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  BH3-mimetics: recent developments in cancer therapy

  Townsend, Paul A; Kozhevnikova, M. V.; Cexus, O. N. F.; Zamyatnin, A. A., Jr.; Soond, S. M.; University of Surrey, Guildford, UK. (2021)

  The hopeful outcomes from 30 years of research in BH3-mimetics have indeed served a number of solid paradigms for targeting intermediates from the apoptosis pathway in a variety of diseased states. Not only have such rational approaches in drug design yielded several key therapeutics, such outputs have also offered insights into the integrated mechanistic aspects of basic and clinical research at the genetics level for the future. In no other area of medical research have the effects of such work been felt, than in cancer research, through targeting the BAX-Bcl-2 protein-protein interactions. With these promising outputs in mind, several mimetics, and their potential therapeutic applications, have also been developed for several other pathological conditions, such as cardiovascular disease and tissue fibrosis, thus highlighting the universal importance of the intrinsic arm of the apoptosis pathway and its input to general tissue homeostasis. Considering such recent developments, and in a field that has generated so much scientific interest, we take stock of how the broadening area of BH3-mimetics has developed and diversified, with a focus on their uses in single and combined cancer treatment regimens and recently explored therapeutic delivery methods that may aid the development of future therapeutics of this nature.
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  On Target 2: updated guidance for image-guided radiotherapy

  McNair, H. A.; Franks, K. N.; van Herk, Marcel; Royal Marsden NHS Foundation Trust, Sutton, UK; Institute of Cancer Research, London, UK (2021)
• Manchester Intermittent versus Daily Diet App Study (MIDDAS): A pilot randomized controlled trial in patients with type 2 diabetes

  McDiarmid, S.; Harvie, Michelle N; Johnson, R.; Vyas, A.; Aglan, A.; Moran, J.; Ruane, H.; Hulme, A.; Sellers, K.; Issa, B. G.; et al. (2021)

  Aims: To test the feasibility and potential efficacy of remotely supported intermittent low energy diets (ILEDs) and continuous low energy diets (CLEDs) in people with type 2 diabetes (T2D) and the feasibility of a Randomized Controlled Trial (RCT) comparing the two approaches. Materials and methods: Seventy-nine adults with overweight/obesity and T2D (≤8 years duration) were randomized 1:1 to CLED (eight weeks/56 days of daily Optifast 820kcal (3430kJ) diet) or isoenergetic ILED (two days of Optifast and five days of a Mediterranean diet/week for 28 weeks). Weight maintenance/continued weight loss was undertaken for the remainder of the 52 weeks. Both groups received frequent telephone and/or the Oviva app support. Feasibility outcomes included study uptake, retention, app usage, dietary adherence, weight loss, and change in HbA1c at 52 weeks. Results: We enrolled 39 ILED and 40 CLED participants and 27 (69%) ILED and 30 CLED (75%) attended 52-week follow-up. Eighty-nine percent (70/79) started using the app and 86% (44/51) still used the app at 52 weeks. Intention-to-treat analysis at 52 weeks showed percentage weight loss was mean (CI) -5.4% (-7.6, -3.1%) for ILED and -6.0% (-7.9, -4.0%) for CLED. HbA1c<48mmol/mol was achieved in 42% of both groups. Mean (CI) changes in the T2D medication effect score (MES) were 0.0008 (-0.3, 0.3) for ILED and -0.5 (-0.8, -0.3) for CLED. Conclusion: The study demonstrates the feasibility and potential efficacy of remotely delivered ILED and CLED programs for weight loss and HbA1c reduction, and the feasibility of an RCT comparing the two approaches.
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  A phase I/II study to assess the safety and efficacy of pazopanib and pembrolizumab combination therapy in patients with advanced renal cell carcinoma

  Chowdhury, S.; Infante, J. R.; Hawkins, Robert E; Voss, M. H.; Perini, R.; Arkenau, T.; Voskoboynik, M.; Aimone, P.; Naeije, I.; Reising, A.; et al. (2021)

  Background: This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma. Patients and methods: This was an open-label, two-part, multicenter study involving treatment-naïve patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted. Results: Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group. Conclusions: Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach.
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  Proton therapy in supradiaphragmatic lymphoma: predicting treatment-related mortality to help optimize patient selection

  Ntentas, G.; Dedeckova, K.; Andrlik, M.; Aznar, Marianne Camille; Shakir, R.; Ramroth, J.; Begum, R.; Kubeš, J.; Darby, S. C.; Mikhaeel, N. G.; et al. (2021)

  Purpose: In some Hodgkin lymphoma (HL) patients, proton beam therapy (PBT) may reduce the risk of radiation-related cardiovascular disease (CVD) and second cancers (SC) compared with photon radiotherapy (photon-RT). Our aim was to identify those who benefit most from PBT in terms of predicted 30-year absolute mortality risks (AMR30) from CVD and SC, taking into account individual background, chemotherapy, radiation and smoking-related risks. Methods and materials: Eighty patients with supradiaphragmatic HL treated with PBT during 2015-2019 were re-planned using optimal photon-RT. To identify patients predicted to derive the greatest benefit from PBT compared to Photon-RT, doses and AMR30 from CVD and SC of the lung, breast and esophagus were compared for all patients and across patient subgroups. Results: For patients with mediastinal disease below the origin of the left main coronary artery (n=66, 82%), PBT reduced mean dose to heart, left ventricle and heart valves by 1.0, 2.7 and 3.6 Gray (Gy) respectively. Based on US mortality rates, PBT reduced CVD AMR30 by 0.2%, from 5.9% to 5.7%. The benefit was larger if the mediastinal disease overlapped longitudinally with the heart by ≥40% (n=23, 29%), where PBT reduced mean dose to heart, left ventricle and heart valves by 3.2, 5.6, and 5.1Gy respectively, and reduced CVD AMR30 by 0.8%, from 7.0% to 6.2%. For patients with axillary disease (n=25, 31%), PBT reduced mean lung dose by 2.8Gy and lung cancer AMR30 by 0.6%, from 2.7% to 2.1%. Breast and esophageal doses were also lower with PBT but effects on AMR30 were negligible. The effect of smoking on CVD and lung cancer AMR30 was much larger than radiation and chemotherapy and the differences between radiation modalities. Conclusions: The predicted benefit of PBT is not universal and is limited to certain categories of lymphoma patients with lower mediastinal or axillary disease. Smoking cessation should be strongly encouraged in smokers requiring thoracic radiotherapy.

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