Citations

ABSTRACT Background Olfactory neuroblastoma (ONB) exhibits variable recurrence patterns, with significant late recurrences occurring years after treatment. We investigated cutoff periods to define late recurrence and identified predictors that distinguish patients at risk of late recurrence from those considered cured. Methods From a multi‐institutional cohort of 219 ONB patients treated at nine centers, we analyzed 77 patients with documented recurrence. Using a 48‐month cutoff to define early (< 48 months) versus late (≥ 48 months) recurrence, we evaluated 35 clinical, anatomic, and treatment variables using Firth penalized logistic regression across three comparisons: (1) late versus early recurrence timing, (2) late recurrence versus no recurrence, and (3) early recurrence versus no recurrence. Results Thirty‐four of the 77 (44.2%) recurrences were classified as late. Among the 77 patients who recurred, smaller tumor volume (OR 0.243, p = 0.035) and lower novel Dulguerov staging (OR 0.802, p = 0.038) were associated with late, rather than early recurrence. When patients with late recurrence were compared to those who remained disease‐free, radiographic skull base bone involvement was the strongest independent predictor (OR 2.90, 95% CI 1.14–8.64, p = 0.025), and this effect strengthened after adjusting for tumor volume (OR 3.80, p = 0.029). Pathologic dural invasion (OR 3.29, p = 0.013), Kadish stage (OR 2.02, p = 0.026), and T‐stage (OR 1.32, p = 0.040) were also significant. Conclusions A 48‐month cutoff effectively stratifies ONB recurrence risk. Skull base bone involvement independently predicts recurrence when compared to nonrecurrent cases and uniquely persists as a risk factor for late recurrence. These findings establish skull base bone involvement as a novel biomarker for risk‐stratified surveillance protocols.

OBJECTIVE Craniopharyngiomas are benign intracranial tumors that can be difficult to manage operatively and often result in postoperative complications and prolonged recovery. Understanding the factors that influence length of stay (LOS), discharge disposition, and readmission can guide perioperative planning and patient counseling. The authors examined the clinical, radiographic, and surgical predictors of extended LOS (eLOS), nonhome discharge, 90-day readmission, and hospitalization ratio (HR) after craniopharyngioma resection using a large, multicenter cohort. METHODS A retrospective analysis was conducted using the Registry of Adenomas of the Pituitary and Related Disorders database, encompassing 469 patients who underwent craniopharyngioma resection at 14 US academic centers from 2011 to 2025. Patients were stratified by 4 outcomes: eLOS (> 75th percentile), discharge to home versus skilled nursing facility/rehabilitation, 90-day hospital readmission, and hospitalization ratio (i.e., integration of initial and readmission LOS). Multivariable logistic regression models identified independent predictors for each outcome among patient and surgical variables. RESULTS An eLOS (> 10 days) was independently associated with preoperative memory loss (OR 3.75, 95% CI 1.95–7.21), gait imbalance (OR 5.90, 95% CI 1.53–22.70), and postoperative complications (OR 4.07, 95% CI 2.34–7.06). The use of a nasoseptal flap was protective against an eLOS (OR 0.52, 95% CI 0.28–0.93). Discharge to home was predicted by an endoscopic approach (OR 3.87, 95% CI 1.78–8.44) and postoperative intact thirst (OR 2.22, 95% CI 1.05–4.66) and negatively predicted by preoperative diabetes mellitus (OR 0.21, 95% CI 0.09–0.50), LOS (OR 0.87, 95% CI 0.84–0.91), and postoperative cognitive dysfunction (OR 0.30, 95% CI 0.13–0.72). Among 385 patients with follow-up data, a 90-day readmission was independently associated with postoperative complications (OR 5.62, 95% CI 3.12–10.13), preexisting coronary artery disease (OR 4.30, 95% CI 1.46–12.69), and postoperative cognitive dysfunction (OR 3.33, 95% CI 1.76–6.44). A higher HR was associated with diabetes mellitus (unstandardized B 0.059, 95% CI 0.010–0.108, p = 0.02), postoperative complications (unstandardized B 0.054, 95% CI 0.021–0.086, p = 0.001), and postoperative cognitive dysfunction (unstandardized B 0.049, 95% CI 0.006–0.092, p = 0.02). Tumor pathologic subtype and size, prior treatment, extent of resection, and surgeon experience were not directly predictive of outcomes. CONCLUSIONS Cognitive and functional status, systemic comorbidities, and postoperative complications, in addition to surgical approach, are important predictors of the early clinical course after craniopharyngioma surgery. Early identification of high-risk patients may help to guide treatment decisions, improve discharge planning, and reduce healthcare utilization.

Importance Adjuvant radiotherapy can improve locoregional control and survival in patients with olfactory neuroblastoma (ONB), particularly with advanced-stage and histologic-grade disease. Standard radiotherapy treatment is with intensity-modulated radiotherapy (IMRT). Proton beam radiotherapy (PBRT) provides theoretical advantages in greater sparing of dose to uninvolved organs at risk. Objective To investigate if there are differences in the effectiveness and radiation treatment–related adverse events (RTAEs) between adjuvant IMRT and PBRT for patients with ONB. Design, Setting, and Participants This propensity score–matched cohort study included patients with ONB treated between February 2005 and April 2021 with either IMRT or PBRT at 9 academic tertiary care centers in North America. Patients were matched 1:2 based on age, modified Kadish stage, and Hyams grade. Data were analyzed from July 2024 to January 2025. Exposure Adjuvant IMRT or adjuvant PBRT. Main Outcomes and Measures Local recurrence-free survival (RFS), any RFS, and overall survival (OS). RTAEs, ie, grade 2 events or higher based on Common Terminology Criteria for Adverse Events, were recorded for both modalities. Results Of 54 included patients, 27 (50%) were female, and the mean (SD) age was 46.2 (15.4) years. A total of 18 were treated with PBRT and 36 were treated with IMRT. Most patients had modified Kadish stage C disease (33 of 54 [61%]), and 24 patients (44%) had Hyams grade III or IV disease. The RTAE rate was 20% (8 of 40); IMRT had a rate of 21% (6 of 29), and PBRT had a rate of 18% (2 of 11). The difference in the point estimates for 10-year RFS showed a potential clinical benefit favoring IMRT, although the wide confidence interval indicates uncertainty (10-year RFS: IMRT, 63.3%; 95% CI, 44.6-89.8; PBRT, 37.8%; 95% CI, 14.2-100; difference, 25.5 percentage points; 95% CI, −17.6 to 68.6). There were no clinically meaningful differences in 10-year local RFS (IMRT, 75.6%; 95% CI, 59.8-95.4; PBRT, 72.7%; 95% CI, 45.2-100; difference, 2.9 percentage points; 95% CI, −35.9 to 41.7) or 10-year OS (IMRT, 61.8%; 95% CI, 42.8-89.1; PBRT, 57.1%; 95% CI, 24.3-100; difference, 4.7 percentage points; 95% CI, −49.2 to 58.6), although wide confidence intervals indicate considerable uncertainty. Conclusions and Relevance Due to the imprecision of estimates, no definitive conclusions can be made regarding the comparative effectiveness of IMRT vs PBRT for patients with ONB. These preliminary data may inform the design of appropriately powered prospective studies evaluating the efficacy of PBRT vs IMRT in this population.

AbstractObjectiveNeck metastases are a poor prognostic factor in olfactory neuroblastoma (ONB). Pathologic dural invasion (pathDI) may increase the risk of neck metastases due to invasion of dural lymphatics. We aim to evaluate the prognostic value of pathDI in predicting rates of neck metastases and recurrence using a large, multicenter database of ONB patients.Data sourcesRetrospective review of a prospective, multicenter database of electronic health records of all patients who presented with ONB between 2005 and 2021 at nine tertiary academic care centers within North America.Review methodsClinicopathologic features including modified Kadish staging systems, margin status, treatment modalities, Hyams grading, follow‐up time, and survival.ResultsOf 258 ONB patients, 189 patients met the inclusion criteria. The 10‐year neck recurrence‐free survival (neck‐RFS) rates were 85.7% (75.6‒97.3) and 61.8% (47.9‒79.8) for patients without and with pathDI, respectively (p = 0.018). Time‐to‐event multivariable regression analysis found pathDI to have an odds ratios of 9.7 (95% confidence interval [CI] 1.2–80.4, p = 0.04) for neck‐RFS and 9.5 for RFS at any site (95% CI 1.1–83.3, p = 0.04).ConclusionIn multivariable analysis, the presence of pathDI appears to be the strongest predictor of neck recurrence and recurrence at any site. Future studies exploring the benefit of elective neck dissection or radiation for patients with pathDI may impact disease management.

Background: Genetic variants in calsequestrin-2 ( CASQ2 ) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2 -CPVT was sought through an international multicenter collaboration. Methods: Genotype-phenotype segregation in CASQ2 -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6–11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3–8.0; P =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6–269.1; P <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. Conclusions: This international multicenter study of CASQ2 -CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.

Background Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous KCNQ1 p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in KCNQ1-encoded Kv7.1. Methods 419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall KCNQ1 transcript levels to assess the effect on splicing. Results For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the total KCNQ1 transcript levels. Conclusions Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants.