Citations

Chimeric antigen receptor T-cell (CAR-T) and CD20xCD3 bispecific antibody (BsAb) therapies are both effective for relapsed/refractory (R/R) follicular lymphoma (FL), but comparative real-world survival outcomes and time toxicity have not been characterized. We performed a multicenter retrospective study of 228 patients with R/R FL treated with standard-of-care CAR-T (n = 141) or BsAb (n = 87) across 17 U.S. academic centers in the third-line or later setting. Progression-free survival (PFS) and overall survival (OS) were stratified by 2 or ≥3 prior lines of therapy (LOT2 or LOT3+), including propensity matching. Time toxicity was measured by physical health care contact days. Median PFS was not reached (NR) with CAR-T and 581 days with BsAb in the LOT2 cohort (p < .0001), and was NR with CAR-T and 584 days with BsAb in the LOT3+ cohort (p = .0064). CAR-T recipients were younger (p < .0001) and had better performance status (p = .007) but were more refractory to prior LOT (p = .017). PFS advantages of CAR-T were independent of these differences. OS did not differ between treatment groups. CAR-T had significantly greater time toxicity over the first year, with higher mean contact days than BsAb in both the LOT2 (58 vs 44) and LOT3+ (69 vs 49) cohorts. In this large multicenter cohort of patients with R/R FL, CAR-T was associated with superior PFS but greater time toxicity compared with BsAb therapy. These findings provide real-world outcomes data and time toxicity benchmarks to support treatment sequencing decision-making in R/R FL.

CD4 + effector T helper 1 (T H 1) cells drive inflammatory bowel disease (IBD). Here, we investigated how integrated signaling, metabolic, and epigenetic programs sustain their pathogenic persistence. We found that enforcing mitochondrial pyruvate metabolism with methyl pyruvate (MePyr) suppressed T H 1 cell effector function and induced the acquisition of a regulatory-like phenotype. MePyr suppressed the activity of glycogen synthase kinase 3β (GSK3β), promoting a metabolic shift from glycolysis toward oxidative phosphorylation (OXPHOS) and limiting the accumulation of intracellular acetyl-CoA. This metabolic reprogramming decreased histone H3 acetylation at genes encoding inflammatory cytokines, thereby decreasing T H 1 cell–associated gene expression. Restoration of inflammatory cytokine production by acetate supplementation or histone deacetylase inhibition established acetyl-CoA–dependent histone acetylation as a mechanistic link between metabolic flux and effector function. Conversely, the cytokine interleukin-21 enhanced T H 1 cell effector activity by promoting a GSK3β-dependent shift from OXPHOS to glycolysis. Single-cell transcriptomic analysis of Crohn’s disease tissue revealed enrichment of glycolytic gene programs in nonregulatory CD4 + T cells. Consistent with these findings, pharmacologic inhibition of GSK3β attenuated disease severity in a T cell–transfer mouse model of colitis. Together, these findings identify a GSK3β-dependent metabolic-epigenetic axis that sustains T H 1 cell pathogenicity and highlight GSK3β as a potential therapeutic target for IBD.

Abstract Everolimus 10 mg daily is the standard dose for advanced neuroendocrine tumors (NETs), but adverse events frequently necessitate dose reduction. As a result, oncologists often adopt a dose‐escalation strategy starting at 5 mg and increasing the dose as tolerated. In this multicenter study, we evaluated the effect of reduced dose (RD) and standard dose (SD) everolimus on survival, progression, and toxicity in patients with advanced NETs. We conducted a multicenter retrospective cohort study of patients with advanced NETs treated with everolimus at Mayo Clinic and University Hospitals (Cleveland, OH). Patients were grouped by starting dose (5 mg vs. 10 mg). Primary endpoints were overall survival (OS), real‐world progression‐free survival (rwPFS), and adverse events. Multivariable Cox models, inverse probability of treatment weighting (IPTW), and time‐varying dose sensitivity analysis were used to account for confounding and dose crossover. Among 170 patients (48 started on 5 mg; 122 on 10 mg), the 5 mg cohort was older, had worse ECOG PS, and was more heavily pretreated. Median OS was 43.7 months (5 mg) versus 81.5 months (10 mg; log‐rank p = .02). However, after multivariable adjustment ( N = 124 G1–G2 patients; 51 events), the association was no longer statistically significant (adjusted HR, 0.59; 95% CI, 0.31–1.12; p = .11). Median rwPFS was 7.0 versus 12.4 months (log‐rank p = .05); the adjusted rwPFS difference was not statistically significant (HR, 0.95; 95% CI, 0.56–1.61; p = .84). Nearly half (46.7%) of 10 mg starters required dose reduction. Any‐grade toxicity was more common with 10 mg (89% vs. 75%; p = .05). The apparent survival advantage of standard‐dose everolimus was substantially attenuated after adjustment. These findings do not establish dose equivalence and should be interpreted in the context of limited statistical power. Given its more favorable observed tolerability profile, RD everolimus warrants prospective evaluation as a starting strategy for patients at increased risk of treatment‐related toxicity who may not tolerate SD.

ABSTRACT The novel HLA‐DQA1*01:217 allele differs from DQA1*01:01:01:12 by a single non‐synonymous change in exon 3′.

Background Transcatheter edge‐to‐edge repair (TEER) and replacement (TTVR) have emerged as new modalities to treat patients with symptomatic significant tricuspid regurgitation. This study aimed to compare invasive hemodynamic and right ventricular (RV) changes and symptom improvement over 1 year. Methods Patients who underwent TEER/TTVR at Mayo Clinic (Rochester, MN, 2017–2024) were included. Hemodynamic profiles were described before and immediately after intervention, in addition to RV enlargement/dysfunction ≥moderate at 30 days and change in symptoms over time. Results Of 100 patients included (50 per group, median age 81 versus 80 years and female 62% versus 42%, in TTVR and TEER, respectively), all had ≥ moderate–severe symptomatic tricuspid regurgitation. Post intervention, mean right atrial pressure decreased in TEER (16 to 14 mm Hg, P <0.001), V wave decreased in both groups (to 16 mm Hg, P <0.001). RV enlargement was less prevalent in both cohorts at 30 days (60%–40% in TEER, P =0.01, and 72 to 58% in TTVR, P =0.07), yet prevalence of RV dysfunction decreased only in TEER (26 to 15%, P =0.17) as opposed to TTVR (31 to 44%, P =0.13). TTVR resulted in a higher stroke volume index and more complete tricuspid regurgitation elimination at 30 days. Both groups resulted in similar improvements in New York Heart Association class, with overall similar survival. Conclusions TEER was associated with a greater reduction in right atrial pressure and more favorable RV remodeling at 30 days, as opposed to TTVR, which achieved more complete and sustained elimination of tricuspid regurgitation with higher forward stroke volume.

OBJECTIVE Multisegmental pathological autofusion is a hallmark feature of ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH), creating a rigid, brittle spine highly susceptible to three-column fractures and devastating neurological injury. This study aimed to evaluate survival outcomes in this patient population and identify clinical and demographic predictors of mortality. METHODS Adults with DISH or AS who sustained a fracture and were admitted to a single tertiary care center for spinal fracture were retrospectively identified using ICD-10 diagnostic codes. Data were extracted on demographics, clinical presentation, fracture characteristics, and details of treatment. RESULTS A total of 383 patients (median age 78 years, 75.2% male) were included. Over a median follow-up of 17.3 months, overall mortality was 38.1%, in-hospital mortality was 5.2%, 30-day mortality was 5.7%, and 1-year mortality was 18.0%. Initial treatment consisted of external orthosis in 220 (57.4%) and surgery in 144 (37.6%), while 19 (5.0%) were left untreated. Patients who died were older (median 83 vs 74 years, p < 0.001), had a lower BMI (29.4 vs 32.3 kg/m 2 , p < 0.001), had higher frailty on the 5-item modified frailty index (mFI-5), and more commonly had congestive heart failure (CHF), cancer, functional dependency, and chronic kidney disease (CKD) (all p < 0.01). Mortality was not associated with fracture location, mechanism of injury, fracture number, or the presence of neurological deficits. Univariable time-to-event analysis showed that decreased survival was predicted by older age (HR 1.08, p < 0.0001), lower BMI (HR per kg/m 2 0.93, p < 0.0001), functional dependency (HR 2.05, p < 0.001), cancer (HR 1.55 p = 0.01), CKD (HR 1.48, p = 0.019), CHF (HR 2.18, p < 0.001), and higher mFI-5 score (HR per point 1.34, p < 0.001). On multivariable analysis, older age (HR 1.06 per year, p < 0.001), lower BMI (HR per kg/m 2 0.95, p < 0.001), and mFI-5 score (HR per patient 1.37, p < 0.001) remained significant independent predictors of mortality. Treatment modality did not predict mortality. CONCLUSIONS AS- or DISH-associated spinal fractures have a high associated mortality, regardless of mechanism or severity. Treatment modality did not affect odds of survival, suggesting that nonoperative management with an external orthosis may be an appropriate option, particularly in older and medically complex patients.

Background. The use of immune checkpoint inhibitors (ICIs) in kidney transplant recipients (KTR) for cancer treatment is limited by concerns of allograft rejection and uncertain oncologic efficacy. Methods. We conducted a single-center retrospective study of KTR with unresectable or metastatic malignancies treated between 2018 and 2025. The primary study cohort included 33 patients treated with ICI, whose outcomes were compared with 20 matched KTR treated with non-ICI systemic chemotherapy (SC). Results. KTR treated with ICI achieved an objective response rate of 36.4% (12/33) versus 30.0% (6/20) with SC, and a clinical benefit rate of 54.5% (18/33) versus 35.0% (7/20); neither difference was statistically significant (objective response rate P = 0.77; clinical benefit rate P = 0.27). Disease progression occurred in 81.8% of ICI-treated patients and 95.0% of SC-treated patients ( P = 0.23), and death because of cancer progression occurred in 63.6% and 75.0%, respectively ( P = 0.58). Median progression-free survival was 7.3 mo (95% confidence interval [CI], 4.3-10.8 mo) in the ICI group versus 4.1 mo (95% CI, 2.8-6.3 mo) in the SC group (log-rank P = 0.156). Median overall survival was 15.1 mo (95% CI, 7.6-37.3 mo) with ICI versus 8.7 mo (95% CI, 4.9-14.8 mo) with SC (log-rank P = 0.079). Posttreatment allograft rejection occurred in 12.1% of ICI-treated patients and 0.0% of SC-treated patients ( P = 0.29), with irreversible graft loss in 3.0%. Grade ≥2 immune-related adverse events occurred in 12.1% of ICI-treated patients, and no treatment-related deaths were observed. Conclusions. ICI therapy was associated with a trend toward longer overall survival when compared with SC and with a low rate of rejection and allograft loss.

ABSTRACT Extracellular vesicles (EVs) are increasingly recognized as mediators of intercellular communication in cancer. We previously demonstrated that re‐expression of the leucine‐rich domain (LRD) of neurofibromin (NF1) suppresses glioblastoma (GBM) invasion and limits microglia/macrophage infiltration into the tumor microenvironment (TME). Given the central role of tumor‐associated microglia/macrophages (TAMs) in GBM progression, we investigated whether NF1‐LRD‐containing EVs (NF1‐LRD‐EVs) could modulate TAM function and remodel the TME. Our results showed that NF1‐LRD‐EVs attenuated microglia and macrophage recruitment in migration assays, consistent with reduced microglia/macrophage recruitment observed in vivo . In parallel, treatment with NF1‐LRD‐EVs enhanced phagocytic activity of both microglia and iPSC‐derived macrophages, accompanied by induction of pro‐inflammatory cytokines TNF‐α, IL‐6, and IL‐1β, and downregulation of immunosuppressive mediators such as Arginase‐1 and IL‐10. Mechanistically, NF1‐LRD‐EVs induced ADAM17‐associated inflammatory signaling, accompanied by NF‐κB activation. Pharmacological inhibition of ADAM17 reduced TNF‐α release and attenuated NF‐κB activation, supporting a role for ADAM17‐dependent signaling in amplifying this inflammatory response. Together, these findings show that NF1‐LRD‐EVs reprogram TAMs toward a pro‐inflammatory phenotype and modulate the GBM immune microenvironment. These results provide a framework for understanding NF1‐LRD‐EV‐mediated immune regulation and support further investigation of EV‐mediated immune modulation of the TME.

Abstract Background Personalized meal planning by registered dietitian nutritionists (RDNs) is time‐intensive. Large language models (LLMs) may automate drafting meal plans, but their nutritional accuracy in clinical practice is uncertain. Methods In this proof‐of‐concept study, five outpatient RDNs and four LLMs (Gemini, CoPilot, ChatGPT 4.0, and customized ChatGPT 4.0) each generated 3‐day meal plans for five validated clinical scenarios. Effectiveness was defined as accuracy in meeting pre‐specified energy, protein, carbohydrate, fat, and sodium targets. Time to create plans and RDN comfort (self‐rated confidence in nutritional accuracy and clinical appropriateness on 1–5 Likert scale) were recorded. Three independent RDNs, blinded to source, analyzed nutrient content using Nutritionist Pro. Group differences were assessed with t ‐test and ANOVA. Results All LLMs and RDNs produced feasible meal plans. LLMs generated meal plans in under 1 min, whereas RDNs required a mean of 44 min per scenario. RDNs reported comfort levels ranging from 3.8 to 4.8. Across most scenarios, LLM plans delivered a smaller proportion of requested energy than RDN plans, which more consistently approached energy targets. Both groups performed similarly for the Mediterranean diet scenario. Overall, protein accuracy did not differ. However, in chronic kidney disease, LLMs undershot the guideline‐based protein target, while RDNs tended to modestly exceed it. Accuracy for low‐carbohydrate, fat, and sodium diets was comparable. Conclusion LLMs can rapidly generate clinically plausible meal plans but are less reliable than RDNs in achieving prescribed energy and selected macronutrient goals. Prompt precision is essential for nutrient‐specific targets. A hybrid model in which RDNs refine LLM‐generated drafts may leverage efficiency without sacrificing clinical accuracy.