarwal Neeraj , Azad Arun , Carles Joan , Chowdhury Simon , McGregor Bradley Alexander , Merseburger Axel Stuart , Oudard Stephane , Saad Fred , Soares Andrey , Panneerselvam Ashok , Wang Fong , Pal Sumanta K.
Published: March 2021

TPS190

Background: Cabozantinib inhibits multiple tyrosine kinases, including MET, VEGFR, RET, and TAM kinases (Tyro3, AXL, MER), involved in tumor growth and angiogenesis, and whose mutations and expression are associated with prostate cancer aggressiveness and poor prognosis. Targeting these kinases with cabozantinib may promote an immune permissive tumor environment and may enhance response to immune checkpoint inhibitors. In the ongoing phase 1b COSMIC-021 study of pts with solid tumors, cabozantinib plus the PD-L1 inhibitor atezolizumab, showed preliminary meaningful clinical activity in soft tissue disease and a tolerable safety profile for 44 pts with mCRPC (Agarwal et al., ASCO 2020; abstract 5564). We present the study design of a phase 3 trial of cabozantinib plus atezolizumab versus second NHT in pts with mCRPC. Methods: This randomized, open-label, controlled phase 3 study (NCT04446117) evaluates the efficacy and safety of cabozantinib plus atezolizumab versus second NHT (abiraterone or enzalutamide) in pts with mCRPC who previously received one NHT to treat metastatic castration-sensitive PC (mCSPC), non-metastatic CRPC (M0 CRPC), or mCRPC. Additional eligibility criteria include histologically or cytologically confirmed adenocarcinoma of the prostate, measurable visceral disease or measurable extrapelvic adenopathy per RECIST 1.1 by investigator, prostate specific antigen progression and/or soft-tissue disease progression, ECOG 0 or 1, and age ≥18 years. Key exclusion criteria include prior nonhormonal therapy for mCRPC and uncontrolled significant illness. Eligible pts (N = 580) are randomized 1:1 to receive cabozantinib (40 mg PO QD) + atezolizumab (1200 mg IV Q3W) vs abiraterone (1000 mg PO QD) + prednisone (5 mg PO BID) or enzalutamide (160 mg PO QD). Designated NHT will differ from previous NHT taken. Randomization is stratified by: liver metastasis (yes, no), prior docetaxel treatment for mCSPC (yes, no), and disease stage for which the first NHT was given (mCSPC, M0 CRPC, mCRPC). Treatment will continue until there is no longer clinical benefit as determined by the treating investigator, unacceptable toxicity, or consent withdrawal. The multiple primary endpoints are progression-free survival per RECIST 1.1 by blinded independent radiology committee (BIRC) and overall survival. Additional endpoints include objective response rate per RECIST 1.1 by BIRC, safety, correlation of biomarkers with outcomes, quality of life and pharmacokinetics. Patient enrollment is ongoing. Clinical trial information: NCT04446117.
Phase II trial of opaganib in patients with metastatic castration-resistant prostate cancer progressing on abiraterone or enzalutamide (NCT04207255).
Authors: Kucuk Omer , Smith Charles , Plasse Terry , Ogretmen Besim , Mehrotra Shikhar , Gourdin Theodore Stewart , Bilen Mehmet Asim , Carthon Bradley Curtis , Nazha Bassel , Goldman Jamie , Lilly Michael B.
Published: March 2021

TPS191

Background: Opaganib (Yeliva, ABC294640) is a first-in-class, sphingosine kinase-2 (SK2) selective inhibitor, with anticancer, anti-inflammatory and anti-viral activities. SK2, a lipid kinase catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P promotes cancer growth, and proliferation and pathological inflammation, including inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, opaganib blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and are also involved in immune-modulation and suppression of innate immune responses from T cells. Opaganib is a sphingosine-competitive inhibitor of SK2 and also inhibits dihydroceramide desaturase. Opaganib has antitumor activity against human and murine prostate cancer cell lines, and in xenograft (LNCaP) and syngeneic (MycCAP, TRAMP-C1) murine tumor models. In addition to its target effect of reducing sphingosine-1-phosphate, opaganib reduces both MYC and AR proteins through its kinase-blocking and desaturase-inhibiting properties, respectively. Methods: The study is open to patients with mCRPC who have been treated with at least one newer androgen antagonist (abiraterone or enzalutamide) and no prior chemotherapy for castration-resistant disease. Patients who are failing either abiraterone or enzalutamide may enroll, with the addition of opaganib. The trial design includes brief safety lead-in cohort 1a (abiraterone + opaganib 250 mg Q 12hr, 3/3 enrolled) and 1b (enzalutamide + opaganib 250 mg Q 12hr, 3/3 enrolled). These cohorts have been completed without any DLTs. We are now enrolling cohort 2 (abiraterone + opaganib 500 mg Q 12hr, 0/27 enrolled) and cohort 3 (enzalutamide + opaganib 500 mg Q 12hr, 8/27 enrolled). A total of 60 patients will be enrolled and response will be evaluated after 4 cycles (28 days/cycle) using a composite metric based on PSA, bone scan and RECIST measurements per PCWG3 criteria. Safety and tolerability will be monitored, and dose modifications will be allowed. Primary endpoint is disease control (stable disease or better) after 4 cycles. Secondary endpoints include overall survival, radiographic progression-free survival and PSA progression-free survival. Correlative studies include assessment of quality of life (QOL), circulating MDSCs, immune cells and clones with amplified AR or MYC. Supported by NIH grant P01 CA203628. Clinical trial information: NCT04207255.
PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).
Authors: Zhang Tian , Ballman Karla V. , Choudhury Atish Dipankar , Chen Ronald C. , Watt Colleen , Wen Yujia , Shergill Ardaman , Zemla Tyler J. , Emamekhoo Hamid , Vaishampayan Ulka N. , Morris Michael J. , George Daniel J. , Choueiri Toni K.
Published: March 2021

TPS366

Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN (A031203) trials. Combination immunotherapy with VEGF therapies has shown benefit over sunitinib in the JAVELIN 101 and KEYNOTE 426 trials. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter phase III trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1 mg/kg and NIVO 3 mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480 mg IV every 4 weeks; pts with progression of disease (PD) switch to CABO 60 mg oral daily; pts with non-CR/non-PD are randomized to NIVO 480 mg IV every 4 weeks versus NIVO 480 mg IV every 4 weeks with CABO 40 mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include progression-free survival, 12-month CR rate, overall response rate based on RECIST 1.1 and iRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR, tissue-based and plasma-based biomarkers will be assessed. Updated enrollment through January 2021 will be presented. Clinical trial information: NCT03793166 .
Denosumab and pembrolizumab in clear cell renal carcinoma (KEYPAD): A phase II trial (ANZUP1601).
Authors: Gedye Craig , Joshi Abhishek Jagdish , Zhang Alison Yan , Martin Andrew James , Joshua Anthony M. , Harris Carole A. , Underhill Craig , Pook David William , Toner Guy C. , Kichenadasse Ganessan , So Jane Yeojeong , Goh Jeffrey C. , Morris Michelle Frances , Lawrence Nicola Jane , Ferguson Tom , Vasey Paul Austin , Prithviraj Prashanth , Subramaniam Shalini , Stockler Martin R. , Davis Ian D. ,   Austraila and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: March 2021

TPS367

Background: Inhibitors of the programmed death-1 pathway (PD-1) are effective in clear cell renal cell cancer (ccRCC). Preclinical data and case reports suggest that denosumab, an inhibitor of Receptor Activator of Nuclear Factor κ-B Ligand (RANKL) signaling, could potentiate the anti-tumour effects of anti-PD1 inhibitors without overlapping toxicities. We aim to determine the activity and safety of combining denosumab and pembrolizumab in advanced ccRCC. Methods: This single arm, multi-center, phase II trial will recruit 70 participants with metastatic or unresectable ccRCC, progressing during or after treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, and with no prior treatment with immunotherapy or denosumab. Participants will receive pembrolizumab 200mg IV every 3 weeks plus denosumab 120mg SC on days 1, 8 and 22 and then every 3 weeks until disease progression, prohibitive toxicity or maximum treatment of 24 months. Response will be assessed at weeks 12, 18, 24, then every 12 weeks until disease progression. Bloods for translational studies are collected at baseline, week 6 and on disease progression. The primary endpoint is objective tumour response rate (OTRR) per RECIST 1.1. Secondary endpoints include OTRR per iRECIST, progression free survival (PFS), time to OTRR, time to first skeletal related event, adverse events, and frequency of treatment delays/discontinuations. Correlative studies will include identification of prognostic and/or predictive biomarkers relating to immune and RANKL signaling. A sample size of 70 provides 90% power with a 1-sided type 1 error rate of 10% to distinguish the observed OTRR (and PFS at 6 months) from an OTRR of 40% (worthy of pursuit) versus 25% (not worthy of pursuit). 15 sites are open across Australia. As of September 23, 2020, 40 patients have been recruited. Clinical trial information: NCT03280667 .
A phase III, randomized, open-label, multicenter, global study of efficacy and safety of durvalumab in combination with gemcitabine plus cisplatin for neoadjuvant treatment followed by durvalumab alone for adjuvant treatment in muscle-invasive bladder cancer (NIAGARA).
Authors: Powles Thomas , Meeks Joshua J , Galsky Matt D. , Van Der Heijden Michiel Simon , Nishiyama Hiroyuki , Al-Ahmadie Hikmat A , Goluboff Erik T. , Hois Stephan , Donegan Sarah E. , Williams Vanessa , Xiao Feng , Catto James WF
Published: March 2021

TPS505

Background: Management of muscle-invasive bladder cancer (MIBC) includes both surgery and systemic therapy. Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved pathologic complete response (pCR), event-free survival (EFS), and overall survival (OS) compared with radical cystectomy alone. Yet at least half of patients will still experience recurrence and will progress to metastatic disease. Durvalumab (anti–PD-L1 antibody) combined with gemcitabine + cisplatin, administered as either neoadjuvant or adjuvant treatment, may increase the rate of pathologic response and prolong long-term survival. This approach will be evaluated in this study in patients with MIBC identified for curable intent, as reflected in the NCCN guidelines. Methods: NIAGARA (NCT03732677) is a phase III, randomized, open-label, multicenter, international trial that will enroll ~1050 patients with MIBC who, prior to radical cystectomy, will be randomized (1:1) to durvalumab and gemcitabine + cisplatin (Arm 1) or gemcitabine + cisplatin (Arm 2). Following radical cystectomy, patients in Arm 1 will receive durvalumab monotherapy for 8 cycles (8 months) while patients in Arm 2 will receive no adjuvant treatment. Eligible patients are aged ≥18 years with resectable MIBC (clinical stage T2-T4aN0/1M0) with urothelial histology eligible for a radical cystectomy. Patients with pure non-transitional cell variant histologies and any small cell histology are not eligible. A tumor tissue sample for biomarker analysis is mandatory as PD-L1 expression is a stratification factor. Primary endpoints are pCR and EFS in patients with adequate renal function. Secondary and exploratory endpoints include proportion of patients who achieve pathologic response < stage II (stages Ta, T1, and carcinoma in situ) at the time of cystectomy following neoadjuvant treatment, EFS at 24 months, metastasis-free survival, efficacy of Arm 1 vs Arm 2 at radical cystectomy and proportion of patients who undergo cystectomy, OS rate at 5 years, safety, patient-reported outcomes, and pharmacokinetics. Immunogenicity and biomarkers are exploratory endpoints. Enrollment opened in Dec 2018. Clinical trial information: NCT03732677.
Hepatic Igf1-Deficiency Protects Against Atherosclerosis in Female Mice
Authors: Sivasubramaniyam Tharini , Yang Jiaqi , Pollock Evan , Chon Joseph , Schroer Stephanie A , Li Yu Zhe , Metherel Adam H , Dodington David W , Bazinet Richard P , Woo Minna
Published: March 2021

Atherosclerosis is the leading cause of cardiovascular disease (CVD), with distinct sex-specific pathogenic mechanisms that are poorly understood. Aging, a major independent risk factor for atherosclerosis, correlates with a decline in circulating insulin-like growth factor-1 (IGF-1). However, the precise effects of Igf1 on atherosclerosis remain unclear. In the present study, we assessed the essential role of hepatic Igf1, the major source of circulating IGF-1, in atherogenesis. We generated hepatic Igf1-deficient atherosclerosis-prone apolipoprotein E (ApoE)-null mice (L-Igf1-/-ApoE-/-) using the Cre-loxP system driven by the Albumin promoter. Starting at 6 weeks of age, these mice and their littermate controls, separated into male and female groups, were placed on an atherogenic diet for 18 to 19 weeks. We show that hepatic Igf1-deficiency led to atheroprotection with reduced plaque macrophages in females, without significant effects in males. This protection from atherosclerosis in females was associated with increased subcutaneous adiposity and with impaired lipolysis. Moreover, this impaired lipid homeostasis was associated with disrupted adipokine secretion with reduced circulating interleukin-6 (IL-6) levels. Together, our data show that endogenous hepatic Igf1 plays a sex-specific regulatory role in atherogenesis, potentially through athero-promoting effects of adipose tissue–derived IL-6 secretion. These data provide potential novel sex-specific mechanisms in the pathogenesis of atherosclerosis.
Integrating Anatomical, Molecular and Clinical Risk Factors in Gastrointestinal Stromal Tumor of the Stomach
Authors: Hølmebakk Toto , Wiedswang Anne Marit , Meza-Zepeda Leonardo A. , Hompland Ivar , Lobmaier Ingvild V. K. , Berner Jeanne-Marie , Stoldt Stephan , Boye Kjetil
Published: March 2021

Background

Adjuvant imatinib for 3 years is recommended to patients with high-risk gastrointestinal stromal tumor (GIST). Risk stratification is inaccurate, and risk assessments are further complicated by the increased use of neoadjuvant treatment. Anatomical criteria for prognostication have not been investigated.

Methods

Clinical, molecular, and anatomical variables were retrospectively studied in a population-based cohort of 295 patients with gastric GIST resected between 2000 and 2018. Gastric subsite was divided into the upper, middle, and lower thirds. Growth pattern was classified as luminal, exophytic, or transmural based on imaging and surgical reports.

Results

Of 113 tumors in the upper third of the stomach, 103 (91.2%) were KIT mutated, 7 (6.2%) were PDGFRA mutated, and 104 (92.0%) harbored genotypes sensitive to imatinib. Transmural tumors were strongly associated with a high mitotic index. Five-year recurrence-free survival (RFS) was 71% for patients with transmural tumors versus 96% with luminal or exophytic tumors (hazard ratio [HR] 8.45, 95% confidence interval [CI] 3.69–19.36; p < 0.001), and, in high-risk patients, 5-year RFS was 46% for patients with transmural tumors versus 83% with luminal or exophytic tumors (HR 4.47, 95% CI 1.71–11.66; p = 0.001). Among 134 patients with tumors > 5 cm, there were 29 recurrences. Only five patients with exophytic or luminal tumors had recurrent disease, of whom four had tumor rupture. Five-year RFS for patients with exophytic/luminal tumors >5 cm without rupture was 98%.

Conclusions

In the upper third, over 90% of tumors were sensitive to imatinib. Patients with exophytic or luminal tumors without rupture, irrespective of size, had an excellent prognosis and may not benefit from adjuvant therapy.
Management options for self-harm scars: non-surgical and surgical modalities
Authors: Abbassi Omar , Kane Ruth , Goutos Ioannis
Published: March 2021

Deliberate self-harm scarring is an increasingly common presentation in dermatology and plastic surgery settings. Most patients seek help with requests to ameliorate the stigmatising pattern of scarring, which can have a detrimental effect on social and personal interactions. This article aims to provide a summary of different management approaches for scar resurfacing, with particular focus on non-surgical interventions.
Maintaining professional boundaries in the care home
Authors: Mendes Aysha
Published: March 2021

Feeling empathy for those you care for is essential, especially in relation to those more vulnerable residents in nursing and residential care settings. However, because of this, maintaining personal and professional boundaries can sometimes be difficult. Aysha Mendes offers guidance for those seeking to look after themselves while they selflessly care for others.
In Silico Study of Ayapana Triplinervis Bioactive Compounds Against Quorum-Sensing System of Pseudomonas Aeruginosa
Authors: Martin King Dave Gloria , Padilla Krystel Grace Vergara , Buan Ivy Joyce Arenas
Published: March 2021

Quorum sensing (QS) is the way bacterial cells communicate can trigger or regulate pathogenicity in Pseudomonas aeruginosa. Targeting the quorum sensing system with the help of docking algorithms can reduce the cost and time to screen for potential anti-quorum sensing drugs. Ayapana triplinervis, an ethnobotanical from the Philippines is a potential source of bioactive compounds to inhibit quorum sensing. This study shows potential compounds present in Ayapana triplinervis that could disrupt the quorum sensing system in Pseudomonas aeruginosa with the use of molecular docking simulations. Selection and identification of bioactive compounds found in Ayapana triplinervis was based from previous metabolite screening reports. This study utilizes virtual screening in order to identify which among the compounds to be the potent quorum sensing inhibitor. The molecular structures of the thirty-one identified bioactive compounds were obtained from PubChem (nih.gov) in SDF file. These molecular structures of the compounds from Ayapana triplinervis served as the ligands and docked to the active site of the PqsR, PqsD, and LasR of the Pseudomonas aeruginosa using Autodock Vina algorithms. The bioactive compounds were virtually screened using Autodock Vina to determine the binding affinity of each compounds to the active site of PqsR, PqsD, and LasR. Compounds with a low binding affinity has a potential to be developed as anti-quorum agent to Pseudomonas aeruginosa. Results showed that out of the 31 compounds, caryophyllene, trans-nerolidol, 2-(Isobutyryloxy)-Thymol methyl ether, β-elemene, and cyperadiene have successfully inhibited the PqsR, PqsD, and LasR based from the computed binding affinity. 2- (Isobutyryloxy)-Thymol methyl ether formed hydrogen bond in the active site of all the proteins related governing the quorum sensing process of Pseudomonas aeruginosa, making the compound a candidate drug to disrupt the signaling pathway of the system.
Synthesis and Screening of Biologically Active Schiff bases of Benzothiazoles and its Zinc and Lanthanum Metal Complexes
Authors: Anuse D. G. , Desale V. J. , Thorat B. R. , Anuse D. D. , Jagadhani S. G. , Abraham K. George , Yamagar R. S.
Published: March 2021

The substituted 2-Aminobenzothiazole and ethyl 2-(4-formyl-3-hydroxyphenyl)-4-methylthiazole-5-carboxylate in methanol mix together and heat the reaction mixture for overnight, It gives Schiff’s bases (derivatives of substituted aminobenzothiazole) 3. This compound 3 when treated with Zinc Chloride it gives Zinc metal complex of Schiff’s bases 4 and if compound 3 was treated with Lanthanum chloride gives Lanthanum metal complex of Schiff’s bases 5, which shows marked biological activities.
Soliton dynamics in quadratic nonlinear media with two-dimensional Pythagorean aperiodic lattices
Authors: Bağci Mahmut
Published: March 2021

The dynamics of two-dimensional Pythagorean lattice solitons are explored in quadratic nonlinear media. The study is focused on variation of sub-lattice depths and the strength of quadratic optical effects that specify characteristics of the considered model. The numerical existence of periodic and aperiodic lattice solitons is demonstrated, and the stability domain of solitons is determined for all parameters in the model. It is shown that, although the existence domain of periodic and aperiodic lattice solitons is identical, the stability region of periodic lattice solitons is narrower than that of aperiodic lattice solitons. It is manifested that stable solitons can exist in both periodic and aperiodic lattices, and decay of unstable solitons can be arrested by increasing the potential depth and decreasing the propagation constant.
Learning receptive field properties of complex cells in V1
Authors: Lian Yanbo , Almasi Ali , Grayden David B. , Kameneva Tatiana , Burkitt Anthony N. , Meffin Hamish
Published: March 2021

There are two distinct classes of cells in the primary visual cortex (V1): simple cells and complex cells. One defining feature of complex cells is their spatial phase invariance; they respond strongly to oriented grating stimuli with a preferred orientation but with a wide range of spatial phases. A classical model of complete spatial phase invariance in complex cells is the energy model, in which the responses are the sum of the squared outputs of two linear spatially phase-shifted filters. However, recent experimental studies have shown that complex cells have a diverse range of spatial phase invariance and only a subset can be characterized by the energy model. While several models have been proposed to explain how complex cells could learn to be selective to orientation but invariant to spatial phase, most existing models overlook many biologically important details. We propose a biologically plausible model for complex cells that learns to pool inputs from simple cells based on the presentation of natural scene stimuli. The model is a three-layer network with rate-based neurons that describes the activities of LGN cells (layer 1), V1 simple cells (layer 2), and V1 complex cells (layer 3). The first two layers implement a recently proposed simple cell model that is biologically plausible and accounts for many experimental phenomena. The neural dynamics of the complex cells is modeled as the integration of simple cells inputs along with response normalization. Connections between LGN and simple cells are learned using Hebbian and anti-Hebbian plasticity. Connections between simple and complex cells are learned using a modified version of the Bienenstock, Cooper, and Munro (BCM) rule. Our results demonstrate that the learning rule can describe a diversity of complex cells, similar to those observed experimentally.
Revised estimates of leprosy disability weights for assessing the global burden of disease: A systematic review and individual patient data meta-analysis
Authors: Nanjan Chandran Shri Lak , Tiwari Anuj , Lustosa Anselmo Alves , Demir Betul , Bowers Bob , Albuquerque Rachel Gimenes Rodrigues , Prado Renata Bilion Ruiz , Lambert Saba , Watanabe Hiroyuki , Haagsma Juanita , Richardus Jan Hendrik
Published: March 2021

Background

Leprosy is a chronic bacterial infection caused by Mycobacterium leprae, which may lead to physical disability, stigma, and discrimination. The chronicity of the disease and disabilities are the prime contributors to the disease burden of leprosy. The current figures of the disease burden in the 2017 global burden of disease study, however, are considered to be under-estimated. In this study, we aimed to systematically review the literature and perform individual patient data meta-analysis to estimate new disability weights for leprosy, using Health-Related Quality of Life (HRQOL) data.

Methodology/principal findings

The search strategy included all major databases with no restriction on language, setting, study design, or year of publication. Studies on human populations that have been affected by leprosy and recorded the HRQOL with the Short form tool, were included. A consortium was formed with authors who could share the anonymous individual-level data of their study. Mean disability weight estimates, sorted by the grade of leprosy disability as defined by WHO, were estimated for individual participant data and pooled using multivariate random-effects meta-analysis. Eight out of 14 studies from the review were included in the meta-analysis due to the availability of individual-level data (667 individuals). The overall estimated disability weight for grade 2 disability was 0.26 (95%CI: 0.18–0.34). For grade 1 disability the estimated weight was 0.19 (95%CI: 0.13–0.26) and for grade 0 disability it was 0.13 (95%CI: 0.06–0.19). The revised disability weight for grade 2 leprosy disability is four times higher than the published GBD 2017 weights for leprosy and the grade 1 disability weight is nearly twenty times higher.

Conclusions/significance

The global burden of leprosy is grossly underestimated. Revision of the current disability weights and inclusion of disability caused in individuals with grade 0 leprosy disability will contribute towards a more precise estimation of the global burden of leprosy.