Survival after live donor versus deceased donor liver transplantation: propensity score-matched study.

BACKGROUND: For individuals with advanced liver disease, equipoise in outcomes between live donor liver transplant (LDLT) and deceased donor liver transplant (DDLT) is uncertain. METHODS: A retrospective cohort study was performed using data extracted from the Scientific Registry of Transplant Recipients. Adults who underwent first-time DDLT or LTDL in the United States between 2002 and 2020 were paired using propensity-score matching with 1:10 ratio without replacement. Patient and graft survival were compared using the model for end-stage liver disease (MELD) score for stratification. RESULTS: After propensity-score matching, 31 522 DDLT and 3854 LDLT recipients were included. For recipients with MELD scores ≤15, LDLT was associated with superior patient survival (HR = 0.92; 95% c.i. 0.76 to 0.96; P = 0.013). No significant differences in patient survival were observed for MELD scores between 16 and 30. Conversely, for patients with MELD scores >30, LDLT was associated with higher mortality (HR 2.57; 95% c.i. 1.35 to 4.62; P = 0.003). Graft survival was comparable between the two groups for MELD ≤15 and for MELD between 21 and 30. However, for MELD between 16 and 20 (HR = 1.15; 95% c.i. 1.00 to 1.33; P = 0.04) and MELD > 30 (HR = 2.85; 95% c.i. 1.65 to 4.91; P = 0.001), graft survival was considerably shorter after LDLT. Regardless of MELD scores, re-transplantation rate within the first year was significantly higher after LDLT. CONCLUSIONS: In this large propensity score-matched study using national data, comparable patient survival was found between LDLT and DDLT in recipients with MELD scores between 16 and 30. Conversely, for patients with MELD > 30, LDLT was associated with worse outcomes. These findings underscore the importance of transplant selection for patients with high MELD scores.

Donor-recipient race-ethnicity concordance and patient survival after liver transplantation.

INTRODUCTION: We assessed the association between patient survival after liver transplantation (LT) and donor-recipient race-ethnicity (R/E) concordance. METHODS: The Scientific Registry of Transplant Recipients (SRTR) was retrospectively analyzed using data collected between 2002 and 2019. Only adults without history of prior organ transplant and recipients of LT alone were included. The primary outcome was patient survival. Donors and recipients were categorized into five R/E groups: White/Caucasian, African American/Black, Hispanic/Latino, Asian, and Others. Statistical analyses were performed using Kaplan-Meier survival curves and Cox Proportional Hazards models, adjusting for donor and recipient covariates. RESULTS: 85,427 patients were included. Among all the R/E groups, Asian patients had the highest 5-year survival (81.3%; 95% CI = 79.9-82.7), while African American/Black patients had the lowest (71.4%; 95% CI = 70.3-72.6) (P < 0.001). Lower survival rates were observed in recipients who received discordant R/E grafts irrespective of their R/E group. The fully adjusted hazard ratio for death was statistically significant in African American/Black (aHR 1.07-1.18-1.31; P < 0.01) and in White∕Caucasian patients (aHR 1.00-1.04-1.07; P = 0.03) in the presence of donor-recipient R/E discordance. CONCLUSION: Disparities in post-LT outcomes might be influenced by biological factors in addition to well-known social determinants of health.

Interaction between cold ischemia time and Kidney Donor Profile Index on postrenal transplant outcomes.

We analyzed whether there is an interaction between the Kidney Donor Profile Index (KDPI) and cold ischemia time (CIT) in recipients of deceased donor kidney transplant (KTs). Adults who underwent KTs in the United States between 2014 and 2020 were included and divided into 3 KDPI groups (≤20%, 21%-85%, >85%) and 4 CIT strata (<12, 12-17.9, 18-23.9, ≥24 hours). Multivariate analyses were used to test the interaction between KDPI and CIT for the following outcomes: primary graft nonfunction (PGNF), delayed graft function (DGF), estimated glomerular filtration rate (eGFR) at 6 and 12 months, patient survival, graft survival, and death-censored graft survival (DCGS). A total of 69,490 recipients were analyzed: 18,241 (26.3%) received a graft with KDPI ≤20%, 46,953 (67.6%) with KDPI 21%-85%, and 4,296 (6.2%) with KDPI >85%. Increasing KDPI and CIT were associated with worse post-KT outcomes. Contrary to our hypothesis, howerver, the interaction between KDPI and CIT was statistically significant only for PGNF and DGF and eGFR at 6 months. Paradoxically, the negative coefficient of the interaction suggested that increasing duration of CIT was more detrimental for low and intermediate-KDPI organs relative to high-KDPI grafts. Conversely, for mortality, graft survival, and DCGS, we found that the interaction between CIT and KDPI was not statistically significant. We conclude that, high KDPI and prolonged CIT are independent risk factors for inferior outcomes after KT. Their interaction, however, is statistically significant only for the short-term outcomes and more pronounced on low and intermediate-KDPI grafts than high-KDPI kidneys.

Living donor liver transplantation for colorectal cancer liver metastases: Midterm outcomes at a single center in North America.

In recent years, liver transplantation has emerged as a treatment for patients with stage IV colorectal liver metastases (CRLM). Given the limited number of available deceased donor grafts, the use of living donor liver transplantation (LDLT) can be an important option. We performed a retrospective analysis of 10 patients that underwent LDLT for CRLM at our institution. A total of 90% of patients were male, with median age of 58 years and median model for end-stage liver disease score of 11 (range: 6-32). The rectum was the most common primary location (40%). Synchronous liver tumors were found in 50%. Pretransplant patients underwent resection (60%), hepatic-artery infusion pumping (50%), and/or radiofrequency ablation (50%). Everybody underwent adjuvant chemotherapy. Median cold ischemia time was 103 minutes (range: 93-207 minutes), and median total OR time was 11.5 hours (range: 8.5-13.9 hours). In total, 30% of patients had postoperative complications requiring reoperation. Mean recurrence-free survival was 2.2 years (95% confidence interval, 1.2-3.2 years), and mean overall survival was 3.0 years (95% confidence interval, 2.5-3.6 years). In total, 30% of patients suffered a recurrence, and 90% of patients are currently alive. This study represents the largest single-center analysis in North America of patients undergoing LDLT for CRLM. LDLT is a safe and effective alternative for patients with CRLM who do not have progressive disease or extrahepatic metastasis.

Effects of the circulating environment of COVID-19 on platelet and neutrophil behavior.

Introduction: Thromboinflammatory complications are well described sequalae of Coronavirus Disease 2019 (COVID-19), and there is evidence of both hyperreactive platelet and inflammatory neutrophil biology that contributes to the thromoinflammatory milieu. It has been demonstrated in other thromboinflammatory diseases that the circulating environment may affect cellular behavior, but what role this environment exerts on platelets and neutrophils in COVID-19 remains unknown. We tested the hypotheses that 1) plasma from COVID-19 patients can induce a prothrombotic platelet functional phenotype, and 2) contents released from platelets (platelet releasate) from COVID-19 patients can induce a proinflammatory neutrophil phenotype. Methods: We treated platelets with COVID-19 patient and disease control plasma, and measured their aggregation response to collagen and adhesion in a microfluidic parallel plate flow chamber coated with collagen and thromboplastin. We exposed healthy neutrophils to platelet releasate from COVID-19 patients and disease controls and measured neutrophil extracellular trap formation and performed RNA sequencing. Results: We found that COVID-19 patient plasma promoted auto-aggregation, thereby reducing response to further stimulation ex-vivo. Neither disease condition increased the number of platelets adhered to a collagen and thromboplastin coated parallel plate flow chamber, but both markedly reduced platelet size. COVID-19 patient platelet releasate increased myeloperoxidasedeoxyribonucleic acid complexes and induced changes to neutrophil gene expression. Discussion: Together these results suggest aspects of the soluble environment circulating platelets, and that the contents released from those neutrophil behavior independent of direct cellular contact.

Systematic review and meta-analysis of open versus laparoscopy-assisted versus pure laparoscopic versus robotic living donor hepatectomy.

The value of minimally invasive approaches for living donor hepatectomy remains unclear. Our aim was to compare the donor outcomes after open versus laparoscopy-assisted versus pure laparoscopic versus robotic living donor hepatectomy (OLDH vs. LALDH vs. PLLDH vs. RLDH). A systematic literature review of the MEDLINE, Cochrane Library, Embase, and Scopus databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (up to December 8, 2021). Random-effects meta-analyses were performed separately for minor and major living donor hepatectomy. The risk of bias in nonrandomized studies was assessed using the Newcastle-Ottawa Scale. A total of 31 studies were included. There was no difference in donor outcomes after OLDH versus LALDH for major hepatectomy. However, PLLDH was associated with decreased estimated blood loss, length of stay (LOS), and overall complications versus OLDH for minor and major hepatectomy, but also with increased operative time for major hepatectomy. PLLDH was associated with decreased LOS versus LALDH for major hepatectomy. RLDH was associated with decreased LOS but with increased operative time versus OLDH for major hepatectomy. The scarcity of studies comparing RLDH versus LALDH/PLLDH did not allow us to meta-analyze donor outcomes for that comparison. There seems to be a marginal benefit in estimated blood loss and/or LOS in favor of PLLDH and RLDH. The complexity of these procedures limits them to transplant centers with high volume and experience. Future studies should investigate self-reported donor experience and the associated economic costs of these approaches.

The closing survival gap after liver transplantation for hepatocellular carcinoma in the United States.

BACKGROUND: Socio-economic inequalities among different racial/ethnic groups have increased in many high-income countries. It is unclear, however, whether increasing socio-economic inequalities are associated with increasing differences in survival in liver transplant (LT) recipients. METHODS: Adults undergoing first time LT for hepatocellular carcinoma (HCC) between 2002 and 2017 recorded in the Scientific Registry of Transplant Recipients (SRTR) were included and grouped into three cohorts. Patient survival and graft survival stratified by race/ethnicity were compared among the cohorts using unadjusted and adjusted analyses. RESULTS: White/Caucasians comprised the largest group (n=9,006, 64.9%), followed by Hispanic/Latinos (n=2,018, 14.5%), Black/African Americans (n=1,379, 9.9%), Asians (n=1,265, 9.1%) and other ethnic/racial groups (n=188, 1.3%). Compared to Cohort I (2002-2007), the 5-year survival of Cohort III (2012-2017) increased by 18% for Black/African Americans, by 13% for Whites/Caucasians, by 10% for Hispanic/Latinos, by 9% for patients of other racial/ethnic groups and by 8% for Asians (All P values<0.05). Despite Black/African Americans experienced the highest survival improvement, their overall outcomes remained significantly lower than other ethnic∕racial groups (adjusted HR for death=1.20; 95%CI 1.05-1.36; P=0.005; adjusted HR for graft loss=1.21; 95%CI 1.08-1.37; P=0.002). CONCLUSION: The survival gap between Black/African Americans and other ethnic/racial groups undergoing LT for HCC has significantly decreased over time. However, Black/African Americans continue to have the lowest survival among all racial/ethnic groups.

Function and longevity of renal grafts from high-KDPI donors.

BACKGROUND: High kidney-donor profile index (KDPI) kidneys have a shorter survival than grafts with lower KDPI values. It is still unclear, however, whether their shorter longevity depends on an inferior baseline function, faster functional decline, or the combination of both. METHODS: We analyzed the estimated glomerular filtration rate (eGFR) of 605 consecutive recipients of deceased donor kidney transplants (KT) at 1, 3, 6, 12, 18, 24, 36, 48, and 60 months. Comparisons were performed among four groups based on KDPI quartile: Group I-KDPI ≤ 25% (n = 151), Group II-KDPI 26-50% (n = 182), Group III-KDPI 51-75% (n = 176), and Group IV-KDPI 〉 75% (n = 96). Linear mixed model analysis was subsequently used to assess whether KDPI was independently associated with the decline in eGFR during the first 5-years after KT. We also analyzed the incidence of delayed graft function (DGF), rejection within the first year after KT, patient survival, graft survival, and death censored graft survival based on KDPI group. FINDINGS: High-KDPI grafts had lower eGFR immediately after KT, had a higher incidence of DGF and rejection. However, there were no signifcant differences in the adjusted rate (slope) of decline in eGFR among the four KDPI groups (P = .06). Although patient survival was signigicantly lower for recipients of high-KDPI grafts, death-censored graft survival was similar among the four KDPI groups (P = .33). CONCLUSIONS: The shorter functional survival of high-KDPI grafts seems to be due to their lower baseline eGFR rather than a more rapid functional decline after KT.

The Role of Neutrophils as a Driver in Hepatic Ischemia-Reperfusion Injury and Cancer Growth.

The innate immune system plays an essential role in the response to sterile inflammation and its association with liver ischemia and reperfusion injury (IRI). Liver IRI often manifests during times of surgical stress such as cancer surgery or liver transplantation. Following the initiation of liver IRI, stressed hepatocytes release damage-associated molecular patterns (DAMPs) which promote the infiltration of innate immune cells which then initiate an inflammatory cascade and cytokine storm. Upon reperfusion, neutrophils are among the first cells that infiltrate the liver. Within the liver, neutrophils play an important role in fueling tissue damage and tumor progression by promoting the metastatic cascade through the formation of Neutrophil Extracellular Traps (NETs). NETs are composed of web-like DNA structures containing proteins that are released in response to inflammatory stimuli in the environment. Additionally, NETs can aid in mediating liver IRI, promoting tumor progression, and most recently, in mediating early graft rejection in liver transplantation. In this review we aim to summarize the current knowledge of innate immune cells, with a focus on neutrophils, and their role in mediating IRI in mouse and human diseases, including cancer and transplantation. Moreover, we will investigate the interaction of Neutrophils with varying subtypes of other cells. Furthermore, we will discuss the role and different treatment modalities in targeting Neutrophils and NETs to prevent IRI.

Role of Immuno-Inflammatory Signals in Liver Ischemia-Reperfusion Injury.

Ischemia reperfusion injury (IRI) is a major obstacle in liver resection and liver transplantation. The initial step of IRI is mediated through ischemia which promotes the production of reactive oxygen species in Kupffer cells. This furthermore promotes the activation of pro-inflammatory signaling cascades, including tumor necrosis factor-alpha, IL-6, interferon, inducible nitric oxide synthase, TLR9/nuclear-factor kappa B pathway, and the production of damage-associated molecular patterns (DAMPs), such as ATP, histone, high mobility group box 1 (HMGB1), urate, mitochondrial formyl peptides and S100 proteins. With ongoing cell death of hepatocytes during the ischemic phase, DAMPs are built up and released into the circulation upon reperfusion. This promotes a cytokines/chemokine storm that attracts neutrophils and other immune cells to the site of tissue injury. The effect of IRI is further aggravated by the release of cytokines and chemokines, such as epithelial neutrophil activating protein (CXCL5), KC (CXCL1) and MIP-2 (CXCL2), the complement proteins C3a and C5a, mitochondrial-derived formyl peptides, leukotriene B4 and neutrophil extracellular traps (NETs) from migrating neutrophils. These NETs can also activate platelets and form Neutrophil-platelet microthrombi to further worsen ischemia in the liver. In this review we aim to summarize the current knowledge of mediators that promote liver IRI, and we will discuss the role of neutrophils and neutrophil extracellular traps in mediating IRI.

Treatment modalities and long-term outcomes of hepatic hemangioendothelioma in the United States.

BACKGROUND: We analyzed the outcomes of patients with hepatic epithelioid hemangioendothelioma (HEHE) in the United States after stratification by their most definitive treatment. METHODS: The National Cancer Data Base was used to identify patients with HEHE between 2004 and 2018. Patients were divided in four treatment groups: no surgical therapy, ablation, liver resection or liver transplantation. Demographics and clinical characteristics were compared, and Kaplan Meier functions and Cox-regression were used for unadjusted and adjusted survival analyses. RESULTS: Among a total of 334 patients, 218 (65.2%) were managed non-surgically, 74 (22.1%) underwent hepatic resections, 35 (10.4%) underwent liver transplantation and 7 (2.1%) underwent ablations. The overall median survival was 111 months (95%CI 73-149) after liver transplantation, 69 months (95%CI 45-92) after hepatic resection, 38 months (95%CI 0-78) after ablation and 80 months (95%CI 70-90) for patients managed by watchful waiting (P < 0.001). After adjustment, patients who underwent liver transplantation were found to have a better survival when compared to other therapies (Hazard Ratio: 0.61, 95% Confidence Interval: 0.38-0.97, p = 0.035). CONCLUSIONS: This study reports the outcomes of the largest cohort of patients with HEHE. The longest survival was observed after liver transplantation, followed by non-surgical management and hepatic resection. Because of selection bias, future studies to better characterize what criteria should be used for the selection of treatment modalities for HEHE are urgently needed.

Readmission After Surgical Resection and Transplantation for Hepatocellular Carcinoma: A Retrospective Cohort Study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. Liver resections and transplantations have increasingly become feasible options for potential cure. These complex surgeries are inherently associated with increased rates of readmission. In the meanwhile, hospital readmission rates are rapidly becoming an important quality of care metric. Therefore, it is very important to understand the effect of 30-day readmission on mortality and the factors associated with increased 30- and 90-day mortality rates. METHODS: This is a retrospective cohort study utilizing data from the National Cancer Database. Patients included were 18 years or older who underwent liver resection or liver transplantation for HCC between 2003 and 2011. Our primary outcomes of interest were 30- and 90-day mortality rates. Our primary independent variable of interest was 30-day readmission. RESULTS: 16 658 patients underwent either a liver resection or transplantation for HCC between 2003 and 2011. For patients with liver transplantations, increased readmission rates were associated with lower risks of 30-day mortality (P = .012) but a trend toward higher 90-day mortality (P = .057). Patients who underwent liver resection for HCC also demonstrated increased readmission rates to be associated with lower risk of 30-day mortality (P = .014) but higher 90-day mortality (P ≤ .001). CONCLUSION: This is the only study to utilize a national database to investigate the association between readmission rates and mortality rates of both liver transplantations and resections for patients with HCC. We demonstrate 30-day readmission to show no increase in 30-day mortality, but rather higher 90-day mortality.

Efficacy of a Nasogastric Tube Educational Intervention for Nursing Staff.

AIM: We performed a single-center teaching intervention with nursing providers on nasogastric tube (NG tube) clinical practice. The initial purpose of this study was the validation of whether the training was sufficient enough to be retained at a later time point. METHODS: We performed a prospective pre-post study examining participants' knowledge before, immediately after, and 4 weeks after training in NG tube management. Training was delivered in face-to-face classroom sessions. Knowledge was assessed using a multiple-choice test (pretest, posttest #1and #2). RESULTS: A total of 137 nursing providers participated in the training intervention. Immediately after training (posttest #1) and again 4 weeks later (posttest #2), participants overwhelmingly recalled and retained the knowledge of NG tube management as compared to pretest results. Paired t-tests showed each participant increased their test score from pretest to posttest #1, t (134) = 12.64, P = .0001. Similarly, participants who took posttest #2 significantly improved their scores from the pretest to posttest #2, t (71) = 10.629, P < .0001. Secondary analysis showed that the NG tube management comfort level and age of provider were not significant in predicting test results. However, years of professional experience and frequency of NG tube care were significant predictors for higher test scores. CONCLUSION: To minimize the risk of NG tubes for patients, it is critical to follow clinical guidelines. This study shows that teaching interventions for providers to increase knowledge on NG tubes are beneficial. In addition, the knowledge is retained at later time points.

Readmission After Surgical Resection for Colon and Rectal Cancers: A Retrospective Cohort Study.

BACKGROUND: Colorectal adenocarcinoma is a leading cause of cancer mortality worldwide, often requiring patients to undergo anatomy-altering surgical interventions leading to increased postoperative readmission. Hospital readmission rates have been correlated with increased mortality. Therefore, it is important to understand the association between 30-day readmission rates and mortality as well as the factors associated with increased readmission rates. STUDY DESIGN: This is a retrospective review utilizing data from the National Cancer Database. Our primary outcomes of interest were 30- and 90-day mortality rates. Our primary independent variable of interest was 30-day readmission. RESULTS: Between 2010 and 2016, 207 299 patients underwent surgery for rectal cancer and 754 895 for colon cancer. The readmission rates within 30 days of discharge were 5.4% and 5.5% for patients after surgery for rectal or colon cancer, respectively. 30-day readmission was not associated with 30-day mortality, but it was independently associated with increased 90-day mortality and inferior long-term survival for both cohorts (P = .001). Independent risk factors significantly associated with increased readmission included race, non-private insurance, and low income. CONCLUSION: This study provides a large, up-to-date, and comprehensive analysis of readmission rates for colon and rectal cancers. We demonstrate that socioeconomic factors are associated with increased 30-day readmission. 30-day readmission is also independently associated with increased 90-day mortality as well as lower overall survival rates. Our study supports the need for implementation of programs that support patients of lower socioeconomic status undergoing surgery to further decrease readmission rates and mortality.

The Use of Machine Learning to Create a Risk Score to Predict Survival in Patients with Hepatocellular Carcinoma: A TCGA Cohort Analysis.

Introduction: Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver malignancies and is currently the fourth most common cause of cancer-related death worldwide. Due to varying underlying etiologies, the prognosis of HCC differs greatly among patients. It is important to develop ways to help stratify patients upon initial diagnosis to provide optimal treatment modalities and follow-up plans. The current study uses Artificial Neural Network (ANN) and Classification Tree Analysis (CTA) to create a gene signature score that can help predict survival in patients with HCC. Methods: The Cancer Genome Atlas (TCGA-LIHC) was analyzed for differentially expressed genes. Clinicopathological data were obtained from cBioPortal. ANN analysis of the 75 most significant genes predicting disease-free survival (DFS) was performed. Next, CTA results were used for creation of the scoring system. Cox regression was performed to identify the prognostic value of the scoring system. Results: 363 patients diagnosed with HCC were analyzed in this study. ANN provided 15 genes with normalized importance >50%. CTA resulted in a set of three genes (NRM, STAG3, and SNHG20). Patients were then divided in to 4 groups based on the CTA tree cutoff values. The Kaplan-Meier analysis showed significantly reduced DFS in groups 1, 2, and 3 (median DFS: 29.7 months, 16.1 months, and 11.7 months, p < 0.01) compared to group 0 (median not reached). Similar results were observed when overall survival (OS) was analyzed. On multivariate Cox regression, higher scores were associated with significantly shorter DFS (1 point: HR 2.57 (1.38-4.80), 2 points: 3.91 (2.11-7.24), and 3 points: 5.09 (2.70-9.58), p < 0.01). Conclusion: Long-term outcomes of patients with HCC can be predicted using a simplified scoring system based on tumor mRNA gene expression levels. This tool could assist clinicians and researchers in identifying patients at increased risks for recurrence to tailor specific treatment and follow-up strategies for individual patients.

Neutrophil Extracellular Traps (NETs) in Cancer Metastasis.

Metastasis is the leading cause of cancer related morbidity and mortality. The metastatic process involves several identifiable biological stages, including tumor cell dissemination, intravasation, and the extravasation of circulating cancer cells to facilitate colonization at a distant site. Immune cell infiltration and inflammation within the tumor microenvironment coincide with tumor progression and metastatic spread and are thought to be the key mediators of this complex process. Amongst many infiltrating cells, neutrophils have recently emerged as an important player in fueling tumor progression, both in animal models and cancer patients. The production of Neutrophil Extracellular Traps (NETs) is particularly important in the pathogenesis of the metastatic cascade. NETs are composed of web-like DNA structures with entangled proteins that are released in response to inflammatory cues in the environment. NETs play an important role in driving tumor progression both in experimental and clinical models. In this review, we aim to summarize the current advances in understanding the role of NETs in cancer, with a specific focus on their role in promoting premetastatic niche formation, interaction with circulating cancer cells, and in epithelial to mesenchymal transition during cancer metastasis. We will furthermore discuss the possible role and different treatment options for targeting NETs to prevent tumor progression.

Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment.

While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs in vivo by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4+ and CD8+ T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.

The Pathobiological Basis for Thrombotic Complications in COVID-19: a Review of the Literature.

Purpose of Review: COVID-19 has rapidly evolved into a global pandemic infecting over two hundred and forty-four million individuals to date. In addition to the respiratory sequelae and systemic infection that ensues, an alarming number of micro and macrovascular thrombotic complications have been observed. This review examines the current understanding of COVID-19-associated thrombotic complications, potential mechanisms, and pathobiological basis for thromboses development. Recent Findings: The endothelium plays a major role in the process due to direct and indirect injury. The immune system also contributes to a pro-thrombotic environment with immune cell dysregulation leading to excessive formation of cytokines, also called cytokine storm, and an eventual promotion of a hypercoagulable environment, known as immunothrombosis. Additionally, neutrophils play an important role by forming neutrophil extracellular traps, which are shown to be pro-thrombotic and further enhanced in COVID-19 patients. A disruption of the fibrinolysis system has also been observed. Summary: Multiple pathways likely contribute synergistically to form a pro-thrombotic milieu. A better understanding of these factors and the complex interplay between them will lead to the improvement of diagnostic and therapeutic interventions.

Impact of Metformin Use on Survival in Patients Undergoing Liver Resection for Colorectal Cancer Metastases.

INTRODUCTION: Resection of colorectal liver metastases provides the best chance for survival in patients with Stage IV colorectal cancer; however, hepatic recurrence is frequent and the main cause of death. Multiple epidemiological studies have documented an association between metformin and anti-neoplastic effects in a variety of cancers. Given the vast literature, we evaluated the incidence on recurrence and survival of patients on metformin who undergo surgery for colorectal liver metastasis (CRLM). METHODS: We selected 270 consecutive patients with known CRLM who underwent hepatic metastases resection at our institution between January 1st 2012 and December 31st 2019. Patients were divided based on their use of metformin (n = 62) or no metformin (n = 208). Adjusted analysis of recurrence-free (RFS) and overall survival (OS) was performed. RESULTS: Patients on metformin had significantly longer RFS (HR: .44, 95% CI: .26-.75, P < .002; Median RFS: 49 months vs 33 months) and OS (HR .60, 95% CI .31-.97, P < .048, Median OS: 72 months vs 60 months). Additional factors associated with shorter RFS on univariate analysis included the following: CEA > 200 ng/ml (HR: 2.23, 95% CI 1.21-4.03, P < .010), positive liver margin (HR: 3.70, 95% CI 2.27-6.03, P < .001), and >1 tumor (HR: 1.98, 95% CI 1.26-3.09, P < .003). Liver margin remained a significant factor for predicting shorter OS (HR: 4.99, 95% CI 2.49-10.0, P < .001). CONCLUSION: In this study, we found that patients with CRLM on metformin have prolonged RFS and OS postliver resection. Further prospective randomized trials need to be carried out to evaluate the anti-neoplastic effect of metformin in diabetic and non-diabetic cancer patients.