Citations

ABSTRACT Background Chronic myelomonocytic leukemia (CMML) is largely a disease of individuals older than 50 years; its occurrence in patients aged 50 years and younger is rare. The authors sought to characterize the clinicopathologic features and genetic profile of young‐onset (age 50 years and younger) CMML (y‐CMML) compared with older onset (older than 50 years) CMML (o‐CMML). Methods The authors conducted a multi‐institutional study of 32 patients with y‐CMML and 119 patients with o‐CMML, analyzing clinical, morphologic, cytogenetic, and molecular data. Results Patients who had y‐CMML frequently presented with splenomegaly (59% vs. 11%; p < .001) and hepatomegaly (25% vs. 2%; p < .001) compared with those who had o‐CMML. Although the overall incidence of cytogenetic abnormalities was similar, patients who had y‐CMML exhibited distinct mutational patterns. PTPN11 mutations were significantly more common in y‐CMML (13% vs. 3%; p = .034) than in o‐CMML, whereas TET2 (6% vs. 57%; p < .001) and SRSF2 (16% vs. 46%; p = .002) mutations were significantly less frequent. In addition, multi‐hit TET2 (6% vs. 34%; p = .002) and TET2‐SRSF2 (3% vs. 29%; p = .003) co‐mutations were rare in y‐CMML. However, the molecular differences did not affect the CMML‐specific risk‐stratification categories because the clinical outcomes, including overall survival and leukemia‐free survival, did not differ between the two groups. Conclusions CMML in patients aged 50 years and younger is rare and presents with unique clinical and mutational features, suggesting a distinct pathogenesis.

Background The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood. Objective The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology. Methods For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology. Results We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004). Conclusions In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.

Background: Anterior vertebral body tethering (AVBT) is a promising fusionless alternative for treating idiopathic scoliosis; however, limited data exist on the learning curve for this procedure. Previous studies are limited by single-center and short-term complication data. This multicenter study assesses the learning curve by evaluating improvements in operative characteristics over time and radiographic measurements up to 2 years postoperatively. Methods: As recorded from a multicenter registry, surgeons with ≥10 index AVBT procedures for patients with idiopathic scoliosis aged 16 years and below were included. Relationships between case number and multiple surgical variables were determined using Pearson correlation and linear regression testing. For identification of an inflection point, consecutive cases were plotted against operative time per level and fitted with a locally weighted scatterplot smoothing curve. Independent samples t test and χ 2 test were used to compare outcomes between cases before and after the inflection point. Outcomes of interest included demographic, surgical, and radiographic information at the baseline, immediate postoperative, and 2-year timepointswhere available. Results: Eight surgeons and 325 index AVBT patients met the inclusion criteria. Inverse relationships were identified between case number and estimated blood loss, operative time, anesthesia time, and fluoroscopic time per level ( P < 0.005). The inflection point was identified at 15 cases. Operative time, anesthesia time, and fluoroscopy time per level were greater in the first 15 cases compared with those after ( P < 0.05). There were no significant differences in demographic variables, intraoperative complications, or length of stay between the early and late cases. Greater correction in the major coronal curve, minor coronal curve, and coronal balance occurred in the cases performed after the inflection point ( P < 0.05). Conclusions: AVBT is a safe alternative to posterior spinal fusion and demonstrates a predictable improvement in surgical performance over time. Large improvements can be expected during the first 15 AVBT cases performed with minimal differences in complications. Level of Evidence: Level III.

Abstract Glioblastoma (GBM) progression and recurrence are often driven by therapy-resistant cellular states emerging within hypoxic tumor niches. While hypoxia is a hallmark of GBM, the spatial transcriptomic heterogeneity that underpins resistance in these regions remains poorly characterized. Here, we employ pimonidazole labeling in conjunction with high-resolution spatial and single cell transcriptomics across 29 primary, treatment-naive human GBM samples, syngeneic mouse models, and patient-derived glioma-initiating cells exposed to hypoxia to define the hypoxia-specific tumor microenvironment and its associated cellular programs. We reveal spatially organized sub-niches within hypoxic regions, each supporting diverse cellular programs yet coexisting tumor lineage states with minimal transitions between cell states. Phylogenetic reconstruction based on inferred copy number variations demonstrates consistent evolutionary trajectories from non-hypoxic to hypoxic tumor loci. Specific copy number alterations were enriched in hypoxic regions and associated with immune infiltration and poor prognosis in MGMT-methylated tumors. Cross-species analyses confirmed the conservation of hypoxia-associated gene programs and spatial architectures. Together, our study delineates the cellular, evolutionary, and spatial complexity of hypoxia in GBM, identifies hypoxia-induced genomic alterations that may promote tumor fitness, and offers insights into new therapeutic vulnerabilities within hypoxic niches.

Abstract BACKGROUND STELLAR was a phase III randomized, open-label trial of eflornithine (ornithine decarboxylase inhibitor) with lomustine versus lomustine alone in patients with recurrent anaplastic astrocytoma (AA). We previously reported an overall survival (OS) and progression free survival (PFS) of the combination in the patients with grade 3 IDH-mutant astrocytoma. Here we report updated OS and PFS outcomes based on additional molecular classification and blinded independent central review (BICR). METHOD Eligibility included: age ≥ 18 years, AA (2016 WHO criteria) with first recurrence ≥ 6 months after radiation, KPS ≥ 70, and no imaging findings consistent with grade 4 glioblastoma. Patients received eflornithine (2.8 g/m2 TID Q 2/3 weeks) with lomustine (90 mg/m2 Q 6 weeks) (Arm A) or lomustine alone (110 mg/m2 Q 6 weeks) (Arm B). Primary endpoint was OS. RESULTS Updated molecular data resulted in re-classification of the 343 AA patients enrolled into 3 WHO 2021 defined tumor subtypes, 196 tumors were IDHmut, CDKN2A/B intact, consistent with diagnosis of astrocytoma, IDHmut, WHO grade 3, 33 tumors had CDKN2A/B loss consistent with astrocytoma, IDHmut, WHO grade 4, 106 tumors were IDHwt consistent with diagnosis of glioblastoma, IDHwt, WHO grade 4. Updated results strengthen initial conclusion that eflornithine plus lomustine resulted in significant survival benefit in the astrocytoma, IDHmut, WHO grade 3 group (mOS 34.9 vs, 23.5 months, HR = 0.64, stratified log rank p =0.0136). PFS with eflornithine was also improved (15.8 vs, 7.2 months, HR = 0.57, stratified log rank p =0.0113). BICR demonstrated a high correlation between investigator and centrally determined PFS (p=0.0305), and high correlation between OS and PFS (p=.0001). CONCLUSION The clinically meaningful OS and PFS benefits observed with eflornithine in the molecularly defined 2021 WHO CNS grade 3 astrocytomas is further confirmed and expanded based on additional molecular classification and BICR of PFS.

ABSTRACT IPTA created the SMARTER Initiative to address persistent gaps in pediatric transplant education worldwide. Through webinars, podcasts, case discussions, and interactive resources, SMARTER provides trainees and allied professionals with accessible, peer‐reviewed content across all major organ systems. The program is designed for global reach, with downloadable modules, mobile compatibility, and recorded sessions to accommodate different regions and time zones. Since its launch, SMARTER has shown strong engagement, with fellows reporting that the platform helps them prepare for board exams, improve clinical decision‐making, and connect learning directly to patient care. Survey feedback highlights high satisfaction and identifies opportunities for further growth, such as expanded case‐based modules, procedural videos, and simulation exercises. By reducing disparities in transplant training and supporting collaboration, SMARTER is positioned to strengthen existing curricula and promote a better‐prepared, more globally connected transplant workforce.

OBJECTIVE While endonasal transsphenoidal surgery (ETS) is the standard treatment for nonfunctioning pituitary adenomas (NFPAs), the postoperative recovery rates of secondary adrenal insufficiency and their predictive factors remain poorly understood. The authors investigated the relationship between the tumor resection rate and adrenal function recovery in patients with NFPAs. METHODS This retrospective study included 450 patients with NFPAs who underwent ETS between January 2013 and November 2023. The rates of preoperative hypopituitarism and postoperative recovery rates of secondary adrenal insufficiency and their associated factors were analyzed. Recovery was defined as normalization of serum cortisol levels without replacement therapy for at least 24 hours, accompanied by symptom resolution. The tumor resection rate was calculated as the percentage of the tumor volume resected. RESULTS The median follow-up period for the entire cohort was 52 months (range 1–131 months). A total of 246 (55%) patients had dysfunction in one or more pituitary axes. Fifty-three (47%) of 114 patients with preoperative adrenal insufficiency showed postoperative adrenal insufficiency recovery. The cumulative adrenal insufficiency recovery rates were 12% at 1 month, 19% at 3 months, 32% at 6 months, and 41% at 12 months. Among the 114 patients with preoperative adrenal insufficiency, the factors associated with postoperative adrenal insufficiency recovery were investigated. Patients with smaller tumor sizes of < 20 mm (log-rank test, p = 0.001) and those with tumor resection rates of more than 85% (log-rank test, p = 0.032) demonstrated better postoperative adrenal insufficiency improvement. Bivariate Cox proportional hazards analysis demonstrated that smaller tumor sizes (continuous, HR 0.97, 95% CI 0.93–0.98; p = 0.043) and higher tumor resection rates (HR 1.03, 95% CI 1.01–1.07; p = 0.001) were significantly associated with better postoperative adrenal insufficiency recovery. Multivariable analysis confirmed that only higher tumor resection rates were significantly associated with better postoperative adrenal insufficiency recovery (HR 1.03, 95% CI 1.01–1.06; p = 0.019). CONCLUSIONS Nearly half of the patients with preoperative adrenal insufficiency achieved recovery after ETS for NFPAs. The enhanced extent of tumor removal was an independent factor associated with better postoperative recovery, indicating that optimizing safe maximal resection procedures may be crucial in enhancing adrenal function.

Abstract Objective: Reading is a complex cognitive process requiring the integration of orthographic, phonological, and semantic information. The visual word form area, located in the ventral occipitotemporal cortex, is critically involved in orthographic decoding, and damage to this region is known to cause alexia. In contrast, the contributions of white matter pathways supporting reading are less well understood. Method: We present a unique neurosurgical case undergoing awake brain surgery for resection of a metastasis in the left occipitotemporal cortex. A tubular retractor was used to access the lesion and during the insertion of the retractor the patient underwent careful, continuous neuropsychological testing, including evaluation of reading. fMRI language mapping and diffusion MRI were performed preoperatively. Postoperative neuropsychological testing was completed two weeks after surgery to assess cognitive outcome. Results: The patient developed an alexia with letter-by-letter reading in real time during insertion of the tubular retractor. Stealth imaging enabled localization of the tubular retractor at the exact onset of the alexia and, by correlating this with tractography, showed that the tubular retractor was in the vertical occipital fasciculus (VOF). Conclusions: We present the first detailed case report linking the VOF to the acute onset of alexia observed intraoperatively during awake brain surgery. We discuss the connectomics of reading and possible contributions of the VOF in reading.