Systemic versus localized Bacillus Calmette Guérin immunotherapy of bladder cancer promotes an anti-tumoral microenvironment: Novel role of trained immunity.

Treatment for higher-risk non-muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG); however, disease recurrence and progression occur frequently. Systemic immunity is critical for successful cancer immunotherapy; thus, recurrence of NMIBC may be due to suboptimal systemic activation of anti-tumor immunity after local immunotherapy. We previously reported that systemically acquired trained immunity (a form of innate immune memory) in circulating monocytes is associated with increased time-to-recurrence in patients with NMIBC treated with BCG. Herein, we used a mouse model of NMIBC to compare the effects of intravesical versus intravenous (systemic) BCG immunotherapy on the local and peripheral immune microenvironments. We also assessed whether BCG-induced trained immunity modulates anti-tumor immune responses. Compared with intravesical BCG, which led to a tumor-promoting immune microenvironment, intravenous BCG resulted in an anti-tumoral bladder microenvironment characterized by increased proportions of cytotoxic T lymphocytes (CTLs), and decreased proportions of myeloid-derived suppressor cells. Polarization toward anti-tumoral immunity occurred in draining lymph nodes, spleen, and bone marrow following intravenous versus intravesical BCG treatment. Pre-treatment with intravesical BCG was associated with increased rate of tumor growth compared with intravenous BCG pre-treatment. Trained immunity contributed to remodeling of the tumor immune microenvironment, as co-instillation of BCG-trained macrophages with ovalbumin-expressing bladder tumor cells increased the proportion of tumor-specific CTLs. Furthermore, BCG-trained dendritic cells exhibited enhanced antigen uptake and presentation and promoted CTL proliferation. Our data support the concept that systemic immune activation promotes anti-tumor responses, and that BCG-induced trained immunity is important in driving anti-tumor adaptive immunity.

Feasibility of Live Video Feed Transmission from Unmanned Aerial Vehicles for Medical Surveillance During the 2022 Montreal Marathon.

INTRODUCTION: In recent years, unmanned aerial vehicles (UAVs) have been increasingly used for medical surveillance purposes in mass-gathering events. No studies have investigated the reliability of live video transmission from UAVs for accurate identification of distressed race participants in need of medical attention. The aim of this study was to determine the proportion of time during which live medical surveillance UAV video feed was successfully transmitted and considered of sufficient quality to identify acute illness in runners participating in the 2022 Montreal Marathon (Canada). METHODS: Four UAVs equipped with high-resolution cameras were deployed at two pre-defined high-risk areas for medical incidents located within the last 500 meters of the race. The video footage was transmitted in real-time during four consecutive hours to a remote viewing station where four research assistants monitored it on large screens. Interruptions in live feed transmission and moments with inadequate field of view (FOV) on runners were documented. RESULTS: On September 25, 2022, a total of 6,916 athletes ran during the Montreal Marathon and Half Marathon. Out of the eight hours of video footage analyzed (four hours per high-risk area), 91.7% represented uninterrupted live video feed with an adequate view of the runners passing through the high-risk areas. There was a total of 18 live feed interruptions leading to a total interruption time of 22 minutes and 19 seconds (median interruption time of 32 seconds) and eight distinct moments with inadequate FOV on runners which accounted for 17 minutes and 33 seconds (median of 1 minute 47 seconds per moments with inadequate FOV). Active surveillance of drone-captured footage allowed early identification of two race participants in need of medical attention. Appropriate resources were dispatched, and UAV repositioning allowed for real-time viewing of the medical response. CONCLUSION: Live video transmission from UAVs for medical surveillance of runners passing through higher risk segments of a marathon for four consecutive hours is feasible. Live feed interruptions and moments with inadequate FOV could be minimized through practice and additional equipment redundancy.

Association of Histone H3 Trimethylation in Circulating Monocytes with Lack of Early Recurrence in Patients with Bladder Cancer following BCG Induction Therapy.

BACKGROUND: The mode of action of Bacillus Calmette-Guérin (BCG) in the treatment of patients with non-muscle invasive bladder cancer (NMIBC) is incompletely understood, but recent studies support an association between BCG-induced trained immunity in circulating monocytes and disease-free survival. OBJECTIVE: We compared epigenetic profiles in monocytes from NMIBC patients with early disease recurrence with those from recurrence-free patients. METHODS: We conducted chromatin immunoprecipitation and DNA sequencing (ChIP-seq) on monocytes from seven patients treated with BCG (four with early recurrences and three recurrence-free after one year) to determine genome-wide distribution and abundance of histone 3 lysine 4 trimethylation (H3K4me3) prior to and after five weeks of induction therapy. RESULTS: Genome-wide H3K4me3 profiles before or after BCG induction distinguished patients with early recurrences from those remaining recurrence-free. Furthermore, H3K4me3 levels at genes involved in specific pathways were increased in the recurrence-free group. Independent quantification showed increased H3K4me3 levels in elements of the Wnt and AMPK signaling pathways in the recurrence-free group before BCG initiation, while elements of the MAPK showed increased levels after five weeks of induction in the same group. Validation of these genes on an independent cohort of four additional patients that remained recurrence-free after one year and three with early recurrences revealed consistent increases in H3K4me3 levels associated with MAPK pathway genes after five weeks of BCG treatment in the recurrence-free group. CONCLUSIONS: Recurrence-free survival following BCG immunotherapy for NMIBC is associated with the accumulation of H3K4me3 at specific gene loci, and could lead to identification of prognostic biomarkers.

Prolonged Impact of COVID-19 on Job Prospects and Training for Pediatric Gastroenterology Fellows in North America.

As the COVID-19 pandemic persisted into the 2020 to 2021 academic year, there was a continued effect on graduate medical education trainees and graduating trainee job attainment. Our survey aims to investigate how the pandemic has continued to affect job search and attainment for pediatric gastroenterology fellows as well as to re-evaluate the pandemic's impact on pediatric gastroenterology fellow educational experiences. Methods: An anonymous survey was distributed to all North American pediatric gastroenterology fellows from May to June 2021. Survey questions included topics related to job search and fellowship training and were tailored to respondent year of training. Results: Of 453 pediatric gastroenterology fellows in the 2020 to 2021 academic year, 158 fellows (35%) responded to the survey. Of graduating fellow respondents with job contracts, 74% reported willingness to make compromises in their job search, 76% reported accepting academic positions that were primary clinical, and 42% estimated staying at their accepted job for less than 5 years. When asked about the impact of COVID-19 on various aspects of fellowship education, a negative impact was reported in the following areas: 76% in research, 94% in clinical experience, 73% in procedural skills, and 84% in didactics. Conclusion: The COVID-19 pandemic continues to make a significant impact on pediatric gastroenterology fellowship education and the job attainment process. Regarding accepted job positions, we found substantial willingness to compromise, a shorter duration to stay at the job than expected, and minimal research focus. This raises concern regarding job preparedness and satisfaction as fellows complete their medical training.

Filling in the "GAPPS": an unusual presentation of a child with gastric adenocarcinoma and proximal polyposis of the stomach.

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS) is a very rare gastric polyposis syndrome characterized by numerous polyps of the gastric fundus and body. We present the unusual case of a 10-year-old Polish-American male with history of eosinophilic esophagitis, who was found to have multiple fundic gland polyps (FGP) with low grade dysplasia on esophagogastroduodenoscopy. Subsequent evaluation including genetic testing confirmed the diagnosis of GAPPS, and after exhaustive multidisciplinary consultation the decision was made to proceed with prophylactic total gastrectomy given the markedly increased risk of gastric adenocarcinoma in GAPPS patients. To our knowledge, this represents the youngest patient diagnosed with GAPPS and the youngest patient who has undergone prophylactic gastrectomy for this disease at age 8 and 10 years, respectively. The pathophysiology, presentation, and treatment of GAPPS in a pediatric patient are discussed.

Tissue-Resident and Recruited Macrophages in Primary Tumor and Metastatic Microenvironments: Potential Targets in Cancer Therapy.

Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast to recruited macrophages originating from marrow precursors, tissue-resident macrophages are seeded before birth and function to coordinate tissue remodeling and maintain tissue integrity and homeostasis. Both recruited and tissue-resident macrophage populations contribute to tumor growth and metastasis and are important mediators of resistance to chemotherapy, radiation therapy, and immune checkpoint blockade. Thus, targeting various macrophage populations and their tumor-promoting phenotypes holds therapeutic promise. Here, we discuss various macrophage populations as regulators of tumor progression, immunity, and immunotherapy. We provide an overview of macrophage targeting strategies, including therapeutics designed to induce macrophage depletion, impair recruitment, and induce repolarization. We also provide a perspective on the therapeutic potential for macrophage-specific acquisition of trained immunity as an anti-cancer agent and discuss the therapeutic potential of exploiting macrophages and their traits to reduce tumor burden.

Black/African American Patients with Pediatric Crohn's Disease Report Less Anxiety and Fatigue than White Patients.

OBJECTIVES: To compare patient-reported outcomes in black/African American patients with white patients participating in IBD Partners Kids & Teens, in order to identify possible racial healthcare disparities in pediatric inflammatory bowel disease (IBD) as future targets for improvement. STUDY DESIGN: This was a cross-sectional analysis comparing patient-reported outcomes in black/African American patients with white patients, aged 9-18 years, with IBD participating in the IBD Partners Kids & Teens cohort from August 2013 to April 2018. Secondary outcomes included number of IBD-related hospitalizations and surgeries, current medication use, and disease activity. RESULTS: We included 401 patients with Crohn's disease (white = 378 [94%]; black/African American = 23 [6%]). For children with Crohn's disease, black/African American patients compared with white patients reported less anxiety (40.7 vs 47.5, P = .001) and fatigue (44.3 vs 48.4, P = .047) despite more frequently reported treatment with biologics (91% vs 61%, P = .006) and antibiotics (17% vs 5%, P = .03) and history of hospitalizations (81% vs 52%, P = .02). CONCLUSIONS: Black/African American children with Crohn's disease were less likely to report anxiety or fatigue than white patients, despite an apparent more severe disease course reflected by greater reported frequency of treatment with biologics and antibiotics and history of hospitalizations.