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Background: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. Patients and methods: We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death. Results: The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90). Conclusions: Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherap

Background: Olaparib has significantly improved outcome and patient-centered endpoints in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer (PSOC). Specific information on efficacy and safety of olaparib for older patients appears of special interest. Methods: 295 patients from the SOLO2 trial randomly assigned to olaparib or placebo were categorized according to age-cutoff at 65 years. Efficacy, tolerability, and quality of life (QoL) of olaparib relative to placebo within in each age group was analyzed. Results: Baseline characteristics were similar in patients ≥65 years (N = 62;21.0%) compared to patients <65 years (N = 233;78.9%). No significant difference in the magnitude of progression-free survival (PFS) benefit from olaparib for older patients (N = 40, hazard ratio [HR]≥65 0.43, 95%-confidence interval [CI] 0.24–0.81) as compared with younger patients (N = 155, HR<65 0.31 (95%-CI 0.22–0.43) was seen (interaction P = 0.33). The overall survival (OS)benefit seen in younger patients in the olaparib arm was not observed in older patients. Older and younger patients had comparable safety profiles and QoL scores although higher discontinuation rates for toxicity, and higher frequency of AML/MDS were noted in the older subset. TWiST analysis revealed clinically meaningful duration of good QoL on olaparib for both age groups (≥65: 13.5 vs <65: 18.4 months, P = 0.05). Conclusions: Results of this large phase III cohort of BRCA1/2-mutated PSOC patients treated with olaparib underline impressive efficacy of olaparib maintenance irrespective of age. Although toxicity and tolerability did not raise significant concerns, some caution, close monitoring, and follow-up needs to be exercised for older patients given higher discontinuation rates, frequency of AML/MDS, and no clear effects on OS.

Retinal vessel calibre metrics were evaluated at baseline and 2 years in a FIELD substudy (n = 208). Central retinal venule calibre was significantly reduced by fenofibrate and unchanged by placebo. Arteriole metrics did not change. Larger studies relating retinal vessel calibre to future diabetes complications and response to therapy are merited.

Background: Olaparib has significantly improved outcome and patient-centered endpoints in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer (PSOC). Specific information on efficacy and safety of olaparib for older patients appears of special interest. Methods: 295 patients from the SOLO2 trial randomly assigned to olaparib or placebo were categorized according to age-cutoff at 65 years. Efficacy, tolerability, and quality of life (QoL) of olaparib relative to placebo within in each age group was analyzed. Results: Baseline characteristics were similar in patients ≥65 years (N = 62;21.0%) compared to patients <65 years (N = 233;78.9%). No significant difference in the magnitude of progression-free survival (PFS) benefit from olaparib for older patients (N = 40, hazard ratio [HR]≥65 0.43, 95%-confidence interval [CI] 0.24–0.81) as compared with younger patients (N = 155, HR<65 0.31 (95%-CI 0.22–0.43) was seen (interaction P = 0.33). The overall survival (OS)benefit seen in younger patients in the olaparib arm was not observed in older patients. Older and younger patients had comparable safety profiles and QoL scores although higher discontinuation rates for toxicity, and higher frequency of AML/MDS were noted in the older subset. TWiST analysis revealed clinically meaningful duration of good QoL on olaparib for both age groups (≥65: 13.5 vs <65: 18.4 months, P = 0.05). Conclusions: Results of this large phase III cohort of BRCA1/2-mutated PSOC patients treated with olaparib underline impressive efficacy of olaparib maintenance irrespective of age. Although toxicity and tolerability did not raise significant concerns, some caution, close monitoring, and follow-up needs to be exercised for older patients given higher discontinuation rates, frequency of AML/MDS, and no clear effects on OS.

BH3 mimetics like venetoclax target prosurvival Bcl-2 family proteins and are important therapeutics in the treatment of hematological malignancies. We demonstrate that endogenous Bfl-1 expression can render preclinical lymphoma tumor models insensitive to Mcl-1 and Bcl-2 inhibitors. However, suppression of Bfl-1 alone was insufficient to fully induce apoptosis in Bfl-1-expressing lymphomas, highlighting the need for targeting additional prosurvival proteins in this context. Importantly, we demonstrated that cyclin-dependent kinase 9 (CDK9) inhibitors rapidly downregulate both Bfl-1 and Mcl-1, inducing apoptosis in BH3-mimetic-resistant lymphoma cell lines in vitro and driving in vivo tumor regressions in diffuse large B-cell lymphoma patient-derived xenograft models expressing Bfl-1. These data underscore the need to clinically develop CDK9 inhibitors, like AZD4573, for the treatment of lymphomas using Bfl-1 as a selection biomarker.Copyright © 2021 American Society of Hematology

BACKGROUND: Migration to India is a common livelihood strategy for poor people in remote Western Nepal. To date, little research has explored the degree and nature of healthcare access among Nepali migrant workers in India. This study explores the experiences of returnee Nepali migrants with regard to accessing healthcare and the perspectives of stakeholders in the government, support organizations, and health providers working with migrant workers in India. METHODS: Six focus group discussions (FGDs) and 12 in-depth interviews with returnee migrants were conducted by trained moderators in six districts in Western Nepal in late 2017. A further 12 stakeholders working in the health and education sector were also interviewed. With the consent of the participants, FGDs and interviews were audio-recorded. They were then transcribed and translated into English and the data were analysed thematically. RESULTS: The interviewed returnee migrants worked in 15 of India's 29 states, most as daily-wage labourers. Most were from among the lowest castes so called-Dalits. Most migrants had had difficulty accessing healthcare services in India. The major barriers to access were the lack of insurance, low wages, not having an Indian identification card tied to individual biometrics so called: Aadhaar card. Other barriers were unsupportive employers, discrimination at healthcare facilities and limited information about the locations of healthcare services. CONCLUSIONS: Nepali migrants experience difficulties in accessing healthcare in India. Partnerships between the Nepali and Indian governments, migrant support organizations and relevant stakeholders such as healthcare providers, government agencies and employers should be strengthened so that this vulnerable population can access the healthcare they are entitled to.

BACKGROUND: Since Nepali cross-border migrants can freely enter, work and stay in India, they are largely undocumented. The majority is involved in semi-skilled or unskilled jobs with limited labour rights and social security, a fact which predisposes them to psychological distress. We aimed to assess the prevalence of and factors associated with psychological morbidity among Nepali migrants upon their return from India. METHODS: A community based cross-sectional study was conducted in six districts of Nepal between September 2017 and February 2018. A total of 751 participants who had worked at least six months in India and returned to Nepal were interviewed from 24 randomly selected clusters. The General Health Questionnaire (GHQ)-12 was used to measure the psychological morbidity. Data were analysed using Poisson regression analysis. RESULTS: The majority was younger than 35 years (64.1%), male (96.7%), married (81.8%), had at least a primary education (66.6%), and belonged to Dalit, Janajati and religious minorities (53.7%). The prevalence of psychological morbidity was 13.5% (CI: 11.2-16.1%). Participants aged 45 years and above (adjusted prevalence ratio (aPR) = 2.74), from the Terai (aPR = 3.29), a religious minority (aPR = 3.64), who received no sick leave (aPR = 2.4), with existing health problems (aPR = 2.0) and having difficulty in accessing health care (aPR = 1.88) were more likely than others to exhibit a psychological morbidity. CONCLUSION: This study demonstrated that psychological morbidity was prevalent in the study participants and varied significantly with individual characteristics, work conditions and health. Multifaceted approaches including psychological counselling for returnees and protection of labour and health rights in the workplace are recommended to help reduce psychological morbidity.