Citations

Abstract Description Antigen receptor (CAR) T cells can be generated in vivo within the natural lymph node (LN) environment as the immune response to a virus infection unfolds. This in situ approach entails priming LNs with intradermal inoculations of replication defective adenoviruses encoding MHC class I and class II allo/xeno-antigens. Universal transplant antigens were devised for LN priming by introducing tryptophan into amino acid position 162 of the MHC HLA-A2:01 class I heavy chain and by using the mouse MHC class II beta chain to form chimeric class II antigens with endogenous class II alleles. The virus encoded mismatched MHC antigen presenting molecules are expressed functionally in the LN following intradermal inoculation provoking polyclonal T cells responses. Three days later CAR T cells are generated by directly injecting retroviruses encoding CARs of interest into the responding LN. Mouse CD19-specifc CAR T cells created in this manner in B6-DQ8 and DQ8/A2 mice effectively target endogenous B cells and are therapeutic in male and female Emu-myc lymphomas demonstrating the potential for the generating functional CAR T cells directly in vivo. While in situ CAR T cells are readily produced in B6, B6-IA0/DQ8, B6-IA0/DQ8/A2, and B6-IA0/DQ6 LNs, functional differences among the strains emerged in the periphery suggesting that properties of the autoimmune-associated HLA DQ8 class II allele is particularly reactive during the production of CAR T cells in vivo. Funding Sources MustangBio, Inc Mayo Clinic Center of Biomedical Research Mayo Clinic Department of Immunology Mayo Clinic Graduate School of Biomedical Science Fraternal Order of Eagles Mayo Clinic Ventures NIH R21 AI 097337 NIH R01 CA 178804 NIH T32 AI 07425 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Abstract Uterine leiomyosarcoma (ULMS) is an orphan disease that frequently recurs and metastasizes, with patients undergoing multiple lines of chemotherapy due to lack of effective therapeutic targets. To address this gap, we used single-cell RNA sequencing and spatial transcriptomic analysis to comprehensively profile ULMS. We uncovered multiple states of tumor cells, including tumor cells with mesenchyme-like features, ischemic tumor cells defined by a MYC program, inflammatory tumor cells with active interferon signaling, and stem cell-like hormone receptor-positive cells. The inferred spatial correlates of these tumor cell states demonstrated unique localization patterns. By correlating these signatures to bulk RNA sequencing data, we demonstrate the relevance of these findings to clinical outcomes. Finally, using the single-cell integration and drug response prediction algorithm (scIDUC), we propose drug predictions that may target specific tumor states. Our findings suggest new avenues for further exploration of individualized and multifaceted therapeutic strategies to treat ULMS.

Background Spontaneous intracranial hypotension (SIH) results from cerebrospinal fluid (CSF) leakage due to spinal dural tears or CSF–venous fistulas. Orthostatic headache is the hallmark presentation, though severe downward displacement of the brainstem may lead to altered consciousness or coma. Definitive treatments include targeted epidural blood patches, venous embolization, or surgical repair. Methods This article reviews the role of the Trendelenburg position as a temporizing measure in the acute management of SIH. We describe the correct technique, physiologic rationale, and practical considerations for its application, with attention to both therapeutic and diagnostic utility. Discussion Positioning the patient with the feet elevated above the head can reduce brain sag and provide short-term symptomatic relief while awaiting definitive treatment. Although the Trendelenburg position is widely used in practice, supporting evidence remains limited, and clinicians must be aware of its benefits, indications, and inherent limitations. Its appropriate application may assist in stabilizing patients with acute or severe SIH, particularly those with impaired consciousness, until more definitive interventions are pursued.

Abstract Purpose: Routine testing for mismatch repair deficiency (dMMR)/microsatellite instability (MSI) in colorectal cancers is recommended for Lynch syndrome screening, prognosis, and treatment guidance. In the metastatic setting, RAS/BRAF mutations guide treatment decisions. The impact of these mutations on the tumor immune microenvironment (TiME) in MSI/dMMR colorectal cancer is not known. Experimental Design: The study involved retrospective analysis of 448 patients with stage I to IV MSI/dMMR colorectal cancer profiled using next-generation sequencing (Tempus xT DNA sequencing of 595–648 genes at 500x coverage and Tempus xR whole-exome capture RNA sequencing). MSI status was determined by assessing 44 or 239 loci using next-generation sequencing. dMMR was determined using IHC. Tumor mutational burden, tumor neoantigen burden (NTB), PD-L1, immune infiltration, and canonical immune pathways (76 gene set signatures) were analyzed. Results: The median age at diagnosis was 67 years (range, 21–86); 59% of patients were female, and 70% were stage III to IV. Among the 448 patients, 100 (22%) harbored RAS mutations (RASmut), 119 (27%) a BRAFV600E mutation, and 229 (51%) were double wild type. RASmut exhibited lower NTB (median, 12 vs. 15 vs. 16; P = 0.003) and PD-L1 (3.6% vs. 13% vs. 24%; P < 0.001) than BRAFV600E and wild-type tumors, respectively. The RASmut TiME had lower overall inflammation and fewer infiltrating CD8+ T cells than wild-type or BRAFV600E tumors. In contrast, BRAFV600E tumors exhibited hyperproliferative characteristics associated with broad metabolic reprogramming but a similarly inflamed TiME compared with wild-type tumors. Conclusions: Our data suggest that MSI/dMMR colorectal cancers harboring RASmut are less immunogenic, and the TiME contains a lower inflammatory profile than wild-type or BRAFV600E tumors. Further analysis and validation are required to confirm these findings.

Importance Total pancreatectomy (TP) is indicated for advanced pancreatic cancer or multifocal tumors. Furthermore, TP may be performed to avoid the risk of pancreatic fistula in selected patients to improve the perioperative risk profile. Objective To define reference values for TP based on a low-risk cohort treated at expert centers. Design, Setting, and Participants This multicenter study analyzed outcomes from patients undergoing primary TP for malignant or benign lesions from 25 international expert centers from January 2017 to November 2023. Low-risk patients undergoing TP (LR-TP) were without vascular resections or significant comorbidities. Exposures TP. Main Outcomes and Measures Twenty reference values were derived from the 75th or the 25th percentile of the median values of all centers. Outcomes of LR-TP were compared with a cohort of TP with vascular resection, TP due to high-risk pancreatic anastomosis, and the benchmark values for low-risk pancreatoduodenectomy. Results Of 994 patients, 333 (33.5%; median [IQR] age, 66 [58-72] years; 171 male [51.4%]) qualified as the LR-TP cohort. Reference values included blood loss (≤1000 mL), major complications (≤37%), 3-month postoperative mortality (<6%), and retrieved lymph nodes (≥29). Compared with TP with vascular resections, reference cutoffs were not met for major complications (51% vs LR-TP ≤37%) and 90-day mortality (11% vs LR-TP ≤6%). For TP due to high-risk anastomosis, failure to rescue rate (38% vs ≤6%) and 90-day mortality (11% vs LR-TP ≤6%) were not met. Compared with pancreatoduodenectomy, reference values for postoperative mortality were 3 times higher for LR-TP (≤2% vs ≤6%) and less for resected lymph nodes (≥16 vs ≥29). Conclusions and Relevance This case-control study provided global reference values for TP, indicating significantly higher postoperative morbidity and mortality compared with pancreatoduodenectomy. Perioperative morbidity of TP was especially increased in patients with vascular resections. These reference values can serve for quality control of pancreatic surgery.

ABSTRACT Background We recently published the first real‐world multicenter and multi‐institutional study of cisplatin, gemcitabine, and durvalumab in patients with advanced biliary tract cancer (BTC). Here we present an expanded patient cohort with an increased sample size and longer median follow‐up. Methods The study population included patients with advanced BTC, who received cisplatin/gemcitabine plus durvalumab at 55 centers across 12 countries in Europe, the United States, and Asia. The primary endpoints of the study were progression‐free survival (PFS) and overall survival (OS). Secondary endpoints were overall response rate (ORR) and safety. Results Overall, 1358 patients were enrolled. Median PFS was 7.6 months (95% CI: 7.2–8.1), and median OS was 15.6 months (95% CI: 14.8–16.5). ORR was 35.6%, and DCR was 82.7%. Any grade AEs occurred in 1213 patients (89.3%). Grade 3–4 AEs occurred in 597 patients (43.2%). The rate of immune‐related AEs (irAE) was 20.3%. Grade 3–4 irAE occurred in 3.0% of patients. At the multivariate analysis for OS, normal albumin level (HR 0.68, 95% CI 0.57–0.81, p < 0.0001), CEA levels within normal ranges (HR 0.68, 95% CI 0.57–0.82, p < 0.0001), NLR < 3 (HR 0.62, 95% CI 0.52–0.74, p < 0.0001), ECOG PS 0 (HR 0.51, 95% CI 0.42–0.61, p < 0.0001), and prior surgery (HR 0.80, 95% CI 0.65–0.99, p = 0.036) were positive prognostic factors. Conclusion The updated findings, derived from an expanded cohort, further support the adoption of durvalumab in combination with gemcitabine and cisplatin in routine clinical practice, reinforcing the efficacy and safety outcomes demonstrated in the phase III TOPAZ‐1 trial.

Abstract BACKGROUND Bevacizumab, an anti-VEGF monoclonal antibody, has become a mainstay in the management of malignant gliomas. Multiple bevacizumab biosimilars have been approved since initial FDA approval of the reference agent and have seen widespread use due to reduced cost. However, real-world data evaluating comparability between reference and biosimilar agents have remained limited. METHODS We performed a retrospective analysis of patients treated with reference bevacizumab (Avastin) versus those receiving bevacizumab-bvzr, a widely used biosimilar agent (Zirabev) for the management of malignant glioma at our institution between 2019 and 2022. RESULTS A total of 161 patients were included in our final analysis; 97 received reference drug (Avastin) while 64 received the biosimilar agent (Zirabev). Demographics and baseline clinical characteristics between the two groups were similar. We performed survival analysis with post-progression survival (PPS) to ensure against lead-time bias. PPS was similar between the Avastin (median PPS 496 days) and Zirabev (median PPS 513 days) groups on univariate analysis (p=0.7654). Similarly, on multivariate Cox regression, there were no differences in PPS when comparing Avastin and Zirabev (HR 1.0673, p=0.6986). MGMT promoter methylation (HR 0.5709, p=0.0238), age at cancer diagnosis (HR 1.0356, p=0.0009), total dose of bevacizumab received (HR 0.9975, p=0.0087) and treatment with anticoagulation (HR 1.8086, p=0.0372) were significantly associated with PPS. Rates of therapy-related adverse effects were also similar between those receiving the reference drug and biosimilar agent (OR 0.9043, p=0.7824). However, concomitant treatment with antiplatelet therapy (OR 3.1447, p=0.0150) or anticoagulant therapy (OR 4.9069, p=0.0010) were significantly associated with increased risk for adverse effects. CONCLUSIONS Bevacizumab-bvzr demonstrated similar clinical efficacy and safety profile compared to reference bevacizumab in our institutional cohort. Concomitant treatment with antiplatelet therapy (OR 3.1447, p=0.0150) or anticoagulation (OR 4.9069, p=0.0010) were significantly associated with increased risk for adverse effects.

The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.

Abstract Advocacy has long been at the core of the infectious diseases (ID) field, with clinicians and researchers advocating to ensure patients can access the care they need on an individual and global scale. The Infectious Diseases Society of America Training Program Directors’ (PD) Committee met in 2024 and discussed ways that advocacy is and should be incorporated into fellowship training, as well as highlighted the role PDs play in advocating for their trainees. Policies with a negative impact on ID clinical care, public health, and research underscore the importance of mobilizing the field of ID to advocate for the patients and communities we serve, as well as for ourselves. This paper presents ideas generated at this meeting and is meant to serve as a reference for ID PDs, as well as the wider ID community, as a call to action for teaching and participating in advocacy work.

Abstract Background Clinical nutrition (CN) is becoming increasingly complex because of the rising prevalence of chronic illness, cancer, and malnutrition‐related conditions such as short bowel syndrome and refeeding syndrome. Despite its clinical significance, nutrition education among US physicians remains limited. Simultaneously, large language model (LLM)–based artificial intelligence assistants (AIAs) have emerged as tools to support complex clinical decision‐making but remain largely untested in CN. Methods This retrospective study evaluated four LLM‐based AIAs—ChatGPT (OpenAI), OpenEvidence (OpenEvidence Inc), Gemini (Google, Google DeepMind), and Copilot (Microsoft Corporation)—using five complex CN cases from our nutrition support service. Each AIA was queried with patient‐specific CN questions. Responses were blinded and reviewed by five physician CN experts using an eight‐item assessment tool evaluating clarity, relevance, evidence, and clinical utility. Results All AIAs produced clinically appropriate responses, with Gemini scoring highest in relevance (4.04) and clarity (4.16). Overall satisfaction scores ranged from 3.08 (Copilot) to 3.84 (Gemini). Citation quality and originality of insights varied and were generally limited, and no consistent differences in performance were observed across the five cases among the four AIAs. Conclusion LLM‐based AIAs can reliably replicate expert reasoning in CN. Although not yet a source of novel clinical insights, the true potential of this approach may lie in its application among physicians without specialized expertise in CN, helping to bridge existing knowledge gaps in nutrition care. Presenting full clinical cases, as shown in this study, could support AIA‐enabled e‐consultation in the future, thereby addressing gaps in CN education.