Citations

ABSTRACT Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage‐specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest‐derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single‐cell RNA sequencing analysis indicating evidence of lineage‐specificity defects. This was supported in an in vitro model using melb‐a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC‐seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere‐associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue‐specific stem cells during aging.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more . PURPOSE To provide evidence-based recommendations for patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS An Expert Panel including patient representation completed a systematic review of the evidence and made recommendations. RESULTS Depending upon prior treatment received, androgen receptor pathway inhibitors (ARPIs: enzalutamide, abiraterone with prednisone), poly(ADP-ribose) polymerase inhibitors (PARPi), chemotherapeutic agents (docetaxel, cabazitaxel), radiopharmaceuticals (radium 223, 177 Lu-prostate-specific membrane antigen [PSMA]-617), and sipuleucel-T have demonstrated an overall survival (OS) benefit for patients with mCRPC. For patients with BRCA1 / 2 alterations who did not receive prior ARPI, the combination of PARPi and ARPI (talazoparib + enzalutamide, olaparib and/or niraparib + abiraterone) has shown clinical benefit. For patients with BRCA1 / 2 alterations who received prior ARPI or ARPI followed by docetaxel, olaparib showed OS benefit. In select patients with microsatellite instability-high/mismatch repair-deficient, pembrolizumab showed clinical efficacy. RECOMMENDATIONS Prior systemic therapy for castration-sensitive prostate cancer will determine subsequent therapy used for mCRPC. Continue androgen-deprivation therapy for patients with mCRPC indefinitely. Early adoption of somatic genetic testing and palliative care is recommended. Patients with mCRPC and bony metastases should receive a bone-protective agent. The panel recommends the combination of ARPI with PARPi in patients with BRCA1 / 2 alterations who did not receive prior ARPI. For patients who received prior ARPI, the panel recommends docetaxel chemotherapy. The panel recommends 177 Lu-PSMA-617 or cabazitaxel chemotherapy for patients who receive prior ARPI and docetaxel chemotherapy. For patients with BRCA1 / 2 alterations who received prior ARPI, the panel recommends PARPi monotherapy. Radium 223 is recommended for patients with symptomatic bone–only disease. Evidence for optimal sequencing for mCRPC regimens is lacking. Additional information is available at www.asco.org/genitourinary-cancer-guidelines .

Abstract Chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) are approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Emerging evidence indicates that delayed CAR T-cell infusion, including prolonged time from leukapheresis to infusion, known as vein-to-vein time (V2Vt), may adversely impact clinical outcomes. We conducted a systematic literature review (SLR) and meta-analysis to identify differences in V2Vt in patients with R/R LBCL treated with axi-cel, tisa-cel, or liso-cel. The impact of V2Vt (<28 days vs ≥28 to <40 days vs ≥40 days) on effectiveness and safety outcomes was evaluated in patients treated with axi-cel enrolled in a post-authorization safety study using the Center for International Blood and Marrow Transplant Research data. SLR and meta-analysis showed that patients treated with axi-cel had the shortest median V2Vt (30.6 days) compared with tisa-cel (48.4 days) or liso-cel (35.9 days). Real-world analysis of patients treated with axi-cel demonstrated that V2Vt ≥40 days was associated with significantly lower complete response rate than V2Vt <28 days (odds ratio [OR], 0.61) or ≥28 to <40 days (OR, 0.66) and significantly worse overall survival than V2Vt <28 days (hazard ratio [HR], 1.33) or ≥28 to <40 days (HR, 1.36). Higher prolonged thrombocytopenia rates were observed in patients with axi-cel V2Vt ≥28 to <40 days or ≥40 days compared with <28 days (OR, 1.44 or 1.95, respectively). Together, these results show the impact of V2Vt on patient outcomes with axi-cel therapy and that earlier infusion with CD19-CAR therapies may be beneficial.

Abstract Objective Data extraction from the published literature is the most laborious step in conducting living systematic reviews (LSRs). We aim to build a generalizable, automated data extraction workflow leveraging large language models (LLMs) that mimics the real-world 2-reviewer process. Materials and Methods A dataset of 10 trials (22 publications) from a published LSR was used, focusing on 23 variables related to trial, population, and outcomes data. The dataset was split into prompt development (n = 5) and held-out test sets (n = 17). GPT-4-turbo and Claude-3-Opus were used for data extraction. Responses from the 2 LLMs were considered concordant if they were the same for a given variable. The discordant responses from each LLM were provided to the other LLM for cross-critique. Accuracy, ie, the total number of correct responses divided by the total number of responses, was computed to assess performance. Results In the prompt development set, 110 (96%) responses were concordant, achieving an accuracy of 0.99 against the gold standard. In the test set, 342 (87%) responses were concordant. The accuracy of the concordant responses was 0.94. The accuracy of the discordant responses was 0.41 for GPT-4-turbo and 0.50 for Claude-3-Opus. Of the 49 discordant responses, 25 (51%) became concordant after cross-critique, increasing accuracy to 0.76. Discussion Concordant responses by the LLMs are likely to be accurate. In instances of discordant responses, cross-critique can further increase the accuracy. Conclusion Large language models, when simulated in a collaborative, 2-reviewer workflow, can extract data with reasonable performance, enabling truly “living” systematic reviews.

Background: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are known safety concerns following chimeric antigen receptor (CAR) T-cell therapy. Axi-cel, a CAR T-cell therapy approved in the US for adults with R/R LBCL after ≥ 1 line of prior therapy (2L+), has been administered in the outpatient setting, where a common cause for post-infusion hospital admissions were CAR T-cell-related toxicities (Furqan et al., 2024). Due to reimbursement policies in the US, patients at higher risk for safety events requiring inpatient care within 3 days of infusion may not be ideal candidates for outpatient care. We sought to identify what pre-infusion characteristics may put patients more at risk for developing early CRS and ICANS after axi-cel. Methods : Patients receiving axi-cel for R/R LBCL 2L+ between 01/2021−10/2023 registered in the Center for International Blood and Marrow Transplant Research (CIBMTR) observational database were potentially eligible for analysis. Patients with prior non-transplant cellular therapy or missing data for analysis were excluded. Primary endpoints were onset of early CRS and early ICANS, defined as an any grade event within 3 calendar days of axi-cel infusion (date of infusion is defined as Day 0 and onset of CRS/ICANS before the end of Day 3 is an early event). Early Grade ≥ 2 and early Grade ≥ 3 CRS and ICANS (onset of CRS/ICANS before the end of Day 3 and maximum Grade ≥ 2 and ≥ 3 per ASTCT Criteria) were also evaluated. Patient demographics, ECOG PS, comorbidities, disease characteristics at diagnosis and prior to infusion, line of therapy (LoT), lab assessments prior to infusion, and infusion-related attributes were evaluated by univariate screening and multivariable regression for development of early CRS or early ICANS. Results: A total of888 patients from 105 centers were included in the analysis. Median age was 63 years (45% ≥ 65 years) and 66% were male. At LBCL diagnosis, 22% of patients had a histological transformation. Prior to infusion, 5% of patients had ECOG PS ≥ 2 and 70% had at least 1 clinically significant comorbidity. Half (50%) of patients received axi-cel with 1 prior LoT (2L) and 10% of patients underwent a prior autologous hematopoietic cell transplant. Median time from leukapheresis to infusion was 30 days (interquartile range [IQR] 27−34). Bridging therapy of any type was administered in 59%, and systemic bridging therapy in 48%, of patients and 14% of patients were intended to be treated in the outpatient setting. Thirty percent of patients had chemo-sensitive disease prior to infusion. Median follow-up post-infusion was 12.3 months (range 3−38). Median time to onset of CRS was 4 days (IQR 2−6) and 84% of patients experienced CRS at any time. Early any grade (Grade ≥ 3) CRS was observed in 47% (3%) of patients. In the multivariate analysis of early any grade CRS, only prior LoT (≥ 2 vs 1) was associated with lower risk (OR 0.71; 95% CI 0.55−0.94), but this association was not seen in the analyses of early Grade ≥ 2 nor early Grade ≥ 3 CRS. Notably, 47% and 52% of patients with ≥ 2 vs 1 prior LoT, respectively, only experienced early Grade 1 CRS (defined as fever only). In the analysis of early Grade ≥ 3 CRS, only ECOG PS 0−1 was associated with lower risk vs patients with ECOG PS ≥ 2 (OR 0.17; 95% CI 0.06−0.48). Median time to onset of ICANS was 7 days (IQR 5−9) and 47% of patients experienced ICANS at any time. Early any grade (Grade ≥ 3) ICANS occurred in 9% (5%) of patients. After multivariate adjustment, age < 65 vs ≥ 65 (OR 0.38 [95% CI 0.23−0.62]) and 1 vs ≥ 2 prior LoT (OR 0.58 [95% CI 0.36−0.95]) were associated with lower risk of early any grade ICANS. Age < 65 vs ≥ 65 was also associated with lower risk of early Grade ≥ 3 ICANS (OR 0.31 [95% CI 0.15−0.61]), as was ECOG PS 0−1 vs ECOG PS ≥ 2 (OR 0.30 [95% CI 0.11−0.83]). Comorbidities were evaluated and no significant associations with early CRS nor early ICANS were found. Conclusions: This analysis of readily available clinical variables in a real-world contemporary cohort of patients treated with axi-cel demonstrates that younger patients and patients with better ECOG PS have lower risk of early CRS and early ICANS. Axi-cel in 2L setting, vs 3L+, is associated with lower risk of early any grade ICANS and comparable early Grade ≥ 2 CRS, but a higher risk of early fever. These results further enable a more informed decision of patient selection for physicians, which is critical for the success of outpatient administration.

Abstract The phosphorylation of histone H2A.X into γH2A.X is a crucial early event in the DNA damage response, marking DNA damage sites and initiating repair processes. While ATM kinase is traditionally recognized as the primary mediator of H2A.X phosphorylation, our study identifies serine/threonine kinase 39 (STK39) as a novel enhancer of this critical signaling pathway. We demonstrate that after DNA damage, STK39 undergoes phosphorylation by the ATM kinase, facilitating its interaction with the Mre11-Rad50-Nbs1 complex and subsequent recruitment to chromatin. This recruitment enables STK39 to further phosphorylate H2A.X, thus amplifying γH2A.X production and promoting homologous recombination repair. Notably, we observe a significant upregulation of STK39 in pancreatic adenocarcinoma (PAAD) tissues, correlating with heightened resistance to PARPi therapy. Furthermore, we demonstrate the synergistic efficacy of combining STK39 inhibition with PARP inhibitors in suppressing and reversing PAAD growth. This study not only provides new insights into the molecular dynamics of H2A.X phosphorylation but also highlights the therapeutic potential of targeting STK39 to enhance PARPi sensitivity in PAAD (created with BioRender).

Stenosis of the left main coronary artery (LM stenosis) is associated with significant mortality and morbidity due to the large area of affected myocardium. Evidence on the use of percutaneous coronary intervention (PCI) for the treatment of LM stenosis is growing. However, the role of Western guidelines on patients in the Asian-Pacific region is unclear due to anatomical variations, substantial heterogeneity in healthcare resources and infrastructure, and the lack of consensus on the optimal management of LM stenosis in the Asia-Pacific region. Hence, an Asian Pacific Society of Cardiology (APSC) working group developed consensus recommendations on the use of PCI in the management of LM stenosis in the Asia-Pacific region. The APSC expert panel reviewed and appraised the available evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Consensus recommendations were developed and put to an online vote. Consensus was reached when 80% of votes for a given recommendation were in support of ‘agree’ or ‘neutral’. The resulting 12 statements provide guidance for clinical practitioners in the region on the use of PCI in the treatment of patients with LM stenosis.