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Abstract Introduction Multiple myeloma (MM) is clinically heterogeneous, and therapeutic response is profoundly influenced by the complex cytokine milieu of the bone marrow microenvironment. Unlike most cancers, MM staging incorporates non–tumor-burden markers such as serum albumin, β₂-microglobulin, and LDH, which are prognostically useful but biologically nonspecific. Although individual cytokines (e.g., IL-6, IL-17, TGF-β) have been linked to disease activity, a comprehensive, systems-level assessment comparing an exhaustive list of cytokines, chemokines, and growth factors across large patient cohorts is lacking. Here, we present evidence for an actionable cytokine panel, using gene expression–derived cytokine bioactivity as a surrogate measure. Methods CD138 enriched bone marrow plasma cell RNA-seq, Seq-FISH, and clinical data were obtained from the MMRF CoMMpass study. Data were TMM-normalized, log₂(x + 1) transformed, and mean-centered. Bioactivity scores for 64 cytokines, chemokines, and growth factors were inferred using CytoSig (National Cancer Institute). CytoSig leverages transcriptomic data from over 20,000 samples treated with individual molecules to model gene expression changes of cytokine regulators, targets, and response elements to provide z-scores. Reverse validation of bioactivity between samples scoring top and bottom quartiles of each cytokine was done using pathway analysis via Gene Set Enrichemnent analysis platform that verifies bioactivity across 7561 well-studied gene sets.(MSigDB C2 2025). Cytokines with upregulation of associated pathways were considered for downstream analyses (Criteria: Normalized enrichment score > 1). Genes were ranked by sign(logFC) × –log₁₀(p), identifying 44 significantly enriched pathways. Univariate Cox regression identified prognostic cytokines. To account for variable correlation and improve prediction, Elastic Net Cox regression (α = 0.5) was used, combining LASSO (L1) and Ridge (L2) penalties. For biological validation, pathway analysis was done between samples with high vs low serum C-Reactive Protein(CRP). Survival kinetics and clinical characteristics were analyzed for the derived model. Results A total of 767 NDMM patients were included (median age 63 years, range 27–93); median overall survival (OS) was 44.4 months (IQR 70.9). Revised International Staging System (R2-ISS) distribution was: Stage I 14.7%, II 24.0%, III 34.7%, and IV 6.4%. Based on the International Myeloma Society–International Myeloma Working Group (IMS–IMWG) definition, 32.2% of patients were classified as high-risk. Supervised analysis identified 30 univariate prognostic cytokines. Elastic Net retained BMP-7, IGF-1, IL-3, NRG1, IL-17A, IL-2, IL-21, and TGF-A (positive coefficients), and IL-4, IL-18, BMP-4, palmitic acid, DHT, and BMP-2 (negative coefficients). In sensitivity analysis, after removing cytokines not passing GSEA validation, the cytokine score (CS) was established using BMP-7, IL-3, TGF-A, IL-17A, BMP-2, IL-18, BMP-4, and IL-4. High serum CRP–associated gene expression was linked to upregulation of IL-17 and BMP pathways and downregulation of IL-4 signaling. Patients with CS ≥ median had higher β2M (p < 0.001) and LDH (p = 0.005); creatinine (p = 0.07) and albumin (p = 0.6) were not significant. CS was higher in patients with del(17p), 1q21 gain, high-risk IGH, t(8;14), and del(1p), and lower in those with hyperdiploidy (all p < 0.01). CS achieved a C-index of 0.67. Median OS was 58.7 months in the high-CS group vs. 102.5 months in the low-CS group (p < 0.001). Adding continuous CS to a model with continuous β2M + continous albumin improved C-index from 0.65 to 0.72. ISS improved from 0.62 to 0.68; R2-ISS from 0.65 to 0.69. A multivariate model with β2M ≥ 5.5, del(1p) + 1q gain, t(4;14), deep del(1p), and del(17p) improved from 0.63 to 0.68 with CS. Discussion These findings require functional validation in patient samples through direct measurement of cytokine levels. BMP-7 remains understudied in MM. Elevated TGF-α, IL-3, and IL-17 promote angiogenesis, bone resorption, and immune dysfunction, while BMP-2 and BMP-4 act as tumor suppressors. IL-18 is being utilised to boost T-cell responses, and IL-4 is consistently reduced in MM. Conclusion This study provides evidence for a robust, clinically translatable cytokine, chemokine, and growth factor panel. IL-17, IL-4, and BMPs emerged as consistently regulated across all analyses. CS is associated with high-risk disease and inferior survival.

Abstract Cardiac involvement in AL amyloidosis significantly impacts both short and long-term survival. Achieving cardiac complete response (CarCR) is linked to excellent survival, comparable to that of the general population. We undertook this study to characterize patients with AL amyloidosis who achieved CarCR. Methods: A single-center retrospective study of patients diagnosed with cardiac AL amyloidosis between 2004 and 2023 and achieved a documented CarCR for at least 12 months. Patients were included if they had evidence of cardiac involvement confirmed by cardiac imaging (transthoracic echocardiogram or cardiac magnetic resonance) and Congo red–positive tissue (non-cardiac or heart biopsy), and were evaluable for cardiac response based on baseline NT-proBNP > 650 pg/mL or BNP > 150 pg/mL. CarCR was defined as a reduction in NT-proBNP to less than 350 pg/mL (or BNP less than 80 pg/mL). Heart transplant patients were excluded. Results: Sixty-three patients were included, representing 4.6% of the cardiac evaluable population in the study period. This proportion increased in the second period compared to the first period (7.5% vs 3.2%, P<0.001). The median age at diagnosis of 57 years (ranging from 29 to 79); 63% were male. Lambda light chain disease was evident in 63% of patients. The median difference between the involved and uninvolved light chain (dFLC) at baseline was 429 mg/L (interquartile range [IQR] 143-708). While all patients had cardiac involvement, 63% also presented with extra-cardiac involvement [kidneys (52%), liver (16%), autonomic nerves (14%), luminal gastrointestinal tract (11%), and peripheral nerves (10%)]. The median baseline NT-proBNP for the entire cohort was 1977 pg/mL (IQR 1393-3026). The median troponin T (n=43) was 0.02 ng/mL (IQR <0.01-0.05) and the median high-sensitivity troponin T (n=19) was 49 ng/L (IQR 38-79 ng/L). Cardiac stage distribution, according to the European modification of the Mayo 2004 staging model, was as follows: 59% stage II, 39% stage IIIa, and 2% stage IIIb. At baseline, echocardiogram features included a median left ventricular (LV) ejection fraction of 63%, a median intraventricular septum thickness of 14 mm, and a median average LV longitudinal strain of -12%. The most common first-line therapies were autologous stem cell transplantation (ASCT; with or without induction, 54%), bortezomib-containing therapy (22%), and daratumumab-containing therapy (13%). Hematological complete response rates at 3-month, 6-month, and best response prior to CarCR were 32%, 49% and 76%, respectively. At CarCR, the median NT-proBNP was 265 pg/mL (IQR 220-307) with a median time from treatment onset to CarCR achievement of 20.6 months. At CarCR, 33% of patients were on loop diuretics. The CarCR rate at 6, 12, 24, 36, 48 and 60 months from treatment onset was 10%, 39%, 81%, 90%, 95% and 96%, respectively. Temporary increase of NT-proBNP above 350 pg/mL with return to CarCR was documented in 46% of patients. Echocardiogram parameters also improved significantly at the time of CarCR, with average left ventricular longitudinal strain showing the greatest median improvement in relation to baseline (from -12% to -17%, p<0.001). However, echocardiographic parameters did not fully normalize in all patients. Cardiac progression was seen in 14% of patients, at a median of 7.6 years from the initial time of CarCR. In addition, subsequent clone-directed therapy was given in 44% of patients at a median of 4.6 years from the initial treatment. With a median follow-up of 9.5 years, eight patients (13%) died, 4 due to causes unrelated to AL. We compared the survival of patients who achieved CarCR to the general U.S. population, matching for age, sex, and the year treatment. The observed survival of CarCR patients was similar to that of the general population (p=0.35). Conclusion: Patients with persistent CarCR >12 months in AL amyloidosis are uncommon and demonstrate excellent outcomes. The achievement of hematological CR was required in 3 out of 4 patients reaching a CarCR. Echocardiographic changes of amyloid infiltration may still persist in this highly favorable cohort, indicating that “complete” response refers primarily to functional and prognostic improvement, not necessarily a full restoration to pre-disease cardiac morphology and function. Achieving CarCR is associated with a low risk of cardiac progression, but the need for subsequent clone-directed therapy remains elevated.

Abstract Background: Gastrointestinal (GI) symptoms are frequent in patients (pts) with systemic light chain amyloidosis (AL), yet their clinical significance remains poorly defined. We investigated the role of symptomatic GI involvement in disease burden, survival, and organ-specific outcomes in a large single-center cohort. Methods From 2010–2025, 4,396 AL pts were evaluated at our center; 560 pts (13%) had provider-attributed symptomatic GI AL. Pts with localized AL or positive biopsy without GI symptoms were excluded (n=38). We analyzed relationships between GI symptoms, anatomic/histologic involvement, laboratory parameters, survival, and need for nutritional support using Wilcoxon rank-sum, Chi-square, Kaplan-Meier, and logistic regression tests. Results GI symptoms included early satiety (n=320/57%), diarrhea (n=189/34%), nausea (n=184/33%), abdominal pain (n=148/26%), dysphagia (n=119/21%), vomiting (n=75/13%), GI bleeding (n=74/13%), and heartburn (n=71/13%). Only nausea and GI bleeding were not associated with cardiac (n=366/65%) renal (n=274/49%) or hepatic (n=84/15%) AL, whereas dysphagia, early satiety and heartburn were more frequent with cardiac (all OR=1.7), abdominal pain and diarrhea with hepatic (OR=2 and 1.6, respectively), and vomiting with renal involvement (OR=2; all p<0.04). Autonomic involvement impacted GI symptoms, often without proof of parenchymal GI amyloid. Of the 124 pts with formal autonomic testing, only 44 (35%) had positive GI biopsies as compared to AL GI pts without proven autonomic involvement (240/436, 55%). Pts with autonomic involvement were more symptomatic than pts with positive GI biopsies, suffering more often from dysphagia (29% vs 19%), diarrhea (41% vs 32%), and gastroparesis (34% vs 9%, all p<0.001). We screened changes in body weight, calcium, VitB12, Hb, PO4, and albumin at diagnosis. Of the 175 pts with documented weight loss in this cohort, pts with GI AL lost more weight compared to those with other organ involvement (21% vs 14% of weight, p=0.002), and had lower phosphate (3.7 vs 4.0 mg/dL, p=0.06). In our cohort of pts with GI symptoms, 298 (53%) had a positive GI biopsy. Biopsy-proven anatomic involvement dictated symptoms (all p<0.05): Of the 20 pts with positive esophageal biopsy, dysphagia was present in 45%; only 33% of the pts without an esophageal biopsy had dysphagia. Similar patterns were seen for the 170 pts with a positive gastric biopsy (n=170) in terms of heartburn (21% vs 11%), for the 165 pts with positive small bowel biopsies in terms of abdominal pain (68% vs 32%), and for the 130 pts with positive colon biopsies and diarrhea (46% vs 33%). Specific histopathological patterns were prognostic. Mucosal involvement (n=161) was an independent risk factor for survival compared to submucosal (n=64) and vascular (n=102) involvement throughout the GI tract (HR 1.83; p=0.03). Three-layer GI infiltration was associated with inferior mOS (2.4 vs 5.1 vs 7.8 y for 3 vs 2 vs 1-layer involvement, HR 3.19/1.56/1; p<0.05). Counterintuitively, vascular involvement had the lowest risk of bleeding in all GI anatomic sites (p=0.02). In the colon, only mucosal involvement was associated with a higher risk of bleeding (OR=5; p=0.04). GI involvement in AL pts did not worsen prognosis (mOS 10.0/6.3y, p=0.02), and pts with isolated GI AL (n=74/13%) had an even better survival (55% surviving at 10 y). Cachexia (n=120; mOS 3.5 vs 7.8 y, p<0.001), need for nutritional support (n=36; mOS 0.9 vs 7.0 y, p<0.001), and diarrhea (mOS 5.8 vs 6.9 y, p=0.06) were risk factors for death. In pts with hematologic response (≥PR), bleeding did not recur within 3 y (n=27), but even with response, diarrhea (n=160) persisted in 39%. Resolution was less frequent without hematologic response (persistence in 69%, OR=3.5). Improvement was most often due to treatment of bacterial overgrowth (11/35 pts; 68%) and loperamide (54/59 pts; 91%). Conclusion In AL, meaningful GI involvement is defined by nausea, diarrhea, occurrence of bleeding, and malnutrition. These are primarily associated with mucosal infiltration. GI symptoms can occur in the face of autonomic involvement. While long-term persistence of GI bleeding is rare after serologic response, cachexia and persistent diarrhea drive morbidity, need for nutritional support, and poor survival.

BACKGROUND: Although obesity and insulin resistance (IR) are established risk factors for left heart dysfunction, their clinical impact in group 1 pulmonary hypertension (PH) remains unclear. We sought to determine the impact of excess adiposity versus IR on biventricular hemodynamic and functional reserve in group 1 PH. METHODS: Homeostasis model of insulin resistance and adiposity indices (body mass index [BMI], fat mass, waist circumference) were measured among group 1 patients with PH recruited to PVDOMICS (Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics). Functional capacity, and dynamic pulmonary capillary wedge pressure (PCWP) and right atrial pressure responses were compared stratified by obesity (BMI≥30 kg/m 2 ) and IR status (HOMA-IR≥2.6) using repeated-measure mixed models. RESULTS: Among patients with group 1 PH (n=418), 158 (38%) had BMI≥30 kg/m 2 (94 [60%] of whom had IR), and 260 (62%) had BMI<30 kg/m 2 (74 [28%] of whom had IR). Among those with waist circumference measurement (n=375), 287 (77%) had excess adiposity by elevated waist/height ratio, with 214 (57%) having elevated waist circumference. Patients with obesity had worse quality of life, exercise capacity and left heart remodeling, along with higher resting/dynamic PCWP, right atrial pressure and cardiac output ( P <0.0001 for all). Higher PCWP response with obesity persisted after adjusting for IR (IR-adjusted PCWP+2.5 mm Hg [95% CI, +1.4 to +3.6]; P <0.0001). All adiposity indices were consistently associated with PCWP response, but IR was not. Similar associations were observed between adiposity indices with higher right atrial pressure and cardiac output. Greater visceral adiposity as measured by body shape index (hazard ratio, 2.01 [95% CI, 1.16–3.47]; P =0.01) or weight-adjusted waist index (hazard ratio, 1.64 [95% CI, 1.10–2.46]; P =0.01) was associated with worse survival. CONCLUSIONS: Excess adiposity is common in group 1 PH, occurring in 4 out of 5 patients by the more sensitive waist/height ratio, in contrast to only 2 out of 5 patients having obesity by traditional BMI criteria. Excess adiposity is associated with higher biventricular filling pressures, cardiac output demand, worse functional status and reduced survival. These data support trials of adipose-reducing therapies in patients with group 1 PH and excess adiposity.

Abstract Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease linked to repetitive traumatic brain injury, but its prevalence and risk factors in the general population remain poorly defined. We investigated CTE neuropathological changes (CTE-NC) in an admixed, population-based clinicopathological cohort. Neuropathological evaluation was conducted on brain samples from 1151 individuals in the University of São Paulo Biobank for Aging Studies collected from 2004 to 2022. CTE-NC and aging-related tau astrogliopathy (ARTAG) were assessed across 14 963 histological slides using p-tau immunostaining. Clinical, cognitive, and neuropsychiatric data were obtained via informant interviews; information on sports exposure and traumatic brain injury history was limited. Seven cases (0.6%) met criteria for CTE-NC, mean age at death 73.4 ± 12.5 years; 1 was female. Dementia was present in 43% of CTE-NC cases; 57% exhibited neuropsychiatric symptoms. Most common co-pathologies were Alzheimer disease-type changes, ARTAG, and argyrophilic grain disease. Comprehensive exposure histories were unavailable for most cases; 2 had documented soccer involvement. These findings indicate that CTE-NC is rare in this population-based Brazilian cohort and predominantly affects males with frequent coexisting neuropathologies. Findings align with reports from high-income countries and support prioritizing primary prevention by reducing exposure to repetitive head impacts in sport and other settings.

Abstract Description Evidence consistent with immunoediting in human cancer has been identified through associative studies. To provide direct evidence that differences in the neoantigen profile are immune-mediated, we compared the neoantigen profiles of cutaneous squamous cell carcinoma (cSCC) from immunocompetent and immunosuppressed patients. Despite consistency in the overall mutational burden and signature, immunocompetent patients have a lower clonal mutational burden compared to immunosuppressed patients. Furthermore, clonal mutations in cSCC from immunocompetent patients have a lower proportion of neoantigens predicted to bind MHC class I, supporting the role of the immune system in shaping the neoantigen profile. In single-cell RNA sequencing of intratumoral CD8+ T cells from a separate cohort of cSCC from immunocompetent and immunosuppressed patients, we observe an increase in exhausted CD8+ T cells in tumors from immunocompetent patients, suggesting an explanation for the persistence of binding neoantigens subclonally. Finally, we compare clonal and subclonal neoantigens as an unbiased screen for characteristics associated with neoantigen immunogenicity. Neoantigens with a large increase in predicted MHC class I binding relative to the normal peptide are enriched in subclonal neoantigens in immunocompetent patients. Overall, this work supports the immune system’s role in sculpting the neoantigen profile of cSCC. Funding Sources Supported by American Cancer Society - Simone Charitable Foundation - Discovery Boost Grant, AZ-DBG-23-1151311-01-IBCD; NIH F30CA281056; R35GM149235 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Background: Depression affects approximately 5.7% of adults worldwide, and around one-third of these individuals develop treatment-resistant depression (TRD). Intravenous (IV) ketamine and esketamine (administered IV or intranasally (IN)) are novel treatment options for TRD; however, only IN esketamine currently holds FDA approval. Objectives: Compare the acute effectiveness of IV ketamine with esketamine (IV or IN) in adults with TRD. Design: Mantel–Haenszel random-effects meta-analysis of head-to-head studies. Response and remission at study end point were co-primary outcomes, expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses explored the impact of diagnosis, study type, and publication format; heterogeneity was quantified with I 2 . Data sources and methods: MEDLINE, Embase, Cochrane, APA Psycinfo, and Scopus were searched from inception through 19 March 2025. Eligible studies enrolled adults with unipolar or bipolar depression directly comparing IV ketamine with esketamine and reporting response or remission. Results: Screening 1089 records identified eight studies ( n = 978). Seven observational studies ( n = 915) comparing IV ketamine with IN esketamine were included in the meta-analysis, while one randomized controlled trial (RCT) comparing IV formulations was summarized qualitatively. Pooled response from six studies gave OR = 1.26 (95% CI, 0.92–1.71; p = 0.15) and remission from seven studies gave OR = 1.31 (95% CI, 0.93–1.86; p = 0.12), both nonsignificantly favoring IV ketamine with negligible heterogeneity ( I 2 = 0%). Sensitivity analyses excluding bipolar depression or abstract-only reports yielded similar effect estimates, reinforcing the robustness of the findings. Evidence across three studies for faster onset with IV ketamine ranged from significant in one study to modest trends in two. Conclusion: Based on the currently available comparative evidence, which is almost entirely observational, IV ketamine and IN esketamine show comparable acute response and remission rates, though IV ketamine may act faster. Large head-to-head RCTs are needed to confirm these findings. Trial registration: The study protocol was prospectively registered on the Open Science Framework (OSF) at https://osf.io/5jzev .

Abstract Background Computational phenotyping from electronic health records (EHRs) is essential for clinical research, decision support, and quality/population health assessment, but the proliferation of algorithms for the same conditions makes it difficult to identify which algorithm is most appropriate for reuse. Objective To develop a framework for assessing phenotyping algorithm fitness for purpose and reuse. Fitness for Purpose Phenotyping algorithms are fit for purpose when they identify the intended population with performance characteristics appropriate for the intended application. Fitness for Reuse Phenotyping algorithms are fit for reuse when the algorithm is implementable and generalizable—that is, it identifies the same intended population with similar performance characteristics when applied to a new setting. Conclusions The PhenoFit framework provides a structured approach to evaluate and adapt phenotyping algorithms for new contexts increasing efficiency and consistency of identifying patient populations from EHRs.

Abstract Introduction/Objective Burnout among trainers can lead to increased human-derived laboratory errors (HDLEs), which can negatively affect patient outcomes. Through implemented improvement strategies, trainer burnout and HDLEs were reduced without impacting the trainee burnout by creating a core training group to ensure consistency in training and providing additional training tools. Methods/Case Report Burnout was assessed using a survey from the Burnout Assessment Tool1. This survey indicates burnout as a numerical score and was given to trainers and trainees at 3 intervals. Pre-implementation concluded trainer burnout average score was 2.47. HDLEs were categorized and totaled in conjunction with the burnout surveys. Pre-implementation data for HDLEs showed 14% were associated with a training event and 14% were associated with a process change that did not have a training event. Results: Conclusion Final data showed a decrease in average burnout score for trainers (pre=2.47, post=2.26). Trainee score was not statistically different. Post-implementation data of HDLEs showed 6% were associated with a training event and 0% were associated with a process change that didn’t have a training event. In review of the project, standardization of training, proper communication of process changes decreases average burnout of trainers and reduces the amount of HDLEs associated with training and process changes.

Abstract A new mouse model for the classical subtype of human glioblastoma (GBM) has been bred using Cre-mediated EGFRvIII overexpression and homozygous p19-ARF deletion, the mouse homolog of human p14ARF/CDKN2A, in GFAP expressing cells. Transgenic mice develop intraparenchymal and/or leptomeningeal brain lesions with some spinal cord invasion as early as 1 month old and 95% of mice die by 6 months due to hydrocephalus and/or paralysis. Mice with high grade tumors have worse survival and similar features to human classical GBM such as necrosis, high levels of mitosis and infiltration of tumor cells into normal brain. Immunohistochemical analysis confirms EGFRvIII overexpression and p19-ARF loss in Cre-expressing cells, along with patchy positive GFAP and high proliferation by Ki67. Bulk RNA sequencing reveals GEC3 tumors cluster closely with human classical GBM and have significant upregulation of downstream markers in the JAK/STAT and P13K/AKT pathways. Adherent and neurosphere primary culture of dissociated tumors indicate that tumor cells maintain EGFRvIII expression in culture and generate xenograft tumors by 3 weeks after intracranial injections into NODSCID mice. Xenograft tumors are reminiscent of the primary tumor, with similar histopathological features and immunohistochemical staining. Our spontaneous glioma model is a powerful tool for future studies focused on the role of the immune microenvironment on glioma recurrence and resistance.