Beyond the Expected: Evaluating Preoperative Predictors of a Difficult Cholecystectomy Aboard the USNS Comfort.

Mini abstract Typical preoperative markers of a difficult laparoscopic cholecystectomy did not apply during the US Naval ShipComfort Deployment in 2019. This prospective study reveals the importance of preparedness for short-term surgical missions, the impact of health care disparities on the severity of disease, and the need for deliberate and thoughtful engagement with host-nation partners.

Evaluation of a Military Global Health Engagement Mission for Critical Wartime Surgical Specialty Readiness.

INTRODUCTION: Surgical volume at Military Treatment Facilities (MTFs) has been gradually decreasing for roughly the past 2 decades. The Knowledge, Skills, and Abilities (KSA) Clinical Readiness Program linked surgical volume and readiness using a tool known as the KSA metric. However, the extent to which military medical missions contribute to the readiness of critical wartime specialties has not been evaluated using this metric. METHODS: In this study, a retrospective analysis was conducted using the surgical case logs from the US Naval Ship (USNS) Comfort missions in 2018 and 2019. The comprehensive case log data were categorized by year, surgeon, procedure, and location. The analysis focused on providing detailed descriptive statistics, including percentages pertaining to the types of procedures performed during these missions. The 2018 mission was 11 weeks in duration, and supported activities in Ecuador, Peru, Colombia, and Honduras. The USNS Comfort mission in 2019 lasted 6 months (June-November 2019), and visited 12 countries in Central America, South America, and the Caribbean. RESULTS: The 2019 mission case log, spanning 6 months, was evaluated using the KSA score in order to assess readiness and compare against 6 months of MTF KSA values within the same calendar year. In 2019, the orthopedic surgeon aboard the USNS Comfort had a total KSA score of 44,006, but the 6-month USNS Comfort mission only contributed 5,364 points (12% of the annual score). The general surgery practice aboard the USNS Comfort produced lower KSA scores compared to each surgeon's respective MTF practice (Table III). Analyzing the cases logged by general surgeons also highlights minimal surgical diversity during these missions, with more than 90% of cases being hernia repairs or laparoscopic cholecystectomies (Table I). In addition, 35% of total procedures performed in 2018 and 2019 were performed laparoscopically. CONCLUSIONS: The analysis of operative data from the 2019 USNS Comfort mission, in comparison with the surgeons' work at their respective MTFs, reveals limited benefit in the ability of hospital-ship missions to bolster surgical readiness as measured by the KSA score. However, this is not a reflection on the value of Global Health Engagement (GHE) itself but a review of the way in which it is leveraged to support surgical readiness. Military surgeons participate in GHE as part of a larger strategy to strengthen relationships with partner nations, improve military medical force interoperability, and bolster partner nation medical capacity and capabilities. The KSA score offers an excellent tool to compare readiness metrics across significantly different GHE missions, and facilitates the opportunity for future prospective studies to improve case volume, diversity, and ultimately readiness.

Radiotherapy Cooperates with IL15 to Induce Antitumor Immune Responses.

Focal radiotherapy can promote cross-presentation of tumor antigens to T cells, but by itself, it is insufficient to induce therapeutically effective T-cell responses. The common gamma-chain cytokine IL15 promotes and sustains the proliferation and effector function of CD8+ T cells but has limited activity against poorly immunogenic tumors that do not elicit significant spontaneous T-cell responses. Here, we show that radiotherapy and subcutaneous IL15 had complementary effects and induced CD8+ T-cell-mediated tumor regression and long-term protective memory responses in two mouse carcinoma models unresponsive to IL15 alone. Mechanistically, radiotherapy-induced IFN type I production and Batf3-dependent conventional dendritic cells type 1 (cDC1) were required for priming of tumor-specific CD8+ T cells and for the therapeutic effect of the combination. IL15 cooperated with radiotherapy to activate and recruit cDC1s to the tumor. IL15 alone and in complex with a hybrid molecule containing the IL15α receptor have been tested in early-phase clinical trials in patients with cancer and demonstrated good tolerability, especially when given subcutaneously. Expansion of natural killer (NK) cells and CD8+ T cells was noted, without clear clinical activity, suggesting further testing of IL15 as a component of a combinatorial treatment with other agents. Our results provide the rationale for testing combinations of IL15 with radiotherapy in the clinic.

Invariant natural killer T cells regulate anti-tumor immunity by controlling the population of dendritic cells in tumor and draining lymph nodes.

BACKGROUND: Invariant natural killer T (iNKT) cells are CD1d-restricted T cells, which respond rapidly to antigen recognition and promote development of anti-tumor immunity in many tumor models. Surprisingly, we previously found that mice deficient in iNKT cells developed spontaneous CD8(+) T cells responses partially effective at inhibiting metastases in mice bearing the 4T1 mammary carcinoma, and showed a markedly improved response to treatment with local radiotherapy and anti-CTLA-4 antibody compared to wild type (WT) mice. METHODS: To understand the mechanisms of the immunosuppressive function of iNKT cells, dendritic cells (DCs) were analyzed by immunohistochemistry and flow cytometry in WT and iNKT-deficient (iNKT(-/-)) mice. The effects of antibody-mediated blockade of CD1d on DC number and phenotype, priming of anti-tumor T cells, and tumor response to treatment with local radiotherapy and anti-CTLA-4 antibody were evaluated. To determine if the improved response to treatment in the absence of iNKT cells was independent from the immunotherapy employed, 4T1-tumor bearing WT and iNKT(-/-) mice were treated with local radiotherapy in combination with antibody-mediated CD137 co-stimulation. RESULTS: DCs in 4T1 tumors and tumor-draining lymph nodes but not distant lymph nodes were significantly reduced in WT mice compared to iNKT(-/-) mice (p < 0.05), suggesting the selective elimination of DCs cross-presenting tumor-associated antigens by iNKT cells. Consistently, priming of T cells to a tumor-specific CD8 T cell epitope in mice treated with radiotherapy and anti-CTLA-4 or anti-CD137 was markedly enhanced in iNKT(-/-) compared to WT mice. CD1d blockade restored the number of DC in WT mice, improved T cell priming in draining lymph nodes and significantly enhanced response to treatment. CONCLUSIONS: Here we describe a novel mechanism of tumor immune escape mediated by iNKT cells that limit priming of anti-tumor T cells by controlling DC in tumors and draining lymph nodes. These results have important implications for the design of immunotherapies targeting iNKT cells.

Invariant NKT cells as novel targets for immunotherapy in solid tumors.

Natural killer T (NKT) cells are a small population of lymphocytes that possess characteristics of both innate and adaptive immune cells. They are uniquely poised to respond rapidly to infection and inflammation and produce cytokines that critically shape the ensuing adaptive cellular response. Therefore, they represent promising therapeutic targets. In cancer, NKT cells are attributed a role in immunosurveillance. NKT cells also act as potent activators of antitumor immunity when stimulated with a synthetic agonist in experimental models. However, in some settings, NKT cells seem to act as suppressors and regulators of antitumor immunity. Here we briefly review current data supporting these paradoxical roles of NKT cells and their regulation. Increased understanding of the signals that determine the function of NKT cells in cancer will be essential to improve current strategies for NKT-cell-based immunotherapeutic approaches.