Citations

Importance Hypopigmented mycosis fungoides (HMF) is uncommon in adults, and data on clinicopathologic features and long-term outcomes remain sparse. Objective To investigate the clinicopathologic features and outcomes of adults with HMF in a large multicenter cohort. Design, Setting, and Participants This retrospective multicenter cohort study conducted from January 2011 to October 2023 at 6 US tertiary referral centers and included adults (18 years or older at diagnosis) with biopsy-confirmed HMF and hypopigmentation documented at diagnosis, with a median (range) follow-up of 39 (1-347) months. Data were analyzed from February to December 2025. Exposures Clinical variant, immunophenotype predominance, and polymerase chain reaction–based T-cell receptor ( TCR ) gene rearrangement in peripheral blood and/or skin. Main Outcomes and Measures Best overall response, defined as complete response, partial response, stable disease, or progressive disease, and progression to a higher stage. Results The cohort included 224 adults with HMF (median [range] age, 44 [18-74] years), of whom 164 (73%) were women (60 men [27%]), 5 (2%) were Asian individuals, 1 (0.4%) was a Hispanic/Latino individual, 1 (0.4%) was a Middle Eastern individual, 19 (8%) were White individuals, and 186 (83%) were Black individuals; 219 (98%) presented with early-stage disease. Most had hypopigmented lesions only (159 [71%]), whereas 65 (29%) exhibited mixed-variant mycosis fungoides; outcomes were similar between groups. Among 141 patients with available immunophenotyping, 88 (63%) had CD8-positive predominance. Among 207 treated patients, most (179 [90%]) received skin-directed therapy alone. Among 198 evaluable patients, the best overall response was complete response for 52 (26%), partial response for 101 (51%), stable disease for 34 (17%), and progressive disease for 11 (6%). Over a median (range) follow-up of 39 (1-347) months, 14 of 224 patients (6%) experienced progression to a higher stage, including 5 of 219 patients (2%) with early-stage disease at baseline who experienced progression to advanced-stage disease. Peripheral blood TCR monoclonality was detected in 23 of 85 tested patients (27%) and was associated with poorer treatment response but not with disease progression. Conclusions and Relevance The finding of this cohort study suggest that adult HMF demonstrated a generally indolent course, with favorable response to skin-directed therapy, irrespective of immunophenotype or mixed-variant presentation. Peripheral blood TCR monoclonality was associated with lower treatment response but not disease progression.

Abstract Rationale Patients with interstitial lung disease related to systemic autoimmune rheumatic diseases (SARD-ILD) may develop progressive pulmonary fibrosis (PPF), characterized by irreversible loss of lung function and high mortality risk. The risk of PPF by SARD subtype is not well characterized in large, representative real-world data sources. We characterized patients with SARD-ILD and compared the risk of PPF by SARD subtype in a multicenter cohort derived from the national Patient-Centered Clinical Research Network (PCORnet). Methods Harmonized electronic health record (EHR) data was collected from seven PCORnet centers. Included patients had at least two ICD-9/ICD-10 codes for ILD between 2015-2021, an ILD diagnosis that persisted following chest CT and/or lung biopsy, at least one year of potential follow-up, and sufficient lung function data to assess PPF. The presence of SARD, subtypes of which were classified by ICD codes, was also required. PPF was defined by ≥ 5% absolute decline in FVC, lung transplantation or death. The incidence of PPF was compared across SARD subtypes using Kaplan Meier estimates and Cox proportional hazards models adjusted for age, sex, enrolling center and baseline FVC. Results The cohort included 6,288 patients with SARD-ILD, of whom 68.4% were female, with a mean (SD) age of 61.2 (13.9) years. The most common underlying SARD was rheumatoid arthritis (RA, 42.8%), followed by systemic sclerosis (SSc, 22.3%), mixed connective tissue disease (MCTD, 21.5%), Sjögren’s syndrome (16.9%), systemic lupus erythematosus (SLE, 14.5%) and polymyositis/dermatomyositis (PM/DM, 12.0%). Mean FVC and DLCO at baseline were 78.7 (22.9) % and 51.9 (21.3) % of predicted, respectively. Patients with PM/DM had the lowest mean FVC (70.4 [SD 21.3]) % of predicted) and DLCO (45.1 [SD 18.5] % of predicted). During the follow-up period, antifibrotic, corticosteroid, and non-steroidal immunosuppressive drugs were used by 7.6%, 89.3% and 77.5% of the overall cohort, respectively. The cumulative incidence of PPF, transplant or death at one year ranged from 20.6% to 29.0%, depending on SARD-ILD subtype, with higher risk among those with RA, SSc or MCTD as compared with PM/DM (figure). Conclusions In a large, harmonized EHR dataset, the risk of PPF at one year among patients with SARD-ILD was high. Variability of PPF risk by SARD-ILD subtype was similar to that observed in traditional cohort studies, with lower risk among patients with myositis despite poorer lung function at baseline. These findings establish the feasibility of PCORnet as a tool to understand PPF among patients with SARD-ILD. This abstract is funded by: Genentech

ABSTRACT Intraocular lymphomas, including vitreoretinal and choroidal lymphoma, can simulate the clinical presentation of other benign and malignant ocular diseases resulting in diagnostic delays. Multimodal imaging features can raise early clinical suspicion to support appropriate subspecialty referrals and treatment for patients affected by these conditions. This review synthesises current evidence on the diagnostic and prognostic value of characteristic imaging features of these rare malignancies. Findings are reviewed based on imaging modality, including fundus photography, optical coherence tomography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, optical coherence tomography angiography, and ultrasound. We emphasise discriminative biomarkers that heighten suspicion for either vitreoretinal or choroidal lymphoma, as well as key findings to discriminate between lymphoma and alternative diagnoses. We further describe longitudinal changes in multimodal imaging features that can facilitate tracking disease progression or treatment response. By consolidating modality‐specific findings, this review aims to facilitate early referral and accurate diagnosis of these rare malignancies.

Abstract Background Brain insulin resistance and cerebrovascular dysfunction emerge early in late-onset Alzheimer’s disease, but how amyloid-β (Aβ) disrupts insulin signaling at the cerebrovascular blood–brain barrier—a major site of insulin receptor signaling and transport into the brain—remains unclear. Methods We exposed two distinct human blood-brain-barrier endothelial cell models to soluble Aβ40 or Aβ42 for 1 h, followed by 100 nM insulin for 10 min. Protein and phosphoprotein responses were quantified by reverse-phase protein array, and differential expression was evaluated using linear models. Results Aβ40 reduced insulin-stimulated Akt activation and converted insulin’s normal inhibition of AMPK into modest stimulation. Aβ42 did not alter insulin-stimulated Akt signaling but moderately suppressed basal Akt activation. Conclusions These findings suggest that Aβ40 acutely impairs insulin signal transduction in BBB endothelial cells, supporting a model in which vascular Aβ exposure contributes directly to the early development of brain insulin resistance in AD.

ABSTRACT Background Immunomodulatory agents (IMiDs) are a cornerstone in the successful management of multiple myeloma (MM). However, acquired IMiD resistance leading to disease relapses remains a major barrier. Hydrogen peroxide generation and oxidative stress are key mediators that determine IMiD's effectiveness in MM. Iron plays a key role in the generation of oxidative stress; therefore, cellular iron levels are tightly governed. FTH1 is the major iron storage protein that tightly regulates cellular iron availability. Hence, the present study is targeted to investigate the role of FTH1 in MM and IMiD resistance. Methods IMiD‐sensitive and IMiD‐resistant MM cells were analyzed for expression of iron‐metabolism genes. CRISPR‐cas9‐mediated knockout of FTH1 was performed and the after‐effects were assessed through multiple experiments. Results Initial analysis showed a positive correlation between FTH1 expression and IMiD resistance in MM cells. FTH1 ‐KO reduced IMiD sensitivity in the KMS11 cell line but had no effect on the RPMI8226 cell line. RNA‐seq data showed downregulation of ER‐stress and calcium signaling genes after FTH1 ‐KO. Further, KMS11‐ FTH1 KO cells exhibited lower intracellular ROS, labile‐iron, and mitochondrial superoxide levels along with increased CD63, suggesting activation of L‐ferritin secretory pathways. Conclusion Data reveals a link between FTH1 , labile iron, ROS, and IMiD resistance in MM cells.

Introduction Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes mellitus (T2D), has potential associations with higher rates of diabetic retinopathy (DR) complications including proliferative DR (PDR) and diabetic macular edema (DME). The purpose of this study was to determine whether an association exists between semaglutide and PDR and treatment-requiring DR/DME. Research design and methods This was a retrospective cohort study of 14 databases (six administrative claims and eight electronic health records) in the Observational Health Data Sciences and Informatics Evidence Network. Adults with T2D on semaglutide, other GLP-1RA (dulaglutide, exenatide), or non-GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from 1 December 2017 to 31 December 2023 were included. The association between semaglutide and PDR or treatment-requiring DR/DME was assessed using an active-comparator cohort design comparing new users of semaglutide as second-line T2D treatment to those on other GLP-1RAs and non-GLP-1RAs. Propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs). Network-wide HR estimates were generated using a random-effects meta-analysis. Results The study included 810 390 new semaglutide users for T2D. PDR risk for semaglutide was similar to dulaglutide (HR 0.81, 95% CI 0.42 to 1.54, p=0.51), empagliflozin (HR 0.83, 95% CI 0.53 to 1.30, p=0.41) and sitagliptin (HR 0.83, 95% CI 0.45 to 1.55, p=0.57) but was lower than glipizide (HR 0.59, 95% CI 0.39 to 0.88, p=0.01). The risk for treatment-requiring DR/DME for semaglutide was similar to empagliflozin (HR 0.66, 95% CI 0.43 to 1.02, p=0.06) but lower than dulaglutide (HR 0.53, 95% CI 0.31 to 0.91, p=0.02), sitagliptin (HR 0.46, 95% CI 0.26 to 0.81, p=0.008) and glipizide (HR 0.55, 95% CI 0.33 to 0.91, p=0.02). Conclusions and relevance We did not identify increased risk for either PDR or treatment-requiring DR/DME comparing semaglutide with other GLP-1RAs or non-GLP-1RAs. Patients with T2D should still undergo close eye care follow-up, particularly when initiating new antihyperglycemic medications.

The indications for immune checkpoint inhibitor (ICI) use in cancer treatment continue to expand. This is attributable to their proven anticancer activity in addition to their tolerability and favorable toxicity profile as compared to conventional chemotherapeutic agents. ICIs work by blocking the inhibitory signals between tumor cells and T-cells, thereby enhancing the T-cell cytotoxic activity to inhibit tumor growth. Because of their immune-stimulating effect, ICIs are linked to adverse renal outcomes in both native and transplanted kidneys. The risk of kidney allograft rejection in the setting of ICI use has been reported to be around 40%, leading to an increased risk of graft loss. In this report, we review the literature examining outcomes in kidney transplant recipients receiving ICIs for various oncologic indications.

Abstract RAS pathway (RASp) mutations induce proliferative features, and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASp mutations remain unexplored. To characterize the landscape, architecture, and implications of unique RASp mutations in CMML, we evaluated a cohort of 814 patients with CMML. We identified 461 RASp mutations among 342 patients (42%). N/KRAS and CBL mutations were the most common, frequently involved the P-loop or RING domains, respectively, and frequently appeared as dominant events (63% and 65%, respectively). BRAF, NF1, and PTPN11 mutations spanned throughout the gene structure, and frequently appeared as subclonal events (75%, 64%, and 59%, respectively). CBL mutations frequently occurred in codominance with SRSF2 and multihit TET2, and were enriched for KIT mutations. PTPN11 mutations more frequently co-occurred with SETBP1 and DNMT3A mutations, and were infrequently codominant with TET2 or ASXL1. RASp mutations predicted for shorter overall survival (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.15-2.07; P = .0075) and leukemia-free survival (LFS; HR, 1.67; 95% CI, 1.26-2.20; P = .0011), influenced outcomes of myelodysplastic and TET2 mutant CMML, and cooperated with IDH2 and RUNX1 mutations to induce shorter LFS. These data set the bases for refined genomic classifications of CMML, and underscore the need to develop RAS-directed therapies for patients with CMML.

Context.— Complexity of ordering and transfusing blood is particularly evident in the pediatric population. Simplification, clarification, and standardization of blood orders can decrease complexity and improve patient safety. Objective.— To improve patient safety by optimizing electronic ordering of blood components in pediatrics through a collaborative process improvement initiative. Design.— A multidisciplinary working group, formed as part of a value stream analysis to improve transfusion safety at Children’s Healthcare of Atlanta (Atlanta, Georgia), focused on decreasing variability and providing clarity when ordering, preparing, and transfusing blood using the electronic health record. Through benchmarking with other pediatric institutions and a collaborative design process with multiple local stakeholders, an extensive redesign in the existing orders and order sets occurred. Metrics were collected to determine if a change was an improvement. Results.— Nurse and laboratory informaticists, a pathology informaticist, and a transfusion medicine specialist built the new orders based on the design. The new orders focused on the following changes: standardization, introduction of logic, naming conventions, clarifying definitions, adding calculations, improving transparency of history and laboratory data, removing aliquots, clarifying communication, and implementing additional modules to inform the provider of necessary information about the patient. Metrics included a decrease in the number of orders changed within an hour, decreased calls from the blood bank to the provider to clarify the order, and an absence of overtransfusions and transfusion-related serious safety events for a year following implementation. Conclusions.— This collaborative initiative, using standard process improvement tools, resulted in standardized blood orders improving transfusion safety.

ABSTRACT Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage‐specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest‐derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single‐cell RNA sequencing analysis indicating evidence of lineage‐specificity defects. This was supported in an in vitro model using melb‐a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC‐seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere‐associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue‐specific stem cells during aging.