Citations

Abstract Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

Abstract Smith-Lemli-Opitz syndrome (SLOS) is a rare, autosomal recessive disorder characterized by congenital malformations, intellectual disability, and behavioral abnormalities. SLOS results from mutations in the DHCR7 gene, leading to impaired cholesterol biosynthesis due to dysregulation of 7-dehydrocholesterol reductase. Cholesterol plays crucial roles in neurophysiology, including synaptic formation and neurotransmitter receptor regulation, which likely contribute to neurological manifestations in SLOS patients. While astrocytes are the main cholesterol producing cells in the brain, their specific role in SLOS pathogenesis remains unclear. In this study, we utilized induced pluripotent stem cell (iPSC)-derived astrocytes from a SLOS patient with DHCR7 c.C278T mutation and the isogenic control. We found decreased lipid droplet formation in SLOS iPSC astrocytes compared to controls, accompanied with diminished efflux of cholesterol and apolipoprotein E. Lipidomics revealed reduced cholesterol and cholesterol esters, as well as altered profiles of other lipids in SLOS iPSC astrocytes. While RNA-sequencing identified various genes and pathways affected by the disease status, those related to mitochondria functions were top-ranked. Mitochondrial electron transport chain oxidative phosphorylation gene expression decreased in SLOS iPSC astrocytes, alongside impaired mitochondrial respiration. Furthermore, SLOS iPSC astrocytes less effectively mediated neuroprotection on iPSC neurons than control astrocytes in serum-starvation conditions. SLOS iPSC astrocytes also poorly contributed to synaptic networks when co-cultured with iPSC neurons. Overall, our findings provide mechanistic insights into how DHCR7 disruption impacts astrocyte function, contributing to SLOS neuropathology by dysregulating lipid metabolism, mitochondrial respiration, and impaired neuroprotection.

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a functional imaging modality that can quantify tissue permeability and blood flow. Due to vasculature changes resulting from radiation therapy (RT), DCE-MRI quantitative parameters should be significantly different in regions receiving a high radiation dose compared to regions receiving a low radiation dose. This study sought to determine whether a significant difference exists in post-head-and-neck-cancer (HNC)-RT DCE-MRI quantitative parameters (Ktrans and ve) between regions of the mandible receiving a high radiation dose and regions of the mandible receiving a low radiation dose. Methods: DCE-MRI was acquired from HNC subjects post-RT. The DCE-MRI quantitative parameters Ktrans and ve were obtained through Tofts model fitting. Four mandible sections (left ramus, left body, right ramus, and right body) were delineated on subject mandible contours. Two Friedman tests comparing the mean Ktrans and ve in low-dose (≤60 Gy) areas of the four mandible regions were computed. If the Friedman test determined that a significant difference for a parameter between mandible regions exists, post hoc Wilcoxon signed-rank tests were completed comparing the four mandible regions. If the Friedman test determined that there was no significant difference between mandible regions, a Wilcoxon signed-rank test was used to determine whether a significant difference exists in the parameter between high-dose (>60 Gy) and low-dose (≤60 Gy) mandible regions. Results: 48 HNC subjects were included in the analysis. The Friedman tests showed no significant difference in ve means between mandible regions (χ(3)2 = 1.63, p = 0.44) and a significant difference in Ktrans means between mandible regions (χ(3)2 = 10.29, p = 0.005). Post hoc testing between Ktrans mandible regions found that the left body and right body differed significantly from the left ramus and right ramus. The Wilcoxon signed-rank test comparing the mean ve between high- and low-dose mandible regions found a significant difference (W = 214, p = 0.00013). Conclusions: no inherent difference in the DCE-MRI quantitative parameter ve was observed within subject mandibles, but a significant difference was observed between ve means in high- and low-radiation-dose mandible regions. These results provide evidence of the utility of DCE-MRI to monitor mandible vasculature changes resulting from head and neck cancer radiation therapy. Monitoring post-HNC-RT mandible vasculature changes is important to initiate earlier toxicity management and ultimately improve HNC survivors’ quality of life.

Abstract Purpose: Isocitrate dehydrogenase (IDH) 1/2–isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance. Patients and Methods: This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin–gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed. Results: Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma. Conclusions: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.

Purpose Genitourinary syndrome of menopause (GSM) describes the symptoms and physical changes that result from declining estrogen and androgen concentrations in the genitourinary tract during the menopausal transition. This guideline provides information to clinicians regarding identification, diagnosis, counseling, and treatment for patients with GSM to optimize symptom control and quality of life while minimizing adverse events. Methods The systematic review used in the creation of this guideline is based on research conducted by the Minnesota Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality and funded by the Patient Centered Outcomes Research Institute. The EPC synthesized effectiveness and/or harms outcomes from 68 publications. An additional 66 articles evaluating 46 nonhormonal interventions were described in an evidence map. Results Clinicians diagnose GSM based on symptoms, with or without related physical findings, and after ruling out other etiologies or co-occurring pathologies. There is a large body of evidence examining the use of hormonal and nonhormonal treatment options to manage the symptoms of GSM; however, the local low-dose vaginal estrogen has the most robust evidence base. Conclusion The strategies defined in this document were derived from evidence-based and consensus-based processes. Given that there is insufficient information to recommend one hormonal therapy over another, this guideline is not meant to support a stepwise progression through different hormonal approaches. The clinician should make treatment decisions in the context of shared decision-making, considering patient goals and preferences, using the evidence of efficacy and adverse events of each possible intervention as a guide.

ABSTRACT Introduction Sinonasal sarcomas are exceedingly rare entities, constituting less than 7% of head and neck sarcomas. Their complex histology needs specialized treatment, which is often based on multimodal approaches including surgery, radiation therapy, and/or chemotherapy. This manuscript aims to gather expert opinions to establish common management principles for sinonasal sarcomas. Methods This international consensus followed a modified Delphi method in seven steps, including statements definition by the core group, expert panel recruitment, and a two‐round survey. Sixty‐two statements on sinonasal sarcoma management were developed. Experts from multiple continents participated, and results were anonymized and analyzed between March and May 2025. Results A total of 44 invited experts were recruited, 43.2% otorhinolaryngologists/head and neck surgeons, 31.8% medical oncologists, and 25% radiation oncologists. Participants varied in age and experience, representing Europe (70.5%), North America (18.2%), South America (6.8%), and Asia (4.5%). Among all histologies, biphenotypic sarcoma, chondrosarcoma, leiomyosarcoma, and myofibrosarcoma are principally treated with an upfront surgical management, differently from Ewing sarcoma and rhabdomyosarcoma in which chemotherapy, eventually associated with radiotherapy, is often chosen. In the remaining histologies (angiosarcoma, liposarcoma, malignant peripheral nerve sheath tumor [MPNST], osteosarcoma, and synovial sarcoma), a precise multimodal treatment is less standardized and needs to be discussed on a case‐by‐case basis. Conclusion Sinonasal sarcomas require a histology‐driven approach to determine upfront treatment, whether surgical, medical, or multimodal. Despite this structured strategy, prognosis remains highly variable across subtypes. Multidisciplinary evaluation and individualized management in referral centers are crucial to address the biological diversity and anatomical complexity of these rare malignancies.

Abstract Minimally invasive image-guided tumor ablation techniques have been established as safe, effective methods to treat a variety of unresectable soft tissue tumors. Standard thermal ablation methods include radiofrequency ablation, microwave ablation, and cryoablation. However, newer non-thermal and/or non-invasive ablation techniques are now available as alternative options to treat soft tissue tumors, particularly those that are near critical structures or otherwise susceptible to thermal energy sink effects. The 4 types of emerging ablation techniques discussed in this review are as follows: irreversible electroporation, pulsed electric field, high-intensity focused ultrasound, and histotripsy. While the clinical trials evaluating the safety and efficacy of these ablation techniques are in their early stages, initial results are promising in the treatment of various cancers at different stages. These include potential synergistic effects when combined with chemotherapy and immunotherapy.

Abstract Background Physical activity is associated with lower colorectal cancer (CRC) risk, but its association with molecular subtypes defined by genetic and epigenetic alterations of the disease is unclear. Such information may enhance the understanding of the mechanisms related to the benefits of physical activity. Methods Pooled observational (cases: n = 5386; controls: n = 6798; studies n = 5) and genome-wide association data (cases: n = 8178; controls: n = 10 472; studies n = 5) were used. We used multivariable logistic regression models and Mendelian randomization to assess the association between physical activity and the risk of CRC subtypes defined by individual tumor markers (and marker combinations), namely microsatellite instability status, CpG island methylator phenotype status, and BRAF and KRAS mutations. We used case-only analysis to test for differences between molecular subtypes. We applied Bonferroni correction to account for multiple tests. Results In the pooled observational analysis, higher levels of physical activity were associated with lower CRC risk (Obs-per 1SD, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.90 to 0.97), with an association that was stronger in males (Obs-per 1SD, OR = 0.91, 95% CI = 0.87 to 0.96) than in females (Obs-per 1SD, OR = 0.97, 95% CI = 0.91 to 1.03; Pinteraction = .04). Higher physical activity was associated with a lower risk of CRC across all molecular subtypes, especially in males. There was no difference in the associations by subtypes by pooled observational or Mendelian randomization analyses. The findings did not differ by study design, anatomical site, and early or late age onset of CRC. Conclusions Our findings suggest that physical activity is not differentially associated with the 4 major molecular subtypes involved in colorectal carcinogenesis, indicating that its benefits extend broadly across colorectal cancer pathogenesis.

Abstract Objective: The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded EDRN defined phase 2 Biomarker Bakeoff study of eight promising biomarker panels using pancreatic cancer ductal adenocarcinoma (PDAC) case and general population healthy control samples from three institutions. The scientific questions were to determine whether panels could discriminate PDAC cases from controls with Receiver Operating Characteristic Area Under the Curve (AUC) > 0.8, compare panel performance head-to-head via 95% confidence intervals (CI), and determine whether the panel improved upon serum CA19-9 alone. A secondary goal was to perform modeling to discover a new panel consisting of individual biomarkers. Methods: Eligible biomarkers were required to have had a prior EDRN defined phase 2 validation study published and be ready for validation in a sample set from multiple institutions. Three institutions submitted a total of 140 cases and 140 controls frequency matched to cases on age and sex. Four consortium member institutions submitted for validation eight panels consisting of ten plasma, serum and DNA genotyping biomarkers in addition to CA19-9. Locked panel formulas were submitted prior to specimen distribution. The primary metric was AUC with bootstrapped 95% CIs. LASSO penalized regression was used for exploratory panel building. Nested cross validation and internal-external validation were performed, and optimism-corrected performance estimates were computed. Results: The overall sample (N=280) was 51% female, median age of 67 years, and 94% were of non-Hispanic white race and ethnicity. Controls had median BMI 27.3, 56% never smokers, and 12% type II diabetes mellitus (DM2); cases (staged I to IV) had median BMI 26.6, 42% never smokers, and 26% DM2. Overall panel AUC estimates ranged from 89.9 to 96.3 and all were significantly larger than the null hypothesis value of 0.8 (p<0.05). The apparent serum CA19-9 AUC was 91.7 (87.8, 95.6). Two panels were significantly different from serum CA19-9, a panel with FUT2/3 genotype with serum CA19-9 (p=0.002) and a panel containing tissue factor pathway inhibitor (TFPI), tenascin C (TNC), and plasma CA19-9 (p=0.01). In subset analyses by PDAC stage, no panel improved upon the null hypothesis value of 0.8 in stage I (p>0.05), all panels improved upon the null hypothesis value of 0.8 in stage II and III (p<0.05), and only serum CA19-9 did not improve upon the null hypothesis value of 0.8 in stage IV. All biomarkers but two microRNAs were retained in a LASSO model that had optimism corrected AUC=96.4 (95% CI: 94.0, 98.9). Conclusions: All submitted panels performed well overall in this blinded study, with the panel containing FUT2/3 genotype performing the best. Panel discovery improved upon serum CA19-9, though optimism corrected AUC 95% CIs overlap with those of apparent CA19-9 performance. Further work is needed to prioritize promising biomarkers and to improve detection of early stage PDAC. Citation Format: Ann L. Oberg, William R. Bamlet, Grant Izmirlian, Seetharaman Balasenthil, Surinder K. Batra, Masataka Hayashi, Daniel Herman, Michael A. Hollingsworth, Maneesh Jain, Ann M. Killary, Brianna M. Krusen, Suyu Liu, Gopalakrishnan Natarajan, Subrata Sen, Lynette M. Smith, Sudhir Srivastava, Brian M. Wolpin, Kenneth S. Zaret, Michael G. Goggins. Pancreatic Cancer Detection Consortium biomarker bake-off: A consortium Phase 2 blinded biomarker validation and panel discovery study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B070.