Citations

Abstract Background Despite advancements in care, pregnant individuals with congenital heart disease (CHD) face disproportionately high risks. Objectives To address these challenges, a national consortium was established to improve maternal outcomes in CHD through multidisciplinary collaboration and patient engagement. Study design As part of a 2.5‐year multi‐phase consortium initiative, an in‐person research summit followed by three virtual focus groups (Project PHASE 3) was conducted with patients, clinicians, researchers, advocates, and policy representatives. Qualitative data were collected, and reflexive thematic analysis was performed to identify shared priorities. Results A total of 48 individuals participated in the in‐person meeting, including 18 patients (83% female; 11% Black/African American, 17% Asian, 11% Hispanic, 61% White) and 30 clinicians/researchers. An additional 19 patients (100% female; 32% rural/non‐urban; 16% Black/African American, 10% Hispanic, 74% White) participated in virtual focus groups. Key priorities identified included improved patient–healthcare provider communication, expanded access to multidisciplinary and adult CHD‐specialized care, and greater inclusion of patient voices in reproductive planning and research. Focus groups underscored racial disparities in care, limited CHD education for patients of color, and the need for culturally tailored resources. Participants emphasized the importance of representative research cohorts, integration of genetic counseling, and dissemination of research in accessible, plain‐language formats. Conclusions Findings demonstrate the value of integrating patient expertise and partnership in shaping cardio‐obstetric research, care models, and education. Addressing maternal health concerns in CHD research requires both structural changes and community‐driven, inclusive research strategies.

Abstract Background The incidence of type 2 diabetes mellitus among young adults has been increasing over the past few decades. There are limited data on contemporary national cardiovascular mortality rates in young adults with diabetes mellitus (DM). Methods We queried the Centers for Disease Control and Prevention's Wide‐Ranging Online Data for Epidemiologic Research database for patients aged 15 to 44 years from 1999 to 2019 in the primary analysis. A secondary analysis included data from 2020 to 2022 to examine the effect of the COVID‐19 pandemic. We analysed patients in whom cardiovascular diseases (CVD) were listed as the main cause of death and DM as a contributing cause of death. In calculating age‐adjusted mortality rates (AAMR) per 100 000 individuals, we used CVD mortality in young adults with comorbid diabetes as the numerator and the overall population as the denominator. We determined temporal trends by estimating the average annual percent change (AAPC) using the Joinpoint regression program. Results Among 3 309 079 individuals aged 15–44 years who died, 30 978 deaths were due to CVD with comorbid DM listed as a contributing cause. The overall AAMR increased from 1.08 per 100 000 individuals in 1999 to 1.23 per 100 000 individuals in 2019, with an average APC of 0.75 (95% CI, 0.31–1.20). Compared with 1999, the percentage increase in CVD deaths in 2019 among young adults with comorbid DM was +6.2%, whereas a decrease of 19.9% was observed among those without comorbid DM. Males had a higher AAMR than females (1.60 vs. 0.97). Non‐Hispanic Black individuals and non‐Hispanic American Indian/Alaska Native individuals had the highest AAMRs of 2.99 and 2.89, respectively. The AAMR was higher in rural regions compared to urban areas (1.63 vs. 1.23). The overall AAMR increased markedly from 1.23 in 2019 to 1.60 in 2022, with a similar pattern observed across demographic subgroups. Conclusion Our study reveals a rising trend in CVD mortality in young adults with DM as a contributing cause. Males, non‐Hispanic Black individuals, and individuals from rural regions had higher AAMR than their counterparts. This warrants the development of specific healthcare policies aimed at these at‐risk populations. Lay summary Our study shows that cardiovascular disease (CVD) deaths are increasing in young adults with diabetes mellitus listed as a contributing cause.

Background/Objectives: Individuals with type 2 diabetes (T2D) achieve less total body weight loss (TBWL) with obesity medications compared to those without T2D. The individualized metabolic surgery (IMS) score, originally developed to predict T2D remission after bariatric surgery, inversely correlates with TBWL response to semaglutide. IMS reflects T2D severity, incorporating HbA1c and T2D duration and medication use. This study aims to evaluate TBWL with tirzepatide across IMS severity categories and identify predictors of response in a real-world cohort. Methods: This retrospective analysis included 717 adults with T2D using tirzepatide for overweight or obesity within the Mayo Clinic Health System. Patients were stratified by IMS severity (mild, moderate, severe) and quartiles. Primary endpoint: TBWL% at 15 months. Secondary endpoints: categorical thresholds (≥5%, ≥10%, ≥15%, ≥20%) and predictors of TBWL%. Linear mixed-effects models and regression models were employed. Results: At 15 months, TBWL was greater in mild versus severe IMS groups (14.8% vs. 11.0%, p = 0.015), with similar trends across quartiles. The proportion achieving ≥ 20% TBWL was nearly two-fold higher in mild versus severe IMS (27% vs. 14%, p = 0.03). Female sex independently predicted greater TBWL, whereas insulin use, higher T2D medication burden (particularly weight-promoting agents), and HbA1c > 7% were associated with less TBWL. Conclusions: Tirzepatide produced clinically meaningful TBWL across all IMS categories, although TBWL declined with increasing IMS severity. Glycemic control and T2D medication use emerged as strong predictors of TBWL. The IMS score may serve as a practical tool to anticipate weight-loss trajectories, guide personalized treatment decisions, and inform patient counseling.

Abstract Background Alzheimer's disease (AD) exhibits significant genetic heterogeneity, with no single model fully explaining its inheritance pattern. Structural variants (SVs) may contribute to the missing heritability of AD, particularly in disease pathology and familial AD, which remain largely unexplored. Method Structural variants (SVs) were analyzed in unrelated 1,162 individuals from the ROSMAP study (687 cognitively normal (CN), 475 AD patients), as well as 197 Non‐Hispanic White (NHW) families (926 individuals, 58.5% with AD) and 214 Caribbean Hispanic (CH) families (1,340 individuals, 59.17% with AD). Large insertions and deletions were identified using Manta, Absinthe, and MELT from whole‐genome sequencing, supplemented by Sniffles2 and external SV call sets. This approach generated a unified VCF file containing 45,251 insertions and 76,566 deletions. After filtering for missingness rate and allele counts, a total of 9,290 insertions and 9,529 deletions were retained for analysis. Genome‐wide SV analyses were performed with AD‐related metrics in ROSMAP, adjusting for age, sex, and principal components, and validated in an independent ADSP replication cohort comprising 29,055 unrelated individuals (17,110 CN and 11,945 AD patients). Result We identified nine SVs (one insertion and eight deletions) segregating in AD families. An insertion near PDCD10 in NHW families reached genome‐wide significance ( p <5×10 ‐8 ) for AD risk in the replication cohort. Two deletions in KIF26B and SPHKAP were found in both CH and NHW families, while five appeared only in NHW and one in CH. All eight deletions showed genome‐wide significance for AD risk. SV GWAS on AD pathologies in ROSMAP revealed an insertion in INPP4B with the strongest association to global brain pathology (β=0.19; p = 2.32×10 ‐5 ), also linked to pathological AD, diffuse plaques, and Braak staging. A deletion near ADGRB1 (β=1.53; p = 5.05×10 ‐6 ) was associated with neuritic plaques, and another near ARMC2 (β=1.66; p = 2.17×10 ‐6 ) was linked to diffuse plaques. All three SVs associated with AD ( p <5×10 ‐6 ) in replication. Conclusion Our findings reveal numerous SVs segregating in familial AD across both CH and NHW families, as well as additional SVs linked to sporadic AD. Prioritizing these SVs based on their potential effects on gene function and expression will provide deeper insight into their contributions to both familial and sporadic AD.

PURPOSE Previous studies suggest that SPOP mutations result in increased sensitivity to androgen receptor pathway inhibitors (ARPIs) but are limited by lack of granular data. We hypothesize that SPOP mutations are associated with improved outcomes across the spectrum of advanced prostate cancer (PC). METHODS Using the real-world clinicogenomic Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort database, we analyzed outcomes based on SPOP mutation status. The primary end point was overall survival (OS) from the diagnosis of metastatic disease. Secondary end points included real-world progression-free survival (PFS) and PSA90 response. RESULTS Among 2,097 patients with metastatic PC, 5.5% (N = 115) had SPOP -mutated tumors. Compared with SPOP wild-type, patients with SPOP mutations were older at diagnosis (median 65 v 63 years; P = .001) and had higher (≥8) Gleason sum (68% v 54%; P = .02), higher incidence of lung metastasis (17% v 6%; P = .001), and increased frequency of intraductal features (13% v 5%; P < .001). SPOP mutations were associated with improved PSA90 response with first ARPI exposure in the castrate-resistant setting (60% v 40.6%; OR, 2.20 [95% CI, 1.15 to 4.19]; P = .02) but not in the castrate-sensitive setting (78.9% v 71.5%; OR, 1.49 [95% CI, 0.66 to 3.37]; P = .43). Median PFS with first ARPI did not differ in SPOP- mutated versus wild-type group in both the castrate-sensitive (24.2 v 19.2 months; hazard ratio [HR], 0.80 [95% CI, 0.49 to 1.32]; P = .39) and castrate-resistant settings (15.0 v 12.4 months; HR, 0.81 [95% CI, 0.58 to 1.12]; P = .20). In multivariable analysis, SPOP mutations were associated with improved OS (HR, 0.65, P = .02). CONCLUSION SPOP mutations were associated with longer OS despite the presence of aggressive clinical features. The distinct clinical and molecular features of SPOP -mutated PC support its consideration as a unique molecular subtype with prognostic implications.

Abstract Pyroptosis is a form of programmed cell death characterized by the cleavage of the gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and the release of proinflammatory cytokines. In this study, we performed immunohistochemistry for cleaved gasdermin D (GSDMD), gasdermin E (GSDME) N-terminus, and gasdermin C (GSDMC) in 2 different cohorts of diffuse large B-cell lymphoma (DLBCL) and analyzed the impact of GSDM expression on prognosis and immunity. The results showed frequent cleaved GSDMD (N-terminal) expression. Only cytoplasmic GSDMD N-terminal expression correlated with significantly better patient survival in the 2 cohorts. In contrast, GSDME was mainly expressed in the vascular endothelium, and correlated with significantly adverse prognostic effect. Correlating with the multiplex fluorescent immunohistochemistry results, we found that cytoplasmic GSDMD N-terminal expression was associated with increased CD38+ (activated) M1 macrophages in both cohorts, cognate interactions between live DLBCL cells and activated M1 macrophages (and T cells), and lower PD-1/PD-L1 expression in the analyzed cases. In contrast, T-cell pyroptosis, lymphoma cell-resistance to cell death, and phagocytosis by M2 macrophages were observed in tissues with predominantly nuclear GSDMD N-terminal expression. Bulk gene expression profiling and deconvolution analysis revealed associations of cytoplasmic GSDMD N-terminal expression with downregulation of “Don’t eat me”–signaling genes, upregulation of many RNA genes, decreased frequency of “inflammatory” lymphoma microenvironment subtype, increased frequencies of prognostically favorable cell states and ecotypes, and decreased frequency of T-cell exhaustion state. In summary, this study showed distinct cellular and subcellular patterns of 3 GSDM proteins and their associated immune response phenotypes and prognostic effects, with implications for novel therapeutic strategies for B-cell lymphoma.

Abstract Background: Treatment of multiple myeloma (MM) has advanced dramatically over the past decade with median overall survival (OS) for newly diagnosed MM patients (pts) now exceeding 10 years. However, outcomes in pts with high-risk disease remain poor. While most pts with high-risk disease are identified through baseline cytogenetic risk stratification, presence of extramedullary disease, or R-ISS stage, there is also a population of pts who may or may not have these traditional high-risk factors who relapse earlier than expected and have similarly poor outcomes. These pts are often delineated as “functional high-risk,” but a standardized definition of this population in the era of modern myeloma therapy is lacking. Methods: Using the ASH Research Collaborative (ASH RC) Data Hub, we retrospectively searched 7,249 pts across 10 participating institutions for those with newly diagnosed multiple myeloma (NDMM) treated with a triplet or quadruplet induction regimen (with or without autologous stem cell transplant) who had response data available. We evaluated duration of response from first line therapy (PD1) on post-PD1 clinical outcomes such as: time to next treatment (TTNT), time to subsequent progression and/or death (PFS2), and OS. We also analyzed characteristics of those who did vs. did not progress at prespecified time points of interest (12-, 18-, 24-, and 36-months) from the start of induction. We utilized recursive partitioning analyses to iteratively explore all possible cutpoints and identify which one(s) provide the greatest differentiation in the risk of subsequent progression and/or death. Results: We identified 1,305 pts who met the eligibility criteria. Of these, 264 had PD1 data including 201 who had response follow-up (f/u) after PD1. Median f/u after PD1 in this population was 3.2 years, and median PFS2 f/u after PD1 (n=201) was 4.4 years. Months to PD1 was significantly associated with PFS2 (p=0.038). All prespecified time points examined showed inferior PFS2 compared to those with PD1 &gt;36 mos, although each subgroup was not statistically significant, likely due to limited numbers in each group: PD1 &lt;12 mos HR=1.44 (n=43; 95% CI: 0.90 – 2.30; p=0.126), PD1 12-24 mos HR=1.65 (n=30; 95% CI: 0.95 – 2.85; p=0.073), and PD1 24-36 mos HR=1.58 (n=52; 95% CI: 0.98 – 2.53; p=0.059). Similarly, timing of PD1 was also associated with OS post-PD1; pts with PD1 &lt;12 mos had significantly lower OS compared to those with PD1 &gt;36 mos (HR=2.35, 95% CI: 1.27 – 4.32; p=0.006). Our recursive partitioning analysis identified 30-months at the cutoff that produced the greatest differential in outcomes between those above vs. below the landmark. Approximately 23% of the pts analyzed had PD1 within 30 mos, and these pts had significantly lower OS compared to those with PD1 ≥30 mos (HR=1.99, 95% CI: 1.21 – 3.27; p=0.006). Similarly, pts who progressed within 30 mos of starting 1L therapy (n=98) had significantly shorter PFS2 (median=12.5 mos vs 22.8 mos; HR=1.55, 95% CI: 1.09 – 2.20; p=0.014) than those who did not (n=103). Those pts who progressed within 30 mos were more likely to have a higher R-ISS stage at diagnosis (p=0.048), but were not more likely to have high-risk cytogenetics (p=0.66) compared to pts with PD1 ≥30 mos. Interestingly, receiving SCT as part of 1L therapy was not significantly associated with improved PFS2 (HR=0.89, 95% CI: 0.62 – 1.29; 0.54) but was significantly associated with improved OS (HR=0.53, 95% CI: 0.31 – 0.90; 0.018) by univariate analysis. Conclusion: Our study is the first to use a large, multicenter, cohort to evaluate the definition of functional high-risk MM in the era of novel induction therapies. Our data suggest that pts who progress within 30 mos of induction on triplet or quadruplet regimens (irrespective of whether they underwent stem cell transplant) have poorer outcomes than those who progress at 30 mos or later, and that progression prior to 30 mos represents functional high-risk disease. These pts represent a clear unmet medical need, and additional focus should be taken to identify them early with the goal of designing trials to optimize their subsequent therapies.

Abstract Background: IgG4-related disease (IgG4-RD) is a rare, immune-mediated fibroinflammatory condition characterized by tissue infiltration with IgG4-positive plasma cells. While solid organ involvement is well documented, data on hematologic manifestations and associated outcomes remain limited. Understanding hematological burden and real-world treatment patterns is essential to guide comprehensive management. Methods: We conducted a multicenter, retrospective cohort study using the TriNetX Research Network, comprising electronic health records from multiple U.S. healthcare systems. Adults (≥18 years) with a diagnosis of IgG4-RD (ICD-10 codes) were included. Patients with a prior diagnosis of hematologic malignancy were excluded. Demographic characteristics, hematologic manifestations, treatment patterns, and overall mortality were assessed. The median follow-up duration was 519 days. Results: A total of 2,596 patients with IgG4-RD were identified, of whom 554 (21.3%) exhibited at least one hematologic manifestation. The mean age was 58.1 ± 15.9 years; 53% were male (n=1,379), and 57% were White (n=1,492). Hypertension was the most common comorbidity (44%, n=1,136). Among those with hematologic involvement, key manifestations included lymphadenopathy (n=605, 23.3%), hepatomegaly (n=114, 4.4%), splenomegaly (n=73, 2.8%), eosinophilia (n=71, 2.7%), pancytopenia (n=31, 1.2%), hypergammaglobulinemia (n=71, 2.7%), and monoclonal gammopathy (n=86, 3.3%). Regarding outcomes, 127 of 2,596 patients (4.9%) died during the follow-up period. Among those with hematologic manifestations, 36 of 554 (6.5%) died, indicating a numerically higher mortality rate in this subgroup. Treatment data revealed that all patients received corticosteroids as initial therapy. Additionally, 531 patients (20.4%) received steroid-sparing immunosuppressants. The most used agents included rituximab (6%), azathioprine (6%), mycophenolate mofetil (5%), and methotrexate (3%). Conclusion: In this large, real-world cohort of patients with IgG4-RD, hematologic manifestations were observed in over one-fifth of patients and were associated with a numerically higher mortality rate. Lymphadenopathy was the most common hematologic feature. Despite the widespread use of corticosteroids, a substantial proportion of patients required steroid-sparing agents. These findings highlight the hematologic complexity of IgG4-RD and underscore the need for multidisciplinary management and prospective studies focused on hematologic outcomes.

Abstract Introduction: Despite advent of multiple tyrosine kinase inhibitors (TKIs) and newer treatment methods for AML and ALL, the outcomes of patients (pts) with chronic myeloid leukemia in blast phase (CML-BP) remain poor. Consensus guidelines on treatment of CML-BP are scarce. A recent study from the European leukemia network blast phase registry on 240 pts reported marked heterogeneity in treatment patterns and lack of an accepted standard. Hence, we undertook this study through the H Jean Khoury Cure CML Consortium (HJKC3) to describe the treatment patterns and outcomes of pts with CML-BP in the US. Methods: This is a multi-institution, retrospective study. IRB approval was obtained at each institution and data sharing agreements were executed. All pts diagnosed with CML-BP based on modified MD Anderson Criteria (≥30% blasts in the blood or bone marrow or extramedullary (EM) disease) from 2010 to 2025 were included. Categorical variables were compared using Chi-square test. Overall survival (OS) was calculated from time of diagnosis of CML BP to death from any cause. Event free survival (EFS) was calculated from date of best response to event (death or relapse). Results: Of the 283 pts with CML-BP, 96 (33.9%) were female and 187 (66.1%) were males. At the time of diagnosis, 183 (64.6%) had CML-CP, 21 (7.4%) pts had CML-AP and 79 (27.9%) pts had de-novo CML-BP. For the 204 pts that were initially diagnosed with CML-CP or CML-AP, the median time to progression to CML-BP was 22.5 months (1-207 months). Median age at diagnosis of CML-BP was 50 years (range 16-86 years). EM disease was present in 78 (27.6%) pts (38 myeloid sarcoma, 30 central nervous system and 10 skin). Blasts were of myeloid phenotype in 168 (59.4%), lymphoid in 103 (36.4%) and mixed in 9 (3.2%) pts. The bcr-abl protein was p210 in 229 (80.9%), p190 in 8 (2.8%) and p230 in 2 (0.7%) pts. ABL kinase domain mutation was seen in 42.1% (80/190) pts, with T315I being the most common (n=32), followed by E255K (n=16). Next generation sequencing was performed in 117 pts. The most common mutations were ASXL1 (n=27), RUNX1 (n=14), BCOR (n=4), DNMT3A (n=4) and BCORL1 (n=3). Of the 283 pts, 269 underwent CML-BP directed therapy. 63 (23.4%) pts were treated with TKI monotherapy, 184 (68.4%) pts were treated with a combination of chemotherapy (chemo) and TKI and 22 (8.2%) pts were treated with chemo alone. Response rate after CML-BP directed therapy was 75.3% (n=213). Best response was return to CML-CP in 49 pts, CHR with PCyR in 18 pts, CCyR in 31 pts, MMR in 31 pts, MR4 in 18 pts, MR4.5 in 19 pts and MR5 in 47 pts. Rate of response with 2G and ponatinib was significantly better than imatinib (85.3% and 77.3% vs 63.6%; p=0.04). 149 (55.4%) pts proceeded to alloSCT. Of the 213 pts that responded, 59 (27.7%) relapsed. At a median follow-up of 47 months, the median OS for all pts was 19.7 months (95% CI: 16.3-40.2 months), with 5-year OS rate of 38% (95% CI: 32-45%). Pts with myeloid phenotype had a significantly lower OS compared to lymphoid and mixed phenotype (Median OS 14.9 vs 45.9 and 31.1 months respectively; p=0.02). OS of pts that were treated with a combination of TKI and chemo was significantly longer compared to pts treated with TKI or chemo alone (52.9 vs 16.1 or 7.5 months; p&lt;0.0001). Dasatinib (n=99; 34.9%) and ponatinib (n=97; 34.3%) were the most used TKIs followed by imatinib (n=23; 8.1%), nilotinib (n=21; 7.4%), bosutinib (n=8; 2.8%) and asciminib (n=3; 1.1%). Pts treated with ponatinib had a numerically longer OS compared to 2G-TKI and imatinib, however this was not statistically significant (40.1 vs 30.6 and 20.3 months; p=0.52). EFS for pts treated with ponatinib was significantly longer compared to 2G-TKI or imatinib (25.9 vs 17.6 and 15.9 months; p=0.03). In a landmark analysis, pts that underwent alloSCT within 6 months of diagnosis had a significantly longer OS compared to those who did not (69.3 vs 16.0 months; p=0.006). Conclusion: CML-BP continues to have poor prognosis. Treatment is heterogenous involving various combinations of TKI and chemo. In our analysis, treatment with 2G-TKI or ponatinib led to better responses. CML-BP with myeloid phenotype had worse OS. Treatment with ponatinib was associated with a numerically longer OS and significantly longer EFS compared to 2G-TKI and imatinib. In addition, treatment with chemo in combination with TKI and alloSCT led to improved OS.