Citations

Abstract Background Early tumor shrinkage and depth of response have emerged as potential prognostic indicators in metastatic colorectal cancer (CRC). However, their associations with overall survival, progression-free survival (PFS), and postprogression survival in patients receiving anti–epidermal growth factor receptor (EGFR) antibodies or bevacizumab remain unclear. Methods We analyzed 3219 treatment-naive patients with RAS wild-type metastatic CRC from 8 randomized studies (CRYSTAL, OPUS, PRIME, CAIRO2, CALGB80405, WJOG4407G, ATOM, PARADIGM) in the Aid and Research in Digestive Cancerology database. Early tumor shrinkage was defined as a 20% or more reduction in tumor size at 8 ± 2 weeks, whereas depth of response was assessed by maximum tumor shrinkage at nadir. Cox regression models evaluated the associations of early tumor shrinkage and depth of response with overall survival, PFS, and postprogression survival, adjusting for confounders. A 2-sided test was conducted with a significance level of .05. Results Early tumor shrinkage and depth of response substantially stratified overall survival, PFS, and postprogression survival outcomes across all treatment groups. Early tumor shrinkage positivity was associated with improved overall survival, PFS, and postprogression survival in anti-EGFR and bevacizumab-based therapies, with a trend toward better outcomes in the anti-EGFR group. The depth of response analysis revealed optimal cutoff values of 0.55 for anti-EGFR–based therapy and 0.47 for bevacizumab-based therapy to achieve a median overall survival of approximately 32 months. Conclusions Early tumor shrinkage and depth of response serve as valuable prognostic markers in RAS wild-type metastatic CRC, particularly for patients treated with anti-EGFR antibodies. These findings highlight the potential role of early tumor shrinkage and depth of response in guiding treatment strategies and improving outcomes for patients with CRC.

Abstract Aims Pronounced sex-differences are known in the incidence of atrial fibrillation (AF). In this study, we aimed to investigate the atrial electrophysiological properties that may underlie sex-differences in AF incidence in the younger population, focusing on IK1, a cardiac ion current important for action potential (AP) stability and triggered activity. Methods and results We assessed sex-differences in P-wave morphology in 12-lead ECG in healthy young New Zealand White rabbits. Males presented longer PWD and larger P-wave area compared to females. Patch-clamp experiments were performed in isolated rabbit atrial cardiomyocytes (CMs). Male atrial CMs presented higher delayed after depolarizations (DAD) incidence, amplitude, and area under the curve (AUC) than females, potentially facilitating the presence of atrial triggered activity in males. Male atrial CMs showed a less hyperpolarized resting membrane potential (RMP), a 50% smaller IK1, and a 26% reduction in Kir2.1 protein expression, a pore forming subunit of IK1, than females. Dihydrotestosterone (DHT) effects were investigated acutely and semi-chronically ex vivo. Experiments showed that the sex-difference in IK1 could be mimicked by DHT. In female atrial CMs, acute and semi-chronic (24 h) DHT administration reduced IK1. In the presence of a PKC-inhibitor, DHT-mediated IK1 reduction was not observed in atrial female CMs, suggesting it to be PKC-mediated. Chronic DHT-effects were investigated in vivo in female rabbits after hormone-releasing pellet implantation. After 2 weeks, animals showed a significantly prolonged and larger P-wave, a smaller atrial IK1 and a trend towards an increased DAD amplitude and AUC. Conclusion Sex impacts on atrial electrophysiology, leading to sex-differences in P-wave morphology, triggered activity, RMP, and IK1. These sex-differences can be mimicked by sex hormone-treatment, suggesting that sex hormones—particularly DHT—play a pivotal role in mediating sex-differences in atrial electrophysiology. Such sex-differences might impact on the propensity to develop AF, particularly in the younger population.

Abstract Introduction: Multiple myeloma (MM) is a B-cell-derived malignancy associated with immune dysregulation. Anti-CD38 monoclonal antibodies (mAbs) therapies have shown improved outcomes in patients with MM. Silbermann et al. showed that anti-CD38 mAb-containing therapies lead to profound hypogammaglobulinemia and reduction in Ig gene repertoire. The effect of modern therapies such as CAR-T and bispecific antibodies (BsAbs) on B-cell repertoire has not been well described. In this study, we sought to investigate the effect of these therapies on B-cell repertoire in patients with MM. Methods: This is a single-institution retrospective observational study evaluating MM patients treated with anti-BCMA CAR-T and BsAbs. Baseline characteristics, laboratory data, treatment history, were extracted from medical records. Total unique sequences (TUS) and total sequences of IgH, IgK, and IgL were identified and quantified using clonoSEQ. Patients were classified in two groups: CAR-T and BsAbs. The primary objectives were (1) characterize changes in TUS and total sequences within IgH, IgK, and IgL before and after treatment, and (2) examine how the sequences evolve over time following CAR-T. Results: 76 MM patients received CAR-T or BsAbs. Among those, 22 CAR-T and 5 BsAbs patients had pre- and post-treatment sequences available. Median age at initiation of treatment was 66 years in the CAR-T group (42-81 y) and 65 years in the BsAbs group (48-71 y). Based on mSMART v3 criteria, 72% of CAR-T and 60% of BsAbs recipients were classified as high-risk. Median number of prior lines of therapy was 5 (2-8) in the CAR-T group and 6 (5-13) in the BsAbs group.CAR-T recipients were classified into early (<40 days) and late (>40 days), based on when the post-CAR-T treatment clonoSEQ assay was performed. Changes in TUS and total sequences of IgH, IgK, and IgL were calculated, and the averages were assessed independently. The mean early and late change in total unique IgH sequences were (-75, 586 and 131, 038, p=0.052), unique IgK (-57, 797 and 52, 586, p=0.020), and unique IgL (-22, 354 and 25, 056, p=0.011). A subgroup of 8 patients with sequential MRD reports post-CAR-T therapy were identified, six patients showed improvement in B-cell sequence dynamics and two patients showed a decrease over time. For patients who received BsAbs, results indicated a similar pattern, with an early decrease in B-cell repertoires, characterized by reductions in sequence diversity and quantity. Conclusions: Our analysis of B-cell repertoires following CAR-T revealed changes before and after treatment. Patients receiving CAR-T therapy showed a decline in the number of TUS and total sequences of IgH, IgK, and IgL, likely due to the lymphodepletion regimen, followed by a gradual restoration reflecting immune recovery. Longer follow-up and a larger cohort will be necessary to assess the implications of these B-cell repertoire changes on patient outcomes. Citation Format: Feba Miriam Jacob, Rodolfo Garza-Morales, Joseph G Hentz, Alex Wonnaparhown, Julia E. Wiedmeier-Nutor, Mariano Arribas, Gabriela Alatorre, Sharene Best, Jayden Poulignot, Udit Yadav, Saurabh Chhabra, P. Leif Bergsagel, Rafael Fonseca, Talal Hilal. Dynamics of B-cell repertoires following CAR-T and bispecific antibody therapy in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4537.

OBJECTIVE The objective of this study was to develop a deep learning model for automated pituitary adenoma segmentation in MRI scans for stereotactic radiosurgery planning and to assess its accuracy and efficiency in clinical settings. METHODS An nnU-Net–based model was trained on MRI scans with expert segmentations of 582 patients treated with Leksell Gamma Knife over the course of 12 years. The accuracy of the model was evaluated by a human expert on a separate dataset of 146 previously unseen patients. The primary outcome was the comparison of expert ratings between the predicted segmentations and a control group consisting of original manual segmentations. Secondary outcomes were the influence of tumor volume, previous surgery, previous stereotactic radiosurgery (SRS), and endocrinological status on expert ratings, performance in a subgroup of nonfunctioning macroadenomas (measuring 1000–4000 mm 3 ) without previous surgery and/or radiosurgery, and influence of using additional MRI modalities as model input and time cost reduction. RESULTS The model achieved Dice similarity coefficients of 82.3%, 63.9%, and 79.6% for tumor, normal gland, and optic nerve, respectively. A human expert rated 20.6% of the segmentations as applicable in treatment planning without any modifications, 52.7% as applicable with minor manual modifications, and 26.7% as inapplicable. The ratings for predicted segmentations were lower than for the control group of original segmentations (p < 0.001). Larger tumor volume, history of a previous radiosurgery, and nonfunctioning pituitary adenoma were associated with better expert ratings (p = 0.005, p = 0.007, and p < 0.001, respectively). In the subgroup without previous surgery, although expert ratings were more favorable, the association did not reach statistical significance (p = 0.074). In the subgroup of noncomplex cases (n = 9), 55.6% of the segmentations were rated as applicable without any manual modifications and no segmentations were rated as inapplicable. Manually improving inaccurate segmentations instead of creating them from scratch led to 53.6% reduction of the time cost (p < 0.001). CONCLUSIONS The results were applicable for treatment planning with either no or minor manual modifications, demonstrating a significant increase in the efficiency of the planning process. The predicted segmentations can be loaded into the planning software used in clinical practice for treatment planning. The authors discuss some considerations of the clinical utility of the automated segmentation models, as well as their integration within established clinical workflows, and outline directions for future research.

Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.

ABSTRACTImmune thrombotic thrombocytopenic purpura (iTTP) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular occlusion secondary to acquired ADAMTS13 deficiency. Contemporary data regarding iTTP treatment practices in the US, including the use of caplacizumab, are lacking. We aimed to characterize the demographics and therapies, including medications and apheresis practices, in patients with iTTP in the US. We retrospectively analyzed iTTP cases at 15 sites in the US that provide comprehensive care for patients with iTTP. The time‐period assessed was from January 1, 2017 to December 31, 2021. Our primary objective was to analyze data by iTTP episode, inclusive of initial episodes and relapses. A total of 390 iTTP episodes were reported for 280 unique individuals (187 females, 93 males). Thirty‐day mortality was 3.7% (14/374), and 6‐month mortality was 7.4% (27/367). TPE details were reported for 343 episodes, among which 261 underwent at least one procedure (median 6, IQR 3–11). Among the 261 episodes with at least one therapeutic plasma exchange (TPE) performed, 82.0% (214/261) used only plasma. Caplacizumab was used either alone or in combination with other agents in 43 (11.0%) episodes. Management strategies for iTTP remain varied across centers in the US, with a variety of combinations for TPE replacement fluids and therapeutic agents, as well as limited use of caplacizumab. Further research and standardization of treatment regimens may further reduce mortality in this condition.

BACKGROUND: Patients presenting with cervical artery dissection (CAD) are at risk for subsequent ischemic events. We aimed to identify characteristics that are associated with increased risk of ischemic stroke after initial presentation of CAD and to evaluate the differential impact of anticoagulant versus antiplatelet therapy in these high-risk individuals. METHODS: This was a preplanned secondary analysis of the STOP-CAD study (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection), a multicenter international retrospective observational study (63 sites from 16 countries in North America, South America, Europe, Asia, and Africa) that included patients with CAD predominantly between January 2015 and June 2022. The primary outcome was subsequent ischemic stroke by day 180 after diagnosis. Clinical and imaging variables were compared between those with versus without subsequent ischemic stroke. Significant factors associated with subsequent stroke risk were identified using stepwise Cox regression. Associations between subsequent ischemic stroke risk and antithrombotic therapy type (anticoagulation versus antiplatelets) among patients with identified risk factors were explored using adjusted Cox regression. RESULTS: In all, 4023 patients (mean age was 47.4 years; 44.5% were women) were included. By day 180, subsequent ischemic stroke occurred in 5.3% of the cohort. In adjusted Cox regression, factors associated with increased risk of subsequent ischemic stroke were prior history of ischemic stroke (adjusted hazard ratio [aHR], 7.31 [95% CI, 1.61–33.13]; P =0.010), presentation within 7 days from first symptoms (aHR, 3.04 [95% CI, 1.04–8.91]; P =0.043), infarct on baseline imaging (aHR, 9.85 [95% CI, 3.65–26.58]; P <0.001), and occlusive dissection (aHR, 2.34 [95% CI, 1.03–5.34]; P =0.043). Only patients with occlusive dissection demonstrated a reduced risk of subsequent ischemic stroke when treated with anticoagulation versus antiplatelets (aHR, 0.36 [95% CI, 0.16–0.80]; P =0.01). CONCLUSIONS: In this post hoc analysis of the STOP-CAD study, several factors associated with subsequent ischemic stroke were identified among patients with CAD. Furthermore, we identified a potential benefit of anticoagulation in patients with CAD with occlusive dissection. These findings require validation by meta-analyses of prior studies to formulate optimal treatment strategies for specific high-risk CAD subgroups.

ABSTRACTForensic anthropology must embrace standards and credentialing that align with other medicolegal disciplines, such as forensic pathology and forensic odontology. This involves establishing itself more firmly as an essential specialty in the medicolegal system and limiting practice to qualified professionals. Without educational or professional requirements to practice forensic anthropology, the competencies of those involved in medicolegal cases vary, despite the potentially serious legal impact of errors. Negligent work can impede decedent identification or wrongly convict or free a suspect. Erroneous and unprofessional work also misrepresents the field and may deter agencies from utilizing forensic anthropologists. This commentary aims to convey the need to further professionalize forensic anthropology through the standardization of education, qualifications, and practice. Differences between certification and licensure and their implications are discussed. Recent and upcoming developments in the field highlight progress, including the development of a multi‐level certification system and list of core competencies by the American Board of Forensic Anthropology (ABFA). Additionally, the Anthropology subcommittee of the Organization of Scientific Area Committees for forensic science (OSAC) is developing a standard for qualifications in forensic anthropology. These developments emphasize the importance of certification and standardization in education and training for the advancement of forensic anthropology. Standardization efforts such as these will foster a cohesive, respected practice to serve the evolving needs of the medicolegal system.

Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy. Diagnosis is clinical, but ~90% of patients have pathogenic variants in SCN1A . ATP6V0C has recently been proposed as a novel candidate gene for epilepsy, with or without developmental delay. Here we describe two adult patients with a clinical diagnosis of DS associated with ATP6V0C variants. Methods Patients with developmental and epileptic encephalopathies were evaluated by physicians who are experts in DS, and their clinical diagnosis was correlated with genetic findings. A subgroup of those patients with DS but without known genetic causes were evaluated through gene panels, whole exome sequencing, and chromosome microarray. Phenotype was determined by pediatric and adult chart reviews, interviews, and physical examinations. Results Of 753 patients with DS, two unrelated individuals with classic features of DS during childhood and adulthood were identified with heterozygous de novo missense variants in ATP6V0C (c.319G > C, p.(Gly107Arg) and c.284C > T, p.(Ala95Val), respectively). Both variants were absent in normal populations and computational prediction algorithms suggested deleterious effects on protein structure and/or function. No disease‐causing variants in other genes previously associated with DS were found. Significance Here we describe two adult patients with Dravet‐like syndrome and pathogenic/likely pathogenic variants in ATP6V0C . We propose that abnormal ATP6V0C function can, at the severe end of the clinical spectrum, be associated with Dravet‐like phenotype. This is relevant, as these patients would not qualify for disease‐modifying antisense nucleotide or gene therapies targeting SCN1A .

ABSTRACT Background The continuum of metabolic syndrome encompasses a spectrum of dysfunctions impacting obesity‐linked insulin resistance, glucose homeostasis, lipid metabolism and pro‐inflammatory immune responses. The global prevalence of metabolic diseases, including diabetes, chronic liver disease, cardiometabolic disease and kidney disease, has surged in recent decades, contributing significantly to population mortality. Metabolic dysfunction‐associated steatotic liver disease (MASLD), formerly known as non‐alcoholic fatty liver disease, is a leading cause of liver disease worldwide. MASLD poses a significant global health challenge with its rising prevalence, placing a substantial burden on healthcare systems, impacts patient well‐being and incurs significant economic costs. Addressing MASLD requires a comprehensive understanding of its interconnected factors, including its prevalence, healthcare burden and economic implications. Lack of awareness, imprecise non‐invasive diagnostic methods and ineffective preventive interventions are core components of the MASLD‐related problem. Aim The aim of this article was to summarise the global burden of MASLD from the payer's perspective. Methods We carried out a review of the global comprehensive burden of MASLD. These topics led to discussions and insights by an expert panel during the 7th Metabolic Continuum Roundtable meeting, which took place in November 2023. This meeting focused on the burden, patient‐reported outcomes and health economics, from payor and societal perspectives, and aimed to identify opportunities for improving patient care, optimise resource allocation and mitigate the overall impact on individuals and society related to MASLD. During the roundtable, an emphasis emerged on the need for greater awareness and strategic deployment of diagnostic, therapeutic and preventative measures to address MASLD effectively. Conclusion The global burden of MASLD is high and growing. Prioritising the prevention of metabolic dysregulation and timely therapeutic interventions can yield a holistic strategy to combat MASLD, its progression and potentially lower disease costs. Trial Registration: NCT06309992