VA Greater Los Angeles Healthcare System

Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy against solid tumors, which often reside in highly immunosuppressive tumor microenvironments (TMEs). TMEs can be highly abundant in vascular endothelial growth factor A (VEGF), which contributes to immunosuppression and abnormal tumor vasculature. Here, we found that CAR T cells engineered to secrete an anti-VEGF single-chain variable fragment (CAR-αVEGF T cells) achieved superior antitumor efficacy against multiple in vivo models of ovarian cancer and glioma, outperforming conventional CAR T cells with and without combination anti-VEGF antibody therapy. Microscopy, flow cytometry, and transcriptomic analyses revealed that armoring the CAR T cells with anti-VEGF single-chain variable fragments enhanced their activation and mitochondrial fitness and enriched immune-stimulatory signatures among endogenous immune cells in the tumor-bearing brain. Moreover, CAR-αVEGF T cells circumvented multiple detrimental effects associated with on-target CAR T cell therapy, including infiltration of suppressive myeloid cells, exaggerated vasculature abnormalities, and hypoxia. Together, our results provide rationale for the clinical translation of CAR-αVEGF T cells as a safe and potent therapy for solid tumors characterized by elevated VEGF.

To examine long-term and oncologic outcomes of broad-spectrum perioperative antimicrobial prophylaxis, compared with standard care antibiotics, in patients undergoing pancreatoduodenectomy. A registry-linked randomized clinical trial demonstrated a reduction in surgical site infection (SSI) in patients undergoing pancreatoduodenectomy who received piperacillin-tazobactam as perioperative prophylaxis compared to cefoxitin. However, long-term outcomes remain undefined. Participant records from the American College of Surgeons National Surgical Quality Improvement Program database were matched to the National Cancer Database. Associations between treatment arm, perioperative complications, and oncologic outcomes were assessed. Logistic regression models investigated associations with oncologic outcomes. Survival analyses used Kaplan Meier and Cox proportional hazard modeling. Of 778 patients, 471 (60.5%) were treated at Commission on Cancer accredited hospitals and eligible for linkage. Of those, 426 (90.4%) were matched in the NCDB including 203 (47.7%) treated with piperacillin-tazobactam and 223 (52.3%) with cefoxitin. Among patients with indications for chemotherapy, chemotherapy omission rates were similar between the treatment arms (9.4% in piperacillin-tazobactam vs 15.4% in cefoxitin; P=0.097). There was no association between the receipt of indicated adjuvant chemotherapy and receipt of piperacillin-tazobactam (OR 1.49; 95% CI 0.56-3.95) or presence of SSI (OR 0.58; 95% CI 0.21-1.65). Postoperative SSI was associated with poorer 3-year overall survival (HR 1.69, 95% CI 1.20-2.38). While patients experiencing an SSI had poorer survival, piperacillin-tazobactam prophylaxis did not significantly affect oncologic care delivery. These results cement the long-term implications of perioperative complications in patients with cancer and highlight leveraging cancer registries for clinical trial data analysis.

Use of complementary and integrative health (CIH) therapies has increased over the past two decades. Accumulating evidence supports the effectiveness of CIH therapies for a range of health outcomes and an association between CIH therapy use and reduced use of opioid therapy. To describe differences in the use of evidence-based CIH therapies among individuals with chronic pain on long-term opioid therapy (LTOT) by sociodemographic and clinical characteristics. This was an observational study using a national retrospective cohort of patients developed from Veterans Affairs (VA) electronic health record data. The sample comprised 281,903 patients receiving LTOT upon cohort entry between July 1, 2017, and December 31, 2021, with a health care encounter in one of 54 VA medical centers. CIH therapy use was defined as chart-documented use of any of eight priority CIH therapies or chiropractic care in the year prior to cohort entry. LTOT was defined as having a prescribed opioid analgesic for ≥90 consecutive days, allowing ≤30 days between fills. Sociodemographic and clinical characteristic variables were assessed as covariates of CIH therapy use. Among the full cohort, the CIH therapy use rate was 9.5%. Use increased with each cohort entry year relative to 2017. In a multivariable model, variables associated with greater odds of CIH therapy use included being female, having a musculoskeletal pain condition, obesity, opioid use disorder, anxiety, depression, post-traumatic stress disorder, and receiving services in a flagship site. Lower odds of use were associated with being older, unmarried, prescribed higher opioid doses, smoking, and rural residence. CIH therapy use has increased over time, consistent with national trends; however, differential patterns of exposure suggest the need to explore pathways to use. These may elucidate opportunities to broaden access to these evidence-based therapies for patients with chronic pain.

Nocturia (i.e., waking to void during the primary sleep period) of two or more times per night affects nearly one-third of older adults and can have a severe impact on sleep, contributing to insomnia symptoms. Current treatment approaches for nocturia often overlook non-lower urinary tract factors that may contribute to nighttime awakenings. Nocturia management, for example, may benefit from more effective integration of cognitive behavioral therapy for insomnia (CBT-I) principles that address other factors underlying insomnia symptoms, and early evidence suggests it also reduces nocturia and the bother it causes. Because nocturia treatment crosses specialties, coordinated delivery of urological and sleep therapies is a treatment barrier. The overall purpose of this trial is to determine whether a promising coordinated, integrated behavioral, non-pharmacological, non-surgical treatment that simultaneously addresses both the urological and insomnia factors contributing to nocturia is efficacious for improving nocturia, sleep, and daytime function. This multicenter parallel-group randomized, efficacy trial compares a 5-week integrated behavioral treatment program delivered by a single interventionist (psychologist, nurse practitioner, or physician assistant) to a health education control program in adults aged 60years or older (proposed n = 192) recruited from sites in Atlanta and Los Angeles, who report typically getting up to urinate two or more times per night (International Consultation on Incontinence Questionnaire-Overactive bladder [ICIQ-OAB] nocturia item) and insomnia symptoms (Insomnia Severity Index > 7). The integrated program includes components of CBT-I and pelvic floor muscle exercise-based behavioral therapy for nocturia. The primary outcome is ICIQ-OAB-measured nocturia frequency 4months after randomization. Secondary outcomes are sleep diary-measured wake after sleep onset (mean minutes) and Insomnia Severity Index total score. The interdisciplinary trial team has developed a program aimed at improving nocturia symptoms and overall sleep of older adults in an efficient and safe manner. The integrated behavioral program has the potential to address nocturia, which is a challenging symptom because it has many etiologies that cross multiple specialties. Findings will provide rigorous evidence of the efficacy of the integrated behavioral treatment program to reduce nocturia frequency as well as sleep disturbance in older adults. Clinicaltrials.gov NCT06110091, registered 10/25/2023.

Higher abundance of oral human papilloma virus (HPV), Porphyromonas gingivalis (Pg) and Fusobacterium nucleatum (Fn) correlate with worse survival of head and neck squamous cell carcinoma (HNSCC). One-third of males globally are HPV-positive, one-fifth have high-risk HPV-16 and is transmitted through oral sex. In our ex vivo clinical study of HNSCC patients, HPV ELISA detected viruses in 100% of saliva and 75% of oral-rinse samples (n = 44). Cell culture studies showed 1000-fold higher Pg/Fn in their saliva and 100-fold higher in oral-rinse samples than non-cancer control participants. Bean-lectin (FRIL) gum (trapped) aggregated 93% of HPV in saliva and 80% in oral-rinse samples in ELISA. Single dose of bean gum + protegrin-1 (antimicrobial peptide) reduced Pg/Fn > 99% in saliva and oral-rinse samples (n = 42). Although protegrin was effective against anaerobic Pg/Fn, it did not kill capsule forming bacteria including Streptococci, providing selectivity and protection of oral commensal bacteria. These findings from ex vivo clinical studies support potential value of advancing these biologics to clinical trials as adjuncts to current therapeutic strategies or as prophylaxis to control pathogenic microbes associated with HNSCC.

ABSTRACTIntroductionA non‐invasive test to accurately diagnose and quantify vocal fold (VF) scarring from other confounding pathologies would be advantageous to reduce the need for operative diagnostic laryngoscopy. Dynamic optical contrast imaging (DOCI) technology uses tissue autofluorescence to obtain real‐time information of tissue composition. In this study, we describe a novel application of DOCI to identify scar tissue formation in rabbit VFs.MethodsRabbits underwent endoscopic unilateral VF cordectomy to induce scar formation. After 2 months, VFs were excised and a bench‐top DOCI (UCLA) system was employed to capture images from sections. Results were verified with histologic staining for scar tissue.ResultsThe DOCI system was capable of distinguishing healthy VF from contralateral scarred VF with discriminating power at the 405 low‐pass filter (LPF), 440, 460–532, and 560–580 nm wavelengths (p < 0.05). All DOCI images of healthy and scarred VF sections correlated with histological assessment.ConclusionOur study demonstrated that DOCI technology can discriminate between normal and scarred VFs noninvasively and in real time with similar accuracy to that of histological analysis. This work lays the foundation for the development of a DOCI‐based endoscope for diagnosis and quantification of VF scar formation as well as a tool to measure treatment response.

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