Citations

Abstract Introduction: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an aggressive auto-inflammatory disorder defined by somatic UBA1 mutations. UBA1 mutations arise in hematopoietic stem cells and bias differentiation toward myeloid lineages. Clonal involvement of monocytes and neutrophils in VEXAS is frequent. Recently, natural killer (NK) cells have been recognized within the UBA1 mutant clone; mutated NK cells have an exhausted phenotype and impaired cytotoxicity (Ganesan BioRxiv 2025; Breillat et al, Blood 2025). A unique NK-like T cell type (CD3+CD16+[CD56-] T cells) has a role in the immunopathogenesis of severe COVID-19, resulting in heightened cytotoxicity and tissue damage (Georg et all, Cell 2022). As NK cells do not typically express CD3, and as the activation of inflammatory pathways is not restricted to myeloid cells in VEXAS, (Mizumaki et al, Nat Comm 2025) we sought to assess the CD3+ cell populations for co-expression of CD16 using single-cell (sc) multiomic data from VEXAS patients. Methods: After IRB approval, we performed sc-proteogenomic sequencing using a custom-made gene panel (Tapestri, MissionBio) in 2 VEXAS patients. Libraries were sequenced on an Illumina NovaSeq instrument. In one case, we performed in parallel CITE-Seq in parallel and used canonical correlation analysis (CCA) to integrate these immunophenotypic and transcriptomic data with matching cell populations identified from proteogenomic sequencing. We used pathway analysis (IPA) and gene ontology enrichment (gProfiler), as well as differential gene expression (RNA-seq) to identify significant gene signatures. T-tests with Welch's correction were performed for statistical significance on surface markers from proteogenomic data which were transformed by center log ratio. Our observations were then validated in sc-proteogenomic data from two additional VEXAS patients profiled at the NIH. Results: We used a sc-multiomic strategy to study CD3+ T cell subsets in VEXAS patients. In the first UBA1 mutant (mt) sample, using clusters defined by UMAP overlay of CITE-Seq/proteogenomic data, we defined positive expression of CD3 expression in the non-UBA1mt T cell cluster. We then examined the proteogenomic data (n=700 cells) to identify CD3+ cells (n=89 UBA1mt, n=42 UBA1wt). We then divided the CD3+ fraction into CD56+ vs CD56- to obtain CD3+CD56+ (n=25 UBA1mt, n=12 UBA1wt) and CD3+CD56- (n=64 UBA1mt, n=0 UBA1wt) cells. The CD3+CD56- cells were not only entirely UBA1mt, but also co-expressed CD16, significantly elevated from CD3+CD56+ UBA1wt cells (p<0.0001; and no significance from granulocyte populations): 10% of UBA1mt cells were CD3+CD16+CD56-. This cell subset was detected in an additional 3 VEXAS samples, and, in each case, there was no significant difference between UBA1mt/UBA1wt CD3 expression (both were T cell subsets) and no significant difference in CD56 expression. There was a significant increase in CD16+ expression in UBA1mt over UBA1wt (p<0.0001) cells, but not between UBA1mt cells and other granulocytes. Finally, we assessed the CITEseq data from the first UBA1mt case and focussed on gene expression and pathway differences between CD3+ and CD3+CD16+(CD56-) cell populations. Using IPA, we found top differentially expressed pathways included neutrophil degranulation, inflammation, cell killing, and IL-8 activity. Differentially expressed genes included FCGR3B, TLR2, IL1R2, FCGR2A, CCR1, CXCL8, and CXCR1, some of these overlapping with what was reported in similar cells (CD3+CD16+) detected in COVID-19 (Georg et all, Cell 2022). Conclusion: We identify a unique NK-T cell like [CD3+CD16+(CD56] subset of cells within UBA1mt cells in patients with VEXAS. This cell type has been reported in patients with severe COVID-19 as having increased cytotoxic functions and associated with fatal outcomes. Rare or aberrant cell clusters defined by standard clustering analysis may mis-identify some cell types, especially if they aberrantly express CD3+CD16+, as either marker could be used to pre-gate cells into larger clusters of lymphoid or myeloid cells. Prospective and functional profiling of this cell type in VEXAS patients is ongoing.

Abstract Introduction: Sexual health is an important part of overall well-being for adolescents and young adults (AYAs) after hematopoietic stem cell transplantation (HCT). AYAs have unique sexual health needs as they navigate development, relationships, and identity formation. AYA patients may experience sexual dysfunction due to conditioning chemotherapy/radiation therapy, graft-versus-host disease (GVHD), changes in body image, mental health effects, relationship shifts, and the challenges of dating with a serious illness. We surveyed both pediatric and adult HCT providers at our institution to assess current practices of discussing sexual health needs with AYAs as well as barriers to these discussions in order to guide interventions to improve communication. Methods: Adult and pediatric HCT physicians, advanced practice providers, and nurse coordinators in the Mayo Clinic Rochester HCT program completed an online survey to understand their perspectives about addressing sexual health needs in AYA HCT survivors. This survey covered current practice patterns in discussing sexual health and managing sexual health needs, barriers to providing sexual health care, and recommendations for provider education. Results: This survey included responses from 25 HCT providers (35% response rate): 22 adult providers and 3 pediatric providers. The respondents comprised of 10 physicians (40%), 8 advanced practice providers (32%), and 7 nurses (28%). Most of the providers saw 6-10 AYA patients per month (48%), while others reported: 1-5 AYAs (36%), 11-15 AYAs (12%), and 16-20 AYAs (4%); no provider saw 21 or more. While all respondents felt sexual health was an important topic for AYA HCT patients, most (80%) also reported rarely (44%) or only sometimes (36%) discussing sexual health with AYA patients. Primary barriers included inadequate knowledge of resources for referrals (72%), insufficient training on this topic (60%), limited time for discussion (56%), discomfort discussing sexual health with AYAs (32%), and concern about patient discomfort (28%). When it came to screening for GVHD, 28% of respondents reported not regularly screening for genitourinary GVHD and 40% indicated feeling uncomfortable or very uncomfortable managing it. Frequently discussed topics included fertility (64%) and contraception (52%). Almost all respondents (96%) expressed interest in further education. Topics of interest included an overview of common sexual health issues in AYA HCT survivors (88%), medical management of sexual health concerns such as erectile dysfunction, low libido, and vaginal dryness (72%), management of psychosocial concerns impacting body image and relationships (64%), cultural considerations for addressing sexual health (56%), providing inclusive care for lesbian, gay, bisexual, trans, queer or questioning (LGBTQ) AYAs (56%), genitourinary GVHD (56%), and safer sex practices during and after transplant (52%). Discussion: Although regular sexual health assessment in HCT survivors is recommended, most providers at our institution did not routinely discuss sexual health with AYAs. While genitourinary GVHD is an important HCT-specific sexual health topic, screening for this condition is not consistently performed. Providers were eager for further education and identified several topic areas for future educational interventions. Our data will aid in the development of an educational intervention for providers covering key sexual health issues in AYA HCT survivors, including medical and psychosocial management of sexual health concerns, as well as inclusive care for intercultural and LGBTQ AYAs, with the aim of improving frequency of sexual health discussions and provider confidence. Time constraints were identified as a key barrier, so patient-focused educational interventions that can occur outside of the clinical appointment may be an opportunity to deliver information and empower patients to raise specific concerns during their visits. In combination with healthcare provider-focused education, this may promote critical sexual health-related discussions during appointments.

Abstract Anaplastic large cell lymphomas (ALCLs) are CD30+ T-cell lymphomas that share pathologic features but differ in presentation, outcome, and genetics. Current classification incorporates clinical presentation and anaplastic lymphoma kinase (ALK) status but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 patients with ALCL in the LLMPP (Lymphoma/Leukemia Molecular Profiling Project) and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple negative), and immunohistochemistry for phosphorylated STAT3Tyr705. RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression. Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II). Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched for non–tyrosine kinase pathways, particularly epigenetic regulators such as EZH2. Immunohistochemistry showed overexpression of EZH2 and its trimethylated substrate H3K27. Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies 4 molecularly distinct ALK− ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II). This classification can be easily implemented on paraffin tissue in routine practice or clinical trials, and stratifies ALCL into diagnostically, prognostically, biologically, and potentially therapeutically relevant subtypes.

Importance Despite treatment advances, metastatic recurrence continues to be a leading cause of morbidity and mortality. Empirical data on the incidence and survival after metastatic recurrence remain limited, as cancer registries historically do not collect data on recurrence. Objective To estimate the cumulative incidence (CMI) of metastatic recurrence among adolescents and young adults diagnosed with earlier-stage disease and compare survival to those with metastatic disease at diagnosis. Design, Setting, Participants This was a retrospective cohort study of adolescents and young adults aged 15 to 39 years who were diagnosed with nonmetastatic cancers from 2006 to 2018. Adolescents and young adults were identified from the California Cancer Registry linked with statewide hospitalization, emergency department, and ambulatory surgery encounters from the California Department of Health Care Access and Information. Data were analyzed from December 2023 to June 2025. Exposures Cancer types, including melanoma, sarcoma, and breast, cervical, colorectal, testicular, and thyroid cancers. Main Outcomes and Measures Metastatic recurrence was identified using International Classification of Diseases, Ninth Revision, Clinical Modification, and Tenth Revision, Clinical Modification, metastatic disease codes at least 6 months after cancer diagnosis or from an underlying cancer cause of death. Follow-up was through December 31, 2020. Results Of a total of 48 406 adolescents and young adults (median [IQR] age at diagnosis, 33.0 [28.0-37.0] years; 67.4% female), 9.2% had metastatic disease at diagnosis, and 9.5% had metastatic recurrence. Among 43 935 adolescents and young adults who presented with nonmetastatic disease, the 5-year CMI of metastatic recurrences was highest among patients with sarcoma (24.5%; 95% CI, 22.6%-26.6%) and colorectal cancer (21.8%; 95% CI, 20.3%-23.4%) and intermediate for cervical (16.3%; 95% CI, 15.0%-17.6%) and breast (14.7%; 95% CI, 14.0%-15.4%) cancers. The CMI for metastatic recurrence increased with increasing stage at diagnosis, with 5-year CMIs higher than 30% for all stage III cancers (except thyroid). The 5-year CMI of metastatic recurrence also increased over time for cervical cancer (2006-2009: 12.7% [95% CI, 10.8%-14.8%]; 2015-2018: 20.4% [95% CI, 17.5%-23.6%]) and decreased for colorectal cancer (2006-2009: 24.4% [95% CI, 21.3%-27.6%]; 2015-2018: 19.2% [95% CI, 16.4%-22.2%]). Survival after metastatic recurrence was worse than metastatic disease at diagnosis for all cancer types, except for testicular and thyroid cancers. Conclusions and Relevance The findings from this cohort study highlight the overall burden of metastatic disease in adolescents and young adults, expanding the knowledge of metastatic recurrences that help improve care for adolescent and young adult survivors throughout the cancer survivorship spectrum.

Background Recent studies suggest that general surgery (GS) residents perform more operations related to their future specialty compared with their peers. In this multi-institutional study, we examined the process of early specialization among GS residents pursuing a career in vascular surgery (VS). Methods Data from the US Resident OPerative Experience (ROPE) Consortium, comprising 20 Accreditation Council for Graduate Medical Education (ACGME)-accredited GS residency programs across the United States, were queried. Case volume and type were compared between GS residents pursuing vs fellowship and all other residents. Effect size was evaluated using Cohen’s d statistic. Effect size was considered large if d > 0.8, moderate if 0.5 ≤ d < 0.8, small if 0.2 ≤ d < 0.5, and inconsequential if d < 0.2. Results A total of 1343 GS residents graduated from 2010-2020 across all programs participating in ROPE, of which 135 (10.1%) pursued vs fellowship. Total major vascular case volume was significantly greater among residents pursuing vs fellowship (138 [100-207] vs 100 [80-139], P < 0.0001) with a large effect size (d = 1.81). Vascular cases reported in a surgeon chief role (27 [9-53] vs 10 [2-29], P < 0.0001, d = 0.76, moderate effect) and surgeon junior role (107 [79-154] vs 88 [62-118], P < 0.0001, d = 1.00, large effect) were also greater among GS residents pursing a vs specialty. Nearly all vascular operative categories demonstrated similar trends ( P < 0.01 each). Conclusions GS residents pursuing a vs fellowship perform more vascular cases compared with their peers. Given the differences in both surgeon chief and surgeon junior roles, career focus may begin as early as the junior resident years.

ABSTRACT Central venous catheters (CVCs) are a cornerstone of hematopoietic stem cell transplantation (HSCT), facilitating the delivery of chemotherapy, parenteral nutrition, medications, and blood products. Despite CVCs’ essential role, prolonged use can lead to complications such as increased risk of infection, thrombosis, mechanical issues, and psychosocial burden. However, the timing of CVC removal remains highly variable across institutions. Additionally, there are no standardized guidelines to balance the benefits of extended access against the risks of prolonged use. This narrative review examines the existing literature on CVC management post‐HSCT, highlighting key factors influencing the removal timing, such as patient characteristics, disease‐specific considerations, and institutional practices. The review emphasizes the urgent need for multi‐institutional research and standardized protocols to improve outcomes, reduce complications, and enhance the quality of care for HSCT patients.

Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by drug‐resistant seizures and developmental slowing. Although cognitive and executive function deficits have been described, their early trajectory is not well understood. Methods The prospective ENVISION natural history study (NCT04537832) assessed cognitive, executive, and adaptive function in children younger than 5 years of age with SCN1A + DS every 6 months for up to 2 years using Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID‐III), Wechsler Preschool & Primary Scale of Intelligence, 4th Edition (WPPSI‐IV), Vineland Adaptive Behavior Scales, 3rd Edition (VABS‐3), Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF‐P), and Pediatric Evaluation of Disability Inventory (PEDI). Results Fifty‐eight children were enrolled, with 47% younger than age 2 years. At least 80% of children did not achieve age‐appropriate milestones. Mean BSID‐III Cognitive raw scores increased minimally, with age‐equivalent gains of only 3 months over 1.5 years. Mean Cognitive Composite scores declined significantly by Month 12 (from 81.6 to 72.2; change: –11.0, 95% confidence interval [CI]: −15.3 to −6.8), signaling a widening gap compared with neurotypical development. Executive function worsened, with mean BRIEF‐P Global Executive Composite T‐scores increasing by 3.2 points/year. For some participants, scores were 5 standard deviations (SD) above the normative mean, reflecting abilities profoundly below age expectations (bottom .00003% of the population). Adaptive functioning worsened, with mean VABS‐3 Adaptive Behavior Composite decreasing from 78.7 to 68.1 over 1.5 years (change: –9.0, 95% CI: −11.9 to −6.1) and greater decline among children <2 years at enrollment, with scores decreasing by ~15 points (1 SD). Over half of children >3 years could not remove clothing independently; and when placed on a toilet, 48% could not use it. Significance Infants and young children with SCN1A + DS show significant and progressive developmental slowing across several domains, highlighting urgent need for therapies to mitigate the devastating impact on individuals and families.

ABSTRACT Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder causing hypogammaglobulinemia. Although rare, nodular regenerative hyperplasia is the most common liver complication in CVID, which can progress to noncirrhotic portal hypertension. We report a case of a young male with CVID presenting with recurrent parastomal bleeding secondary to noncirrhotic portal hypertension from CVID-associated nodular regenerative hyperplasia.

Background: Acquired and congenital limb length discrepancies often coexist with deformities of the distal femur. Lengthening of the femur along its anatomic axis changes the limb's mechanical alignment. Angular correction and lengthening can be achieved at the same site if a retrograde lengthening nail is used with a specific preoperative planning method (“reverse planning”) which permits patient-specific selection of the final mechanical axis. Methods: A consecutive cohort series of children, adolescents, and young adults (mean 15.6 ± 4.8 years) undergoing retrograde implantable femoral lengthening between the years 2011 and 2024 were analyzed. Surgical details, lengthening parameters, Limb Lengthening and Reconstruction Society (LLRS)–AIM index, accuracy of final correction, and complications were reviewed and classified. Patients were eligible only if the distal femoral physis was closed. Results: Seventy-three lengthening were eligible in the study period. Average lengthening was 4.2 ± 1.4 cm (range 2.0-8.0 cm), and consolidation index was 39.4 ± 21.9 days/cm. Deformities and length discrepancies were moderately complex, with a mean LLRS AIM score of 6 (range 1-13). Complication rates were similar to previous reports of intramedullary femoral lengthening, comparable between congenital (12 of 31, 39%) and acquired etiologies (16 of 42, 38%). Preoperative coronal alignment ranged from 14° varus to 20° valgus, while final coronal alignment was 0.4° ± 3.4° of neutral (range 7° valgus to 13° varus). Coronal deformities up to 20° and sagittal deformities up to 23° were corrected acutely at the lengthening site. Conclusions: Retrograde intramedullary femoral lengthening with acute deformity correction at the same site is an alternative to antegrade lengthening with separate osteotomy of the distal femur in children and adolescents. The reverse planning method allows reproducible length and deformity correction at the same location. Specific intraoperative technical adjuncts are used to achieve and maintain the desired alignment. Level of Evidence: Diagnostic Level IV . See Instructions for Authors for a complete description of levels of evidence.