Demographic and MRI characteristics of patients involved in stage 1, stage 2, and stage 3.

Video telehealth visits (VTV) have emerged as a critical tool for oncology care delivery, with potential to address longstanding access disparities. We examined the association between broadband internet availability, individual digital literacy factors, and VTV utilization among patients with cancer. In a retrospective cohort of 13,897 patients across a multi-site practice, VTV utilization was significantly lower in areas with ≤1 internet service provider (ISP) offering download speeds ≥25 Mbps (p = 0.0009). Validation in a regional cohort (n = 6665) confirmed lower VTV utilization in low-broadband areas. Among 1134 surveyed patients, higher digital literacy was the strongest predictor of VTV use (OR 2.5; p < 0.001), even where broadband was limited. This study demonstrates that while both broadband availability and digital literacy independently influence VTV utilization, individual digital skills can partially offset structural limitations, underscoring the need for concurrent investment in broadband infrastructure and targeted digital literacy initiatives to advance access to care.

Evaluating the effect on model performance (AUC) when performing ensemble across an increasingly larger number of models. Five independent sets of 5-fold cross-validation were evaluated. One 5-fold cross-validation set denotes performing ensemble across the resulting k = 5 models. Two 5-fold cross-validation sets denote ensemble across 10 models, three sets denote ensemble across 15 models, four sets denote ensemble across 20 models, and five sets denote ensemble across 25 models.

Cartoon comparing AUC and cross entropy loss on five GBM patients and five CNS-DLBCL cases. Grey denotes GBM and black denotes CNS-DLBCL. All models have the same AUC (AUC=100%); however, Model 4 has the smallest cross entropy loss.

Model performance on the 256 GBM and 73 CNS-DLBCL independent test cases from stage 3 from the model developed using the ensemble approach (A) overall, (B) stratified by sex, and (C) stratified by age. Results for the model developed using the loss approach (D) overall, (E) stratified by sex, and (F) stratified by age. AUCs (95% CI) are provided.

Violin plots showing the model scores from the 240 retrospective GBM cases in stage 2 from the models developed using the (A) ensemble approach and (B) loss approach.

BACKGROUND:Current literature suggestsisocitrate dehydrogenase (IDH)-mutant astrocytoma contains several molecular subgroups. In this study, we are interested in determining the connection between different molecular subgroups with grade and/or survival. METHODS:A cohort of 470 Mayo Clinic adult patients (≥18 years, 56.2% male) with primary IDH-mutant astrocytoma diagnosed by World Health Organization (WHO) 2021 criteria were examined. Results were validated in an independent cohort of 614 Mayo Clinic Neuropathology consult patients and 235 The Cancer Genome Atlas (TCGA) patients. RESULTS:The Mayo Clinic Practice cohort confirmed the association of CDKN2A/B deletion with overall survival (OS, homozygous vs hemizygous vs intact, 2.7 vs 9.6 vs 17.2 years, P < .001). Phosphatase and tensin homolog (PTEN) deletion was also associated with poor OS (7.3 vs 17.4 years, P < .001). Increased number of copy number alterations was associated with OS (continuous variable, HR = 1.027, P < .001). Carrying one or more copies of the germline risk allele at rs55705857 was associated with earlier age of onset (median age 33 vs 35 years, P = .01), and a shorter OS after adjusting for age, grade, sex and treatment (HR = 1.81, P = .007). The Mayo Clinic Neuropathology Consult cohort and TCGA were utilized to validate age of onset and survival, respectively. Unsupervised clustering of the copy number alterations identified several clinically significant groups that may define pathways to disease progression. Losses of chromosomes 11p, 13q, 1p, and 10q were all associated with reduced overall survival in the Mayo Clinic cohort. CONCLUSIONS:Patients with hemizygous loss of CDKN2A/B, loss of PTEN, increased number of copy number alterations, specific chromosomal arm losses or rs55705857 germline risk allele have reduced overall survival.

Sensitivity and specificity of the loss model applied to the stage 3 cohort. All possible model score thresholds from the loss model are shown. The yellow highlighted row denotes the score threshold required to obtain 90% sensitivity. The orange highlighted row denotes the score threshold required to obtain 90% specificity.

Diffuse hemispheric glioma, H3 G34-mutant (DHG-H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high-resolution copy number profiling of a series of 60 DHG-H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187-gene mutation and fusion targeted neuro-oncology next-generation sequencing panel (n = 60) and Oncoscan chromosomal microarray (n = 26) by a single laboratory (2018-2022). A subset of cases had immunohistochemical results for OLIG2 (n = 42), p53 (n = 48), and ATRX (n = 46), and methylation array data (n = 8). Median age at testing was 21 years (range, 12-50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3-3A G34 mutations included G34R (n = 56; 94%), G34V (n = 3), and a non-canonical G34E (n = 1). Concurrent mutations most often involved TP53 (n = 55; 92%), ATRX (n = 50; 83%), and PDGFRA (n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy-neutral loss of heterozygosity (cnLOH) encompassing TP53. This copy number profile was reminiscent of that seen in Grade 4 IDH-mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high-resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG-H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH-a copy number abnormality that has been largely unrecognized-for this new 2021 World Health Organization central nervous system tumor type.

Supplementary Materials and Data show the cell culture and western blot data

Abstract Therapeutic resistance limits the efficacy of radiation therapy in many tumors and provides a compelling rationale to develop novel treatments to enhance radiation sensitivity. DNA-dependent protein kinase (DNA-PK) is a major mediator of DNA repair following radiation, and DNA-PK inhibitors are effective radiosensitizers. WNC0901 is a potent DNA-PK inhibitor in both a cell-free kinase assay (IC50 = 0.073 nM) and a cell-based assay (IC50 = 76 nM). WNC0901 has a 30-fold specificity for DNA-PK relative to other PI3K-related kinases. In a broader kinome screen (363 kinases), 1 μM WNC0901 resulted in >25% inhibition of only five other kinases. There is robust inhibition of radiation-induced DNA-PK autophosphorylation (Ser-2056), as analyzed by Western blotting, with maximal effect at 300 nM WNC0901 in A549 (lung carcinoma), U2OS (osteosarcoma), and HT29 (colorectal) cells. The efficacy of WNC0901 as a radiosensitizer was evaluated in clonogenic assays across these same three radioresistant tumor models. Following treatment with graded concentrations of WNC0901 (0-1000 nM) combined with 2.5 Gy radiation, maximal effects were observed at a 300 nM concentration in A549 (88-fold reduction in relative clonogenic survival compared to RT alone, p<0.001), U2OS (5.8-fold decrease, p=0.002), and HT29 (59-fold decrease, p=0.008) In a full radiation clonogenic, the sensitizer enhancement ratio at 10% survival (SER10) was 3.8 (A549), 2.3 (U2OS), and 1.8 (HT29). In vitro metabolism studies have identified demethylated WNC0901 (WNC0901-M) as a major metabolite. Similar to the parent drug, WNC0901-M is a potent DNA-PK inhibitor with maximal radiosensitizing effects of the metabolite observed at 300nM with SER10 of 2.4 (A549), 1.9 (U2OS), and 1.8 (HT29). The in vivo efficacy of 50 mg/kg WNC0901 combined with 8 Gy was evaluated and compared to another DNA-PK inhibitor, 50 mg/kg peposertib, in A549 tumor heterotopic xenografts. Compared to placebo (median time to endpoint 63 days) or RT alone (median 72 days), the combination of WNC0901 and RT significantly delayed tumor regrowth (median 169 days; p=0.002 compared to RT). Interestingly, peposertib + RT was ineffective (median 83 days; p=0.332 compared to RT). In a second study, similarly robust sensitizing effects of WNC0901 was observed in HT29 xenografts (placebo - median 45 days; RT - median 75 days; RT + WNC0901 - median >110 days; p=.03 relative to RT). Together, these findings demonstrate the robust radiosensitizing effects of WNC0901 in radioresistant tumors and provide a rationale for continued development of this drug. Citation Format: Jessica L. Abraham, Ann C. Mladek, Sonia Jain, Shiv K. Gupta, Paul A. Decker, Matthew L. Kosel, Katrina K. Bakken, Brett L. Carlson, Lauren L. Ott, Danielle M. Burgenske, Jeanette E. Eckel-Passow, Wei Zhong, Jann N. Sarkaria. WNC0901 is a novel DNA-PK inhibitor and potent radiosensitizer of otherwise radioresistant solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6608.

The MRI model was run on 34 patients with tumefactive demyelination. (A) Distribution of predicted MRI score for the 34 patients. (B) Distribution of predicted MRI score by age at diagnosis. The blue line denotes a loess fit and the grey shaded area denotes the 95% confidence interval. (C) Distribution of predicted MRI score by gender (F=female, M=Male). (D) Distribution of predicted MRI score by MRI manufacturer. (E) Distribution of predicted MRI score by MRI field strength. (F) Distribution of predicted MRI score by T1Gd acquisition type. T2 acquisition type is not shown because 33 of the 34 patients were sequenced using 2D.

Violin plots showing the model scores for the 256 GBM and 73 CNS-DLBCL cases in stage 3, obtained from the models developed using the (A) ensemble approach and (B) loss approach.

Description of the three-stage study design.

Supplemental Figure 1 shows bar graph of quantification of cells that have >25 gH2AX foci per cell in M15 cell line, after treatment with peposertib and radiation

Background Imaging-based glioma monitoring is confounded by treatment-related changes. D-2-hydroxyglutarate (D-2-HG), produced by the isocitrate dehydrogenase (IDH) mutation, is detectable in cerebrospinal fluid (CSF), which can be sampled from cranial or lumbar compartments. We evaluated CSF D-2-HG as a serially accessible biomarker for IDH-mutant gliomas, including the optimal compartment for longitudinal sampling.Methods Lumbar and cranial CSF samples were collected from patients with IDH-mutant gliomas or IDH-wild-type central nervous system pathologies via surgical field collection, lumbar punctures, and CSF access devices. CSF D-2-HG was quantified via our CLIA-certified gas chromatography mass spectrometry assay.Results D-2-HG was significantly higher in cranial than lumbar CSF from IDH-mutant glioma patients. Consistent with low D-2-HG abundance in lumbar CSF, lumbar samples could not discriminate IDH-mutant gliomas from IDH-wild-type lesions. In contrast, cranial CSF D-2-HG was significantly higher in IDH-mutant gliomas than wild-type lesions, providing an adequate baseline for initial evaluations of monitoring capabilities. Across 75 samples from 7 consecutive patients with grade 4 IDH-mutant astrocytomas, serial cranial CSF D-2-HG decreased with cytoreduction, remained unchanged with stable disease, and increased with disease progression, but not pseudoprogression.Conclusions Serial cranial CSF D-2-HG shows promise as a monitoring biomarker for IDH-mutant gliomas.

Glioblastoma (GBM), isocitrate dehydrogenase wild-type (IDHwt) and central nervous system diffuse large B-cell lymphoma (CNS-DLBCL) are aggressive brain tumors with overlapping MRI features, yet distinct treatment approaches. Noninvasive tools are needed to aid in differential diagnosis. Deep learning on T1 postcontrast and T2-weighted MRI sequences were used to differentiate GBM and CNS-DLBCL. A three-stage temporal study design was utilized. Model development was performed on 146 patients with CNS-DLBCL and 146 age-matched, sex-matched, and MRI year-matched patients with GBM diagnosed at Mayo Clinic between 1998 and 2019. Models were tested on independent temporal test cohorts. Initial testing included 240 independent GBM diagnosed at Mayo Clinic between 1998 and 2019. The prospective test cohort included 37 patients with CNS-DLBCL and 256 patients with GBM diagnosed at Mayo Clinic after January 1, 2020, and 36 patients with CNS-DLBCL diagnosed at an external institution. Of the patients diagnosed at Mayo Clinic, 47% had MRIs generated from non-Mayo institutions. Two different model approaches were compared: (i) ensemble approach using area under the receiver operating characteristic curve (AUC) and cross-validation for model selection and (ii) loss approach minimizing cross-entropy loss and cross-validation to evaluate prediction performance. The AUCs on the prospective test cohort were 0.84 [95% confidence interval (CI), 0.78-0.90] and 0.83 (95% CI, 0.77-0.88) for the ensemble and loss approaches, respectively. Stability of ensemble prediction improved with the increasing number of models. Stratified AUC analysis demonstrated consistent performance across sex and age. We utilized a robust temporal study design and applied 2 different analytic approaches to develop a classification model. The findings confirm the feasibility of using MRI-based deep learning models to differentiate GBM from CNS-DLBCL. SIGNIFICANCE:GBM, IDHwt and CNS-DLBCL are aggressive brain tumors with overlapping MRI features, yet distinct treatment approaches. Noninvasive tools are needed to aid in differential diagnosis. We developed MRI-based deep learning models to differentiate GBM, IDHwt from CNS-DLBCL using a rigorous three-stage temporal design that included prospective validation. The model AUC on a prospective cohort was 0.84.

Abstract Introduction: Lung cancer rates differ across rural and urban areas, but few studies have evaluated rural-urban differences across the risk-screening continuum. We examined smoking, cessation interventions, and lung cancer screening patterns across the rural-urban continuum in a geographically defined area over 10 years. Materials and Methods: A retrospective cohort study (2014-2023) was conducted using clinical data from the Rochester Epidemiology Project, derived from healthcare encounters in a 27-county region of the midwestern United States. Patients ages 40-80 were included. We used Rural-Urban Commuting Area codes to assign residence as urban, rural, or highly rural. We examined yearly smoking prevalence, cessation intervention (pharmacotherapy, counseling), and low-dose computed tomography (LDCT) lung cancer screening. Results: Over the 10-year study period, the sample size ranged from 305,530 to 340,411 people annually with 36-38% urban, 56-57% rural, and 6-7% highly rural. Current smoking prevalence declined from 14 to 12% over the 10-year period (range=12-16%; p=0.06) and was consistently lower in urban areas (range=10-14%) than rural (range=12-17.0%) and highly rural areas (range=12-18%; p=<0.001). Among individuals who currently smoked with no history of lung cancer, yearly smoking cessation intervention ranged from 16% to 23%, increasing over the 10-year period (p=<0.001). Cessation medication (varenicline, bupropion, or nicotine replacement) prescription consistently increased overall over time but remained higher in urban than rural and highly rural areas (p=<0.001). Cessation counseling rates also increased overall over time and were similar between urban and rural areas and lower in highly rural areas (p=<0.001). Among people who had ever-smoked aged 50-80 years with no diagnosis of lung cancer, LDCT screening increased from 0.0% to 3.1% over the study period. Increases were higher in urban areas (0.0-3.6%) and similar in rural and highly rural areas (0.0-2.8% and 0.0-2.9%, respectively; p=<0.001). Among people who currently smoked, LDCT screening also increased over the study period (0.0-6.4%), with higher increases in urban (0.1-8.0%) than rural (0.0-5.7%) or highly rural (0.1-6.1%) areas (p=<0.001). After the new screening guidelines in 2021, rates in all areas increased year-on-year. Conclusion: In this cohort, we found that smoking prevalence, cessation interventions, and lung cancer screening improved from 2014-2023 across the rural-urban continuum. Unfortunately, smoking prevalence remained higher and cessation interventions and screening rates lower in rural compared to urban areas. The persistent patterns underscore the need for strategies to overcome barriers for rural residents and improve lung cancer prevention and early detection in all areas. Citation Format: Brianna Tranby, Paul A. Decker, Jiang Ruoxiang, David Midthun, Lori C. Sakoda, Melinda C. Aldrich, Debra Friedman, Adoma Manful, Oindrila Bhattacharyya, Christi Patten, Chyke A. Doubeni. Patterns of tobacco use, cessation interventions, and lung cancer screening in rural vs. urban areas over time; a 10-year retrospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5045.