Citations

Abstract The CoMMpass study (NCT01454297) is a prospective, longitudinal observational study involving 1,141 newly diagnosed multiple myeloma (NDMM) patients. Bone marrow aspirates from the study participants were collected for comprehensive molecular characterization of tumor (using bulk RNA sequencing and whole genome sequencing) and tumor immune microenvironment using 3’ single-cell RNA sequencing (scRNA-seq). To support exploration of this rich multi-omic dataset, we developed CoMMpass Explorer (CE), an intuitive interactive platform that enables real-time analysis of clinical and genomic data from CoMMpass. A central feature of CE is cohort building, where users can filter and stratify patients by clinical, genomic, and survival data elements to create custom cohorts for analysis. CE provides five main views: Overall Summary for clinical feature distribution, Kaplan-Meier curves, and multivariate Cox proportional hazards models; Mutational Profile for visualizing and comparing somatic mutations; Tumor Profile for bulk differential expression and gene set enrichment; Immune Microenvironment for comparing cell type abundance and cell cycle dynamics between cohorts using scRNA-seq data; and Pseudo-Bulk, which aggregates single-cell expression by cell type to enable cohort-level comparisons of transcriptional programs using DEseq2. CE reproduces prior CoMMpass studies, including WEE1 expression being associated with poorer progression-free survival (Simhal, et al.) and different mutation frequencies between African American and European American patients (Manojlovic, et al.). We further demonstrate CE’s utility by interrogating the 2025 Consensus Genomic Staging (CGS) risk classification system (Avet-Loiseau, et al). We compared CGS high-risk (HR, n=249) vs. CGS standard-risk (SR, n=573) patients. HR patients have significantly worse progression-free survival, overall survival, and time to second-line therapy compared with SR patients. Univariate models recapitulated expected differences in the clinical features that define CGS risk. Bulk tumor RNA-seq and ssGSEA highlighted a more proliferative and genomically unstable transcriptional program in HR group, with upregulation of angiogenesis and cell-cycle-related pathways. In the immune microenvironment, monocytes were more abundant in the SR group. Pseudo-bulk RNA-seq of plasma cells showed overexpression of ANXA1, NSD2, IGF1R, MAF and related genes in HR. CE democratizes access to the CoMMpass multi-omic resource, allowing researchers to interrogate clinical and molecular heterogeneity. By enabling hypothesis generation and replication of published results, CE serves as a valuable tool for identifying prognostic biomarkers and meaningful patterns in gene expression, mutation profiles, and the immune microenvironment. Citation Format: Wanxing Zhang, Chaitanya R. Acharya, Steven M. Foltz, David E. Avigan, Samir Parekh, Ravi Vij, Shaji Kunnathu Kumar, Taxiarchis Kourelis, Sagar Lonial, Hearn Cho, Ioannis S. Vlachos, Sacha Gnjatic, Li Ding, Manoj Bhasin, George Mulligan. CoMMpass Explorer: An interactive platform to explore clinical and genomic data from newly diagnosed multiple myeloma patients from the landmark CoMMpass observational study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5504.

Abstract Background: Multiple myeloma is the second most common adult blood cancer and remains incurable, despite recent advances. The IMWG/IMS recently published updated risk criteria, Consensus Genomic Staging (CGS), combining genomic events with clinical measures to identify high-risk patients (Avet-Loiseau, et al. JCO 2025). We applied CGS risk criteria to baseline samples from the Multiple Myeloma Research Foundation CoMMpass Study (NCT01454297), a prospective, longitudinal observational study that enrolled more than1100 participants between 2011-2017. Methods: We assessed patient risk following CGS criteria. Criteria 1: del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation. Criteria 2: an IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32). Criteria 3: monoallelic del(1p32) along with 1q+ or biallelic del(1p32). Criteria 4: beta-2 microglobulin >= 5.5 mg/L with normal creatinine. Patients meeting one or more criteria were classified as High Risk. To test if risk showed association with genetic ancestry, we grouped patients into those with high African genetic ancestry and those with low African genetic ancestry. Genetic ancestry was measured using ADMIXTURE in comparison to 1000 Genomes. Results: We evaluated the CGS risk status of 877 CoMMpass patients, finding 69.2% (573/828) to be Standard Risk (SR) and 30.8% (255/828) to be High Risk (HR). HR patients showed worse progression-free survival (median PFS 26.3 months vs. 42.5 months; log rank test, p < 0.0001) and overall survival (median OS 63.9 months vs. median not reached; p < 0.0001). 10.6% (91/858) of patients met Criteria 1, 10.7% (93/873) met Criteria 2, 5.6% (49/877) met Criteria 3, and 8.7% (73/835) met Criteria 4. We found 14.2% (123/867) of patients to have high African-like genetic ancestry (AFR-high) and 85.8% (744/867) to have low African-like genetic ancestry (AFR-low). We observed significantly fewer HR patients within the AFR-high group (20%, 23/115) than in the AFR-low group (32.4%, 231/712) (Fisher’s exact test, p = 0.0065). The AFR-high group met HR criteria at a lower rate across all criteria, but only with Criteria 3 was the difference significant (p-value = 0.03). Higher levels of creatinine in AFR-high patients may have impacted meeting the normal creatinine requirement of Criteria 4. Conclusions: HR patients comprise 30.8% of CoMMpass subjects and show significantly worse PFS and OS than SR patients. AFR-high patients met HR criteria at a lower rate than AFR-low patients according to the CGS criteria. Clinical trials that utilize CGS criteria to determine patient eligibility may be challenged to enroll a representative patient population, including AFR-high patients. Screening and eligibility criteria should be carefully considered to mitigate potential enrollment disparities. Citation Format: Steven M. Foltz, Chaitanya R. Acharya, Alexander Gout, Yuxin Jin, David E. Avigan, Ravi Vij, Shaji Kunnathu Kumar, Sagar Lonial, Hearn Cho, Katie Wozniak, Jonathan J. Keats, Craig Cole, John D. Carpten, George J. Mulligan. Multiple myeloma risk classification of CoMMpass using Consensus Genomic Staging identifies differences between patients with high and low African genetic ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3887.

Introduction: Upper limb spasticity can result from a variety of insults to the central nervous system. Disruption of the closely regulated spinal reflex arc, owing to loss of brain inhibition, results in an imbalance between antagonist and agonist muscle groups, leading to a loss of fluid coordination of motion across joints. Management strategies: A detailed, individualized assessment of each patient is mandatory in a multidisciplinary setting. Although there are objective parameters which guide treatment, variation and customization of strategies are needed for each patient, including defining a functional vs. a non-functional hand, and whether mobility or stability is the primary goal for surgery. Challenging areas in spasticity management: Surgical options include bony, tendon and nerve procedures. These aim to reduce tone, release contractures or reanimate paralysed muscles. This article examines four challenging areas in decision making for choosing these options: lengthening vs. hyperselective neurectomy for tone management, stability vs. mobility in wrist spasticity, grasp and release recovery through finger flexion and extension, and dystonia. Evidence-based treatments are discussed where available, along with key unresolved issues and future research directions. Conclusion: Restoring balance in the spastic upper limb, especially when voluntary control is lost, remains one of the most complex challenges in hand surgery. A thorough understanding of biomechanical principles and neurological pathways is necessary for the hand surgeon. Furthermore, working within a multidisciplinary team is essential to utilize a comprehensive array of assessment tools, ensuring accurate diagnosis and individualized patient care.

Abstract Most clinical large language model (LLM) benchmarks rely on clean, concise vignettes that do not reflect the noisy, long-form documentation typical of real clinical records. How LLM performance degrades under realistic chart conditions remains poorly characterised. Here we test whether structured retrieval workflows protect National Institutes of Health Stroke Scale (NIHSS) scoring accuracy under systematic context stress. Using 100 de-identified acute stroke cases and a fully crossed 4 x 4 x 3 x 3 condition matrix (144 conditions per case), we vary context acquisition method, document length, distractor load and critical-information position across four Gemini models (57,047 retained runs). Structured retrieval reduces mean absolute error (MAE) from 4.58 to 2.96 points relative to non-agentic baselines (mean gain 1.62 MAE points; 95% CI 1.57–1.67; 35% relative reduction), with consistent gains across all 36 stress combinations. Lower-cost models show disproportionately larger gains (2.76 versus 0.45 MAE points). Tool-retrieved pipelines outperform retrieval-augmented generation in 33 of 36 combinations. These findings indicate that retrieval architecture, rather than model scale alone, is a tractable lever for robust, equitable clinical LLM deployment.

OBJECTIVE: A definition of refractory septic shock is necessary to guide diagnosis, management, prognostication, research, and future guidelines for this most severe form of the disease. We sought to achieve consensus on clinical criteria that would be used to define refractory septic shock. DESIGN: Review of literature, expert panel position statements, and Delphi rounds with an international expert group. SETTING: Consensus was defined as having at least 75% of panellists in agreement or disagreement on the three highest or lowest levels of a 7-point Likert scale or based on responses to single- or multiple-choice questions, respectively. SUBJECTS: A panel of multinational, multiprofessional and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (57 invitations and 56 participants). MEASUREMENTS AND MAIN RESULTS: A five-round Delphi process was conducted for consensus and stability. The steering committee proposed 34 statements, and five of them were rejected by panel experts after round 2. Among 29 statements selected from eight domains, consensus was reached for 13. The panel agreed on the need for a comprehensive consensus set of clinical criteria for refractory septic shock. Markers of organ dysfunction (75%, 2 rounds), tissue perfusion (91.1%, 2 rounds) including lactate (94.6%, 2 rounds) and capillary refill time (76.8%, 2 rounds), assessment of fluid-responsiveness after initial resuscitation (92.9%, 5 rounds), and use of vasoactive drugs at norepinephrine equivalents greater than 0.5 µg/kg/min (75.0%, 3 rounds), were selected as clinical criteria of refractory septic shock. The use of critical care ultrasound (CCUS) (92.9%, 3 rounds) was the single diagnostic modality that reached a consensus-based agreement. CONCLUSIONS: A consensus for 13 criteria to frame the definition of refractory septic shock was reached. Refractory septic shock is characterised by persistently elevated lactate concentrations and or prolonged capillary refill time in patients with septic shock who are fluid unresponsive, require a norepinephrine base equivalent dose greater than 0.5 micrograms per kilogram per minute, and undergo CCUS assessment when mixed shock is suspected.

Abstract Lentigo maligna (LM) is a subtype of cutaneous melanoma in situ that develops on chronically sun‐damaged skin in elderly individuals. Its diagnosis and management remain challenging due to its slow progression, frequent occurrence on cosmetically sensitive areas in frail individuals, and tendency for subclinical peripheral extension. Despite its potential for invasive transformation, the natural history of LM remains incompletely understood and evidence‐based management strategies for this specific entity remain limited. This work aims to bridge the gap between scarce high‐quality evidence and the clinicians' need for practical guidance on LM management by formulating evidence‐based and expert consensus‐driven recommendations for diagnosis, treatment and follow‐up. Under the coordination of the International Dermoscopy Society, a global, multidisciplinary consortium of 53 experts—including dermatologists, dermato‐oncologists, dermatologic surgeons, radiologists, radiotherapists, pathologists and epidemiologists—formulated recommendations through structured consensus, informed by a comprehensive review of current scientific evidence and clinical practice standards. Optimal management of LM requires accurate diagnosis and individualized treatment planning. Non‐invasive skin imaging techniques, especially dermoscopy and reflectance confocal microscopy, aid in diagnosis, biopsy orientation, lesion delineation and post‐treatment monitoring. Multiple partial biopsies help confirm diagnosis and rule out invasion. Complete surgical excision remains the first treatment option. No definitive safety margins can be recommended for standard surgery; margin‐controlled techniques are preferable for large or ill‐defined lesions. Topical imiquimod and radiotherapy are effective alternatives where surgery is unsuitable. Topical imiquimod is useful as primary, adjuvant or neoadjuvant therapy. Blind destructive methods should be avoided. Close clinical and imaging follow‐up is needed. Patient‐centred care, shared decision‐making, and a multidisciplinary approach are critical for optimal outcomes. These international consensus recommendations summarize current best practices for LM management, offering practical, evidence‐informed guidance to clinicians while acknowledging the potential of future research in refining these conclusions.

ABSTRACT Introduction Non‐muscle invasive bladder cancer (NMIBC) is a chronic disease with a lifelong treatment burden that may cause substantial urinary morbidity. Such quality‐of‐life changes remain understudied. We therefore evaluated the incidence and predictors of treatment for overactive bladder (OAB) among older adults following diagnosis of NMIBC. Materials and Methods We identified adults aged 66–89 years with newly diagnosed NMIBC from 2007 to 2017 in the linked SEER‐Medicare database. We examined the incidence of treatment initiation for OAB following initial transurethral resection of bladder tumor (TURBT) and evaluated associations with baseline characteristics using Cox regression. Results We identified 9,819 patients, of whom 68% had Ta disease, 29% had T1 disease, and 4% had CIS. Within the first 12 months of TURBT, 7% of patients received treatment for OAB, and this increased to 15% of patients at 5 years. In the first year, the most utilized therapies were anticholinergic medications (early 3.72%, late 2.74%) and beta‐3 agonists (early 0.11%, late 0.32%), while procedural OAB therapy utilization was rare (0.2%). On multivariable analysis, female gender (HR 1.26, 95% CI 1.11–1.42), congestive heart failure (HR 1.21, 95% CI 1.03–1.43), and T1 tumor stage (HR 1.27, 95% CI 1.12–1.44 vs. Ta) were independently associated with an increased risk of OAB treatment. Conclusions The incidence of OAB requiring treatment among patients with NMIBC is substantial, with approximately one in six patients receiving treatment by 5 years after diagnosis. Predictive clinicopathologic features for OAB treatment—including, sex, high‐risk tumor features, and repeat TURBT—may be useful for clinical counseling.

Abstract Platinum-based chemotherapy remains a cornerstone of treatment for triple-negative breast cancer (TNBC), yet the molecular determinants governing platinum response remain poorly defined. By leveraging the randomized Phase II INFORM trial, which compared neoadjuvant cisplatin to anthracycline-based therapy in BRCA1/2 -mutant breast cancer—we identified miR-362-3p as a specific regulator of cisplatin sensitivity. Higher plasma miR-362-3p expression was exclusively associated with favorable clinical outcome in the cisplatin arm, with no association observed in the AC arm, decoupling platinum-specific vulnerability from general chemotherapy response. We used gain- and loss-of-function TNBC models to establish that miR-362-3p functions as a potent sensitizer to cisplatin in vitro and in vivo . Integrated TCGA analysis and experimental validation identified BCLAF1, a key regulator of DNA damage response, as a direct repression target of miR-362-3p. We uncovered a novel role for the miR-362-3p/ BCLAF1 axis in overcoming platinum resistance in TNBC.

ABSTRACT Background Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1‐year prospective follow‐up study on PLS and efforts to distinguish it from ALS. Methods Seventy‐six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1‐year follow‐up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification. Results Seventy participants completed 1‐year follow‐up. Five of the 70 were reclassified to ALS (7.1%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94% specificity and 60% sensitivity. No other features predicted reclassification to ALS. Conclusions In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow‐up (7.1%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1‐year follow‐up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.