Citations

Abstract Background: Pyroptosis is a form of programmed cell death characterized by cleavage of gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and release of pro-inflammatory cytokines. Its pro-inflammatory potential has garnered significant research attention in recent years but has not been studied in lymphoma. Patients and Methods: We performed immunohistochemistry for cleaved GSDMD (n-terminal) in two large cohorts of diffuse large B-cell lymphoma (DLBCL) with multiplex fluorescent IHC (mfIHC) data, and analyzed for prognostic and immune impact. Results: Cleaved GSDMD was frequently expressed in DLBCL, and only the cytoplasmic (versus nuclear) form of expression correlated with significantly better patient survival in two DLBCL cohorts. To understand the expression at the single-cell level, we examined mfIHC results, which revealed that GSDMD+cells were tumor or immune cells, and varied in Ki-67, BCL2, and MYC expression. Cases with cytoplasmic cleaved GSDMD expression had higher mean and median levels of CD38+ (activated) M1 macrophages in two cohorts and lower PD-1/PD-L1 expression, as well as phenotypes of cognate interactions between live activated M1 macrophages, DLBCL cells, and T cells in spatially resolved immune landscape by mfIHC. In contrast, phagocytosis of pyroptotic lymphoma cells by M2 macrophages and cell death of T cells were observed in cases with predominantly nuclear form of cleaved GSDMD expression. Bulk gene expression profiling analysis identified a large proportion of RNA genes upregulated in DLBCLs with cytoplasmic cleaved GSDMD expression, and deconvolution analysis found decreased frequency of the “Inflammatory” lymphoma microenvironment (LME) subtype, increased frequency of cell states and ecotypes with favorable prognostic associations, and decreased frequency of T cell exhaustion states. Summary: Analysis of pyroptosis-inducing cleaved GSDMD (n-terminal) expression in a large number of DLBCL patients revealed dinstinctive cytoplasmic and nuclear expression patterns in live and pyroptotic cells associated with different prognostic and immune effects. Cytoplasmic cleaved GSDMD expression is a marker of cognate interactions between live cells (e.g., activated M1 macrophages) associated with adaptive responses and favorable prognostic effects, whereas nuclear cleaved GSDMD expression is associated with immunosuppressive mechanisms, including T cell death and phagocytosis by M2 macrophages.

Abstract Background: Prior work has indicated racial, ethnic and geographic disparities in treatment access and outcomes for acute myeloid leukemia (AML). However, the relationship between social vulnerability and AML outcomes remains understudied. The study examines the association between overall Social Vulnerability Index (SVI) and its domains with crude mortality rate (CMR) in AML patients from 2010 to 2020 and describes temporal trends. Methods: County-level SVI data aggregating 15 census variables into four domains-(1) socioeconomic status, (2) household composition and disability, (3) minority status and language, and (4) housing type and transportation, assign each county a percentile score from 0 (least vulnerable) to 1 (most vulnerable). Counties were categorized into four quartiles based on SVI scores: Q1:0-0.25 (least vulnerable) to Q4:0.75-1 (most vulnerable). CMR per 100,000 patients were abstracted from CDC WONDER database for adult patients (≥25 years) with AML and reported for patients <65 and ≥65 years of age in Q1 and Q4 counties. Counties with <10 deaths (<1% deaths) were excluded. Poisson regression models, using Q1 as reference, assessed the relationship of CMR and overall SVI in each age group, and reported rate ratios (RR) and 95% confidence intervals (CI). Each SVI domain's independent association with CMR was examined in each age group. Temporal trends were assessed by comparing CMR in 2010-2014 and 2016-2020 cohorts. Results: From 2010 to 2020, 103,411 deaths in AML patients occurred (overall CMR: 5.61 per 100,000). Unexpectedly, higher overall SVI was associated with lower mortality: CMR 5.96 in Q1 vs. 5.01 in Q4. As expected, adults aged<65 had a lower mean CMR (1.74 in Q1 vs. 1.77 in Q4) compared to those ≥65 (18.81 in Q1 vs. 15.60 in Q4). In adults aged <65, higher overall social vulnerability was not significantly associated with mortality (Q2 RR 1.01, 95% CI 0.96-1.06, p = 0.75; Q3 RR 1.02, 95% CI 0.98-1.07, p = 0.33; Q4 RR 0.96, 95% CI 0.91-1.00, p=0.054). However, there were significant associations for each SVI domain. A higher SVI in the Minority Status and Language was surprisingly associated with a significantly lower CMR (RR 0.39, 95% CI 0.36-0.43, p<0.001); for the other 3 domains, a higher SVI was associated with higher mortality: Socioeconomic status (RR 1.14, 95% CI 1.04-1.25, p=0.004), Household Composition & Disability (RR 1.31, 95% CI 1.22-1.42, p<0.001) and Housing & Transportation (RR 1.13, 95% CI 1.05-1.22, p=0.001). In adults > 65, higher overall SVI quartiles were linked to lower CMR (Q2 RR 0.96, 95% CI 0.94-0.98, p < .001; Q3 RR 0.91, 95% CI 0.89-0.94, p < .001; Q4 RR 0.84, 95% CI 0.82-0.86, p < .001). As for the domains, Socioeconomic (RR 0.81, 95% CI 0.78-0.85, p<.001) and Minority status and Language (RR 0.77, 95% CI 0.75-0.80, p<.001) were associated with a lower CMR rate. Housing & Transportation was associated with a 12% higher mortality rate (RR 1.12, 95% CI 1.08-1.17, p<.001) and Household Composition & Disability had no significant effect (p=0.214). Mortality decreased over time. In adults aged <65, CMR in Q1 counties improved from 1.94 in 2010-2014 to 1.71 in 2016-2020 and from 1.72 in 2010-2014 to 1.66 in 2016-2020 in Q4 counties. In adults aged ≥65, CMR in Q1 counties improved from 19.62 in the earlier cohort to 18.70 in later cohort but worsened from 16.32 in 2010-2014 to 16.48 in Q4 counties from 2016 to 2020. Conclusions: 1. Mortality for AML has improved over time for most of the population, except among adults in high vulnerability counties. 2. As expected, mortality is higher for older patients. 3. For adults aged <65, a surprising finding was lower mortality in counties with a higher social vulnerability in the minority and language domain, whereas a higher SVI in the socioeconomic, household, and housing domains was associated with higher mortality. 4. For adults aged ≥65, higher SVI in both the socioeconomic and minority domains was associated with a lower mortality rate, and higher SVI in the housing domain with a higher mortality rate. The authors hypothesize that urban areas with a more diverse population, and therefore a higher SVI in Minority Status and Language Domain, may offer more comprehensive care to patients with AML. In addition, the SVI does not capture important clinical and treatment variables that may impact outcomes. Further research is needed to explore more specific, population based indicators to identify at-risk patients with AML.

Abstract BACKGROUND Ivosidenib is an oral inhibitor of mutant isocitrate dehydrogenase type I (IDH1) currently approved for the treatment of IDH1 mutated acute myeloid leukemia and myelodysplastic syndrome (MDS). Hematopoietic stem and progenitor cells carrying preleukemic mutations, referred to as clonal hematopoiesis (CH), are the origin of myeloid neoplasms (MN). Individuals who have cytopenias and CH, but do not meet diagnostic criteria for a hematologic malignancy, are classified as having Clonal Cytopenias of Undetermined Significance (CCUS), a condition associated with a high risk of progression to MN. While CCUS patients (pts) can have multiple mutations, they show lower mutational burden on average compared to MN. Thus, we hypothesized that treatment with ivosidenib would improve cytopenias in IDH1-mutant CCUS. METHODS; We performed a decentralized phase II single-arm study to characterize the safety and efficacy of ivosidenib in IDH1-mutant CCUS (NCT0503044). Drug was shipped to pts with local oncologists performing standard-of-care clinical exams supplemented by study team lead interviews for adverse event monitoring. Research labs were drawn by local providers or through Quest. QT corrected interval (QTc) was monitored through a mobile electrocardiogram device (AliveCor). Eligible patients were aged ≥ 18 years and had confirmed IDH1-mutant CCUS with at least 6 months of unexplained cytopenias (hemoglobin<10 g/dL, platelets<100 x109/L or absolute neutrophil count <1.8 x109/L). The primary endpoint was hematologic response of at least 8 weeks in duration based on the IWG 2006 criteria for MDS. RESULTS 20 pts with IDH1-mutant CCUS have been enrolled. Most were male (70%) with a median age of 66 (range 41-79). Overall, 74% had a self-reported race of non-Hispanic white, 11% of Hispanic white, 5% of Asian and 11% of black or African American. Most pts presented with neutropenia (95%) including some with co-occurring thrombocytopenia (21%). One pt presented with anemia and thrombocytopenia without neutropenia. Prior to treatment, the average number of co-mutations beyond IDH1 was 2 (range 0-3), with most pts (74%) harboring a co-occurring spliceosome gene mutation. The IDH1 variant allele fraction (VAF) was lower in the blood (mean=19%, range 3-35%) than in the bone marrow (mean=31%, range 18-43%) in most (93%) patients. Out of the 20 enrolled pts, 17 received at least 8 weeks of therapy at the time of our data cutoff (7/29/2025) and were included in the efficacy analysis. Grade ≥3 adverse events (AEs) occurred in five patients (26%) including two with grade ≥3 treatment-related adverse events (pancytopenia and sepsis in the first pt, rash in the second pt). The most common all-grade treatment-related adverse events were nausea (n=5, 26%), prolonged QTc (n=3, 16%), anemia (n=3, 16%), and diarrhea (n=3, 16%). There were no instances of reported differentiation syndrome. Overall, 82% of pts achieved a hematologic response (14/17) including improvement in neutropenia (88%) and thrombocytopenia (75%). With a median follow-up of 16 months (range 0.6-24 months), the median duration of hematologic response was not reached. Among responders, 86% had a continued response at one year. Two pts progressed to MDS after 4 and 17 months of treatment characterized by recurrence of cytopenias and the emergence of new clones. A surveillance bone marrow biopsy was performed at 18 cycles for the 8 pts who remained on treatment with none showing disease progression. Most pts (90%, N=9/10) treated for at least 12 months had a decrease in IDH1-mutant CH VAF over time and 40% (N=4/10) showed IDH1 mutation clearance (VAF <2%) with a median time to clearance of 9 months. Among those with decreasing IDH1 clonal burden, all had a corresponding decrease in other co-occurring mutations present at baseline with one responder showing emergence of a newly detectable CHEK2 mutation without disease progression. CONCLUSIONS Decentralized trials represent a feasible solution for the conduct of clinical trials in rare hematologic neoplasms and precursor conditions. Ivosidenib was well-tolerated and induced durable hematologic remissions in IDH1-mutant CCUS. Most pts showed a reduction in clonal burden with mutation clearance commonly seen with long-term treatment demonstrating that ivosidenib modifies the natural history of IDH1-mutant CCUS.

Abstract Background Hairy cell leukemia (HCL) is a rare, indolent B-cell malignancy accounting for ~1% of all lymphoid neoplasms. While purine analogs remain the standard first-line therapy, the increasing use of combination regimens and targeted agents has expanded the therapeutic landscape. Data on long-term outcomes in real-world practice remain limited. Methods This is a retrospective, multicenter cohort study. We included 104 patients aged ≥18 years with a diagnosis of HCL who had at least one oncology visit from January 1, 2010, to July 17, 2025. Patients diagnosed prior to 2010 were left-truncated to account for survivorship bias. Data were abstracted from electronic medical records. Key outcomes included treatment patterns, response rates, overall survival (OS), and progression-free survival (PFS). Results The median age at diagnosis was 56.9 years (range 32.1–83.8), and 80% were male. Most patients (77%) were diagnosed during or after 2010. The most frequent frontline therapies were cladribine (63%), cladribine with rituximab (12%), rituximab monotherapy (9.7%), vemurafenib-based regimens (7.7%), splenectomy with or without interferon (3.8%), interferon monotherapy (2.9%), and other (1.9%). The overall complete response (CR) rate to first-line therapy was 63%, with 15% achieving a partial response (PR) and 22% having stable or no response. For patients receiving cladribine with rituximab first-line (n = 12), 92% had a CR. For patients receiving cladribine monotherapy first-line (n = 65), 63% had a CR and 12% had a PR. For patients receiving rituximab monotherapy first-line (n = 10), 50% had a CR and 20% had a PR. For patients receiving vemurafenib-based regimens first-line (n = 8), 75% had a CR. Among the 39 patients who received second-line therapy, the most common regimens included cladribine (31%), rituximab (26%), cladribine plus rituximab (18%), and vemurafenib-based regimens (13%). The CR rate after second-line therapy was 72%. For patients receiving cladribine with rituximab second-line (n = 7), 86% had a CR and 14% had a PR. For patients receiving cladribine monotherapy second-line (n = 12), 67% had a CR. For patients receiving rituximab monotherapy second-line (n = 10), 80% had a CR and 10% had a PR. For patients receiving vemurafenib-based regimens second-line (n = 5), 40% had a CR and 20% had a PR. Among the 17 patients who received third-line therapy, the most common regimens included rituximab (41%), cladribine (18%), and vemurafenib-based regimens (18%). The CR rate after third-line therapy was 50%. For patients receiving rituximab monotherapy third-line (n = 7), 43% had a CR and 14% had a PR. For patients receiving cladribine monotherapy third-line (n = 3), 33% had a CR. For patients receiving vemurafenib-based regimens third-line (n = 3), 67% had a CR and 33% had a PR. Overall, treatment-related hospitalizations for first-line therapy occurred in 27% of patients. 50% of patients receiving first-line cladribine with rituximab had treatment-related hospitalizations. 25% of patients receiving first-line vemurafenib-based treatment had treatment-related hospitalizations. 23% of patients receiving first-line cladribine monotherapy had treatment-related hospitalizations. 20% of patients receiving first-line rituximab monotherapy had treatment-related hospitalizations. Overall, after a median follow-up of 6.6 years (range 0.1–46), estimated OS was 96.6% at 5 years, 85.7% at 10 years, and 80.3% at 15 years. The median OS was 24.5 years [95% CI: 18.3, not reached]. Estimated PFS was 95.1% at 1 year, 89.9% at 3 years, 74.8% at 5 years, and 50.8% at 10 years. Median PFS was 12.2 years [95% CI: 7.0, not reached]. Estimated OS for first-line cladribine monotherapy was 100% at 5 years and 86.5% at 10 years. Estimated OS for first-line vemurafenib-based treatment was 85.7% at 5 years and 85.7% at 10 years. Conclusions This large real-world cohort provides important insights into the long-term management of HCL. Cladribine-based regimens remain the predominant first-line approach, with high response rates and durable remissions. However, treatment-related toxicity is common. Outcomes in later lines remain favorable, particularly with re-treatment using purine analogs or combination regimens. These findings underscore the importance of individualized treatment planning and the continued need for real-world evidence to inform care in rare hematologic malignancies.

Abstract Objective Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high seizure burden and mortality risk. Stiripentol, one of the first DS‐specific therapies, received FDA approval in 2018 but its real‐world use and impact post‐approval in the USA remain insufficiently characterized. The STIRUS study aimed to assess treatment patterns, clinical efficacy, and quality of life outcomes associated with stiripentol in a contemporary US cohort. Methods STIRUS was a retrospective, multicenter chart review of 98 DS patients who initiated stiripentol after FDA approval and were treated for at least 3 months. Data were collected from 10 USA epilepsy centers on seizure types and frequency, status epilepticus (SE), rescue medication use, emergency room visits, and quality of life, at baseline and during the first and final 3 months on stiripentol. Changes over time were assessed using generalized estimating equation models. Results Initiation of stiripentol was associated with a significant reduction in bilateral convulsive seizure frequency (OR = 2.16, p < 0.006) and a nearly 50% decrease in SE episodes (OR = 2.9, p < 0.003). Importantly, there was a marked decline in rescue medication use and seizure‐related hospital visits: the proportion of patients requiring no rescue medications increased from 23% to over 53%, and those needing frequent emergency interventions dropped from 39% at baseline to 14% during the final 3 months. Quality of life improved in more than half of patients and caregivers. Significance The STIRUS study supports the real‐world efficacy of stiripentol in reducing seizure burden and healthcare utilization in DS. Despite its demonstrated benefits and approval for use in infants, stiripentol remains underutilized and often introduced late in the treatment course. Early and broader adoption may help improve clinical outcomes and quality of life in this vulnerable population. Plain Language Summary The STIRUS study found that stiripentol, an anti‐seizure medication specifically approved for Dravet Syndrome, helped reduce seizures and hospital visits for children living with this severe form of epilepsy. Patients had fewer convulsive seizures, needed fewer rescue medicines, and reported better quality of life. Despite these benefits, stiripentol is still not widely used and often started too late in treatment, suggesting earlier use could further improve outcomes.

Introduction: Psychosocial assessments by behavioral health (BH) professionals before metabolic and bariatric surgery (MBS) are recommended by national guidelines. Accordingly, insurance companies often require patients to undergo psychosocial assessments before MBS. This paper reviews the historical evolution of the MBS psychosocial assessment, clarifies the role of BH professionals within the team before and after MBS, and describes strategies to effectively utilize psychosocial assessments to optimize patient outcomes. Methods: Authors conducted a manual search of the available literature and completed a narrative review. Results: The original intent of the psychosocial assessment for MBS was to correlate psychiatric profiles to weight loss outcomes or identify which patients were predicted to succeed or “fail” after MBS. Historically, these evaluations were gatekeeping mechanisms, which invalidates the myriad ways that psychosocial assessments can identify and support patients. Controversy exists about the necessity of these evaluations, leading some MBS team members and patients to see it as an unavoidable “checkbox” with little clinical utility outcomes. Conclusion: Viewing the psychosocial assessment as a checkbox minimizes the potential benefits to patients and MBS team members. Additionally, it diminishes the expertise of BH professionals who are uniquely trained to support this patient population toward an optimal surgical outcome.

Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD). The pathogenesis of HLHS is poorly understood, and due to the likely oligogenic complexity of the disease, definitive HLHS-causing genes have not yet been identified. Postulating impaired cardiomyocyte proliferation as a likely important contributing mechanism to HLHS pathogenesis, and we conducted a genome-wide siRNA screen to identify genes affecting proliferation of human iPSC-derived cardiomyocytes (hPSC-CMs). This yielded ribosomal protein (RP) genes as the most prominent class of effectors of CM proliferation. In parallel, whole genome sequencing and rare variant filtering of a cohort of 25 HLHS proband-parent trios with poor clinical outcome revealed enrichment of rare variants of RP genes. In addition, in a familial CHD case we identified a rare, predicted-damaging promoter variant affecting RPS15A that was shared between the HLHS proband and a distant relative with CHD. Functional testing with an integrated multi-model system approach reinforced the idea that RP genes are major regulators of cardiac growth and proliferation, thus potentially contributing to the hypoplastic phenotype observed in HLHS patients. Cardiac knockdown (KD) of RP genes with promoter or coding variants (RPS15A, RPS17, RPL26L1, RPL39, RPS15) reduced proliferation in generic hPSC-CMs and caused malformed hearts, heart-loss or even lethality in Drosophila. In zebrafish, diminished rps15a function caused reduced CM numbers, heart looping defects, or weakened contractility, while reduced rps17 or rpl39 function caused reduced ventricular size or systolic atrial dysfunction of the atrium, respectively. Importantly, genetic interactions between RPS15A and core cardiac transcription factors TBX5 in CMs, Drosocross, pannier and tinman in flies, and tbx5 and nkx2-7 (nkx2-5 paralog) in fish, support a specific role for RP genes in heart development. Furthermore, RPS15A KD-induced heart/CM proliferation defects were significantly attenuated by p53 KD in both hPSC-CMs and zebrafish, and by Hippo activation (YAP/yorkie overexpression) in developing fly hearts. Based on these findings, we conclude that RP genes play novel critical roles in cardiogenesis and constitute an emerging class of gene candidates likely involved in HLHS.