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BACKGROUND Colonic self-expandable metal stents (SEMSs) are usually placed through an endoscope under fluoroscopic guidance. In this retrospective study, we measured the safety and efficacy of through-the-scope colonic stent placement without fluoroscopic guidance. MATERIALS AND METHODS We included consecutive patients with malignant colonic obstruction who underwent SEMS placement through the endoscope without fluoroscopic guidance (NF group) from 2016 to June 2019 in a single tertiary medical center. Technical and clinical success rates and complication rates were compared with those of a historical control group consisting of consecutive patients who underwent stent placement through the endoscope under fluoroscopic guidance (F group) from 2012 to 2015. RESULTS Of 136 patients analyzed, 67 were in the NF group and 69 were in the F group. For the NF and F groups, technical success rates were 97.0% and 95.7%, respectively (P=0.763); clinical success rates were 92.5% and 89.9%, respectively (P=0.581). Major complications included perforation (NF group, 1.5%; F group, 1.4%), stent migration (NF group, 0; F group, 1.4%), and stent occlusion (NF group, 1.5%; F group, 2.9%) (P=0.425). The median procedure time was significantly lower in the NF group (25.90±18.68 min) than in the F group (44.23±20.40 min) (P

Rationale: Light pollution leads to high risk of obesity but the underlying mechanism is not known except for the influence of altered circadian rhythm. Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism, but its role in circadian-related obesity is not clear. Methods: Wild-type (WT) and Ppara-null (KO) mice on a high-fat diet (HFD) were treated with neon light at night for 6 weeks. Body weights were recorded and diet consumption measured. The hypothalamus, liver, adipose and serum were collected for mechanism experimentation. Results: WT mice on a HFD and exposed to night neon light gained about 19% body weight more than the WT control mice without light exposure and KO control mice on a HFD and exposed to night neon light. The increase in adipose tissue weight and adipocyte size led to the differences in body weights. Biochemical analysis suggested increased hepatic lipid accumulated and increased transport of lipid from the liver to peripheral tissues in the WT mice that gained weight under neon light exposure. Unlike KO mice, the expression of genes involved in lipid metabolism and the circadian factor circadian locomotor output cycles kaput (CLOCK) in both liver and adipose tissues were elevated in WT mice under neon light exposure. Conclusions: PPARα mediated weight gain of HFD-treated mice exposed to night neon light. More lipids were synthesized in the liver and transported to peripheral tissue leading to adaptive metabolism and lipid deposition in the adipose tissue. These data revealed an important mechanism of obesity induced by artificial light pollution where PPARα was implicated.

Contains fulltext : 220820.pdf (Publisher’s version ) (Open Access) BACKGROUND: Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers. METHODS: We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review. RESULTS: In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P

27 Background: ctDNA testing offers additional opportunities for homologous recombination repair (HRR) gene alteration determination in patients who are not able to access tumor tissue testing. Alteration testing in ctDNA, for BRCA1, BRCA2 and ATM alterations was performed retrospectively in the PROfound study (phase 3 trial of olaparib versus physician’s choice of abiraterone or enzalutamide in men with HRR gene-mutated mCRPC [NCT02987543]). Methods: ctDNA samples were sequenced at FMI, using the FoundationOne Liquid CDx assay for alterations in BRCA1, BRCA2 (BRCA) and ATM, using plasma samples collected during screening in PROfound. Only patients who consented and provided plasma samples from Cohort A (BRCA/ ATM alteration positive by tissue testing) were tested for ctDNA alterations. Radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) in patients positive for alterations in ctDNA was analysed via stratified log-rank test. Additional efficacy endpoints (Objective Response Rate [ORR], Overall Survival[OS]) were also assessed. Results: In total, 181/245 (73.9%) Cohort A patients consented and provided a plasma sample for ctDNA testing, of which 139/181 (76.8%) had a ctDNA result reported (either mutation positive or mutation negative) and 42 patient samples failed testing due to insufficient DNA yield or a technical failure of the test.BRCA/ ATM alterations were identified in111/139 (79.9%) patients and 28/139 patients did not report a BRCA/ATM mutation either due to lack of ctDNA shedding from the tumour or ctDNA levels below the sensitivity of the assay. Patients who carried BRCA/ ATM ctDNA alterations had comparable demography, baseline characteristics and proportions of BRCA1, BRCA2 and ATM mutated patients to the overall Cohort A patients. rPFS by BICR results, in patients with BRCA/ ATM alterations in ctDNA, are presented in the Table. Key secondary efficacy endpoints (ORR, OS) will also be reported for ctDNA alteration positive patients. Conclusions: ctDNA testing in patients with mCRPC is feasible and most, but not all patients have concordant results. Patients who were positive for alterations in BRCA1, BRCA2 or ATM showed a consistent rPFS improvement (hazard ratio [HR] 0.33 [0.21, 0.53]) when compared with the ITT population identified by tumor tissue testing (HR 0.34 [0.25, 0.47]). This suggests that using ctDNA to identify patients carrying BRCA1, BRCA2 or ATM alterations who will benefit from olaparib may be beneficial. Clinical trial information: NCT02987543. [Table: see text]

126 Background: The Phase 3 PROfound trial (NCT02987543) met its primary endpoint and key secondary endpoints, including improved overall survival (OS) for olaparib in men with mCRPC with alterations in BRCA1, BRCA2, or ATM (Cohort A). We report gene-by-gene analysis of olaparib antitumor activity among the 15 prespecified homologous recombination repair (HRR) genes. Methods: Pts were randomized to olaparib (300 mg bid; n=256) or physician’s choice of enzalutamide or abiraterone (control; n=131). Exploratory analyses in pts with alterations in BRCA1 and/or BRCA2 (BRCA, regardless of co-occurring alterations with other HRR genes) or in single genes were conducted. Results: Evidence of olaparib antitumor activity was observed in subgroups with >10 pts (table). Data for pts with alterations in only BRCA1, BRCA2, PPP2R2A, RAD51B, RAD54L, PALB2, BRIP1, CHEK1, BARD1, and RAD51D will be reported (no FANCL or RAD51C enrolled). Conclusions: Small subgroups limit interpretation for some genes. Olaparib antitumor activity is greatest in pts with BRCA alterations, with a spectrum of clinical sensitivity to olaparib as defined by rPFS and OS across the broader population with alterations in other HRR genes. Clinical trial information: NCT02987543. [Table: see text]

5539 Background: In the randomized Phase III PROfound trial (NCT02987543), olaparib significantly prolonged radiographic progression-free survival compared with physician’s choice of new hormonal agent (pcNHA, enzalutamide or abiraterone) in men with mCRPC and HRR gene alterations, whose disease had progressed on prior NHA. Olaparib significantly improved time to pain progression in Cohort A. We report additional patient reported outcome measures of HRQoL in the overall study population (Cohorts A+B). Methods: HRQoL was assessed in the overall study population using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, comprising 5 subscales: physical wellbeing (PWB), functional wellbeing (FWB), emotional wellbeing, social wellbeing, and prostate cancer subscale (PCS). The Trial Outcome Index (TOI; PWB+FWB+PCS) and FACT Advanced Prostate Symptom Index (FAPSI-6: derived from 6 FACT-P items) were also calculated. Adjusted mean change and time to deterioration in scores were statistically analyzed. Results: Baseline FACT-P total score was similar for both treatment arms. FACT-P total and subscale scores during treatment were all higher for olaparib vs pcNHA, with clinically meaningful differences between treatment arms in the adjusted least square (LS) mean changes from baseline in all but FWB and FAPSI-6 (Table). The time to deterioration in FACT-P total and TOI, FAPSI-6, PWB and PCS scores favored olaparib but were not statistically significant, with hazard ratios ranging from 0.68 to 0.94. Further HRQoL results for cohort A will also be presented. Conclusions: Olaparib delayed deterioration in HRQoL scores vs pcNHA and was associated with better HRQoL functioning over time compared with pcNHA in men with mCRPC and HRR gene alterations. Clinical trial information: NCT02987543 . [Table: see text]

Signal transducer and activator of transcription 3 (STAT3) is abundantly expressed in the adipose tissue of obese mice and humans, but the role of STAT3 in adipogenesis is still not fully understood. In the present study, we discovered an activation of STAT3 during the early differentiation stage of mouse 3T3-L1 preadipocytes. Stat3 knockdown using siRNA blocked cell cycle progression of both preadipoctes and early differentiating cells. Moreover, accumulation of lipid droplets was inhibited by Stat3 knockdown. Importantly, in the nucleus of early differentiating cells, we demonstrated that STAT3 protein co-localized with high-mobility-group protein AT-hook 2 (HMGA2), which was reported to promote adipogenesis in a previous study. Taken together, our data indicate that STAT3 and HMGA2 cooperatively promote adipogenesis which highlight a more detail understanding of STAT3 related transcription factor network during adipogenesis.

TPS340 Background: A Phase II trial showed olaparib (tablets, 300 mg bid) in combination with abiraterone (1000 mg od plus prednisone/prednisolone 5 mg bid) significantly prolonged radiologic progression-free survival (rPFS) compared with abiraterone alone (median 13.8 vs 8.2 months; hazard ratio 0.65, 95% CI 0.44–0.97, P=0.034) in patients (pts) with mCRPC in the second-line metastatic setting who received prior docetaxel (Clarke et al. Lancet Oncol 2018). Treatment benefits were achieved irrespective of homologous recombination repair (HRR) mutation status, suggesting potential synergy between the two treatments that could impact a broader patient population. PROpel (EudraCT: 2018-002011-10) is the follow-on study to this, and the first Phase III trial to assess a PARP inhibitor in combination with abiraterone as first-line treatment in a genetically unselected mCRPC pt population. Methods: PROpel is a double-blind, placebo-controlled, international, multicenter study of pts randomized (1:1), as for the Phase II trial, to abiraterone (1000 mg od plus prednisone/prednisolone 5 mg bid) plus either olaparib (tablets, 300 mg bid) or placebo. Pts must not have received prior chemotherapy, new hormonal agents or other systemic treatment at mCRPC stage (except docetaxel at metastatic hormone-sensitive prostate cancer stage [mHSPC]). Randomization is stratified according to site of metastases (bone only vs visceral vs other) and docetaxel treatment at mHSPC stage (yes, no). The primary endpoint is investigator-assessed rPFS (RECIST v1.1 [soft tissue] and Prostate Working Cancer Group 3 [PCWG-3 criteria; bone]). Secondary objectives include time to first subsequent therapy or death, time to pain progression, overall survival, and health-related quality of life. Safety and tolerability will also be described. Exploratory endpoints include HRR subgroup analyses to confirm that efficacy is independent of HRR status. Screening across ~200 sites in 20 countries is being conducted to identify a target sample of ~720 pts. Enrollment is expected to begin in October 2018. (Study 8, NCT01972217). Clinical trial information: NCT03732820.

5538 Background: In the Phase III PROfound study (NCT02987543) olaparib significantly improved radiographic progression-free survival (primary endpoint) vs pcNHA (enzalutamide or abiraterone) in patients (pts) with mCRPC and homologous recombination repair (HRR) gene alterations. In pts with alterations in BRCA1, BRCA2 and/or ATM (cohort A), time to pain progression was also significantly improved by olaparib vs pcNHA. We report additional pain analyses evaluated in the overall study population (cohort A and B). Methods: Pts were randomized to olaparib tablets (300 mg bid; n=256) or pcNHA (n=131). Pts completed the Brief Pain Inventory-Short Form (BPI–SF) questionnaire (electronic administration) every 4 weeks up to 6 months after progression or treatment crossover. Responses were analysed to determine time to progression to worst pain, pain severity and first opiate use for cancer-related pain (Kaplan-Meier), and also pain interference in daily activity (mixed model for repeated measures). Results: 85% and 76% of olaparib pts were free of pain progression (worst pain item) compared with 75% and 51% in the pcNHA arm, respectively at 6 and 12 months. The proportion of pts without pain progression (overall pain severity) also favoured olaparib (Table). Median time to first opiate use was significantly prolonged in olaparib arm compared with pcNHA arm; 18 months for olaparib vs 9 months for pcNHA (Table). BPI-SF pain interference scores were also more favourable for olaparib than pcNHA; difference in overall adjusted mean change from baseline score −0.75 (95% CI: −1.14, −0.36) P=0.0002. Further pain burden results for cohort A will also be presented. Conclusions: Olaparib reduced the burden of pain and time to first opiate use in pts with mCRPC and HRR gene alterations vs pcNHA, demonstrating a clinical and symptomatic patient benefit. Clinical trial information: NCT02987543 . [Table: see text]

134 Background: Optimal sequencing of therapies for mCRPC is not established. In the Phase III PROfound study (NCT02987543), ola significantly prolonged radiographic progression-free survival (rPFS) vs physician’s choice of new hormonal agent (pcNHA) in pts with mCRPC and an alteration in genes with a direct or indirect role in HRR. We report exploratory subgroup analyses by prior taxane (yes vs no). Methods: Men with mCRPC that had progressed on prior NHA were randomized to ola (tablets; 300 mg bid) or pcNHA (enzalutamide or abiraterone). Pts had alterations in BRCA1, BRCA2 or ATM (Cohort A) or ≥1 of 12 other prespecified genes with a direct or indirect role in HRR (Cohort B). Stratification factors were prior taxane use and measurable disease. rPFS was assessed by blinded independent central review with RECIST v1.1 + PCWG3. Results: Subgroup analyses of rPFS and overall survival (OS) favored ola vs pcNHA irrespective of prior taxane in Cohort A, Cohorts A+B and pts with a BRCA1 and/or BRCA2 or CDK12 alteration (Table). In the ATM subgroup hazard ratio (HR) point estimates for rPFS and OS were lower in pts who had received prior taxane vs pts who had not, but 95% CIs overlapped and pt numbers were small so data should be interpreted with caution. Conclusions: The benefit of ola over pcNHA in pts with mCRPC and HRR gene alterations was generally independent of prior taxane status in the overall study population. Clinical trial information: NCT02987543. [Table: see text]