Citations

ABSTRACT Background Immune checkpoint inhibitors (ICIs) have emerged as promising agents for the management of advanced HCC. By reducing tumour burden, ICIs may serve as a downstaging/bridging tool to improve transplant candidacy. The aim of this study was to assess the safety of patients receiving pre‐LT ICIs. Methods Multicenter, retrospective cohort study from January 2018 to December 2024, including 48 patients who received ICIs prior to LT (ICI cohort). A control cohort (non‐ICI cohort) was built (1:3) using propensity score matching including 144 patients who underwent LT for HCC without prior ICI. Results Within the ICI cohort ( N = 48) rejection occurred in 9 patients (18.8%), all biopsy‐proven, with a median onset of 31 days post‐LT (12.0–182.0). The median washout period was 60 days (13–96). Patients experiencing rejection had shorter washout periods ( p = 0.029). All rejection episodes were successfully managed; two were steroid‐resistant, one requiring re‐transplantation. There were no rejection‐related deaths. Of the 5 patients with HCC recurrence, 60% received ICI for < 90 days ( p = 0.027). Comparison between the ICI and non‐ICI cohort revealed no significant differences in rejection rates (18.8% vs. 19.4%, p = 0.916), graft failure, HCC recurrence, or overall mortality. Overall survival (OS) did not differ between ICI and non‐ICI patients ( p = 0.625) or between those with and without rejection ( p = 0.119). Rejection was not associated with increased mortality, with deaths primarily attributed to infection or HCC recurrence. Conclusion Our results demonstrate that rejection rates were similar in patients receiving ICIs pre‐LT and it can be safely managed.

Abstract When using real-world data to construct an external comparator arm for a single-arm trial, there may be differences in how and when patients are assessed for disease between trial and real-world settings. Such differences can generate outcome measurement error when comparing time-to-event endpoints and lead to biased findings. Recent methods have been developed to mitigate measurement error bias in real-world endpoints; however, they rely on the existence of a validation sample, ie, data on a set of patients where both the “true” trial-like and “mis-measured” real-world measures are collected. We demonstrate how novel statistical methods can be leveraged as quantitative bias analyses (QBA) to contextualize real-world evidence findings when outcome measurement error is of concern, but validation samples are infeasible to collect. Quantitative bias analyses allow researchers to set plausible ranges for the amount of error when not directly measurable. We highlight how to conduct QBA with two recent methods, cumulative incidence curve correction and survival regression calibration, and illustrate how to generate plausible parameter values through simulation. We provide an illustrative QBA example in a cohort of real-world patients with newly diagnosed multiple myeloma and provide practical guidance to apply QBA for outcome measurement error and interpret results.

Abstract Metabolic disorders such as obesity, type 2 diabetes, and dyslipidaemia are major drivers of cardiovascular risk and have reached epidemic levels in Western populations. Recent advances in clinical research have uncovered unexpected and often beneficial effects of pharmacological classes of metabolic drugs on cardiovascular outcomes, revealing complex interactions between metabolism and cardiac pathology. Despite their clinical efficacy, the molecular and cellular mechanisms through which many of these agents act remain only partially understood. This gap in knowledge underscores the urgent need for fundamental research that not only dissects the biology of metabolic disorders and cardiovascular disease but also reveals the mechanistic basis of existing and emerging therapies, thereby enabling rational therapeutic development. This scientific statement, developed by researchers from the European Society of Cardiology (ESC) Council on Basic Cardiovascular Science and several ESC Working Groups, provides a state-of-the-art overview of the emerging molecular and cellular pathways linking metabolic abnormalities with vascular and cardiac disease. By illuminating these critical connections and unresolved questions, this article aims to catalyse innovation in the prevention and management of cardiovascular disease in the context of metabolic dysfunction and to suggest new directions for future research.

Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

OBJECTIVE Early discharge following uncomplicated endonasal resection of pituitary adenoma has been described as safe and feasible. Discharge on postoperative day (POD) 1 is not a widely implemented practice in the United States. This study aimed to evaluate the safety of routine POD1 discharges by assessing postoperative unplanned medical care rates compared with those of patients discharged on POD 2 or later (POD2+). The secondary endpoint was to identify predictors of delayed discharge in the POD2+ cohort. METHODS A retrospective database review of the medical records of 534 patients who underwent endonasal resection of pituitary adenoma at the Mayo Clinic was performed. Relevant demographics, tumor characteristics, and perioperative metrics were abstracted from the medical record, including intraoperative CSF leakage, postoperative complications, emergency department visits, or inpatient readmissions within 30 days. Descriptive, univariate, and multivariate analyses were performed. RESULTS In comparison to 422 (79%) patients discharged on POD1, 112 (21%) patients discharged on POD2+ had a higher unplanned medical care rate (13% vs 5.5%, p = 0.019). There were significantly more men in the POD1 group (48%) than in the POD2+ group (37%) (p < 0.04). The most common reasons for POD1 unplanned care were endocrine dysfunction (2.4%), split evenly between syndrome of inappropriate antidiuretic hormone and adrenal insufficiency, whereas the most frequent reason in the POD2+ cohort was medical (0.06%). Univariate analyses indicated that female sex, higher BMI, intensive care unit (ICU) admission, obstructive sleep apnea, continuous positive airway pressure dependence, intraoperative CSF leakage, and diabetes insipidus (DI) increased the likelihood of POD2+ discharge. The reduced logistic regression model demonstrated a higher likelihood of POD2+ discharge with older age, ICU admission, intraoperative CSF leakage, and DI (p < 0.001). Common factors contributing to discharge after POD1 included endocrine (n = 66, 35%) and/or medical (n = 65, 34%) reasons. CONCLUSIONS Routine patient discharge on POD1 following uncomplicated endonasal resection of pituitary adenoma is a safe practice, as evidenced by the significantly lower rates of unplanned medical care and complications compared with those of patients discharged on POD2 or later. Delayed discharge was associated with older age, ICU admission, intraoperative CSF leakage, and DI. The most frequent reasons for POD1 readmission were endocrine versus medical reasons for POD2+. Preoperative identification of risk factors for delayed discharge and preemptive management of endocrine and medical complications may reduce the length of stay and return to medical care.

Abstract Background The Alzheimer's disease (AD) Braak staging is a key framework for classifying tau pathology progression in AD based on histopathological post‐mortem brain examinations. However, adapting it to PET imaging can be challenging due to differences in tracer uptake patterns and binding properties, which affect sensitivity, specificity, and regional staging. This study compares Braak staging across four tau PET tracers: Flortaucipir, MK6240, PI2620, and RO948. Methods We assessed 90 participants across the AD spectrum (46 CU, 31 MCI, 13 dementia; mean age 66.1 ± 7.8) using Aβ PET and four tau PET tracers: (Flortaucipir, MK6240, PI2620, and RO948). Braak positivity was defined based on Aβ− CU individuals (mean +2.5 SD, SUVR). To evaluate systematic bias and agreement between tracers, we computed pairwise differences at corresponding Braak stage estimates and applied the Bland‐Altman method to assess mean bias and limits of agreement. Additionally, Tau PET Braak region trajectories were modeled as functions of Aβ burden (Centiloid scale) using the Lowess method. Results Braak stage trajectories as a function of Aβ differ depending on the tracer and the sequential order of abnormality is highly variable. For instance, while for MK6240, RO948 and PI2620, Braak I is the first region to became abnormal, for Flortaucipir the earliest region to became abnormal is Braak IV (Figure 1). This variable pattern of abnormality impacts in the concordance of Braak staging between tracers with the highest Braak staging agreement resulting in concordance levels of approximately 70%. The highest levels of agreement between tracers usually happen at Braak 0 or Braak IV‐V, with intermediate stages showing very low concordance (Figure 2). The Bland‐Altman analysis identified wide limits of agreement, suggesting high variability and high tracer‐specific differences (Figure 3). On the other hand, it also identified that mean differences between tracers were small, indicating minimal systematic bias. Conclusion These preliminary findings reveal discrepancies in Braak staging when comparing Flortaucipir, MK6240, PI2620 and RO948. These findings suggest that while the tracers provide comparable stages on average, they may not be fully interchangeable in individual cases.

Abstract Chimeric antigen receptor (CAR) T-cell therapy enriched for a memory-like phenotype may persist and function longer than a nonenriched product, thereby improving duration of response (DOR). We conducted a phase I study with bb21217 (NCT03274219), an anti–B-cell maturation antigen CAR T-cell therapy manufactured in the presence of the phosphoinositide 3-kinase inhibitor bb007 to enrich for T cells with a memory-like phenotype, in patients with relapsed/refractory multiple myeloma (N = 72). No new safety concerns were raised with bb21217 therapy (three cases each of grade ≥3 cytokine release syndrome and grade ≥3 neurotoxicity were observed). The objective response rate was 69.4% and the median DOR was 23.8 (95% confidence interval, 16.8–34.8) months. Analysis of the drug product established an association between early memory phenotype and robust expansion and depth of response. Examination of baseline characteristics indicated that tumor burden and prior therapies influenced DOR. The data indicate that generation of CAR T cells early in a disease course when tumor burden is lower and source material exhibits a more naïve phenotype may maximize the clinical benefit potential of the drug product.

Abstract Background There is an unmet need for ulcerative colitis (UC) treatments that show improved effectiveness while maintaining safety profiles comparable with existing advanced therapies. Dual targeted therapy (DTT) has been proposed as a strategy to combine benefits of different advanced therapies to improve outcomes. The ExiGem study (NCT06095128) aims to assess the efficacy and safety of combined therapy with vedolizumab (VDZ) and tofacitinib (TOF) in adults with UC. We report results for the induction phase from the first 24 patients. Methods ExiGem is an ongoing phase 4, single-arm, multicentre study including adults with moderately to severely active UC (complete Mayo [cMayo] score of 6–12 with a rectal bleeding subscore ≥ 1 and centrally read endoscopic subscore ≥ 2). Eligible patients have previously had an inadequate response, loss of response, or intolerance to 1 or 2 anti-tumour necrosis factor α treatments. Patients receive induction therapy with intravenous (IV) VDZ 300 mg at weeks 0, 2, and 6 plus twice-daily oral TOF 10 mg for 8 weeks and then VDZ 300 mg IV monotherapy as maintenance from week 14. The primary endpoint is the proportion of patients in clinical remission by cMayo score at week 8. Secondary endpoints include clinical response and clinical remission by modified Mayo (mMayo) score at week 8. Changes in faecal calprotectin (FCP) levels and endoscopic improvement were evaluated. Efficacy data were analysed using non-responder imputation. For the final analysis a pre-specified Bayesian approach will be used. The safety profile of DTT was evaluated. Results Patient baseline characteristics are shown in Table 1. At week 8, 12/24 patients (50%) and 14/24 patients (58%) had clinical remission assessed by cMayo and mMayo scores, respectively; these rates were higher than pre-specified benchmark rates (Figure 1). Clinical response was observed in 21/24 patients (88%). At week 8, 14/24 patients (58%) showed endoscopic improvement, and 12/21 patients (57%) had normalization of FCP levels (&lt; 250 µg/g). Treatment-emergent adverse events (TEAEs) were experienced by 10 patients (42%), and 1 serious TEAE was reported (suspected viral infection). One severe adverse event (AE; cough) and 2 moderate AEs (herpes zoster, drug intolerance) were considered related to TOF. No moderate or severe AEs were considered related to VDZ. One patient withdrew from the study before week 8 owing to intolerance to TOF. Conclusion Initial data suggest that induction with a combination of VDZ and TOF can produce improved rates of response and remission in patients with UC with a comparable safety profile to existing advanced monotherapies. Further data, including outcomes of VDZ maintenance as monotherapy, are pending. Conflict of interest: Prof. Dr. Yarur, Andres: Andres Yarur has served as an advisory board member for Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Roche/Genentech, and Takeda. This study was funded by Takeda Pharmaceuticals U.S.A., Inc. Medical writing support was provided by Adam Errington PhD of PharmaGenesis Cardiff, Cardiff, UK, and funded by Takeda Pharmaceuticals U.S.A., Inc. Barnes, Edward: Personal Fees: Consultant for Takeda, Pfizer, Roche, Merck, Abbvie, Eli Lilly. Bristol Myers Squibb, Celltrion, Johnson and Johnson. Deepak, Parakkal: Parakkal Deepak has received research support under a sponsored research agreement unrelated to the data in the abstract from AbbVie, Johnson and Johnson, Sanofi, Merck, Teva, Direct Biologics, Tr1x, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals, Roche Genentech, Eli Lilly, AstraZeneca, Spyre and Agomab, has received consulting fees from Johnson and Johnson, Abbvie, Merck, Sobi, Celltrion, Fresenius Kabi, Asahi Kasei Pharma, Sandoz and CorEvitas, LLC and has served on the board of the Srategic Alliance for Intercultural Advocacy in GI. Ha, Christina: Christina Ha has served as an advisory board member for AbbVie, Bausch Health, Johnson & Johnson, Lilly, Merck, Takeda, and Sanofi has received educational programming support from AbbVie, Celltrion, Johnson & Johnson, Lilly, Pfizer, and Takeda and has received consulting fees from AbbVie. Hudesman, David: Consultant: Abbvie, Abivax, BMS, Biocon, Eli Lilly, Fresenius Kabi, Pfizer, Prometheus, CorEvitas, Takeda, Johnson and Johnson, Sanofi Research Support: Johnson and Johnson, Pfizer Jairath, Vipul: Consulting Fees: Abbvie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, BMS, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Janssen, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma. Lukin, Dana: Dana Lukin has served as a consultant/advisory board member for AbbVie, AltruBio, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Palatin, Pfizer, Prime, PSI, Takeda, and Vedanta has received grants from Boehringer Ingelheim and Johnson & Johnson and serves as a speaker for AbbVie and Johnson & Johnson. Rubin, David T.: Grant support: Takeda Pharmaceuticals. Consultant: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Mirador, Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx. Schreiber, Stefan Wolfgang: Stefan Schreiber has received consulting fees from AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Eli Lilly, Ferring, Fresenius, Galapagos, Genentech, Gilead, GlaxoSmithKline, I-MAB Biopharma, Janssen, Merck, Novartis/Sandoz, Pfizer, Protagonist, Takeda, and Ventyx Biosciences. Gower, Megan: Megan Gower is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Jones, Stephen: Stephen Jones is an independent medical consultant who provides services for Takeda Pharmaceuticals U.S.A., Inc. Robinson, Ian: Ian Robinson is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Sanchirico, Marie: Marie Sanchirico is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Yajnik, Vijay: Vijay Yajnik is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc.

This guideline has been updated. This ASCO Living Guideline is reviewed on an eight-week cycle. Please see the online dynamic version for the latest updates. Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information ( Appendix 1 and Appendix 2 ). Updates are published regularly and can be found at www.asco.org/genitourinary-cancer-guidelines .