Citations

Abstract Obesity has been associated with non‐Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome‐wide association studies of European ancestry ( N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist‐to‐hip ratio (WHR), and waist‐to‐hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.18, 95% confidence interval (95% CI): 1.05–1.33, p = .005]. This finding was consistent with Mendelian randomization analyses, which demonstrated a similar increased risk of DLBCL with higher genetically determined BMI (OR per SD = 1.12, 95% CI: 1.02–1.23, p = .03). No significant associations were observed with other NHL subtypes. Our study demonstrates a positive link between a genetically determined BMI and an increased risk of DLBCL, providing additional support for increased adiposity as a risk factor for DLBCL.

Importance In the literature, there is a lack of data reporting tumor control rates after radiotherapy in actively growing vestibular schwannomas (VS). Data for this rarely studied population are needed. Objective To estimate tumor control rates in radiologically growing VS treated with first-line radiotherapy. Design, Setting, and Participants This international, multicenter cohort study used prospectively collected data from patients with growing unilateral VS treated first-line with radiotherapy between January 2000 and December 2023 from 8 tertiary referral skull base units. The data were analyzed in June 2025. Exposures Radiotherapy as an initial treatment for VS. Main Outcomes and Measures The primary outcome was treatment failure, ie VS growth postradiotherapy, which was predefined as an increase in maximum intracranial tumor diameter (ICTD) of 3 mm or greater within the first 2 years after radiotherapy or 2 mm or greater thereafter. Secondary outcomes were treatment failure based on different definitions of VS growth: (1) an increase in ICTD of 2 mm or greater, (2) an increase in ICTD of 3 mm or greater, and (3) conversion to surgery. Results A total of 1883 patients (975 female individuals [51.8%]; median age at diagnosis, 63 years [IQR, 53-71 years]) were included in the study. Using the primary definition of treatment failure (an increase in ICTD of ≥3 mm within the first 2 years postradiotherapy or ≥2 mm thereafter), the Kaplan-Meier estimate yielded a 10-year tumor control rate of 76.1% (95% CI, 72.7%-79.2%). For secondary outcome definitions, 10-year tumor control rates were 60.1% (95% CI, 57.5%-64.3%) for an ICTD increase of 2 mm or greater, 78.3% (95% CI, 75.0%-81.2%) for an increase of 3 mm or greater, and 92.6% (95% CI, 90.4%-94.3%) for conversion to surgery. Neither pretreatment tumor size nor tumor location (intracanalicular vs extracanalicular) were significantly associated with treatment failure. Conclusions and Relevance The results of this cohort study provide tumor control outcomes for radiologically growing VS treated with radiotherapy using several clinically relevant definitions of growth. By focusing exclusively on this rarely isolated subgroup, the findings offer targeted data to potentially inform treatment expectations and future research.

PURPOSE Patients with advanced, well-differentiated extrapancreatic neuroendocrine tumors (epNETs) have limited systemic treatment options. Pazopanib, an oral multikinase inhibitor with activity against vascular endothelial growth factor receptor (VEGFR)-2 and -3, PDGFR-alpha and-beta, and c-Kit, was tested for efficacy in epNET. PATIENTS AND METHODS We conducted a multicenter, randomized, double-blind, phase II study of pazopanib (800 mg once daily) versus placebo in low- to intermediate-grade epNET with radiologic progressive disease (PD) within 12 months of study entry. Previous somatostatin analog (SSA) was required for midgut tumors, and concurrent SSA was allowed. The primary end point was progression-free survival (PFS) by blinded independent central review. Unblinding and crossover were allowed if PD was confirmed by central review. RESULTS One hundred seventy-one patients (97 pazopanib and 74 placebo) were randomly assigned between September 2013 and October 2015. The majority had a midgut primary site (75%) and previous SSA treatment (93%). About half (49%) of the patients had functional tumors. The median follow-up was 61 months (95% CI, 60 to 63). Median PFS was 11.8 versus 7.6 months in pazopanib versus placebo, respectively (hazard ratio, 0.54 [95% CI, 0.37 to 0.79]; P < .001); 49 placebo patients crossed over to pazopanib. There was no significant difference in overall survival between the treatment arms. Rates of grade 3 or greater adverse events (regardless of attribution) were higher in pazopanib versus placebo (84% v 47%; P < .001), as were grade 5 death events (8% v 0%, P = .017). CONCLUSION Pazopanib compared with placebo significantly improves PFS in patients with progressive epNET, confirming that the VEGF signaling pathway is a valid target for therapy in epNET. However, after integrating the associated risks relative to the benefits, further development of pazopanib in this clinical context is not planned.

ABSTRACT Introduction Children with hepatoblastoma (HB) and other solid tumors frequently undergo intraoperative blood transfusion (IBT) with unknown impact on oncologic outcomes and scant data to guide transfusion in this population. This study tested the hypothesis that IBT is associated with poorer survival in children with HB. Methods A multicenter retrospective observational study of patients aged <18 years with HB who underwent primary tumor resection, including liver transplantation, from 2010 to 2019 was performed at 19 institutions. The association of IBT with risk of recurrence and death were determined using propensity score reweighted (PSR) Cox proportional hazards regression analyses. Results There were 338 patients identified who met inclusion criteria and had sufficient data for inclusion. Of those, 257 (76%) received IBT, including 253 (98%) who received packed red blood cells (pRBC), 84 (33%) who received plasma, and 28 (11%) who received platelets. IBT was associated with higher pretreatment extent of disease ( p < 0.001), presence of annotation factors (+VPEFR: 50%, n = 129 vs. 37%, n = 30, p = 0.035), and complex resections (extended, meso‐, or total hepatectomy: 54%, n = 139 vs. 27%, n = 22, p < 0.001); these differences were mitigated after applying propensity score weighting. Patients who received IBT had greater postoperative hemoglobin (g/dL) (median 10 (I8–11) vs. 9 (8–10), p = 0.013) and required more postoperative plasma and platelet transfusions ( p < 0.05). Median follow‐up was 4.4 (2.0–8.3) years. Compared with non‐IBT patients, those with IBT had higher incidence of death (PSR HR 2.35, 95% CI 1.10–5.02). Recurrence did not significantly differ across groups (PSR HR = 0.82, 95% CI 0.45–1.48). Conclusion IBT was associated with greater hazard of death. Postoperative hemoglobin levels suggested that unnecessary transfusions occurred and a pRBC‐focused approach to IBT led to coagulopathy. Development of optimal transfusion strategies for HB are needed to minimize unnecessary transfusions.

Abstract Objective This study explores and documents the patient experience during the prodrome phase of migraine. Background Migraine attacks can be divided into four stages: the prodrome (or premonitory phase), the aura, the headache phase, and postdrome. Qualitative data on the range of symptoms during the prodrome and their timing relative to headache onset are sparse. Prodromal symptoms may predict the onset of migraine headache pain and provide a clinically useful benchmark for initiation of treatment early in an attack before pain begins. Design/Methods Eligible participants with a clinician‐confirmed diagnosis of migraine and at least one prodromal symptom were consented, screened, and then participated in 60‐min interviews. The interview guide included open‐ended questions to elicit spontaneous reports and specific probes about prodromal symptoms based on a clinician‐established list. A theory approach was used to analyze the qualitative data collected in interviews to identify key themes and gather insights; data were analyzed using ATLAS.ti. Results Data collection for this study occurred from March 8, 2022, to May 16, 2022. Twenty interviews were conducted, and analyses demonstrated that concept saturation was achieved. Participants reported 36 unique prodromal symptoms, and each participant experienced a mean of 13 symptoms (standard deviation [SD] = 6.6) and a median of 11 symptoms (interquartile range [IQR] = 7.8–17.0) during the prodrome phase. The most commonly reported prodromal symptoms were nausea ( n = 17/20, 85%), fatigue/tiredness ( n = 16/20, 80%), sensitivity to light ( n = 13/20, 65%), neck pain/stiffness ( n = 12/20, 60%), and dizziness/vertigo/light‐headedness ( n = 10/20, 50%). Of the symptoms reported by at least four participants ( n ≥ 4/20, 20%), neck pain/stiffness was rated most bothersome (8.9 out of 10) and sensitivity to light was rated most severe (8.5 out of 10). Almost 40% of all symptoms reported occurred less than 2 h before the start of migraine headache. Of the commonly reported symptoms, nausea (0.8h), sensitivity to light (1.0 h), and dizziness/vertigo/lightheadedness (2.0 h) began closest to headache onset; fatigue/tiredness (4.0 h) and neck pain/stiffness (4.8 h) were the most remote from headache onset. Conclusion This study identified frequently reported prodromal symptoms, with participants commonly reporting that a migraine headache would follow their experience of prodrome within a 1‐ to 6‐h window. Characterizing the prodrome experience may improve measurement strategies for the burden of migraine and create opportunities to treat during the prodromal phase to prevent the onset of moderate or severe headaches.

Objective Individuals with serum elevations of anti–cyclic citrullinated peptide (anti‐CCP) antibodies are at increased risk for future rheumatoid arthritis (RA). No pharmacologic interventions have been approved for the prevention of RA in such at‐risk individuals. However, hydroxychloroquine (HCQ) is used without supporting clinical trial evidence. Methods In this phase 2 randomized trial, individuals at risk for RA with anti‐CCP3 ≥2 times the upper limit of normal (ULN) were assigned to receive HCQ or placebo for 12 months, with up to 24 months of postdrug follow‐up. The primary outcome was the development of clinical RA, as defined in the protocol, at 36 months. Secondary outcomes included safety, development of inflammatory arthritis (IA), and participant‐reported joint symptoms. Results Of 144 randomized participants, 71 were assigned to HCQ and 73 to placebo. In the modified intent‐to‐treat population, clinical RA occurred in 21 of 69 (30.4%) participants in the HCQ group and 24 of 73 (32.9%) in the placebo group. The risk of clinical RA at 36 months was 0.336 with HCQ and 0.394 with placebo (difference −0.058; 95% confidence interval −0.336 to 0.220; P = 0.52). Results for IA were similar. The occurrence and severity of joint symptoms were not observed to differ between groups. Adverse event incidence was similar between groups. Conclusion In this trial involving individuals with anti‐CCP3 levels ≥2 times the ULN, 12 months of HCQ did not prevent the development of clinical RA at 36 months. image

Abstract INTRODUCTION Plasma biomarkers’ utility for predicting incident mild cognitive impairment (MCI) remains unclear. We evaluated associations of plasma Alzheimer's disease (AD) biomarkers and amyloid positron emission tomography (PET) with transitions from cognitively unimpaired (CU) to MCI in the Mayo Clinic Study of Aging (MCSA) and BioFINDER‐2 studies. METHODS Associations of continuous baseline plasma biomarker levels and amyloid PET Centiloid with progression to MCI, adjusting for age, sex, and education, were evaluated with Cox proportional hazards models. RESULTS The study included 381 MCSA and 584 BioFINDER‐2 participants. Amyloid PET and percent phosphorylated to non‐phosphorylated tau217 (%p‐tau217) were strong predictors of progression to MCI in both cohorts: hazard ratios of 1.49 and 1.23 in the MCSA and 1.72 and 1.65 in BioFINDER, respectively. Amyloid beta 42/40 was a significant predictor in BioFINDER‐2 only (hazard ratio 2.20). DISCUSSION Plasma %p‐tau217 was associated with progression from CU to MCI in both cohorts, although differences in biomarker associations may be related to differences in the two cohorts. Highlights Mass‐spectrometry‐based plasma phosphorylated tau217 was associated with cognitively unimpaired to mild cognitive impairment (MCI) progression. Plasma amyloid beta 42/40 was a significant predictor in BioFINDER but not the Mayo Clinic Study of Aging (MCSA). Amyloid positron emission tomography (PET) was the strongest predictor of progression to MCI in the MCSA. Plasma had added value to amyloid PET in BioFINDER but not the MCSA. Biomarker performance may vary with cohort and biomarker measurement differences.