Citations

ABSTRACT Telemedicine is a broad term that encompasses all aspects of utilizing information and communication technologies to provide health services at distant sites. The primary goal of telementoring is the education and training of gastrointestinal (GI) endoscopists particularly in areas where there is a shortage of endoscopy trainers. Telementoring in GI endoscopy can help to provide teaching and skills training both in simulator‐based learning, and endoscopic skills training in the context of patient care. This position statement aims to outline the role of telementoring within GI endoscopy, offering a general model for the introduction and evaluation of a telementoring program that incorporates both simulators for junior trainees and skills training for practicing endoscopists. We hope to highlight its utility and implementation in remote locations. WEO recognizes that telementoring is valuable to expand access to high‐quality endoscopy training especially in parts of the world where there is a shortage of endoscopy trainers and this document can serve as a guide in the planning and implementation of telementoring programs.

Abstract Background Children’s Oncology Group ACNS0333 treated atypical teratoid/rhabdoid tumor (ATRT) with surgery, chemotherapy (induction and consolidation) and radiation therapy (RT). M0 had focal RT and M+ had physician-selected focal RT or craniospinal (CSI). Methods Forty patients (29 M0, 11 M+) received RT. Pre-RT chemotherapy response was complete, partial, or stable disease. RT timing (age/stage-based) was pre-consolidation (RT-first) or post-consolidation (consolidation-first). Event-free survival (RT-EFS), overall survival (RT-OS), and cumulative incidence of local relapse (CILR) or distant relapse (RT-CIDR) were calculated. Analyses included log-rank tests and relative hazard rates with 95% confidence intervals to estimate proportional hazards regression. Results Four-year RT-EFS was 56.8% and 4-year RT-OS was 58.8% focal RT: 34 patients, CSI: 6 patients). A trend for superior RT-EFS for M+ compared to M0 (P = .0625, RHR 0.26; 95% CI 0.06-1.18) was shown. RT-EFS was improved for consolidation-first compared to RT-first timing (P = .037, RHR 0.43; 95% CI 0.13-1.37). Pre-RT chemotherapy response was associated with improved RT-EFS (P = .031) and RT-OS (P = .0069). Four-year RT-CILR was 7.84%; no differences in RT-CILR were shown for higher primary RT dose (≥5400 cGy, P = .38) or gross total resection (P = .80). 4-year RT-CIDR was 27.8% for M0 and 9.1% for M+ patients (P = .22). M+ had CSI (n = 6) or focal RT (n = 5). Fatal necrosis potentially-attributable to RT occurred in 3 RT-first patients (occuring either 1.6, 4.6, or 16.2 months post-treatment). Conclusions RT with intensive systemic therapy showed promising survival outcomes and effective primary disease control in ATRT. Sequencing RT prior to myeloblative chemotherapy, rather than post-consolidation, may be associated with increased risk of fatal radionecrosis.

Abstract Description Coccidiomycosis is an endemic fungal infection caused by Coccidioides spp., and diagnosis is often made with serology. Coccidiomycosis is especially problematic for immunocompromised patients, with greater risk for disseminated infection and mortality. This study evaluated current strategies for detecting antibodies to Coccidioides, including enzyme immunoassay (EIA), immunodiffusion (ID) and complement fixation (CF) and applied a new ID assay for improved sensitivity and specificity. Clinical sensitivity and specificity studies were done using 1544 unique serum specimens for which Coccidioides EIA testing was clinically requested. A full panel of EIA IgG, EIA IgM, ID and CF was performed on each, comparing our in-house immunodiffusion assay using reagents from Cactus Bio, LLC to our current reference laboratory. Full method validation was completed, as prescribed by CLIA. Using existing reference lab testing as the standard, a sensitivity of 96.9%, specificity 85.9%, PPV 54.9%, NPV 99.4% was achieved. Additional chart review demonstrated the in-house ID improved to 98.0% sensitivity, 94.6 specificity, 84.2% PPV, 99.4% NPV. Such high NPV supports using reflex testing, which allowed our lab to eliminate hundreds of unnecessary CF referrals each month, saving diagnostic time, financial waste and lab resources. A reflexive testing algorithm paired with this enhanced ID assay is especially useful for the immunosuppressed, for which Coccidioides infections carry a greater risk. Topic Categories Translational and Interventional Immunology (TI)

Background Converging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD). Objective We investigated total intracranial volume (TIV), a neuroimaging marker of neurodevelopment, and years of education differences between adult mutation carriers and familial non-mutation carriers, as measures of the structural and functional neurodevelopmental effects of FTD-causing genetic mutations. Methods This cross-sectional cohort study, facilitated through the FTD Prevention Initiative (FPI), included 902 adult pathogenic mutation carriers of GRN , MAPT , or C9orf72 , and 532 familial non-carriers. ANCOVAs were computed to compare TIV and education between groups per gene. Pearson's correlations were used to examine associations between TIV and education. Results Mutation carriers (mean ± SD age = 50.0 ± 13.2 years, sex = 55% female, n ( GRN ) = 298, n( MAPT ) = 187, n ( C9orf72 ) = 417) were compared to familial non-carriers (age = 48.0 ± 12.9 years, sex = 58% female, n ( GRN ) = 201, n( MAPT ) = 114), n ( C9orf72 ) = 217). Consistent with prior findings in young adults, GRN carriers showed larger TIV, on average by 20531 mm 3 , compared to familial non-carriers (95% CI [85.4, 40977], p = 0.049, η 2 p = 0.008). Larger TIV correlated with higher years of education in GRN carriers (95% CI [0.01, 0.24], r (295) = 0.12, p = 0.03) and GRN non-carriers (95% CI [0.08, 0.34], r(198) = 0.21, p = 0.002). MAPT carriers demonstrated smaller TIV than non-carriers, on average by 29896 mm 3 (95% CI [–58248, −1545], p = 0.039, η 2 p = 0.02). Models with C9orf72 and education as outcome variables did not reveal significant differences. Conclusions In support of the neurodevelopmental hypothesis of FTD, GRN and MAPT mutations are linked to structural neurodevelopmental changes in TIV. Further research is needed to identify mechanisms underlying neurodevelopmental influences of FTD mutations and ascertain their suitability as intervention targets.

Objective: To characterize patient outcomes after primary stereotactic radiosurgery (SRS) for the management of sporadic facial nerve schwannoma. Study design: Retrospective cohort study. Setting: Six tertiary referral centers across the United States and United Kingdom. Patients: Adults undergoing SRS from 2000 through 2023 for sporadic facial nerve schwannoma along any segment of the facial nerve were included. Patients with NF2-related schwannomatosis were excluded. Intervention: Stereotactic radiosurgery. Main outcome measure: Long-term tumor control. Results: Among 60 patients meeting inclusion, the median age at SRS was 52 years (IQR: 41 to 64) with a median tumor size of 19.5 mm (IQR: 14.7 to 22.8). Tumors commonly involved the internal auditory canal (73%), cisternal (49%), geniculate/labyrinthine (47%), and tympanic segments (22%). Two patients experienced SRS failure and underwent salvage treatment; salvage-free survival rates (95% CI; number still at risk) at 1, 3, 5, and 10 years after SRS were 100% (100 to 100; 55), 100% (100 to 100; 36), 100% (100 to 100; 18), and 87% (72 to 100; 9), respectively. Among 31 (52%) patients with House-Brackmann (HB) grade I facial function at presentation, only 6 demonstrated worse facial function at a median of 3.2 years (IQR: 1.7 to 6.6) after SRS. Of 18 patients with serviceable hearing (AAO-HNS class A/B) at SRS, 13 maintained serviceable hearing at a median of 1.0 years (IQR: 0.5 to 4.9) of post-SRS audiometric follow-up. Conclusions: Durable tumor control after primary SRS for sporadic facial nerve schwannoma is achieved in most patients. Among those with HB grade I facial function at presentation, treatment with SRS harbors limited additional risk of facial paresis beyond observation alone.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). In CTE, hyperphosphorylated tau (p-tau) aggregates are found in neurons at the depth of cortical sulci close to the gray matter/white matter (GM/WM) boundary. To date, CTE can only be diagnosed postmortem by neuropathological examination. Traumatic encephalopathy syndrome (TES) is the clinical syndrome purported to be associated with CTE pathology. The aim of this study is to investigate microstructural properties at the GM/WM boundary in individuals with a history of exposure to RHI and clinical features of CTE (i.e., TES). Diffusion magnetic resonance imaging (dMRI), TES diagnoses, and cerebrospinal fluid (CSF) biomarkers were acquired from 165 male former American football players (age: 57.29 ± 8.23 years) from the DIAGNOSE CTE Research Project, a multicenter, observational cohort study. Fractional anisotropy (FA) was measured at the GM/WM boundary of the whole brain. In addition, a widely used method (tract-based spatial statistics [TBSS]) was applied to measure FA of central WM. We used analyses of covariance to test associations between FA and TES. Furthermore, we used linear regressions to test associations between FA and nine CSF biomarkers (i.e., p-tau-181, -217, -231, total tau, amyloid β [Aβ] 1–40 , Aβ 1–42 , glial fibrillary acidic protein [GFAP], neurofilament light [NfL], and soluble triggering receptor expressed on myeloid cells-2 [sTREM2]). We report an association between higher FA at the GM/WM boundary and higher levels of certainty for CTE pathology ( F (1, 147) = 5.781, 95% confidence interval (CI) = 0.0003–0.003, p = 0.035) as well as neurobehavioral dysregulation ( F (1, 148) = 7.559, 95% CI = 0.001–0.009, p = 0.020), and functional dependence/dementia ( F (1, 148) = 5.046, 95% CI = 0.0004–0.006, p = 0.039). In addition, we report an association between higher FA at the GM/WM boundary and higher CSF p-tau-181 (β = 0.272, 95% CI = 0.078–0.466, p = 0.029) and p-tau-217 (β = 0.295, 95% CI = 0.102–0.488, p = 0.027). FA of the central WM was not associated with TES diagnoses. Taken together, these findings suggest that dMRI at the GM/WM boundary could be used to investigate microstructural alterations suggestive of tau pathology-associated neurodegeneration in individuals with TES, the clinical presentation of CTE. Future studies are needed to validate this approach and to identify clinically useful cutoff values for dMRI metrics.

Abstract Diffuse midline glioma (DMG) is a universally fatal pediatric brainstem cancer. Outside of clinical trials, palliative radiotherapy (RT) remains the only approved treatment, with a median overall survival (OS) of <12 months. The brain-penetrant oral therapy dordaviprone (ONC201) has demonstrated early clinical efficacy by activating the overexpressed mitochondrial protease ClpP, inducing mitochondrial dysfunction. Our previous studies identified that dordaviprone triggers compensatory energy production via the PI3K/mTOR pathway to avoid cell death. To overcome this adaptation, we combined dordaviprone with the brain-penetrant pan-PI3K/mTOR inhibitor paxalisib, showing synergistic anti-tumor effects across multiple immunocompromised patient-derived xenograft models. These results led to the international Phase II clinical trial (PNOC022/NCT05009992), where >20% of patients enrolled pre-radiation achieved survival beyond 2 years. However, approximately 20% of patients experienced immune-related toxicities-mucositis, colitis, and skin reactions, likely driven by paxalisib’s pan-PI3K inhibition, as PIK3CG (p110γ) and PIK3CD (p110δ) are enriched in hematopoietic cells. In contrast, PIK3CA (p110α) is a known genetic dependency in DMG. We hypothesized that the brain-penetrant, p110α-selective inhibitor GCT-007 could maintain therapeutic efficacy while reducing immune toxicity. DMG patient-derived cell lines showed comparable sensitivity to paxalisib and GCT-007 (mean IC50: 0.659 μM vs. 0.775 μM, respectively). Unbiased proteomic profiling in two DMG lines treated with GCT-007 identified robust downregulation of PI3K/AKT/mTOR signaling, confirmed via immunoblotting. Pathway enrichment further showed upregulation of oxidative phosphorylation, reinforcing the rationale for synergistic combination with dordaviprone. In aggressive immunocompetent syngeneic models, GCT-007 significantly extended overall survival (median 53 vs. 40 days, p=0.0001). When combined with dordaviprone, enzastaurin, or immune checkpoint inhibitors (ICI), GCT-007 increased survival in immune-competent DMG models by an average of 53% to 77% compared to vehicle (p=0.001), with 25% of mice in the GCT-007 + ICI cohort achieving long-term survival. Ongoing spatial profiling of the tumor immune microenvironment and organ-toxicity screening is underway to support translation.