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Abstract: This multicenter study sponsored by the GETH-TC investigates the incidence and predictors of early (first 100 days) and late cardiac events (CEs; ECEs and LCEs, respectively) after allo-HCT in patients with acute myeloid leukemia (AML) treated with anthracyclines, focusing on exploring the impact of PTCY on cardiac complications and the impact of CEs on OS and NRM. A total of 1020 patients with AML were included. PTCY was given to 450 (44.1%) adults. Overall, 94 (9.2) patients experienced CEs, with arrythmias, pericardial complications, and heart failure the most prevalent. ECEs occurred in 49 (4.8%) patients within a median of 13 days after allo-HCT, whereas LCEs were diagnosed in 45 (4.4%) patients within a median of 3.6 years after transplant. Using PTCY increased the risk for ECEs in multivariate analysis (hazard ratio [HR], 2.86; P = .007) but did not significantly affect the risk for LCEs (HR, 1.06; P = .892). The impact of variables on outcomes revealed was investigated using multivariate regression analyses and revealed that the diagnosis of CEs decreased the likelihood of OS (HR, 1.66; P = .005) and increased the likelihood of NRM (HR, 2.88; P < .001). Furthermore, despite using PTCY increased ECEs risk, its administration was beneficial for OS (HR, 0.71; P = .026). In conclusion, although the incidence of CEs was relatively low, it significantly affected mortality. Standard doses of PTCY increased ECE risk but were associated with improved OS. Therefore, protocols for preventing cardiac complications among these patients are needed., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Patients with chronic myeloid leukemia (CML) who have failed conventional tyrosine kinase inhibitors (cTKIs) and asciminib constitute a complex group of patients with few therapeutic options. A retrospective descriptive multicenter observational study was carried out including patients with CML who had presented a therapeutic failure to ≥ 2 cTKIs and asciminib, and had received or were not candidates to ponatinib. Of the 19 patients enrolled, 8 patients failed asciminib due to intolerance and 11 due to resistance. The most common strategy for intolerant patients was to initiate a previously administered cTKI (6/8) with dose adjustments or symptomatic management of adverse events (AEs). Of the patients who failed due to resistance, only patients who underwent progenitor transplantation achieved profound long-term responses. A frequent strategy was to use ponatinib (4/11) in patients previously considered non-candidates, with poor responses in patients in whom dose reductions were used, and severe AEs in patients at standard doses. In the remaining patients, cTKIs and other agents (interferon, hydroxyurea, citarabine, busulfan) were used with poor responses. Patients who progressed to advanced stages had a dismal prognosis. With a median follow-up of 11.2 months, overall survival of the global cohort was 73%; 100% for intolerant patients, 71% for resistant patients and 25% for those who discontinue asciminib in accelerated/blastic phase., (© 2024. The Author(s).)

Testicular germ cell tumors are the most common tumors in adolescent and young men. They are curable malignancies that should be treated with curative intent, minimizing acute and long-term side effects. Inguinal orchiectomy is the main diagnostic procedure, and is also curative for most localized tumors, while patients with unfavorable risk factors for recurrence, or those who are unable or unwilling to undergo close follow-up, may require adjuvant treatment. Patients with persistent markers after orchiectomy or advanced disease at diagnosis should be staged and classified according to the IGCCCG prognostic classification. BEP is the most recommended chemotherapy, but other schedules such as EP or VIP may be used to avoid bleomycin in some patients. Efforts should be made to avoid unnecessary delays and dose reductions wherever possible. Insufficient marker decline after each cycle is associated with poor prognosis. Management of residual masses after chemotherapy differs between patients with seminoma and non-seminoma tumors. Patients at high risk of relapse, those with refractory tumors, or those who relapse after chemotherapy should be managed by multidisciplinary teams in experienced centers. Salvage treatment for these patients includes conventional-dose chemotherapy (TIP) and/or high-dose chemotherapy, although the best regimen and strategy for each subgroup of patients is not yet well established. In late recurrences, early complete surgical resection should be performed when feasible. Given the high cure rate of TGCT, oncologists should work with patients to prevent and identify potential long-term side effects of the treatment. The above recommendations also apply to extragonadal retroperitoneal and mediastinal tumors., (© 2024. The Author(s).)

Gastric cancer (GC) is the fifth most common cancer worldwide with a varied geographic distribution and an aggressive behavior. In Spain, the incidence is lower and GC represents the tenth most frequent tumor and the seventh cause of cancer mortality. Molecular biology knowledge allowed to better profile patients for a personalized therapeutic approach. In the localized setting, the multidisciplinary team discussion is fundamental for planning the therapeutic approach. Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors, and chemoradiation + surgery + adjuvant immunotherapy for the GEJ are current standards. For the metastatic setting, biomarker profiling including Her2, PD-L1, MSS status is needed. Chemotherapy in combination with checkpoint inhibitors had improved the outcomes for patients with PD-L1 expression. Her2 positive patients should receive antiHer2 therapy added to chemotherapy. We describe the different evidences and recommendations based on the literature., (© 2024. The Author(s).)

Autologous hematopoietic cell transplantation (AHCT) is a commonly used treatment in multiple myeloma (MM). However, real-world global demographic and outcome data are scarce. We collected data on baseline characteristics and outcomes from 61 725 patients with newly diagnosed MM who underwent upfront AHCT between 2013 and 2017 from nine national/international registries. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), relapse incidence (RI) and non-relapse mortality (NRM). Median OS amounted to 90.2 months (95% CI 88.2-93.6) and median PFS 36.5 months (95% CI 36.1-37.0). At 24 months, cumulative RI was 33% (95% CI 32.5%-33.4%) and NRM was 2.5% (95% CI 2.3%-2.6%). In the multivariate analysis, superior outcomes were associated with younger age, IgG subtype, complete hematological response at auto-HCT, Karnofsky score of 100%, international staging scoring (ISS) stage 1, HCT-comorbidity index (CI) 0, standard cytogenetic risk, auto-HCT in recent years, and use of lenalidomide maintenance. There were differences in the baseline characteristics and outcomes between registries. While the NRM was 1%-3% at 12 months worldwide, the OS at 36 months was 69%-84%, RI at 12 months was 12%-24% and PFS at 36 months was 43%-63%. The variability in these outcomes is attributable to differences in patient and disease characteristics as well as the use of maintenance and macroeconomic factors. In conclusion, worldwide data indicate that AHCT in MM is a safe and effective therapy with an NRM of 1%-3% with considerable regional differences in OS, PFS, RI, and patient characteristics. Maintenance treatment post-AHCT had a beneficial effect on OS., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Cancer-related anorexia-cachexia syndrome (CACS) is a debilitating condition afflicting up to 80% of advanced-stage cancer patients. Characterized by progressive weight loss, muscle wasting, and metabolic abnormalities, CACS significantly compromises patients' quality of life and treatment outcomes. This comprehensive review navigates through its intricate physiopathology, elucidating its stages and diagnostic methodologies. CACS manifests in three distinct stages: pre-cachexia, established cachexia, and refractory cachexia. Early detection is pivotal for effective intervention and is facilitated by screening tools, complemented by nutritional assessments and professional evaluations. The diagnostic process unravels the complex interplay of metabolic dysregulation and tumor-induced factors contributing to CACS. Management strategies, tailored to individual patient profiles, encompass a spectrum of nutritional interventions. These include dietary counseling, oral nutritional supplements, and, when necessary, enteral nutrition and a judicious use of parenteral nutrition. Specific recommendations for caloric intake, protein requirements, and essential nutrients address the unique challenges posed by CACS. While pharmacological agents like megestrol acetate may be considered, their use requires careful evaluation of potential risks. At its core, this review underscores the imperative for a holistic and personalized approach to managing CACS, integrating nutritional interventions and pharmacological strategies based on a nuanced understanding of patient's condition., (© 2024. The Author(s).)

Background: LAMVYX was a multicenter, single-arm, phase 2 trial designed to validate the safety and efficacy of CPX-351 in patients aged 60-75 years with newly diagnosed, secondary acute myeloid leukemia and to generate evidence on key issues not addressed in the preceding regulatory pivotal trial., Methods: The primary end point of the study was the complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate after induction. Eligible patients were recommended to undergo allogeneic hematopoietic stem cell transplantation after the first consolidation cycle. Alternatively, patients could undergo up to six maintenance cycles with CPX-351., Results: Twenty-nine patients (49%; 95% exact confidence interval [CI], 37%-62%) patients achieved a CR/CRi after one or two cycles of induction, with a measurable residual disease negativity rate of 67% as assessed by centralized, multiparameter flow cytometry. Among patients who had serial next-generation sequencing analyses available, clearance of somatic mutations that were present at diagnosis was achieved in 7 (35%). The median follow-up among survivors was 16.8 months (range, 8.7-24.3 months). The median event-free survival was 3.0 months (95% CI, 1.4-7.3 months), and the median overall survival was 7.4 months (95% CI, 3.7-12.7 months). In landmark analyses at day +100 from diagnosis, the 1-year overall and event-free survival rate among patients who underwent allogeneic hematopoietic stem cell transplantation was 70% (95% CI, 47%-100%) and 70% (95% CI, 47%-100%), respectively. The corresponding values were 89% (95% CI, 71%-100%) and 44% (95% CI, 21%-92%), respectively, for patients who entered the maintenance phase. No significant longitudinal changes were observed in severity index or quality-of-life visual analog scale scores., Conclusions: The current data provide novel insights that might inform the clinical positioning and optimal use of CPX-351, complementing previous results (ClinicalTrials.gov identifier NCT04230239)., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Peripheral T-cell lymphomas are aggressive non-Hodgkin lymphomas with few treatment options for relapsed or refractory disease. Valemetostat tosylate (valemetostat) is a potent, novel, dual inhibitor of EZH2 and EZH1. We investigated the clinical activity and safety of valemetostat in patients with relapsed or refractory peripheral T-cell lymphoma, and its safety in patients with relapsed or refractory adult T-cell leukaemia/lymphoma., Methods: VALENTINE-PTCL01 was a multicentre, open-label, single-arm, phase 2 trial performed at 47 hospitals in 12 countries across Asia, Europe, North America, and Oceania. Patients with either peripheral T-cell lymphoma or adult T-cell leukaemia/lymphoma, aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2 received oral valemetostat at 200 mg per day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for patients with peripheral T-cell lymphoma was the CT-based objective response rate by blinded independent central review (BICR) using 2014 Lugano response criteria. Patients who received valemetostat and had a confirmed eligible peripheral T-cell lymphoma subtype on central review were included in the efficacy analysis. The primary endpoint for patients with adult T-cell leukaemia/lymphoma was the safety and tolerability of valemetostat. Safety in both cohorts was assessed in all patients who received at least one dose of valemetostat. The trial is registered with ClinicalTrials.gov, NCT04703192, and EudraCT, 2020-004954-31, and is closed to enrolment., Findings: Between June 16, 2021, and Aug 10, 2022, 133 patients with relapsed or refractory peripheral T-cell lymphoma (median age 69·0 years [IQR 58·0-74·0]; 91 [68%] were male, and 42 [32%] were female) and 22 patients with adult T-cell leukaemia/lymphoma (66·5 years [54·0-73·0]; 15 [68%] were male, and seven [32%] were female) were enrolled. The median follow-up time was 12·3 months (95% CI 11·8-13·8). 52 (44%; 95% CI 35-53) of 119 efficacy-evaluable patients with relapsed or refractory peripheral T-cell lymphoma had an objective response. The most common grade 3-4 adverse events were thrombocytopenia (31 [23%] of 133 patients in the peripheral T-cell lymphoma group and 11 [50%] of 22 patients in the adult T-cell leukaemia/lymphoma group), anaemia (25 [19%] and ten [46%]), and neutropenia (23 [17%] and four [18%]). Serious treatment-emergent adverse events were reported in 53 (40%) patients with peripheral T-cell lymphoma and 15 (68%) patients with adult T-cell leukaemia/lymphoma; nine (7%) patients and one (5%) patient had a serious treatment-emergent adverse event considered to be treatment related, respectively. No treatment-related deaths were reported., Interpretation: These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma, with a manageable safety profile., Funding: Daiichi Sankyo., Competing Interests: Declaration of interests PLZ has received consulting fees from lncyte, Novartis, BeiGene, and SOBI, and honoraria from Takeda, AstraZeneca, MSD, Bristol Myers Squibb (BMS), lncyte, Roche, Gilead, Recordati, Kyowa Kirin, Novartis, BeiGene, Janssen, and SOBI, unrelated to this study. KIz has received manuscript support from Daiichi Sankyo to their institution, related to this work; research funding Chugai, BMS, Incyte, Genmab, LOXO Oncology, Daiichi Sankyo, BeiGene, AbbVie, AstraZeneca, Regeneron, Yakult, Chugai, Otsuka, Novartis, Pfizer, MSD, Bayer, Kyowa Kirin, Eisai, Janssen, Ono Pharmaceutical, Gilead, Astellas, and Amgen to their institution, unrelated to this work; consulting fees from AstraZeneca, Ono Pharmaceutical, Mitsubishi Tanabe, Eisai, Chugai, BMS, AbbVie, Takeda, Zenyaku, Genmab, Kyowa Kirin, MSD, Carna Biosicences, Novartis, Yakult, Nihon Shinyaku, Novartis, and BeiGene, unrelated to this work; and honoraria from AstraZeneca, Ono Pharmaceutical, Eisai, Chugai, Janssen, Symbio, BMS, Daiichi Sankyo, Otsuka, AbbVie, Takeda, Eli Lilly, Genmab, Kyowa Kirin, MSD, Astellas, Pfizer, Meiji Seika Pharma, Novartis, Nihon Kayaku, and Gilead, unrelated to this work. NM-S has received research funding from AstraZeneca, BMS, C4 Therapeutics, Celgene, Corvus Pharmaceuticals, Daiichi Sankyo, Dizal Pharmaceuticals, Genetech/Roche, Incyte, Innate Pharmaceuticals, Secura Bio, Verastem, and Yingli Pharmaceuticals, to their institutions, unrelated to this work; consulting fees from AstraZeneca, Kyowa Hakka Kirin, Karyopharm, Ono Pharmaceuticals, Secura Bios, Daiichi Sankyo, Genentech, and Janssen, unrelated to this work; and participated on a data safety monitoring board and an advisory board for Daiichi Sankyo, unrelated to this work. SKB received manuscript support from Daiichi Sankyo, related to this work; consulting fees and honoraria from Acrotech, Kyowa Kirin, and Seagen, unrelated to this work; and participated on a data safety monitoring board or advisory board for Janssen, unrelated to this work. KIs has received manuscript support from Daiichi Sankyo, related to this work; research funding from Ono Pharmaceutical and Kyowa Kirin to their institutions, unrelated to this work; honoraria from Kyowa Kirin, Takeda, Chugai Pharmaceutical, Celgene, BMS, Daiichi Sankyo, Ono Pharmaceutical, Astellas, Eisai, Pfizer, Otsuka, Sanofi, CSL Behring, AbbVie, Yakult, Janssen Pharmaceutical, and Nippon Shinyaku, unrelated to this work; participated on data safety monitoring board or advisory board for Meiji Seika Pharma and Daiichi Sankyo, unrelated to this work; and received materials from Ono Pharmaceutical to their institution, unrelated to this work. SK has received support from Daiichi Sankyo, related to this work; research funding from Chugai, Kyowa Kirin, and Janssen, unrelated to this work; and honoraria from Daiichi Sankyo, Chugai, Kyowa Kirin, and Janssen, unrelated to this work. EB has received research funding from Amgen and BMS, to their institution, unrelated to this work; honoraria from Novartis, Kite/Gilead, Roche, Takeda, Janssen, and AbbVie, unrelated to this work; support for attending meetings or travel from Roche and Kite/Gilead, unrelated to this work; and participated on data safety monitoring board or advisory board from Novartis, Kite/Gilead, Roche, Incyte, ADC Therapeutics, and AbbVie, unrelated to this work. KC received consulting fees from Roche, Takeda, Celgene, and AbbVie, unrelated to this work; honoraria from Roche and Takeda, unrelated to this work; support for attending meetings or travel from Roche, Takeda, and BMS, to their institution; and participated on data safety monitoring board or advisory board for Daiichi Sankyo, unrelated to this work. GG received honoraria from Ideogen and Takeda, unrelated to this work; support for attending meetings or travel from Roche, Kite-Gilead, Sandoz, BeiGene, and Janssen, unrelated to this work; and participated on data safety monitoring board or advisory board for AbbVie, Roche, Takeda, Kite-Gilead, Italfarmaco, Ideogen, and Genmab, unrelated to this work. EJ received research funding from Celgene, Merck, Pharmacyclics, and F Hoffman-LaRoche, unrelated to this work; honoraria from Merck, Daiichi, BMS, and Bayer, unrelated to this work; and has patents planned, issued, or pending with UpToDate, unrelated to this work. TF has received research funding from ADCT, AstraZeneca, BMS, Corvus, Daiichi, Genmab, Kymera, Merck, Seagen, TESSA, Trillium, Alexion, and Portola, unrelated to this work; consulting fees from ADCT, AstraZeneca, BMS, Epizyme, Genmab, Seagen, Pharmacyclics, and Celgene, unrelated to this work; honoraria from Takeda, Seagen, Genmab, Epizyme, ADCT, AstraZeneca, BMS, Pharmacyclics, AbbVie, and Pfizer, unrelated to this work; and owns stock in OMI and Genomic Testing Cooperative, unrelated to this work. DE received research funding from Nippon Shinyaku Pharmaceutical, Chugai Pharmaceutical, and Eisai Pharmaceutical, to their institution, unrelated to this work; and honoraria from Eisai Pharmaceutical, Chugai Pharmaceutical, SymBio Pharmaceuticals, BMS, Kyowa Kirin Pharmaceutical, and Nippon Shinyaku Pharmaceutical, unrelated to this work. EDD received consulting fees from Takeda, unrelated to this work; honoraria from Takeda and BeiGene, unrelated to this work; and funding for attending meetings or travel from Takeda, unrelated to this work. JZ received research funding from Secura Bio, Astex, CRSPR, Myeloid Therapeutics, and Daichi Sankyo, unrelated to this work; consulting fees from Seattle genetics, Secura Bio, Kyowa Kirin, and Myeloid Therapeutics, unrelated to this work; and honoraria from Kyowa Kirin, unrelated to this work. JJ, SW, TM, AI, and KN are employed by Daiichi Sankyo. TM has received support for attending meetings or travel from Daiichi Sankyo, unrelated to this work. AI, TM, and YC own stock options in Daiichi Sankyo, unrelated to this work. KN owns stock in Daiichi Sankyo, unrelated to this work. SH received research funding from the US National Institutes of Health/National Cancer Institute Cancer Center, (support grant P30 CA008748); research funding from ADC Therapeutics, Affimed, Aileron, Celgene, Crispr Therapeutics, Daiichi Sankyo, Forty Seven, Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio; and honoraria from Abcuro, Autolus, Auxilius Pharma, Corvus, Cimeio Therapeutics, Daiichi Sankyo, Dren Bio, Kyowa Hakko Kirin, March, Bio, Ono Pharmaceuticals, SecuraBio, Shore line, Biosciences, Takeda, Tubulis and Yingli Pharma. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Physical activity has emerged as a modifiable behavioral factor to improve cognitive function. However, research on adherence to remote monitoring of physical activity in older adults is limited., Objective: This study aimed to assess adherence to remote monitoring of physical activity in older adults within a pilot cohort from objective user data, providing insights for the scalability of such monitoring approaches in larger, more comprehensive future studies., Methods: This study included 22 participants from the Boston University Alzheimer's Disease Research Center Clinical Core. These participants opted into wearing the Verisense watch as part of their everyday routine during 14-day intervals every 3 months. Eighteen continuous physical activity measures were assessed. Adherence was quantified daily and cumulatively across the follow-up period. The coefficient of variation was used as a key metric to assess data consistency across participants over multiple days. Day-to-day variability was estimated by calculating intraclass correlation coefficients using a 2-way random-effects model for the baseline, second, and third days., Results: Adherence to the study on a daily basis outperformed cumulative adherence levels. The median proportion of adherence days (wearing time surpassed 90% of the day) stood at 92.1%, with an IQR spanning from 86.9% to 98.4%. However, at the cumulative level, 32% (7/22) of participants in this study exhibited lower adherence, with the device worn on fewer than 4 days within the requested initial 14-day period. Five physical activity measures have high variability for some participants. Consistent activity data for 4 physical activity measures might be attainable with just a 3-day period of device use., Conclusions: This study revealed that while older adults generally showed high daily adherence to the wearable device, consistent usage across consecutive days proved difficult. These findings underline the effectiveness of wearables in monitoring physical activity in older populations and emphasize the ongoing necessity to simplify usage protocols and enhance user engagement to guarantee the collection of precise and comprehensive data., (© Huitong Ding, Kristi Ho, Edward Searls, Spencer Low, Zexu Li, Salman Rahman, Sanskruti Madan, Akwaugo Igwe, Zachary Popp, Alexa Burk, Huanmei Wu, Ying Ding, Phillip H Hwang, Ileana De Anda-Duran, Vijaya B Kolachalama, Katherine A Gifford, Ludy C Shih, Rhoda Au, Honghuang Lin. Originally published in JMIR Aging (https://aging.jmir.org).)

Senescence, marked by permanent cell cycle arrest may contribute to the decline in regenerative potential and neuronal function, thereby promoting neurodegenerative disorders. In this study, we employed whole exome sequencing to identify a previously unreported biallelic missense variant in SVBP (p.Leu49Pro) in six patients from three unrelated families. These affected individuals present with a complex hereditary spastic paraplegia (HSP), peripheral neuropathy, verbal apraxia, and intellectual disability, exhibiting a milder phenotype compared to patients with nonsense SVBP mutations described previously. Consistent with SVBP's primary role as a chaperone necessary for VASH-mediated tubulin detyrosination, both patient fibroblasts with the p.Leu49Pro mutation, and HeLa cells harboring an SVBP knockdown exhibit microtubule dynamic instability and alterations in pericentriolar material (PCM) component trafficking and centrosome cohesion. In patient fibroblasts, structural abnormalities in the centrosome trigger mitotic errors and cellular senescence. Notably, premature senescence characterized by elevated levels of p16INK4, was also observed in patient peripheral blood mononuclear cells (PBMCs). Taken together, our findings underscore the critical role of SVBP in the development and maintenance of the central nervous system, providing novel insights associating cytokinesis failure with cortical motor neuron disease and intellectual disability., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Objective: We report patient-reported outcomes (PROs) measuring health-related quality of life (HRQoL) from the ROSEWOOD trial (NCT03332017), which demonstrated superior efficacy and a manageable safety profile with zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) in patients with heavily pretreated relapsed/refractory follicular lymphoma (R/R FL)., Methods: PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) and EQ-5D-5L questionnaires at baseline and subsequently every 12 weeks. All QLQ-C30 domains and EQ-5D-5L visual analog scale (VAS) scores were analyzed descriptively. At the key clinical timepoints (weeks 12 and 24), a mixed model for repeated measures (MMRM) analysis was used to evaluate the key PRO endpoints, including global health status, physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting. Clinically meaningful change was defined as a  ≥ 5-point mean difference from baseline and between the ZO and O arms., Results: Patients were randomized to ZO ( n  = 145) or O ( n  = 72). By week 48, descriptive analysis results indicated that patients in the ZO arm demonstrated improved outcomes in role functioning and fatigue and nausea/vomiting symptoms, compared with those in the O arm. Both groups experienced improvements in pain symptoms. EQ-5D-5L VAS scores showed no observable differences between treatment arms through week 48. MMRM analysis revealed that the global health status/quality of life of patients treated with ZO improved, as did fatigue, at week 12. At week 24, patients in the ZO arm experienced a clinically meaningful improvement in role functioning, pain, and fatigue., Conclusions: In patients with R/R FL, ZO was associated with improved PROs compared with O. These findings suggest that zanubrutinib contributed clinically meaningful benefits to patient HRQoL when added to obinutuzumab., Trial Registration: The ROSEWOOD trial is registered on ClinicalTrials.gov (BGB-3111-212; ClinicalTrials.gov identifier: NCT03332017).

Background and Objective: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024., Methods: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists")., Key Findings and Limitations: Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis., Conclusions and Clinical Implications: The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To assess the clinical outcome of patients with recurrent glioblastoma treated with salvage reirradiation., Methods: Between 2005 and 2022, data from adult patients with glioblastoma treated with surgery and radio-chemotherapy Stupp regimen who developed a local in-field relapse and received stereotactic radiotherapy (SRT) were retrospectively reviewed., Results: The study population included 44 patients with recurrent glioblastoma (median of 9.5 months after the first radiotherapy). Reirradiation alone was given to 47.7% of patients. The median maximum diameter of the recurrence was 13.5 mm. The most common SRT regimen (52.3%) was 35 Gy in 10 fractions. Acute toxicity was mild, with transient worsening of previous neurological symptoms in only 15% of patients. After a median follow-up of 15 months, 40% presented radiological response, but a remarkable number of early distant progressions were recorded (32.5%). The median time to progression was 4.8 months, being the dose, the scheme, the size of the recurrence or the strategy (exclusive RT vs. combined) unrelated factors. The median overall survival (OS) was 14.9 months. Karnofsky index < 70 and the size of the recurrence (maximum diameter < 25 mm) were significant factors associated with OS. Radiological changes after reirradiation were commonly seen (> 50% of patients) hindering the response assessment., Conclusions: Reirradiation is a feasible and safe therapeutic option to treat localized glioblastoma recurrences, able to control the disease for a few months in selected patients, especially those with good functional status and small lesions. Hypofractionated schemes provided a suitable toxicity profile. Radiological changes were common., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma arising in an immune-privileged site and has recently been recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). We describe the genetic features of TLBCL and compare them with published series of nodal DLBCL and primary large B-cell lymphomas of the CNS (PCNSL). We collected 61 patients with TLBCL. We performed targeted next-generation sequencing, copy number arrays, and fluorescent in situ hybridization to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. BCL6 rearrangements were detected in 36% of cases, and no concomitant BCL2 and MYC rearrangements were found. TLBCL had fewer copy number alterations ( p  < 0.04) but more somatic variants ( p  < 0.02) than nodal DLBCL and had more frequent 18q21.32-q23 ( BCL2 ) gains and 6q and 9p21.3 ( CDKN2A/B ) deletions. PIM1 , MYD88 L265P , CD79B , TBL1XR1 , MEF2B , CIITA , EP300, and ETV6 mutations were more frequent in TLBCL, and BCL10 mutations in nodal DLBCL. There were no major genetic differences between TLBCL and PCNSL. Localized or disseminated TLBCL displayed similar genomic profiles. Using LymphGen, the majority of cases were classified as MCD. However, we observed a subgroup of patients classified as BN2, both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile. TLBCL has a distinctive genetic profile similar to PCNSL, supporting its recognition as a separate entity from DLBCL and might provide information to devise targeted therapeutic approaches., Competing Interests: Ferran Nadeu has received honoraria from Janssen, AbbVie, AstraZeneca, and SOPHiA GENETICS for speaking at educational activities; has received research support from Gilead; and has licensed the use of the protected IgCaller algorithm to Diagnóstica Longwood. Tycho Baumann has received consulting fees or honoraria from Janssen, Roche, Novartis, Merck, Gilead/Kite, Incyte, Lilly, Abbvie, AstraZeneca, and BeiGene. Alejandro Martin García‐Sancho has received consulting fees or honoraria from Janssen, Roche, BMS/Celgene, Kyowa Kirin, Clinigen, EUSAPharma, Novartis, Gilead/Kite, Incyte, Lilly, Takeda, ADC Therapeutics America, Miltenyi, Ideogen, Abbvie, and BeiGene. Elías Campo has been a consultant for GenMab, and Takeda; has received research support from AstraZeneca; received honoraria from Janssen, EUSPharma, Takeda, and Roche for speaking at educational activities; and is an inventor on a Lymphoma and Leukemia Molecular Profiling Project patent “Method for subtyping lymphoma subtypes by means of expression profiling” (PCT/US2014/64161) and a bioinformatic tool (IgCaller) licensed to Diagnostic Longwood. Eva Giné has received honoraria or consulting fees from Gilead, Kite Pharma, Janssen, Genmab, Miltenyi, and Lilly; has received research support from Janssen and travel expenses from Gilead and Kite Pharma. Armando López Guillermo served on the advisory board of Roche, Celgene, Novartis, and Gilead/Kite, received grants from Celgene and Gilead/Kite, and travel expenses from Kite/Gilead. The remaining authors declare no competing interests., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Paired related homeobox 1 (PRRX1) is an inducer of epithelial-to-mesenchymal transition (EMT) in different types of cancer cells. We detected low PRRX1 expression in nevus but increased levels in primary human melanoma and cell lines carrying the BRAF V600E mutation. High expression of PRRX1 correlates with invasiveness and enrichment of genes belonging to the EMT programme. Conversely, we found that loss of PRRX1 in metastatic samples is an independent prognostic predictor of poor survival for melanoma patients. Here, we show that stable depletion of PRRX1 improves the growth of melanoma xenografts and increases the number of distant spontaneous metastases, compared to controls. We provide evidence that loss of PRRX1 counteracts the EMT phenotype, impairing the expression of other EMT-related transcription factors, causing dysregulation of the ERK and signal transducer and activator of transcription 3 (STAT3) signaling pathways, and abrogating the invasive and migratory properties of melanoma cells while triggering the up-regulation of proliferative/melanocytic genes and the expression of the neural-crest-like markers nerve growth factor receptor (NGFR; also known as neurotrophin receptor p75NTR) and neural cell adhesion molecule L1 (L1CAM). Overall, our results indicate that loss of PRRX1 triggers a switch in the invasive programme, and cells de-differentiate towards a neural crest stem cell (NCSC)-like phenotype that accounts for the metastatic aggressiveness., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Invasive fungal infections (IFI) pose a significant complication after hematopoietic stem cell transplantation (HSCT). Isavuconazole (ISV) is a new generation azole with a favourable adverse effect and interaction profile approved for the treatment of invasive aspergillosis and mucormycosis. We analyzed the indications, effectiveness, adverse event profile and drug interaction management of ISV in the real-world setting in adults who received allogeneic-HSCT (allo-HSCT) within the Spanish Group of HSCT and Cell Therapy (GETH-TC). We conducted a multicenter retrospective study of all consecutive adult allo-HSCT recipients (≥18 years) who received ISV either for IFI treatment or prophylaxis, from December 2017 to August 2021, in 20 centers within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cell Therapy (GETH-TC). A total of 166 adult allografted patients who received ISV from 2017 to 2021 were included. Median age was 48 years with 43% females. In 81 (49%) patients, ISV was used for treatment of IFI, and in 85 (51%) for prophylaxis. Median duration of ISV administration for IFI treatment was 57 days (range 31-126) and 86 days (range 33-196) for prophylaxis. Most frequent indication for treatment was invasive aspergillosis (78%), followed by mucormycosis (6%). Therapeutic success (45%) was the most frequent reason for ISV withdrawal. In the prophylaxis group, the resolution of IFI risk factors was the most frequent reason for withdrawal (62%). Six (7%) breakthrough IFI were reported. The majority of patients (80%) presented pharmacologic interactions. Twenty-one patients (13%) reported adverse events related to ISV, mainly liver biochemistry abnormalities, which led to ISV withdrawal in 7 patients (4%). ISV was effective and well tolerated for IFI treatment and prophylaxis, with a manageable interaction profile., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR)-T cell therapy is approved for the treatment of relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, elderly patients might not be candidates for this therapy due to its toxicity, and criteria for candidate selection are lacking. Our aim was to analyze efficacy and toxicity results of CAR-T cell therapy in the population of patients 70 years and older as compared to those obtained in younger patients in the real-world setting. A multicentric retrospective study was performed including patients with R/R aggressive LBCL who received commercial CAR-T cell therapy with either tisagenlecleucel or axicabtagene ciloleucel within the Spanish Group of Hematopoietic Transplant and Cell Therapy/Spanish Group of Lymphomas and Autologous Transplant (GETH-TC/GELTAMO) centers between 2019 and 2023. As of August 2023, 442 adult patients with aggressive LBCL underwent apheresis for CAR-T cell therapy as third or subsequent line and follow-up data was collected. Of 412 infused patients, 71 (17%) were 70 years or older. Baseline characteristics, product selection, and characteristics at apheresis (including disease status, Ann Arbor stage, revised international prognosis index (R-IPI), bulky disease, lactate dehydrogenase [LDH] and ECOG [Eastern Cooperative Group performance status]) were comparable between groups. Median time from both approval to infusion and apheresis to infusion did not differ. No differences were found between groups in overall and complete response rates at 1 and 3 months. With a median follow-up of 12.2 months (range 1-44), 12-month progression-free survival (PFS) and overall survival (OS) were comparable between groups (35.2% in <70 years vs. 35.9% in ≥70 years (P = .938) and 51.1% and 52.1% (P = .885), respectively). Age ≥70 years did not affect PFS (hazard ratio (HR) 0.98, P = .941) and OS (HR 0.97, P = .890) in the univariate and multivariate analysis. Cytokine release syndrome (CRS) was observed in 82% of patients <70 years old and 84.5% in ≥ 70 years old (P = .408). Grade ≥3 CRS was more frequent in the older group (5% vs. 15%, P = .002). In the multivariate analysis, age ≥70 years was associated with an increased risk of grade ≥3 CRS (OR 3.7, P = .013). No differences were observed in terms of overall neurotoxicity (35% vs. 42%, P = .281) or grade ≥3 (12% vs. 17%, P = .33). The proportion of patients with infections, admission to the intensive care unit within the first month, and non-relapse mortality were similar between both groups. CAR-T cell therapy in patients older than 70 years showed similar efficacy to that observed in younger patients in the real-world setting. However, age ≥70 years was an independent risk factor for grades 3-4 CRS. The need for additional strategies to reduce toxicity in this population should be addressed in future studies., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

This study compared decitabine exposure when administered IV (DEC-IV) at a dose of 20 mg/m 2 for 5-days with orally administered decitabine with cedazuridine (DEC-C), as well as the clinical efficacy and safety of DEC-C in patients with acute myeloid leukaemia (AML) who were ineligible for intensive induction chemotherapy. In all, 89 patients were randomised 1:1 to DEC-IV or oral DEC-C (days 1-5 in a 28-day treatment cycle), followed by 5 days of the other formulation in the next treatment cycle. All patients received oral DEC-C for subsequent treatment cycles until treatment discontinuation. Equivalent systemic decitabine exposures were demonstrated (5-day area under the curve ratio between the two decitabine formulations of 99.64 [90% confidence interval 91.23%, 108.80%]). Demethylation rates also were similar (≤1.1% difference). Median overall survival (OS), clinical response and safety profile with oral DEC-C were consistent with those previously observed with DEC-IV. Next-generation sequencing was performed to identify molecular abnormalities that impact OS and TP53 mutations were associated with a poor outcome. These findings support the use of oral DEC-C in patients with AML., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: To evaluate atezolizumab combined with platinum-based chemotherapy (CT) followed by maintenance niraparib for late-relapsing recurrent ovarian cancer., Methods: The multicenter placebo-controlled double-blind randomized phase III ENGOT-OV41/GEICO 69-O/ANITA trial (ClinicalTrials.gov identifier: NCT03598270) enrolled patients with measurable high-grade serous, endometrioid, or undifferentiated recurrent ovarian cancer who had received one or two previous CT lines (most recent including platinum) and had a treatment-free interval since last platinum (TFIp) of >6 months. Patients were stratified by investigator-selected carboplatin doublet, TFIp, BRCA status, and PD-L1 status in de novo biopsy and randomly assigned 1:1 to receive either atezolizumab or placebo throughout standard therapy comprising six cycles of a carboplatin doublet followed (in patients with response/stable disease) by maintenance niraparib until progression. The primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1., Results: Between November 2018 and January 2022, 417 patients were randomly assigned (15% BRCA- mutated, 36% PD-L1-positive, 66% TFIp >12 months, 11% previous poly [ADP-ribose] polymerase inhibitor after frontline CT, and 53% previous bevacizumab). Median follow-up was 28.6 months (95% CI, 26.6 to 30.5 months). Atezolizumab did not significantly improve PFS (hazard ratio, 0.89 [95% CI, 0.71 to 1.10]; P = .28). Median PFS was 11.2 months (95% CI, 10.1 to 12.1 months) with atezolizumab versus 10.1 months (95% CI, 9.2 to 11.2 months) with standard therapy. Subgroup analyses generally showed consistent results, including analyses by PD-L1 status. The objective response rate (ORR) was 45% (95% CI, 39 to 52) with atezolizumab and 43% (95% CI, 36 to 49) with standard therapy. The safety profile was as expected from previous experience of these drugs., Conclusion: Combining atezolizumab with CT and maintenance niraparib for late-relapsing recurrent ovarian cancer did not significantly improve PFS or the ORR.

This multicenter study investigates the incidence and predictors of cardiac events (CE) following allo-HCT with PTCY in 453 AML patients. CE occurred in 57 (12.3%) patients within a median of 52 days (IQR: 13-289), with day 100 and 5-year cumulative incidences of 7.7% and 13.5%. Early (first 100 days) and late CE occurred at rates of 7.7% and 4.8%. The most prevalent CE were heart failure (n = 18, 31.6%), pericardial complications (n = 16, 28.1%), and arrhythmia (n = 14, 24.6%). The proportions of patients older than 55 years (64.9% vs. 46.1%, P = 0.010), with hypertension (36.8% vs. 18.4%, P = 0.001) and dyslipidemia (28.1% vs. 11.1%, P = 0.001) were higher in patients with CE. Patients undergoing haplo-HCT trend to have more CE (68.4% vs. 56.8%, P = 0.083). The multivariate regression analysis revealed that only hypertension (HR 1.88, P = 0.036) and dyslipidemia (HR 2.20, P = 0.018) were predictors for CE, with no differences according to donor type (haplo-HCT vs. others: HR 1.33, P = 0.323). Among the 57 patients with CE, the mortality rate was 12.2%. Notably, the diagnosis of CE negatively impacted NRM (HR 2.57, P = 0.011) and OS (HR 1.80, P = 0.009), underscoring necessity of aggressively treating cardiovascular risk factors, and implementing post-transplant cardiac monitoring protocols to prevent these complications., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Aim: Characterize the logistical challenges faced by healthcare professionals (HCPs), patients and caregivers during the chimeric antigen receptor T-cell (CAR T) treatment process for non-Hodgkin lymphoma patients. Materials & methods: HCPs in the US and UK experienced with CAR T administration participated in interviews and completed a web-based survey. Results: A total of 133 (80 US, 53 UK) HCPs participated. Two or more logistical challenges were identified by ≥60% of respondents across all stages of the CAR T process. Commonly reported challenges were lengthy waiting periods, administrative and payer-related barriers, limited healthcare capacity, caregiver support and (particularly in the US) patient out-of-pocket costs. Conclusion: The CAR T treatment process presents numerous challenges, highlighting an unmet need for more convenient therapies.

Abstract: A phase 2, international, open-label, nonrandomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary end point was objective response rate (ORR); secondary end points included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n = 38 angioimmunoblastic T-cell lymphoma (AITL), n = 25 PTCL not otherwise specified, and n = 2 other T-cell lymphomas. The ORR was 39.7% (95% confidence interval [CI], 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in patients with AITL (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the nonresponder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pretreated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. This trial was registered at www.ClinicalTrials.gov as #NCT02464228., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Neurotransmission is critical for brain function, allowing neurons to communicate through neurotransmitters and neuropeptides. RVD-hemopressin (RVD-Hp), a novel peptide identified in noradrenergic neurons, modulates cannabinoid receptors CB1 and CB2. Unlike hemopressin (Hp), which induces anxiogenic behaviors via transient receptor potential vanilloid 1 (TRPV1) activation, RVD-Hp counteracts these effects, suggesting that it may block TRPV1. This study investigates RVD-Hp's role as a TRPV1 channel blocker using HEK293 cells expressing TRPV1-GFP. Calcium imaging and patch-clamp recordings demonstrated that RVD-Hp reduces TRPV1-mediated calcium influx and TRPV1 ion currents. Molecular docking and dynamics simulations indicated that RVD-Hp interacts with TRPV1's selectivity filter, forming stable hydrogen bonds and van der Waals contacts, thus preventing ion permeation. These findings highlight RVD-Hp's potential as a therapeutic agent for conditions involving TRPV1 activation, such as pain and anxiety.

We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify novel genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. We collected data from 55 cohorts with a combined sample size of 732,564 participants (87% European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20% of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for the one-degree of freedom tests of interaction and two-degree of freedom joint tests of the main and interaction effect. In the cross-population meta-analyses, the one-degree of freedom variant-sleep interaction test identified 10 loci (P int <5.0e-9) not previously observed for lipids. Of interest, the ASPH locus (TG, LTST) is a target for aspartic and succinic acid metabolism previously shown to improve sleep and cardiovascular risk. The two-degree of freedom analyses identified an additional 7 loci that showed evidence for variant-sleep interaction (P joint <5.0e-9 in combination with P int <6.6e-6). Of these, the SLC8A1 locus (TG, STST) has been considered a potential treatment target for reduction of ischemic damage after acute myocardial infarction. Collectively, the 17 (9 with STST; 8 with LTST) loci identified in this large-scale initiative provides evidence into the biomolecular mechanisms underpinning sleep-duration-associated changes in lipid levels. The identified druggable targets may contribute to the development of novel therapies for dyslipidemia in people with sleep disturbances.

Bruck syndrome is an autosomal recessive form of osteogenesis imperfecta caused by biallelic variants in PLOD2 or FKBP10 and is characterized by joint contractures, bone fragility, short stature, and scoliosis. PLOD2 encodes LH2, which hydroxylates type I collagen telopeptide lysines, a critical step for collagen crosslinking. The Plod2 global knockout mouse model is limited by early embryonic lethality, and thus, the role of PLOD2 in skeletogenesis is not well understood. We generated a novel Plod2 mouse line modeling a variant identified in two unrelated individuals with Bruck syndrome: PLOD2 c.1559dupC, predicting a frameshift and loss of the long isoform LH2b. In the mouse, the duplication led to loss of LH2b mRNA as well as significantly reduced total LH2 protein. This model, Plod2fs/fs, survived up to E18.5 although in non-Mendelian genotype frequencies. The homozygous frameshift model recapitulated the joint contractures seen in Bruck syndrome and had indications of absent type I collagen telopeptide lysine hydroxylation in bone. Genetically labeling tendons with Scleraxis-GFP in Plod2fs/fs mice revealed the loss of extensor tendons in the forelimb by E18.5, and developmental studies showed extensor tendons developed through E14.5 but were absent starting at E16.5. Second harmonic generation showed abnormal tendon type I collagen fiber organization, suggesting structurally abnormal tendons. Characterization of the skeleton by μCT and Raman spectroscopy showed normal bone mineralization levels. This work highlights the importance of properly crosslinked type I collagen in tendon and bone, providing a promising new mouse model to further our understanding of Bruck syndrome., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The aim of the present study was to examine the effects of a rehabilitation program combined with a home-based vibration-assisted therapy on gait parameters in children with cerebral palsy (CP)., Methods: In a retrospective study, 180 children, 101 boys and 79 girls, (mean age 7.2 ± 3.3 years) with CP at Gross Motor Function Classification System (GMFCS) Level I and Level II were examined using gait analyses with the Leonardo Mechanograph® Gangway at three measurement points. The measurements were conducted before (M0) and after a six-month rehabilitation period (M6), as well as 12 months after the commencement of rehabilitation (M12). The difference between measurement points M6-M0 (treatment interval) and M12-M6 (follow-up interval) were compared, and significance was determined using the Wilcoxon test., Results: Children with CP at GMFCS Level I and II demonstrated a significant improvement in gait efficiency (pathlength/distance M6-M0: -0.053 (SD 0.25) vs M12-M6: -0.008 (0.36), p=0.038). There were no significant difference in change of mean velocity and average step length between M6-M0 and M12-M6 (p=0.964 and p=0.611)., Conclusions: The rehabilitation program seems to enhance gait efficiency in children with CP. German Clinical Trial Registry: DRKS0001131 at www.germanctr.de., Competing Interests: The authors have no conflict of interest.

This study aims to assess coping attitudes in primary caregivers of individuals diagnosed with Alzheimer's disease residing in an institution, and to evaluate the association between coping attitudes and levels of guilt, depression, and anxiety among caregivers. The sample of this study consists of 150 individuals with relatives diagnosed with Alzheimer. The Beck Anxiety Inventory, the Coping Attitudes Scale, the Guilt Inventory, and the Beck Depression Inventory were used in the present study. It was determined that the participants' coping levels were below the average score and that they frequently used problem focus coping attitudes. A positive relationship was found between the emotion focused, nonfunctional coping levels of the participants and their continuous guilt, anxiety and depression levels. Depression and guilt has a strong effect on coping attitudes, while anxiety was determined to be a moderate predictive variable. Findings show that caregivers with depression, anxiety and continuous guilt use non-functional and emotional coping more frequently., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population., Methods: AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m 2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184., Findings: Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group)., Interpretation: Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests EB, FG, ER, and SU report grants from Roche to their institution to support the conduct of the study. NC reports personal fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, OncXerna, Pieris, Pfizer, Roche, and Novocure; and grants or research support from GSK and AstraZeneca. KH reports personal fees from AstraZeneca, Chugai, Eisai, MSD/Merck, Taiho, and Takeda; and grants or research support from MSD/Merck, Chugai, Takeda, AstraZeneca, and Daiichi Sankyo. EH reports personal fees from GSK and Clovis. FM reports personal fees from Roche, Eisai, Novartis, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, MSD/Merck, GSK, Clovis, Gilead, Myriad Genetics, Seagen, and Stemline Menarini; grants or research support from Roche; and participation on data safety monitoring or advisory boards for Immutep, Amgen, and Palleos Healthcare. CM reports personal fees from Roche, Novartis, MSD/Merck, AstraZeneca, Pfizer, PharmaMar, ImmunoGen, Daiichi Sankyo, Novocure, BioNTtech, Eisai, and GSK. LF-M reports personal fees from AstraZeneca, GSK, MSD/Merck, Eisai, and Pharma&. YCL reports personal fees from AstraZeneca, and grants or research support from BeiGene. EP reports personal fees from GSK and AstraZeneca. BP reports personal fees from AstraZeneca, GSK, MSD/Merck, and Pharma&. CZ reports personal fees from Roche, Eisai, Novartis, AstraZeneca, Pfizer, QuintilesIMS, Clovis, Eli Lilly, Istituto Gentili, Daiichi Sankyo, Seagen, MSD/Merck, GSK, and Gilead; and grants or research support from Roche, Novartis, AstraZeneca, Pfizer, Eisai, Clovis, Gilead, Seagen, Eli Lilly, Daiichi Sankyo, and MSD/Merck. KT reports personal fees from AstraZeneca, Chugai Pharma, Takeda, MSD/Merck, Nippon Kayaku, Eisai, and Sanofi; and grants or research support from Chugai Pharma. AF reports personal fees from GSK, AstraZeneca, and MSD/Merck. MP reports personal fees from AstraZeneca, Eisai, GSK, and MSD/Merck. MPBG reports personal fees from AstraZeneca, GSK, MSD/Merck, PharmaMar, Clovis Oncology, Eisai, Pharma&, and Kyowa Kirin; and a leadership role for Geico. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Leukocyte telomere length (LTL) is an objective biomarker of biological aging, and it is proposed to play a crucial role in Alzheimer's disease (AD) risk. We aimed at evaluating the cross-sectional association between LTL and cognitive performance in middle-aged cognitively unimpaired individuals at increased risk of AD., Methods: A total of 1520 participants from the ALFA cohort were included. Relative telomere length was measured in leukocytes through qPCR. LTL was residualized against age and sex, and associations with cognitive performance were assessed in short and long groups based on residualized LTL (rLTL). Interactions with sex and genetic risk of AD were tested., Results: Non-linear associations were found between LTL and episodic memory (EM). Better EM was associated with longer rLTL among women in the short rLTL group., Discussion: Results suggest a potential role of telomeres in the cognitive aging process with sex-specific patterns., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests JLM is currently a full-time employee of Lundbeck and has previously served as a consultant or at advisory boards for the following for-profit companies or has given lectures in symposia sponsored by the following for-profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, ProMIS Neurosciences. JDG has received speaker’s or consultant's fees from Philips Nederlands, Roche Diagnostics and Biogen and research support from GE Healthcare, Roche Diagnostics and Hoffmann-La Roche. MSC has served as a consultant and at advisory boards for Roche Diagnostics International Ltd, has given lectures in symposia sponsored by Roche Diagnostics, S.L.U, Roche Farma, S.A and Roche Sistemas de Diagnósticos, Sociedade Unipessoal, Lda. and research support from Roche Diagnostics International Ltd. GSB has served as a consultant for Roche Farma, S.A. ASV has received research funding through his institution and support to attend professional meetings from the California Walnut Commission. The remaining authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Endoscopic ultrasound (EUS)-guided biliary rendezvous (RV) is an EUS-assisted technique described as a rescue method in cases of failed biliary cannulation via endoscopic retrograde cholangiography (ERC). Current literature remains unclear regarding its current role. The study aim was to evaluate the effectiveness for biliary EUS-RV, and comparison between benign vs malignant biliopancreatic disorders., Methods: Retrospective observational study with prospective consecutive inclusion in a specific database from a tertiary-center. All patients with biliopancreatic diseases that underwent a EUS-assisted ERC between October-2010 and November-2022 for failed ERC were included. Main outcomes were technical/overall success. Secondary outcomes were safety, potential factors related to failure/success or safety; and a comparative analysis between EUS-RV and EUS-guided transmural drainage (TMD) in malignant cases., Results: A total of 69 patients who underwent EUS-RV procedures, with benign and malignant pathologies ( n  = 40 vs n  = 29), were included. Technical / overall success and related-adverse events (AEs) were 79.7% (95%CI, 68.3-88.4) / 74% (95%CI, 61-83.7) and 24% (95%CI, 15.1-36.5), respectively. Failed cases were mainly related with guidewire manipulation. Seven failed RV were successfully rescued by EUS-TMD. On multivariable analysis, EUS-RV and malignant pathology was associated with a greater failure rate (technical success: OR,0.21; 95%CI,0.05-0.72; p  = 0.017), and higher AEs rate (OR,3.46; 95%CI,1.13-11.5; p  = 0.034). Also, the EUS-TMD group had greater technical success (OR,16.96; 95%CI,4.69-81.62; p  < 0.001) and overall success (OR, 3.09; 95%CI,1.18-8-16; p  < 0.026) with a lower AEs rate (OR,0.30; 95%CI,0.11-0.78; p  = 0.014) than EUS-RV in malignant disorders., Conclusions: EUS-RV is a demanding technique with better outcomes in benign than in malignant biliopancreatic diseases. Comparison of the EUS-TMD group on malignant disorders showed worse outcomes with EUS-RV. Given these findings, maybe EUS-RV is not the best option for malignant biliopancreatic disorders.

Inhibition of S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice, but the underlying mechanisms are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory senescence-associated secretory phenotype (SASP). Cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, but the specific role of S6K1 has not been determined. Here we show that S6K1 deletion does not reduce senescence but ameliorates inflammation in aged mouse livers. Using human and mouse models of senescence, we demonstrate that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Specifically, we show that S6K1 deletion results in reduced IRF3 activation; impaired production of cytokines, such as IL1β; and reduced immune infiltration. Using either liver-specific or myeloid-specific S6K knockout mice, we also demonstrate that reduced immune infiltration and clearance of senescent cells is a hepatocyte-intrinsic phenomenon. Overall, deletion of S6K reduces inflammation in the liver, suggesting that suppression of the inflammatory SASP by loss of S6K could underlie the beneficial effects of inhibiting this pathway on healthspan and lifespan., (© 2024. The Author(s).)

Background: Multiple organ failure/dysfunction syndrome (MOF/MODS) is a major cause of mortality and morbidity among severe trauma patients. Current clinical practices entail monitoring physiological measurements and applying clinical score systems to diagnose its onset. Instead, we aimed to develop an early prediction model for MOF outcome evaluated soon after traumatic injury by performing machine learning analysis of genome-wide transcriptome data from blood samples drawn within 24 h of traumatic injury. We then compared its performance to baseline injury severity scores and detection of infections., Methods: Buffy coat transcriptome and linked clinical datasets from blunt trauma patients from the Inflammation and the Host Response to Injury Study ("Glue Grant") multi-center cohort were used. According to the inclusion/exclusion criteria, 141 adult (age ≥ 16 years old) blunt trauma patients (excluding penetrating) with early buffy coat (≤ 24 h since trauma injury) samples were analyzed, with 58 MOF-cases and 83 non-cases. We applied the Least Absolute Shrinkage and Selection Operator (LASSO) and eXtreme Gradient Boosting (XGBoost) algorithms to select features and develop models for MOF early outcome prediction., Results: The LASSO model included 18 transcripts (AUROC [95% CI]: 0.938 [0.890-0.987] (training) and 0.833 [0.699-0.967] (test)), and the XGBoost model included 41 transcripts (0.999 [0.997-1.000] (training) and 0.907 [0.816-0.998] (test)). There were 16 overlapping transcripts comparing the two panels (0.935 [0.884-0.985] (training) and 0.836 [0.703-0.968] (test)). The biomarker models notably outperformed models based on injury severity scores and sex, which we found to be significantly associated with MOF (APACHEII + sex-0.649 [0.537-0.762] (training) and 0.493 [0.301-0.685] (test); ISS + sex-0.630 [0.516-0.744] (training) and 0.482 [0.293-0.670] (test); NISS + sex-0.651 [0.540-0.763] (training) and 0.525 [0.335-0.714] (test))., Conclusions: The accurate assessment of MOF from blood samples immediately after trauma is expected to aid in improving clinical decision-making and may contribute to reduced morbidity, mortality and healthcare costs. Moreover, understanding the molecular mechanisms involving the transcripts identified as important for MOF prediction may eventually aid in developing novel interventions., (© 2024. The Author(s).)

Thrombosis may be included in the profile of side effects associated with CDK4/6 inhibitors. Its significance might be greater than reported in randomized clinical trials. To investigate this, a retrospective, multicenter study was conducted. The primary objective was to calculate the incidence of thrombosis associated with CDK4/6 inhibitors. Secondary objectives included examining the impact of thrombosis on survival and identifying predictor variables for the development of venous thromboembolism (VTE) or arterial thrombosis (AT). A total of 986 patients were recruited. The incidence of VTE/AT associated with CDK4/6 inhibitor treatment during the follow-up period was 5.48 %. Survival analysis did not indicate that the development of VTE/AT during CDK4/6 inhibitor treatment significantly impacted patient survival (p = 0.133). In our analysis, two variables were found to be statistically significant (p < 0.05) as predictors of VTE/AT in breast cancer patients receiving CDK4/6 inhibitor therapy. These variables were the presence of central nervous system (CNS) metastasis with an odds ratio (OR) of 3.68 (95 % CI 1.18 - 11.49) and the use of abemaciclib with an OR of 2.3 (95 % CI 1.16 - 4.57)., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to this article., (Copyright © 2024. Published by Elsevier B.V.)

Background: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI., Methods: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable., Results: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months)., Conclusions: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/Objectives: In patients with varus knee osteoarthritis, compensatory changes occur in the foot and ankle joints to compensate for the varus deformity of the knee. The aim of the study was to investigate the changes in the ankle of patients whose knee alignment was corrected with total knee arthroplasty (TKA) and to explore the clinical implications of these findings. Methods : In this retrospective observational study, we analyzed 204 knees of 179 patients who had regular follow-ups out of 431 patients who underwent TKA for varus knee osteoarthritis between January 2019 and July 2021. Patient demographics, body mass index, follow-up time, and radiographs were studied. The hip-knee-ankle (HKA) angle, joint line convergence angle (JLCA), talar tilt (TT) angle, ground talar dome (GT) angle, ground tibia plafond (GP) angle, and the American Orthopaedic Foot & Ankle Society (AOFAS) score were assessed preoperatively and at the last follow-up. Results : A total of 204 knees of 179 patients with a mean follow-up time of 32.50 ± 6.68 months were evaluated. It was found that the change in the HKA had a positive effect on the AOFAS score and a negative effect on the TT, GT, and GP angles. While the clinical score improved in 82 patients, it worsened in 8 patients. The age difference between the groups whose AOFAS score improved and worsened was statistically significant. Conclusions : The correction of the varus malalignment in the knee was shown to also improve the compensatory valgus in the foot and ankle over the mid-term, with a statistically significant improvement in the patients' clinical ankle scores.

Not available.

Patients aged 50 or above diagnosed with myeloid neoplasms (MNs) are typically not candidates for germline testing. However, approximately 8% carry pathogenic germline variants. Allogeneic haematopoietic stem cell transplantation (alloHSCT) remains an option for those aged over 50; neglecting germline testing could mask the risk for relative donor cell-derived MN. We propose a germline-augmented somatic panel (GASP), combining MN predisposition genes with a myeloid somatic panel for timely germline variant identification when initial testing is not indicated. Out of our 133 whole-exome-sequenced MN cases aged over 50 years, 9% had pathogenic/likely variants. GASP detected 92%, compared to 50% with somatic-only panel. Our study highlights the relevance of germline screening in MN, particularly for alloHSCT candidates without established germline-testing recommendations., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

The prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) varies, being influenced by blood-related factors such as transcriptional profiling and immune cell ratios. We aimed to address the contribution of distinct whole blood immune cell components to the prognosis of these patients. This study analyzed pre-treatment blood samples from 152 chemotherapy-naive mCRPC patients participating in a phase 2 clinical trial (NCT02288936) and a validation cohort. We used CIBERSORT-X to quantify 22 immune cell types and assessed their prognostic significance using Kaplan-Meier and Cox regression analyses. Reduced CD8 T-cell proportions and elevated monocyte levels were substantially connected with a worse survival. High monocyte counts correlated with a median survival of 32.2 months versus 40.3 months for lower counts (HR: 1.96, 95% CI 1.11-3.45). Low CD8 T-cell levels were associated with a median survival of 31.8 months compared to 40.3 months for higher levels (HR: 1.97, 95% CI 1.11-3.5). These findings were consistent in both the trial and validation cohorts. Multivariate analysis further confirmed the independent prognostic value of CD8 T-cell counts. This study highlights the prognostic implications of specific blood immune cells, suggesting they could serve as biomarkers in mCRPC patient management and should be further explored in clinical trials.

Environmental temperature strongly influences the adaptation dynamics of amphibians, whose limited regulation capabilities render them susceptible to thermal oscillations. A central element of the adaptive strategies is the transcription factors (TFs), which act as master regulators that orchestrate stress responses, enabling species to navigate the fluctuations of their environment skillfully. Our study delves into the intricate relationship between TF expression and thermal adaptation mechanisms in the Rhinella spinulosa populations. We sought to elucidate the dynamic modulations of TF expression in prometamorphic and metamorphic tadpoles that inhabit two thermally contrasting environments (Catarpe and El Tatio Geyser, Chile) and which were exposed to two thermal treatments (25 °C vs. 20 °C). Our findings unravel an intriguing dichotomy in response strategies between these populations. First, results evidence the expression of 1374 transcription factors. Regarding the temperature shift, the Catarpe tadpoles show a multifaceted approach by up-regulating crucial TFs, including fosB, atf7, and the androgen receptor. These dynamic regulatory responses likely underpin the population's ability to navigate thermal fluctuations effectively. In stark contrast, the El Tatio tadpoles exhibit a more targeted response, primarily up-regulating foxc1. This differential expression suggests a distinct focus on specific TFs to mitigate the effects of temperature variations. Our study contributes to understanding the molecular mechanisms governing thermal adaptation responses and highlights the resilience and adaptability of amphibians in the face of ever-changing environmental conditions., (© 2024. The Author(s).)

Objective: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study., Methods: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA /homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021)., Results: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1 - and BRCA2 -mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions)., Conclusions: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy., Trial Registration Number: NCT02655016., Competing Interests: Competing interests: WSG reports consulting and speaker fees from GSK. BPB reports honoraria, support for attending meetings and/or travel from AstraZeneca, Clovis, GSK, MSD, and PharmaMar and advisory board fees from AstraZeneca, Clovis, GSK, and MSD. DMO reports personal fees (consulting and/or advisory boards) and funding for clinical research from AbbVie, Amgen, AstraZeneca, Clovis, Eisai, Genentech/Roche, GOG Foundation, Immunogen, Iovance, Janssen/J&J, Merck, Mersana, Novocure, Regeneron, SDP Oncology (BBI), Seagen, and Tesaro/GSK; funding for clinical research from Ajinomoto, Array Biopharma, Bristol-Myers Squibb, Cerulean Pharma, EMD Serono, Ergomed, Genmab, INC Research, inVentiv Health Clinical, Ludwig Cancer Research, New Mexico Cancer Care Alliance, PRA Intl, Serono, Stemcentrx, TRACON Pharmaceuticals, VentiRx, and Yale University; personal fees from Myriad Genetics, Rubis, and Tarveda; personal fees and funding for clinical research from Agenus; and personal fees (consulting and/or advisory boards) from Ambry, Arquer Diagnostics, Celsion, Corcept Therapeutics, Elevar, InxMed, Novartis, Roche Diagnostics MSA, Sorrento, Takeda, and Toray. IV reports institutional payments for corporate-sponsored research from Amgen and Roche and contracted research from Genmab and Oncoinvent AS; institutional consulting fee payments from Amgen (Europe) GmbH, AstraZeneca, Carrick Therapeutics, Clovis Oncology, Deciphera Pharmaceuticals, Elevar Therapeutics, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Octimet Oncology, Oncoinvent AS, Sotio AS, Verastem Oncology, and Zentalis; consulting fees from Deciphera Pharmaceuticals, Jazz Pharma, and Oncoinvent AS; honoraria payment from Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, Jazz Pharma, Karyopharm, MSD, Novartis, Novocure, Oncoinvent AS, Seagen, and Sotio AS; institutional travel support from Amgen, AstraZeneca, MSD, Roche, and Tesaro; and advisory board fees from Agenus, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals (2021), Eisai, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, MSD, Novartis, Novocure, Seagen (2021), and Sotio AS. BJM reports consulting fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, VBL, and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. AA reports advisory board fees from GSK and MSD. LJC reports institutional research funding from AbbVie, Advaxis, Agenus, Ajinomoto, Arcus Biosciences, Array BioPharma, AstraZeneca, BeiGene USA, BMS, Cerulean Pharma, Clovis Oncology, Deciphera Pharma, Eisai, EMD Serono, Ergomed Clinical Research, Exelixis, Genentech/Roche, Genmab, GSK, Hoffman–LaRoche, Immunogen, Incyte Corporation, Iovance Biotherapeutics, InVentiv Health Clinical, Jansen R&D, Karyopharm, Leap Therapeutics, Ludwig Institute of Pharmaceuticals, Merck, Mersana Therapeutics, Novocure, OncoQuest, OvaGene, Pfizer, PharmaMar, PRA International, Precision Therapeutics, Regeneron, Sanofi, Seattle Genetics, Serono, Stemcentrx, Sumitomo Dainippon Pharma Oncology, Sutro Biopharma, Tesaro (GSK), TRACON Pharm, and Verastem; personal advisory board fees from A28 Therapeutics, Celsion Corporation, Corcept Therapeutics, Elevar Therapeutics, GSK, Immunogen, InxMed, Luzsana Biotechnology, Myriad Genetics, Onconova, Rubius Therapeutics, Sorrento Therapeutics, Toray Industries, and VBL Therapeutics; and member of the data monitoring committee for Corcept Therapeutics. RS reports support for attending meetings from MSD and advisory board fees from Clovis Oncology, GSK, and MSD. TJH reports personal consulting fees from Aadi, AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genelux, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen; participation on a data safety monitoring board or advisory board for Corcept; and leadership role on the GOG Foundation Board and president of GOG Partners. PF reports payment or honoraria and payment for expert testimony from AstraZeneca, Clovis, Daiichi, GSK, and Novartis and support for attending meetings from AstraZeneca, Daiichi, GSK, and Novartis. BP reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Duality Bio, Eisai, Genentech/Roche, Karyopharm, Merck, Mersana, Seagen, Sutro Biopharma, Takeda Pharmaceuticals, Tesaro/GSK, Toray, and VBL Therapeutics; consulting fees from AstraZeneca, BioNtech, Clovis Oncology, Eisai, GOG Foundation, Lily, Merck, Mersana, Seagen, Sutro Biopharma, Tesaro/GSK, Onconova, and Toray; and travel support from GSK and BioNtech. EIB reports honoraria from AstraZeneca, GSK, and Merck; consulting or advisory roles at AstraZeneca and GSK; institutional research funding from AstraZeneca, Bayer, Clovis, Eisai, GSK, Merck, and Resolve; travel support from AstraZeneca; and relationship with medical director of the North Eastern German Society of Gynecological Oncology (NOGGO). CM reports advisory role fees from AstraZeneca, Clovis, GSK, ImmunoGen, and Merck. AY reports a GEICO grant by GSK. RGM reports personal fees from Fujirebio Diagnostics and research funding from Angle plc. PV reports payment of honoraria to self from MSD, Novartis, and Roche. NR-J reports advisory board fees from Eisai. WY and JH are employees of GSK. AG-M reports fees for different educational or advisory-related activities from Alkermes, Amgen, AstraZeneca, Clovis, Eisai, Genmab, GSK, Hedera Dx, Immunogen, Illumina, Karyopharm, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Regeneron, Roche, Seagen, Sotio, Sutro, Takeda, and Tubulis., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Novel and highly effective drugs for non-melanoma skin cancer (NMSC) improve patient outcomes, but their high cost strains healthcare systems. Spain's decentralized public health system, managed by 17 autonomous communities (AaCc), raises concerns about equitable access., Methods: A cross-sectional survey (July-September 2023) was sent to Spanish Multidisciplinary Melanoma Group (GEM Group) members to assess access to new drugs., Findings: Fifty physicians from 15 Spanish AaCc responded to the survey. Access for drug with approved public reimbursement, Hedgehog inhibitors in basal-cell carcinoma and anti PD-L1 antibody in Merkel carcinoma, was observed in 84% and 86% of centers, respectively. For other EMA-approved treatments, but without reimbursement in Spain access decreased to 78% of centers. Heterogeneity in access was mainly observed intra regions., Conclusion: Unequal financial support for drugs for NMSC with creates a patchwork of access across Spanish hospitals, with variations even within the same AaCc., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Post-transplant diabetes mellitus (PTDM) is a frequent complication after kidney transplantation (KT). This systematic review investigated the effect of different immunosuppressive regimens on the risk of PTDM. We performed a systematic literature search in MEDLINE and CENTRAL for randomized controlled trials (RCTs) that included KT recipients with any immunosuppression and reported PTDM outcomes up to 1 October 2023. The analysis included 125 RCTs. We found no differences in PTDM risk within induction therapies. In de novo KT, there was an increased risk of developing PTDM with tacrolimus versus cyclosporin (RR 1.71, 95%CI [1.38-2.11]). No differences were observed between tacrolimus+mammalian target of rapamycin inhibitor (mTORi) and tacrolimus+MMF/MPA, but there was a tendency towards a higher risk of PTDM in the cyclosporin+mTORi group (RR 1.42, 95%CI [0.99-2.04]). Conversion from cyclosporin to an mTORi increased PTDM risk (RR 1.89, 95%CI [1.18-3.03]). De novo belatacept compared with a calcineurin inhibitor resulted in 50% lower risk of PTDM (RR 0.50, 95%CI [0.32-0.79]). Steroid avoidance resulted in 31% lower PTDM risk (RR 0.69, 95%CI [0.57-0.83]), whereas steroid withdrawal resulted in no differences. Immunosuppression should be decided on an individual basis, carefully weighing the risk of future PTDM and rejection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Atrophic pseudoarthrosis is a serious complication with an incidence of 5-10 % of bone fractures located in the diaphysis of long bones. Standard treatments involve aggressive surgical procedures and re-interventions requiring the use of autografts from the iliac crest as a source of bone-forming biological activity (Standard of Care, SoC). In this context, regenerative ex vivo expanded osteogenic cell-based medicines could be of interest. Particularly, Mesenchymal Stromal Cells (MSC) offer new prospects to promote bone tissue repair in pseudoarthrosis by providing biological activity in an osteoconductive and osteoinductive environment., Methods: We conducted a phase IIa, prospective, randomised, parallel, two-arms, open-label with blinded assessor pilot clinical trial to compare SoC vs. a tissue-engineered product (TEP), composed of autologous bone marrow (BM)-derived MSCs loaded onto allogeneic decellularised, lyophilised spongy bone cubes, in a cohort of 20 patients with non-hypertrophic pseudoarthrosis of long bones. Patients were followed up for 12 months. Radiological bone healing was evaluated by standard X-ray and computed tomography (CT) scanning. Quality of life was measured using the EUROQOL-5D questionnaire., Results: Ten patients were randomized to TEP and 10 to SoC with iliac crest autograft. Manufacturing of TEP was feasible and reproducibly achieved. TEP implantation in the bone defect was successful in all cases and none of the 36 adverse events (AE) reported were related to the treatment. Efficacy analyses were performed in the Full Analysis Set (FAS) population, which included 17 patients after 3 patients withdrew from the study. The degree of consolidation, estimated by measuring Hounsfield units (HU) on CT, showed no significant differences between the two treatment groups at 12 months post treatment (main efficacy variable) (p = 0.4835) or at 6 months., Conclusions: Although only a small number of patients were included in our study, it is notable that no significant differences were observed between the experimental treatment and SoC, thus suggesting TEP as an alternative where autograft is not available or contraindicated., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The ability to weigh a reward against the effort required to acquire it is critical for decision-making. However, extant experimental paradigms oftentimes confound increased effort demand with decreased reward probability, thereby obscuring neural correlates underlying these cognitive processes. To resolve this issue, we designed novel tasks that disentangled probability of success - and therefore reward probability - from effort demand. In Experiment 1, reward magnitude and effort demand were varied while reward probability was kept constant. In Experiment 2, effort demand and reward probability were varied while reward magnitude remained fixed. Electroencephalogram (EEG) data was recorded to explore how frontal midline theta (FMT; an electrophysiological index of mPFC function) and component P3 (an index of incentive salience) respond to effort demand, and reward magnitude and probability. We found no evidence that FMT tracked effort demands or net value during cue evaluation. At feedback, however, FMT power was enhanced for high compared to low effort trials, but not modulated by reward magnitude or probability. Conversely, P3 was sensitive to reward magnitude and probability at both cue and feedback phases and only integrated expended effort costs at feedback, such that P3 amplitudes continued to scale with reward magnitude and probability but were also increased for high compared to low effort reward feedback. These findings suggest that, when likelihood of success is equal, FMT power does not track net value of prospective effort-based rewards. Instead, expended cognitive effort potentiates FMT power and enhances the saliency of rewards at feedback. SIGNIFICANCE STATEMENT: The way the brain weighs rewards against the effort required to achieve them is critical for understanding motivational disorders. Current paradigms confound increased effort demand with decreased reward probability, making it difficult to disentangle neural activity associated with effort costs from those associated with reward likelihood. Here, we explored the temporal dynamics of effort-based reward (via frontal midline theta (FMT) and component P3) while participants underwent a novel paradigm that kept probability of reward constant between mental effort demand conditions. Our findings suggest that the FMT does not track net value and that expended effort enhances, instead of attenuates, the saliency of rewards., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Follicular lymphoma (FL) is the most frequent indolent lymphoma. Some patients (10%-15%) experience histologic transformation (HT) to a more aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL). This study aimed to validate and improve a genetic risk model to predict HT at diagnosis.We collected mutational data from diagnosis biopsies of 64 FL patients. We combined them with the data from a previously published cohort (total n = 104; 62 from nontransformed and 42 from patients who did transform to DLBCL). This combined cohort was used to develop a nomogram to estimate the risk of HT. Prognostic mutated genes and clinical variables were assessed using Cox regression analysis to generate a risk model. The model was internally validated by bootstrapping and externally validated in an independent cohort. Its performance was evaluated using a concordance index and a calibration curve. The clinicogenetic nomogram included the mutational status of 3 genes (HIST1HE1, KMT2D, and TNFSR14) and high-risk Follicular Lymphoma International Prognostic Index and predicted HT with a concordance index of 0.746. Patients were classified as being at low or high risk of transformation. The probability HT function at 24 months was 0.90 in the low-risk group vs 0.51 in the high-risk group and, at 60 months, 0.71 vs 0.15, respectively. In the external validation cohort, the probability HT function in the low-risk group was 0.86 vs 0.54 in the high-risk group at 24 months, and 0.71 vs 0.32 at 60 months. The concordance index in the external cohort was 0.552. In conclusion, we propose a clinicogenetic risk model to predict FL HT to DLBLC, combining genetic alterations in HIST1H1E, KMT2D, and TNFRSF14 genes and clinical features (Follicular Lymphoma International Prognostic Index) at diagnosis. This model could improve the management of FL patients and allow treatment strategies that would prevent or delay transformation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)