Citations

Abstract Purpose: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor, with a median survival of only 15 months. Effective therapeutic advances remain limited, with few clinical trial patients exhibiting robust responses to experimental therapies. This has led to efforts to identify molecular biomarker signatures capable of stratifying patient responses either prognostically (pre-treatment) or diagnostically (post-treatment). This study aims to assess the robustness and reproducibility of published transcriptional GBM biomarker signatures for predicting clinical outcomes in GBM trials. Methods: We analyzed published RNA-seq data from 4 clinical trials involving oncolytic virotherapy and immune checkpoint inhibitors, as well as multiple cohorts of patients treated via the Stupp protocol. The performance of reported immune gene signatures was evaluated across all datasets using both grouped and continuous survival modeling. Intra-patient signature variation between different biopsy sites and timepoints was assessed using longitudinal, multi-site sampling collected by the Break Through Cancer Accelerating GBM Therapies TeamLab. LASSO, multivariate Cox regression, and risk scoring with FDR adjustment were used to identify novel signatures with cross-cohort utility. Key Findings: No single published signature consistently predicted survival across all analyzed trials. A post-treatment ssGSEA antitumor cytokine signature that was associated with survival in the CAN-3110 OV trial (R = 0.74, p < 0.01) was also significantly associated with improved survival in an adjuvant anti-PD1 trial (R = 0.75, p = 0.03) and neoadjuvant anti-PD1 trial (R = 0.30, p = 0.05), but not in standard-of-care controls. PAM clustering of MCP immune signatures, as reported for the DNX-2401 OV+Anti-PD1 trial, also stratified post-treatment survival in the CAN-3110 OV trial (p < 0.01), with the coldest TME subtype consistently predicting worse survival. However, the prognostic value of the most immune enriched TME subtype was inconsistent and did not extend to the Anti-PD1 trials. Furthermore, multi-site, longitudinal biopsy samples revealed marked heterogeneity in biomarker signatures between biopsies from individual patients, even when assessed at the same timepoint. We’ve identified several candidate transcriptomic signatures that show promise for generalizable prognostic value in GBM patient cohorts and are characterizing their spatiotemporal variability. Conclusions: While no individual immune signature is universally predictive in GBM immunotherapy, certain post-treatment cytokine signatures and TME stratifications are significant in multiple immunotherapy contexts, though not in standard-of-care patient cohorts. Marked spatiotemporal heterogeneity in these signatures underscores the need for composite prognostic markers resilient to sampling variance. Citation Format: Christopher M. Jannotta, C Zoe Linke, Charles A. Whittaker, Vikas Patil, Accelerating GBM Therapies TeamLab, Farshad Nassiri, Gelareh Zadeh, E Antonio Chiocca, Alexander L. Ling. Assessing biomarker reproducibility for glioblastoma patient response stratification [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 1055.

ABSTRACT The epidemiology of myelodysplastic syndromes/neoplasms (MDS) is challenging to define due to inconsistent reporting, complex diagnostic procedures, and evolving diagnostic criteria. Using the National MDS Natural History Study—a prospective cohort with centrally adjudicated histopathology and genetic variant review—we characterized the landscape of MDS across the United States and identified differences across demographics. Among 2115 participants, 64% (1346) had an MDS spectrum condition, including MDS (24%), MDS/myeloproliferative neoplasm (5%) and precursor conditions—clonal cytopenia of undetermined significance (22%) and idiopathic cytopenia/dysplasia of undetermined significance (13%). The median age was 74 years, and participants were predominantly male (66%), White (91%), and Non‐Hispanic (92%). Myeloid‐associated variants were detected in 68% of participants, most commonly in TET2, DNMT3A, ASXL1, SF3B1, and SRSF2 . Black, compared to White, participants were younger at diagnosis (69 vs. 74 years, p = 0.01), had equal or increased prevalence of higher‐risk MDS, lower hemoglobin, and higher peripheral blood blasts, yet were less likely to receive MDS‐directed therapy (14% vs. 42%, p = 0.008). Black and Hispanic participants had fewer detectable gene mutations than White participants. Females had lower variant allele frequencies and fewer RNA splicing gene mutations than males. After multivariable adjustment, TP53 mutations, MDS diagnosis, and higher‐risk disease were associated with worse progression‐free and overall survival; age was also associated with overall survival. Black race trended toward improved progression‐free survival. These findings highlight the need for enhanced understanding of MDS pathogenesis across patient groups and refined prognostic tools to improve personalized management of MDS spectrum conditions. Trial Registration: ClinicalTrials.gov identifier: NCT02775383

Variants in TMEM106B and GRN , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

Abstract Frontline therapy for systemic amyloid light chain (AL) amyloidosis has evolved significantly with the approval of daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone, which has significantly improved rates of both hematologic and organ responses. Despite these advances, many patients eventually relapse, and there remains no established standard salvage regimen or optimal timing. In this review, we examine optimal timing of salvage regimens and currently available therapeutic options after daratumumab failure, including next-generation proteosome inhibitors or immunomodulatory drugs, autologous stem cell transplant, BCL-2 inhibitors, and emerging immunotherapeutic agents such as chimeric antigen receptor T-cell therapy and bispecific antibodies.

Objectives: To summarize recent high-quality trials and provide an update to the original 2022 American College of Radiology Appropriate Use Criteria for Treatment of Locoregional Gastric Adenocarcinoma. This multi-specialty-led committee included gastrointestinal radiation and medical oncology, gastroenterology, radiology, and surgical oncology. Methods: Using the population, intervention, comparator, outcome, timing, and study design framework, the evidence was assessed using Cochrane and PRISMA 2020 methodology. Eligible studies included prospective Phase II/II trials and select retrospective studies published between 5/1/2020 and 8/1/2025 in the Embase, Medline, and Pubmed databases. Study type and quality were assessed. Well-established RAND-UCLA consensus methodology (modified Delphi) was used to rate the appropriateness of the treatment options. Results: ARS AUC recommendations include adjuvant FLOT chemotherapy for localized gastric adenocarcinoma after neoadjuvant FLOT and surgery, poCT or perioperative chemoimmunotherapy for localized gastric adenocarcinoma, adjuvant chemotherapy +/− CRT for localized gastric adenocarcinoma that undergoes upfront surgery, and systemic therapy alone for localized gastric adenocarcinoma in a medically inoperable patient. Conclusions: This updated ARS AUC summary provides guidelines for the multimodality treatment of resectable gastric adenocarcinoma.

Abstract Patients at risk for progression from myeloid precursor states (idiopathic cytopenia of undetermined significance [ICUS] and clonal cytopenia of undetermined significance [CCUS]) to myelodysplastic syndrome (MDS) are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another were available in the MDS Natural History Study (NHS), a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens were collected at baseline and follow-up. A total of 1177 (56%) individuals with MDS or MDS-related precursor conditions (ICUS/idiopathic dysplasia of undetermined significance [IDUS], CCUS, and MDS/myeloproliferative neoplasm overlap) were enrolled and diagnosed in the MDS NHS. The median age was 74 years, with 89% aged ≥60 years, and most were male patients. Median follow-up time was 1.6 years and was similar among ICUS/IDUS, CCUS, and MDS. During follow-up period, 68% of participants terminated the study, 35% died, and 38% had disease progression. Using a refined clinical definition of progression, the greatest proportion of progression was observed among higher-risk-MDS (116 [73%]), followed by lower-risk-MDS (170 [52%]); fewer progression events were observed among participants with CCUS (65 [22%]) and ICUS/IDUS (46 [17%]). Predictors of progression are delineated, including female sex, higher quantity of mutations, the presence of TP53 mutation, and poor/very poor cytogenetic score. Based on these prospective data, guidelines for clinical management including monitoring and surveillance are outlined. The MDS NHS provides real-world data to illustrate how clinical and genotypic differences inform the classification, disease course, and approach to therapy, with informed monitoring guidelines for patients. This trial was registered at www.ClinicalTrials.gov as NCT02775383.

Abstract Cellular senescence is a key mechanism of skeletal aging in both physiological and accelerated conditions, such as radiotherapy. This study aimed to identify common differentially regulated microRNAs (miRs) across these contexts. We performed miR sequencing on three models: femurs from young (5-month-old) versus old (24-month-old) mice; focally radiated versus non-radiated femurs; and osteocytes from young versus old mice. Osteocytes were included in the comparison, as they have the longest lifespan in the mineralized bone matrix and they form 90-95% of all mesenchymal bone cell types. Among the three groups, miR-135a-5p and miR-671-5p were the common (i.e., shared) miRs that were downregulated, and miR-183-5p, a miR that regulates the WNT pathway, was the only shared upregulated miR, while miR-155-5p, a miR that regulates the Senescence-Associated Secretory Phenotype (SASP), was elevated in two conditions. The WNT-pathway has been positively associated with bone health and Sclerostin, a WNT-pathway inhibitor produced and secreted by osteocytes, has been implicated in accelerated skeletal deterioration following radiation. Thus, we used a neutralizing antibody to Sclerostin (Scl-Ab), to assess genes related to the WNT pathway and senescence, which are regulated by miR-183-5p and miR-155-5p, respectively. We further performed miR sequencing in radiated bones from mice treated with Scl-Ab and identified miR-133a-3p, a key miR that inhibits bone metabolism and function, which is upregulated in accelerated skeletal aging (i.e., focal radiation) downregulated by Scl-Ab. Overall, our study identifies potential regulatory gene pathways that modulate skeletal aging in the presence and absence of a WNT activator, Scl-Ab.

Background. Acute cellular rejection (ACR) remains a major cause of morbidity after heart transplantation despite advances in immunosuppression. Whole genome transcriptomic profiling offers a systems-based, unbiased approach to elucidate the molecular mechanisms underlying ACR. However, noninvasive, longitudinal biomarker assessments capable of capturing the temporal dynamics of rejection biology remain scarce. Methods. RNA sequencing of peripheral blood from heart transplant recipients before, during, and after ACR was compared with nonrejection controls. Pathway analysis was conducted using differentially expressed genes (DEGs), and a machine learning approach was applied to assess gene-based prediction of ACR. Results. A total of 235 rejection-specific significant DEGs and 863 postrejection DEGs (false discovery rate < 0.05) were identified. During ACR, DEGs were enriched for T-cell activation/differentiation, apoptosis, and B-cell receptor signaling pathways. By combining the 2 sets of DEGs, a panel of 71 common genes was identified that reflected the significant, longitudinal transcriptomic dynamics of ACR. In an elastic net machine learning–based classifier, DYNLL1 and SERF2 were identified as ACR predictive genes, and achieved a cross-validated area under the receiver operating characteristic curve of 0.63. Conclusions. Peripheral blood transcriptomics identify dynamic temporal responses in ACR including T- and B-cell pathways with potential ACR predictive genes that warrant further investigation.