Citations

ABSTRACT The characteristics at diagnosis and clinical course of primary extranodal follicular lymphoma (EFL) have not been extensively described. The International Extranodal Lymphoma Study Group (IELSG) conducted an international retrospective survey aimed to describe the clinical features at diagnosis and the outcomes of FL cases with a clinically dominant extranodal component. The dataset included 605 pathologically reviewed cases from 19 different countries, and their outcomes were compared to those of nodal follicular lymphomas. The two most common presentation sites for EFL were the skin ( n = 334) and the gastrointestinal tract ( n = 72), with 22 cases having primary duodenal localization. These subsets exhibited unique features at diagnosis and significantly different overall survival (OS) patterns. After a median follow‐up of 5.5 years, primary cutaneous lymphomas showed a superior outcome [10‐year OS: 89% (95% CI, 83%–93%)], while primary gastrointestinal lymphomas had an intermediate outcome [10‐year OS: 79% (95% CI, 59%–90%)]. Among the gastrointestinal lymphomas, primary duodenal lymphomas tended toward the best outcome [10‐year OS: 95% (95% CI, 69%–99%)]. Other primary extranodal sites had inferior outcomes [10‐year OS: 59% (95% CI, 48%–68%)], similar to primary nodal lymphomas [10‐year OS: 57% (95% CI, 49%–64%)]. These findings support the identification of specific primary FL localizations as distinct entities with particular clinical and biological characteristics.

ABSTRACT Background Atherothrombosis, the main event leading to acute coronary syndrome (ACS), is strongly linked to disturbed blood flow (d-flow) regions. Although the involvement of the Hippo pathway and its kinases Large Tumor Suppressor Kinase 1and 2 (LATS 1 and 2) in mechanical stress responses is known, the mechanisms by which d-flow simultaneously induces senescence, proliferation, and atherothrombosis remain unclear. Methods The role of endothelial cells (EC)-specific LATS1/2 was examined using EC specific knock-out (EKO) mice in a partial left carotid ligation (PLCL) model. Plaque spatial multi-omics analysis was performed by integrating imaging mass cytometry, sequential immunofluorescence (COMET™), and spatial metabolomics at the single-cell level in human and mouse atherosclerotic plaques. Results In tamoxifen-inducible Lats1 homo( -/- ) / Lats2 homo( -/- ) EC-specific knockout (EKO) mice, deletion of LATS1/2 induced by tamoxifen led to fatal outcomes, characterized by severe systemic edema and markedly increased vascular permeability. In contrast, Lats1 het(+ /- ) / Lats2 homo( -/- ) -EKO mice survived and developed atherothrombotic plaques exhibiting neovascularization even without further additional dietary or genetic intervention. Spatial proteomics analysis revealed that LATS1/2 depletion in ECs triggered a senescence-associated stemness (SAS) phenotype, primarily driven by CD38 upregulation. Complementary spatial metabolomics profiling demonstrated a significant increase in sulfite and taurine within LATS1/2-deficient plaques, indicating lowered sulfite oxidase (SUOX) activity. Mechanistically, CD38 upregulation was found to suppress SUOX expression, induce the reverse mode of mitochondrial complex V, and increase succinate dehydrogenase (SDH) activity along with ATP consumption. Paradoxically, despite ATP depletion, this metabolic disturbance enhanced glutamate metabolism and the tricarboxylic acid (TCA) cycle, sustaining EC proliferation under energetically stressed conditions. The combined effect of LATS1/2 deletion and CD38 activation established a unique EC phenotype defined by increased SAS, leading to proliferation, senescence, and eventual cell death. These pathological processes culminated in the formation of atherothrombotic plaques, which were attenuated by inhibition of CD38. Notably, a similar phenotype—marked by metabolically active ECs—was observed in human atherothrombotic plaques, suggesting translational relevance. Conclusion Loss of LATS1/2 in ECs induces SAS state that promotes excessive EC proliferation, senescent cell accumulation, and the development of structurally fragile, leaky neo vessels—hallmarks of atherothrombotic lesions. CD38-mediated SUOX deficiency further amplifies this pathological process by inducing mitochondrial dysfunction, depleting ATP, and triggering compensatory upregulation of glutamate and TCA cycle metabolism. These findings identify a novel LATS1/2–CD38–SUOX axis in ECs that orchestrates SAS-driven atherothrombosis. Targeting CD38 may represent a promising therapeutic strategy to mitigate vascular dysfunction and plaque instability in high-risk ACS patients. Graphical abstract Under normal physiological conditions, LATS1/2 and Lamin A work together to suppress CD38 expression. Lamin A binds directly to the CD38 promoter to repress transcription, and LATS1/2 interact with Lamin A to reinforce this suppression. This collaboration helps maintain low CD38 activity and preserves cellular NAD⁺ levels. However, under disturbed flow (d-flow), both LATS1/2 and Lamin A are downregulated. The loss of this dual repression leads to increased CD38 NADase expression. Elevated CD38 accelerates NAD⁺ consumption, causing NAD⁺ depletion—a hallmark of cellular senescence. Reduced NAD⁺ disrupts key metabolic and stress-response pathways, contributing to the onset of the senescent state. At the same time, CD38 suppresses sulfite oxidase (SUOX), leading to sulfite accumulation and mitochondrial redox imbalance. This shift activates the reverse mode of mitochondrial Complex V, which decreases ATP production and increases mitochondrial ROS, intensifying metabolic and oxidative stress in endothelial cells (ECs). In response, ECs compensate by upregulating succinate dehydrogenase (SDH), enhancing TCA cycle activity and glutamate metabolism. This metabolic adaptation provides the biosynthetic building blocks needed for cell growth and proliferation. As a result, ECs adopt a paradoxical phenotype: they show classical features of stress-induced senescence (such as NAD⁺ depletion, oxidative stress, and cell cycle arrest signals), while simultaneously undergoing metabolic activation and proliferation, also mediated by YAP. This defines a non-canonical endothelial program known as senescence-associated stemness (SAS), characterized by the formation of abnormal, proliferative, yet fragile neovessels. These dysfunctional vessels contribute to atherothrombosis, setting this process apart from the more stable lesions typical of conventional atherosclerosis.

Background: Clostridioides difficile infection (CDI) treated with bezlotoxumab (BEZ) has been demonstrated to have a lower recurrence rate than placebo in clinical trials. However, real-world data on BEZ’s effectiveness remain limited and heterogeneous. Objectives: To evaluate the real-world effectiveness of BEZ in preventing CDI recurrence through a single-center retrospective cohort and a meta-analysis. Design: A retrospective cohort study and a meta-analysis. Methods: A retrospective study of patients treated with BEZ from 2017 to 2021 was performed at the Mayo Clinic. Demographics, CDI diagnostics, and several prespecified risk factors were analyzed. A literature search was conducted in August 2024 utilizing the Cochrane Central Register of Controlled Trials, Embase, Medline, Scopus, and Web of Science Core Collection. Studies reporting CDI resolution rates with BEZ were included. The random-effects model described by DerSimonian and Laird was used to calculate weighted pooled resolution rates (WPR) with 95% confidence intervals (CI). We assessed heterogeneity with the inconsistency index ( I 2 ) statistic. Results: Across 28 studies and our retrospective cohort, 2639 CDI patients were analyzed. Among 1786 patients treated with BEZ, 1450 achieved clinical resolution (WPR: 81.6%, 95% CI 77.2–85.6%), with significant heterogeneity ( I ² = 77.3%). In subgroup analysis, the pooled relative risk of recurrence was 0.56 (95% CI 0.36–0.88; p < 0.01) for BEZ with SoC compared to SoC alone. A WPR of 83.3% (95% CI 75.5%–91.1%) for patients receiving BEZ with SoC was observed when compared with a WPR of 70.8% (95% CI 62.7%–78.8%) in patients receiving SoC alone on subgroup analysis. In our cohort of 47 patients, the CDI resolution rate was 72.3% (34/47). Conclusion: Our retrospective study and meta-analysis demonstrate the real-world efficacy of BEZ in reducing CDI recurrence. The higher recurrence rates in our cohort likely reflect the high-risk nature of the population, including a greater proportion of immunocompromised patients.

Keratoconus is a progressive ectatic corneal disease characterized by corneal thinning, steepening, and irregular astigmatism, presenting unique challenges for intraocular lens (IOL) calculations in cataract surgery. The use of traditional formulas for IOL calculations in eyes with keratoconus frequently leads to significant refractive prediction errors, often resulting in a hyperopic shift, which can lead to suboptimal outcomes and reduced patient satisfaction. This review examines the impact of keratoconus on IOL calculations and highlights recent advancements in formulas specifically designed for eyes with keratoconus, particularly the Barrett True-K and the Kane Keratoconus formulas. We assess the effectiveness of these formulas based on the current literature and provide clinical recommendations aimed at improving surgical outcomes in this complex patient group.

ABSTRACTObjectiveClinical outcome measures for autoimmune encephalitis (AE) are not yet well defined. Cognitive outcome measures (CogOs) and patient‐reported outcomes (PROs) may capture the symptoms of AE, beyond clinician‐reported outcomes (ClinROs) (the Modified Rankin Scale [mRS] and Clinical Assessment Scale in Autoimmune Encephalitis [CASE]).MethodsThis retrospective cohort study examined LGI‐1‐IgG AE patients at Cleveland Clinic. CogOs included the Rey Auditory Verbal Learning Test (RAVLT) and Brief Visuospatial Memory Test (BVMT). PROs included Neuro‐QoL, PROMIS Global Physical (GPH) and Mental Health (GMH). Abnormal RAVLT, BVMT (≤ −1.5 SD), Neuro‐QoL, and PROMIS (≥ 10 T‐scores) proportions were analyzed. CogOs and PROs were correlated with ClinROs using Spearman's rank correlation.ResultsForty‐four patients (64% male, mean age 68 [SD = 11], median follow‐up 19 months) were included. ClinROs improved, with median mRS decreasing from 2.5 (IQR = 2–3) to 2 (IQR = 1–2), and CASE from 5 (IQR = 3–6) to 3 (IQR = 2–3) (all p < 0.05). RAVLT (n = 15), BVMT (n = 16), Neuro‐QoL (n = 21), and PROMIS (n = 34) were available. At > 12 months from diagnosis, cognition was impaired on BVMT (56%) and RAVLT (20%). PROs showed impairments in Neuro‐QoL lower (38%) and upper (27%) extremity function, cognition (31%), and PROMIS‐GPH (25%). RAVLT correlated with Neuro‐QoL cognition, depression, and stigma, while BVMT correlated with PROMIS‐GMH (all unadjusted p < 0.05). Neither RAVLT nor BVMT correlated with ClinROs. ClinROs correlated with Neuro‐QoL lower extremity function, cognition, and social roles (all p < 0.05).InterpretationLGI‐1‐IgG AE patients have long‐term impairments in cognition, physical health, and social roles, which can be objectively measured using CogOs and PROs and are not captured by ClinROs.

Objective We aimed to understand the impact of Cranial Remolding Orthotic therapy (CRO) on the quality of life of both infants with positional deformational head shape abnormalities (PDHSAs), including plagiocephaly and brachycephaly, and their caregivers. Design Survey study. Setting A single, tertiary academic center. Patients, Participants Families of infants with PDHSAs who underwent CRO between 2007 and 2022. Interventions CRO. Main Outcome Measure(s) Subjective assessment of caregiver perspectives. Results We obtained 242 responses (72% male) from 1013 patients contacted (response rate 23.9%). CRO was initiated at a median age of 6 months (IQR 5-7 months), with a median treatment duration of 4 months (IQR 3-5 months). Insurance covered costs fully for 9.8% of respondents and partially for 47.0%; 43.2% paid completely out-of-pocket. Most were “very satisfied” or “satisfied” with head shape (89.2%) and ear position (93.3%). CRO did not impact children's sleep (75.2%), “never” or “rarely” impacted children's play (90.5%), and never impacted most families’ attendance of social events (91.3%). Hair loss was temporary in 29.9% and permanent in 0.8%. Most families did not find CRO burdensome (73.1%) and “never” or “rarely” felt fatigued (68.5%). Conclusions The study sheds light on the mental and social effects of CRO on patients and caregivers, as well as physical adverse effects associated with treatment. Overall, patients’ families expressed satisfaction with results and felt that administering CRO had minimal negative impacts on themselves and their children.

OBJECTIVE Spinal stereotactic radiosurgery (SSRS) is an established treatment modality for spinal metastatic disease. A common complication of SSRS is postradiation pathologic fracture. The authors evaluated the risk of pathologic fracture in sacral SSRS. METHODS All patients receiving SSRS in 1 to 5 fractions to 1 or more sacral levels between 2011 and 2020 at participating institutions were included. Demographic, histological, anatomical, and outcome data were obtained from electronic medical records. Data were analyzed using SPSS version 28. RESULTS Of 67 total patients, 50 (74.6%) were men and 17 (25.4%) were women. The most common tumor histologies were prostate adenocarcinoma (n = 16 [23.9%]) and renal cell carcinoma (n = 12 [17.9%]). Median (range) age at treatment was 63 (8–87) years. The mean ± SD (range) number of levels treated was 1.5 ± 0.7 (1–4) levels. Mean ± SD (range) bone density at S1 was 208.0 ± 74.4 (−3.0 to 443.3) Hounsfield units (HUs). Median (range) follow-up was 16.6 (1.5–132) months, median ± SD (range) overall survival was 24 ± 21.0 (1.7–83.3) months, and the 1-year local control rate was 83.6%. Fourteen patients (20.9%) experienced fracture within the radiation field. There was no association between fracture and patient sex (p = 0.32), age (p = 0.40), S1 HU (p = 0.28), tumor location according to Denis classification (p = 0.87), presence of pain (p = 0.66), single versus multifraction radiation (p = 0.44), or number of levels treated (p = 0.52). Patients experiencing in-field progression were more likely to experience fracture (61.5% vs 10.2%, p < 0.001), and patients experiencing fracture had a higher average Spine Instability Neoplastic Score than patients without fracture (5.7 vs 4.3, p = 0.049). Only local control remained as a factor associated with sacral fracture in the multivariate analysis. Of the patients experiencing fracture, 10 (71.4%) were symptomatic and 3 of those (30.0%) underwent post-SSRS surgical intervention. CONCLUSIONS Pathologic fracture may occur after sacral SSRS in a significant number of patients and is significantly associated with failure of local control.

PURPOSE Survivors of adolescent and young adult (AYA)-onset cancers require comprehensive cancer surveillance care. Guidelines recommend 1-4 clinician visits annually for 5 years depending on stage and disease. The goal of this study was to identify factors associated with patterns of post-treatment primary and oncology care in a large cohort of survivors of AYA-onset cancers diagnosed within an integrated health care system. METHODS Patients diagnosed with cancer between 2006 and 2020 age 15-39 years were included. Surveillance visits were identified from electronic medical records 2-5 years after diagnosis. Multivariable logistic regression was used to assess associations with zero oncology specialty visits. RESULTS Of 7,925 survivors, 46% were Hispanic, 6% non-Hispanic Black, 11% non-Hispanic Asian, 35% non-Hispanic White, and 65% female. One-quarter had no oncology specialty visits in the first surveillance year rising to 38% in year 5; 31% had 3+ visits in the first year, declining to 13% in year 5. Over the surveillance period, 17% did not have any oncology specialty visits and 6% had no primary care or oncology visits. Those who were male (odds ratio [OR], 1.21 [95% CI, 1.02 to 1.45]), 20-24 years at diagnosis (OR, 1.58, 95% CI, 1.27 to 1.9; v 35 to 39), or non-Hispanic Black (OR, 1.38, 95% CI, 1.05 to 1.82; v non-Hispanic White) or had high-deductible commercial or Medicaid insurance (OR, 1.35, 95% CI, 1.15 to 1.59; OR, 1.42, 95% CI, 1.11 to 1.82, respectively; v no or low deductible commercial) were more likely to be in the 0-visit group for oncology specialty care. CONCLUSION Although the majority of this cohort received either primary or oncology specialty care, our study identifies those who may need tailored outreach for follow-up care. Continued research into development and testing of interventions to improve uptake of appropriate health care for survivors of AYA-onset cancers is critical.