Citations

Abstract Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare central nervous system tumors. Our understanding of the clinical course, prognostic factors, and optimal treatment strategies remains limited. Histologic, molecular, and clinical data were collected and analyzed for 25 patients with DLGNT reviewed at St. Jude Children’s Research Hospital. The median age at diagnosis was 6 years (11 months-20 years). Nineteen (72%) patients were male. The disease was localized at diagnosis in 12 (48.0%) patients, with most tumors localized in the spinal cord. BRAF fusion was present in 22 (95.6%) of 23 patients who had material for testing. Of 18 patients who had tissue for DNA methylation profiling, 3 (16.7%) matched to DLGNT MC-1, 3 (16.7%) to DLGNT MC-2, and 12 (66.7%) did not match to a DLGNT subclass. Median follow-up was 63 months. Twenty-four (96.0%) patients received adjuvant therapy after initial diagnosis or at progression. Thirty-five cytotoxic chemotherapy and 24 single-agent targeted therapy regimens were used in 22 and 13 patients, respectively. With targeted therapy, 3 (12%) patients had partial responses. Eleven (44.0%) received radiotherapy. Median progression-free survival (PFS) after a patient’s first chemotherapy, targeted therapy, or radiotherapy regimen was 44 months (1-77), 11 months (4-39), and 16.5 months (9-23), respectively. The 5-year PFS was 18.7%±9.2, while the 5-year overall survival (OS) was 82.4%±9.2. The 5-year OS was lower in patients older than 9 years at diagnosis (60.0%±21.9 vs 91.7%±8.0, p = 0.02). Ki67 >4% was associated with worse PFS (0%±0 vs 24.6%±11.9 at 5 years, p = 0.03). Initial disease dissemination (localized vs. disseminated) and 1q gain status do not influence PFS or OS. PFS for DLGNT remains poor across all treatment modalities, including targeted therapies, despite the high frequency of BRAF fusions. Due to its rarity, establishing optimal therapeutic strategies for DLGNT requires additional treatment and outcome data and prospective multi-institutional trials.

This cohort study evaluates the reduction in risk of high-grade serous carcinoma among women undergoing opportunistic bilateral salpingectomy in Canada.

ABSTRACT Background Despite histologic remission (HR) being important in management of ulcerative colitis, the impact of endoscopic sampling on newer scoring systems remains uncertain. This study examines the outcome of applying PICaSSO Histologic Remission Index (PHRI) scoring on biopsies collected during routine clinical care and investigates the impact of endoscopic sampling variation on PHRI scoring and HR status. Methods A retrospective survey of UC endoscopic biopsies ( N = 128, 559 bites, 1–13 bites/biopsy) was evaluated using standard H&E stain and myeloperoxidase (MPO) immunohistochemistry to aid neutrophil identification. Convolutional neural networks (CNN), trained on colonic tissue architecture and cytomorphology features, were deployed alongside pathologist interpretations. In silico modeling of bite‐derived virtual biopsies ( N = 19,760) was investigated to determine the impact of sampling variation on PHRI scores and compared with ground truth clinical samples. Results PHRI MPO scoring displayed improved sensitivity and specificity for identifying neutrophils, compared with PHRI H&E . CNN‐derived PHRI scoring was most accurate for chronic active and chronic active with ulceration categories, with greatest variability observed in chronic inactive biopsies. Virtual patient biopsies comprised of < 5 endoscopic bites were impacted most by sampling permutations. Limited variability in PHRI scores was observed in samples consisting of ≥ 5 bites. Conclusions HR status (PHRI = 0) determination was slightly impacted by sampling. Biopsies consisting of < 5 endoscopic bites exhibited the most variability. Conservative sampling of 5–7 endoscopic bites may produce more accurate assessments of microscopic heterogeneity in clinical studies employing quantitative histologic measurements to assess disease activity and remission. Additionally, incorporating MPO increased the sensitivity and specificity of detecting active inflammation for PHRI scoring.

Abstract Introduction: The purpose of this study is to evaluate the effectiveness of opportunistic salpingectomy (OS), a procedure that aims to remove only the fallopian tubes of general population risk women, for the prevention of epithelial ovarian cancer. Currently, the method of prevention for individuals at high risk of ovarian cancer involves a bilateral salpingo-oophorectomy (BSO), a procedure that removes both the fallopian tubes and ovaries. However, this procedure is not recommended for individuals of the general population, who make up about 80% of ovarian cancers, due to negative health implications to the cardiovascular and skeletal systems because of surgically induced menopause. The effectiveness of the OS in preventing ovarian cancers and how the procedure impacts the histotype distribution of ovarian cancers remains unknown. Study Methods: This study uses a population-based approach and a case-based approach to determine the effectiveness of OS and its impact on histotype distribution, respectively. For the population-based analysis, we will search through clinical databases to acquire cases of individuals who have had an OS and a tumor. A control population who have their fallopian tubes in-tact will also be acquired. A cox-proportional hazard analysis will be performed to determine the effectiveness of the procedure. Using pathological records, the case-based ascertainment of tumors from individuals who have had an OS will be selected and reviewed for histotype confirmation. Fallopian tubes of these patients will also be reviewed for precursor lesions. This cohort will be compared to a historical histotype distribution of ovarian cancers. Results: For the population-based approach, we have to date, identified less than five serous ovarian cancers in individuals who have had an OS (n=40, 477). A comparator surgery was used as a control and showed 21 cancers. For the case-based approach, we have partnered with 23 collaborating institutions from around the world to identify tumors in individuals who have had an OS. We have identified 26 epithelial ovarian cancers, with the most lethal gynecological histotype, high grade serous carcinoma (HGSC), accounting for 23.1% of the total proportion of epithelial ovarian cancer cases (n=6/26). This is significantly less than the historical histotype distribution of HGSC, which is 69.3% (Fisher’s exact test, p&lt;0.0001). One HGSC case had a precursor lesion called a serous tubal intraepithelial carcinoma (STIC) while reviewing fallopian tubes of this individual. TP53 mutation analysis on one HGSC tumor sample showed a frameshift mutation in TP53 (c229fs) with the tumor and the corresponding STIC staining negative for p53 protein expression by immunohistochemistry. Conclusion: This evidence demonstrates the effectiveness of opportunistic salpingectomy for the prevention of ovarian cancer and shows a histotype distribution shift, with the most lethal gynecological malignancy having a significant reduction in cases following the procedure. Citation Format: Ramlogan Sowamber, Alice J. Mei, Paramdeep Kaur, Julianne McLeod, Emily McKay, Alex Lukey, Jamie Bakkum-Gamez, Natalia Buza, Paul Cohen, Kyle Devins, Rhonda Farrell, Christine Garcia, Blake Gilks, Ellen Goode, Anjelica Hodgson, Brooke Howitt, Pei Hui, Jutta Huvila, Anthony Karnezis, Kianoosh Keyhanian, Mary Kinloch, Martin Köbel, Felix KF. Kommoss, Lawrence Kushi, Janice S. Kwon, Kara Long-Roche, Anais Malpica, Jessica N. McAlpine, Dianne Miller, Esther Oliva, Andrea Palicelli, Aleksandra Paliga, Carlos Parra-Herran, Celeste Leigh Pearce, Sharnel Perera, Jurgen M. Piek, Haiyan Qiu, Joseph Rabban, Robert Rome, Miranda Steenbeek, Rebecca Stone, Aline Talhouk, Kristin M. Tischer, Britton Trabert, Penelope M. Webb, John R. Zalcberg, Gillian E. Hanley, David G. Huntsman. Evaluating the effectiveness of opportunistic salpingectomy (OS) for the prevention of epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B045.

Abstract Background Acamprosate is an FDA-approved medication for the treatment of alcohol use disorder (AUD), however, only about 50% of patients will respond to acamprosate. Previously, we conducted an acamprosate trial (n=442), which is one of the largest acamprosate clinical studies ever conducted and currently the only study with multi-omics data. To date, no biological measures are utilized to predict response to acamprosate treatment. Aims & Objectives We set out to apply our established pharmaco-omics informed genomics strategy to identify potential biomarkers associated with acamprosate treatment response. Method Our open-label acamprosate clinical trial recruited 442 patients with AUD, all of whom were treated with acamprosate for three months. The primary outcomes were 1) relapse to alcohol use and 2) relapse to heavy drinking. Alcohol consumption was measured using the self-reported timeline follow back method. Plasma protein levels were measured using Olink proximity extension immunoassays. Results Our established “Pharmaco-Omics-informed genome-wide association study (GWAS)” research strategy identified 12 proteins, including interleukin-17 receptor B (IL17RB), that were associated with acamprosate treatment response. A GWAS for IL17RB concentrations identified several genome-wide significant signals. Specifically, the top hit single nucleotide polymorphism (SNP) rs6801605 with a minor allele frequency of 38% in the European American population mapped 4 kilobase (Kb) upstream of IL17RB, and intron 1 of the choline dehydrogenase (CHDH) gene on chromosome 3 (p: 4.8E-20). The variant genotype (AA) for the SNP rs6801605 was associated with lower IL17RB protein expression. In addition, we identified a series of genetic variants in IL17RB that were associated with acamprosate treatment outcomes. Furthermore, the variant genotypes for all of those IL17RB SNPs were protective against alcohol relapse. Finally, we demonstrated that the basal level of mRNA expression of IL17RB was inversely correlated with those of nuclear factor-κB (NF-κB) subunits, and a significantly higher expression of NF-κB subunits was observed in AUD patients who relapsed to alcohol use. Discussion & Conclusions This study illustrates that IL17RB genetic variants might contribute to acamprosate treatment outcomes. This series of studies represents an important step toward generating functional hypotheses that could be tested to gain insight into mechanisms underlying variation in acamprosate treatment response phenotypes.

AbstractINTRODUCTIONThis study investigated the role of the ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.METHODThe SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.RESULTSSubtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS‐activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late‐stage tau biomarkers, microglia, and axonal degeneration.DISCUSSIONThe rise in UPS proteins alongside tau‐related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.Highlights This study investigates the ubiquitin‐proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late‐stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau‐pathology‐driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer’s disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.

484 Background: The histopathological growth patterns (HGPs) of liver metastasis reflect the complicated and varied interactions between tumor cells and the host microenvironment. We studied HGPs of gastric cancer liver metastasis (GCLM) and sought to predict them using radiomic and clinical variables. Methods: Hepatectomy was performed in 62 patients with GCLM at our university hospital between 2011 and 2021. HGPs were evaluated according to international consensus guidelines, and were classified as either desmoplastic HGP (dHGP) or non-dHGP. CD4, CD8, VEGF and CD31 were analyzed by immunohistochemistry. Eight hundred and fifty-one radiomics features were extracted from CT portal venous phase images and the optimal radiomics signature was determined by univariate analysis and LASSO regression. Multivariable regression analyses and ROC curves were used to assess the predictive performance of HGPs with a radiomic and clinical combined model. Results: Among 62 patients, 14 were categorized as dHGP, and 48 as non-dHGP. Non-dHGP vs. d-HGP was associated with higher tumor N stage and CEA level, and with decreased CD8 + T cells, and lower VEGF and CD31 expression. HGP status was independently associated with patient cancer-specific survival (CSS) (P＜0.05) multivariately.Analysis of percent relative contribution revealed that HGP ranked first for CSS (35.9%), ahead of T (28.9%) and N (28.9%) stage. A model with combined radiomic and clinical features demonstrated robust performance with area under the curve (AUC) values of 0.993 and 0.933 in the training and validation sets, respectively. Conclusions: Non-invasive determination of radiomic and clinical features was shown to predict HGPs types. Compared to dHGP, GCLM with non-dHGP exhibited significantly lower immune cell infiltration and decreased angiogenesis. Among features examined in GCLM, HGP was the most robust for prognostication. Univariate and multivariate analysis of prognostic factors for cancer-specific survival. Characteristics Univariate analysis Multivariate rergression analysis HR (95%CI) P HR (95%CI) P Gender ( Women vs Men ) 1.13(0.61-2.09) 0.71 Age ( >60years vs ≤60years) 1.08(0.60-1.70) 0.98 HGP ( non-desmoplastic HGP vs desmoplastic HGP ) 3.63(1.78-7.41) 0.00 3.48(1.37-8.88) 0.01 T stage ( T3-T4 vs T1-T2 ) 2.03(1.08-3.80) 0.03 2.29(1.15-4.58) 0.02 N stage ( N1-N3 vs N0 ) 3.46(1.66-7.23) 0.00 2.54(1.17-5.56) 0.02 CEA ( >5ng/ml vs ≤5ng/ml ) 2.37(1.25-4.48) 0.01 1.56(0.70-3.48) 0.27

483 Background: Heterogeneity exists in recurrence and survival among patients with intestinal-type gastric cancer (IGC). Nucleotyping is the alterations in chromatin organization. We sought to identify the prognostic utility of nucleotyping, tumor stroma ratio (TSR) and DNA ploidy in these patients. Methods: Radical resection of gastric carcinoma (> 15 LNs removed) was performed in 283 patients (stage I, n=73; stage II, n=102; stage III, n=108) at our university hospital between 2010 and 2018. Automated image cytometry tools were used to quantitatively measure nucleotyping, TSR and DNA ploidy. Cutpoints of nucleotyping and TSR were 0.044 and 50%, respectively. Associations of these features with clinicopathological characteristics, time-to-recurrence (TTR) and cancer specific survival (CSS) were analyzed by univariate and multivariate analysis. Results: Among 283 patients, chromatin heterogeneity, high TSR and non-diploid were significantly associated with larger tumor size, higher T and N stage, and poorer TTR and CSS at 5 years. In a Cox multivariable analysis, nucleotyping and TSR were independently associated with TTR and CSS (P＜0.05) (Table). The top three contributors to TTR were N stage (33.9%), nucleotying (29.7%) and TSR (25.5%). The top three contributors to CSS were N stage (35.6%), nucleotying (29.7%) and TSR (18.0%). As a combined variable, the percent relative contribution of nucleotyping and TSR ranked first for TTR and CSS (56.0%, 50.0%), ahead of N stage (33.4%, 34.6%) and TILs (8.4%, 10.6%). Conclusions: Nucleotyping and TSR were each significantly and independently associated with TTR and CSS, and their combined variable was more strongly prognostic than either alone. Cox multivariable analysis of TTR and CSS. Features TTR HR (95%CI) TTR P value CSS HR (95%CI) CSS P value Tumor size (>3cm vs ≤3cm) 1.10 (0.48-2.54) 0.83 0.77 (0.35-1.70) 0.56 T stage (T3-T4 vs T1-T2) 1.07 (0.46-2.49) 0.87 1.41 (0.53-3.76) 0.49 N stage (N2N3 vs N0N1) 2.84 (1.39-5.78) <0.01 7.69 (3.37-17.55) <0.01 Adjuvant Therapy (with vs without) 1.32 (0.72-2.40) 0.37 0.85 (0.48-1.52) 0.59 TB (high vs low) 1.29 (0.62-2.69) 0.50 1.61 (0.85-3.07) 0.15 TILs（low vs high） 1.73 (0.96-3.13) 0.07 1.90 (1.06-3.40) 0.03 Nucleotyping (Chromatin heterogeneous vs Chromatin homogeneous) 2.19 (1.21-3.99) 0.01 3.44 (1.96-6.03) <0.01 TSR (high vs low) 2.12 (1.16-3.82) 0.01 2.51 (1.43-4.41) <0.01 DNA ploidy (Non-diploid vs Diploid) 1.20 (0.55-2.63) 0.65 0.98 (0.44-2.15) 0.95 1 TTR, time-to-recurrence; 2 CSS, cancer specific survival.