Gunshot wound injury to the genitourinary tract: a 4-year retrospective review at an academic level 1 trauma center.

Background: Firearm injuries increased significantly during the coronavirus disease 2019 (COVID-19) pandemic. We aimed to describe our experience with patients admitted to a level 1 trauma center with gunshot-related trauma to the genitourinary (GU) tract before and during COVID-19 pandemic. Methods: Patients sustaining gunshot-related trauma to the adrenals, kidneys, ureters, bladder, scrotum, testicles, penis, and urethra between January 1, 2018 and December 31, 2021 were identified from our institutional trauma database. Patient charts were queried to extract demographic information, management, and follow-up. Results: A total of 117 patients met inclusion criteria with 39 (33%) of GU injuries occurring pre-COVID, and 78 (67%) occurring during or post-COVID. Seventy-two (62%) presented with kidney injury. Patients injured in the pre-COVID period were more likely to participate in a follow-up visit by 2.17 times at 60 days (P=0.017), 1.98 times at 90 days (P=0.030), and 2.04 times at 1-year (P=0.014) than during COVID. Pre-COVID, 46% of patients were injured in the city's northwestern region and 54% from other areas, during COVID 24% of patients came from the northwestern region compared to 76% from other areas (P=0.029). Conclusions: Gunshot wounds (GSW) involving the GU tract increased during the COVID-19 pandemic, with renal injury most frequent. Follow-up visits declined by around half during the pandemic, primarily at 60 days, 90 days, and 1 year post-injury. The number of patients admitted with urologic injuries pre-COVID versus during COVID was significantly different depending on the patient's area of residence. More work is needed to evaluate the outcomes of traumatic GU injuries due to GSW pre- and post-pandemic.

Irreversible electroporation augments ß-glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate ß-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment ß-glucan induced trained immunity in the treatment of PC. METHODS: ß-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. ß-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag-/- mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral ß-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral ß-glucan after IRE was evaluated by mass cytometry. RESULTS: IRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, ß-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered ß-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. ß-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered ß-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE. CONCLUSIONS: These data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.

A Tumor-admixture Model to Interrogate Immune Cell-dependent Tumorigenesis.

A rigorous determination of effector contributions of tumor-infiltrating immune cells is critical for identifying targetable molecular mechanisms for the development of novel cancer immunotherapies. A tumor/immune cell-admixture model is an advantageous strategy to study tumor immunology as the fundamental methodology is relatively straightforward, while also being adaptable to scale to address increasingly complex research queries. Ultimately, this method can provide robust experimental information to complement more traditional murine models of tumor immunology. Here, we describe a tumor/macrophage-admixture model using bone marrow-derived macrophages to investigate macrophage-dependent tumorigenesis. Additionally, we provide commentary on potential branch points for optimization with other immune cells, experimental techniques, and cancer types.

Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis.

Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of reprogramming pre-metastatic niche myeloid cells by inducing trained immunity with whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only to lipopolysaccharide but also to tumor-derived factors. WGP in vivo treatment led to a trained immunity phenotype in lung interstitial macrophages, resulting in inhibition of tumor metastasis and survival prolongation in multiple mouse models of metastasis. WGP-induced trained immunity is mediated by the metabolite sphingosine-1-phosphate. Adoptive transfer of WGP-trained bone marrow-derived macrophages reduced tumor lung metastasis. Blockade of sphingosine-1-phosphate synthesis and mitochondrial fission abrogated WGP-induced trained immunity and its inhibition of lung metastases. WGP also induced trained immunity in human monocytes, resulting in antitumor activity. Our study identifies the metabolic sphingolipid-mitochondrial fission pathway for WGP-induced trained immunity and control over metastasis.

The induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression.

Despite the remarkable success of immunotherapy in many types of cancer, pancreatic ductal adenocarcinoma has yet to benefit. Innate immune cells are critical to anti-tumor immunosurveillance and recent studies have revealed that these populations possess a form of memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, and metabolic reprograming. Here we demonstrate that yeast-derived particulate ß-glucan, an inducer of trained immunity, traffics to the pancreas, which causes a CCR2-dependent influx of monocytes/macrophages to the pancreas that display features of trained immunity. These cells can be activated upon exposure to tumor cells and tumor-derived factors, and show enhanced cytotoxicity against pancreatic tumor cells. In orthotopic models of pancreatic ductal adenocarcinoma, ß-glucan treated mice show significantly reduced tumor burden and prolonged survival, which is further enhanced when combined with immunotherapy. These findings characterize the dynamic mechanisms and localization of peripheral trained immunity and identify an application of trained immunity to cancer.

Lactate supports a metabolic-epigenetic link in macrophage polarization.

Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)­induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate­citrate lyase (ACLY) enzymatic activity. Notably, exogenous acetate rescues defective M2 polarization and histone acetylation following mitochondrial pyruvate carrier 1 (MPC1) inhibition or ACLY deficiency. Lastly, M2 macrophage­dependent tumor progression is impaired by conditional macrophage ACLY deficiency, further supporting a dominant role for glucose/lactate mitochondrial metabolism and histone acetylation in driving immune evasion. This work adds to our understanding of how mitochondrial metabolism affects macrophage functional phenotypes and identifies a unique tumor microenvironment (TME)­driven metabolic-epigenetic link in M2 macrophages.

A specific low-density neutrophil population correlates with hypercoagulation and disease severity in hospitalized COVID-19 patients.

SARS coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Although most COVID-19 cases are asymptomatic or involve mild upper respiratory tract symptoms, a significant number of patients develop severe or critical disease. Patients with severe COVID-19 commonly present with viral pneumonia that may progress to life-threatening acute respiratory distress syndrome (ARDS). Patients with COVID-19 are also predisposed to venous and arterial thromboses that are associated with a poorer prognosis. The present study identified the emergence of a low-density inflammatory neutrophil (LDN) population expressing intermediate levels of CD16 (CD16Int) in patients with COVID-19. These cells demonstrated proinflammatory gene signatures, activated platelets, spontaneously formed neutrophil extracellular traps, and enhanced phagocytic capacity and cytokine production. Strikingly, CD16Int neutrophils were also the major immune cells within the bronchoalveolar lavage fluid, exhibiting increased CXCR3 but loss of CD44 and CD38 expression. The percentage of circulating CD16Int LDNs was associated with D-dimer, ferritin, and systemic IL-6 and TNF-α levels and changed over time with altered disease status. Our data suggest that the CD16Int LDN subset contributes to COVID-19-associated coagulopathy, systemic inflammation, and ARDS. The frequency of that LDN subset in the circulation could serve as an adjunct clinical marker to monitor disease status and progression.

Optimizing the Combination of Immunotherapy and Trans-Arterial Locoregional Therapy for Stages B and C Hepatocellular Cancer.

Hepatocellular carcinoma (HCC), the most common primary hepatic malignancy worldwide, is the second leading cause of cancer-related death. Underlying liver dysfunction and advanced stage of disease require treatments to be optimally timed and implemented to minimize hepatic parenchymal damage while maximizing disease response and quality of life. Locoregional therapies (LRTs) such as trans-arterial chemo- and radio-embolization remain effective for intermediate liver-only and advanced HCC disease (i.e., Barcelona-Clinic liver cancer stages B and C) not amendable to primary resection or ablation. Additionally, these minimally invasive interventions have been shown to augment the immune system. This and the recent success of immune-oncologic treatments for HCC have generated interest in applying these therapies in combination with such locoregional interventions to improve patient outcomes and response rates. This report reviews the use of trans-arterial LRTs with immunotherapy for stages B and C HCC, potential biomarkers, and imaging methods for assessing the response and safety of such combinations.

Identifying Factors Predicting Prolonged Opioid Use After Mastectomy.

BACKGROUND: Women who undergo mastectomy for breast cancer may be prone to prolonged opioid use (POU). However, risk factors for long-term opioid use after mastectomy remain unclear. This study seeks to identify risk factors for POU after mastectomy. PATIENTS AND METHODS: A single-institution database was queried for women who underwent mastectomy for breast cancer between January 2016 and December 2017. Patients were stratified based on opioid use < 90 or ≥ 90 days after mastectomy or completion of their reconstruction. Clinicopathologic and operative parameters as well as preoperative and postoperative opioid usage were compared. RESULTS: Patients with opioid use ≥ 90 days after last procedure (POU) had a history of preoperative opioid use (29.3% vs 8.2%, p = 0.002), were more likely to have concomitant psychiatric illness (70% vs 35.6%, p < 0.001), and had received adjuvant chemotherapy (43.1% vs 24.7%, p = 0.03). Patients with POU also had greater daily opioid doses prescribed upon discharge (59.6 mg vs 44.6 mg, p < 0.001). On multivariable analysis, preoperative opioid use (OR 3.61, 95% CI 1.16-11.22, p = 0.03), daily oral morphine equivalents prescribed at discharge (OME-D) (OR 1.02, 95% CI 1.01-1.05, p = 0.003), and psychiatric illness (OR 4.48, 95% CI 1.85-10.89, p < 0.001) were independently associated with POU. Among opioid-naïve patients, 37% were found to have POU. Among these patients, OME at discharge (OR 1.02, 95% CI 1.003-1.04, p = 0.02) and psychiatric illness (OR 3.23, 95% CI 1.25-8.31, p = 0.02) independently predicted POU. CONCLUSIONS: Preoperative opioid use, psychiatric illness, and daily OME at discharge independently predict POU after mastectomy.