Intrahepatic cholangiocarcinoma: how do hepatectomy outcomes compare to liver metastases and hepatocellular carcinoma?

BACKGROUND: The incidence of intrahepatic cholangiocarcinoma (ICC) continues to rise, and hepatectomy is the only cure. Perioperative outcomes following hepatectomy for colorectal liver metastases (CRLM) and hepatocellular carcinoma (HCC) are better described than for ICC. The aim was to compare post-hepatectomy outcomes for ICC to CRLM and HCC. METHODS: The 2014-2020 ACS NSQIP hepatectomy PUF was utilized. Patients with ICC, CRLM, and HCC were identified and others excluded. Demographic, disease, and procedural characteristics were collected. Univariable and multivariable analyses (Chi-Square for categorical variables; Kruskal-Wallis for continuous variables) were performed for mortality, serious morbidity, bile leak, post-hepatectomy liver failure (PHLF), and 30-day readmission. RESULTS: 17,789 patients underwent hepatectomy including 2377 for ICC, 10,195 for CRLM, and 5217 for HCC. Patients undergoing hepatectomy for ICC vs. HCC vs. CRLM were noted to have higher 30-day mortality (4.8% vs. 2.5% vs. 1.0%, respectively p < 0.05). ICC was associated with higher overall and serious morbidity, bile leak, severe PHLF, and readmission. Multivariable analyses confirmed higher odds ratios for mortality and morbidity (p < 0.05) in patients with ICC. CONCLUSION: Hepatectomy for ICC is associated with worse short-term outcomes than for CRLM or HCC. Surgeons should be aware of these risks during surgical planning.

The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) represents a typical inflammation-associated cancer. Tissue resident innate lymphoid cells (ILCs) have been suggested to control tumour surveillance. Here, we studied how the local cytokine milieu controls ILCs in HCC. DESIGN: We performed bulk RNA sequencing of HCC tissue as well as flow cytometry and single-cell RNA sequencing of enriched ILCs from non-tumour liver, margin and tumour core derived from 48 patients with HCC. Simultaneous measurement of protein and RNA expression at the single-cell level (AbSeq) identified precise signatures of ILC subgroups. In vitro culturing of ILCs was used to validate findings from in silico analysis. Analysis of RNA-sequencing data from large HCC cohorts allowed stratification and survival analysis based on transcriptomic signatures. RESULTS: RNA sequencing of tumour, non-tumour and margin identified tumour-dependent gradients, which were associated with poor survival and control of ILC plasticity. Single-cell RNA sequencing and flow cytometry of ILCs from HCC livers identified natural killer (NK)-like cells in the non-tumour tissue, losing their cytotoxic profile as they transitioned into tumour ILC1 and NK-like-ILC3 cells. Tumour ILC composition was mediated by cytokine gradients that directed ILC plasticity towards activated tumour ILC2s. This was liver-specific and not seen in ILCs from peripheral blood mononuclear cells. Patients with high ILC2/ILC1 ratio expressed interleukin-33 in the tumour that promoted ILC2 generation, which was associated with better survival. CONCLUSION: Our results suggest that the tumour cytokine milieu controls ILC composition and HCC outcome. Specific changes of cytokines modify ILC composition in the tumour by inducing plasticity and alter ILC function.

Metformin treatment rescues CD8+ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) represents the fastest growing underlying cause of hepatocellular carcinoma (HCC) and has been shown to impact immune effector cell function. The standard of care for the treatment of advanced HCC is immune checkpoint inhibitor (ICI) therapy, yet NASH may negatively affect the efficacy of ICI therapy in HCC. The immunologic mechanisms underlying the impact of NASH on ICI therapy remain unclear. METHODS: Herein, using multiple murine NASH models, we analysed the influence of NASH on the CD8+ T-cell-dependent anti-PD-1 responses against liver cancer. We characterised CD8+ T cells' transcriptomic, functional, and motility changes in mice receiving a normal diet (ND) or a NASH diet. RESULTS: NASH blunted the effect of anti-PD-1 therapy against liver cancers in multiple murine models. NASH caused a proinflammatory phenotypic change of hepatic CD8+ T cells. Transcriptomic analysis revealed changes related to NASH-dependent impairment of hepatic CD8+ T-cell metabolism. In vivo imaging analysis showed reduced motility of intratumoural CD8+ T cells. Metformin treatment rescued the efficacy of anti-PD-1 therapy against liver tumours in NASH. CONCLUSIONS: We discovered that CD8+ T-cell metabolism is critically altered in the context of NASH-related liver cancer, impacting the effectiveness of ICI therapy - a finding which has therapeutic implications in patients with NASH-related liver cancer. LAY SUMMARY: Non-alcoholic steatohepatitis represents the fastest growing cause of hepatocellular carcinoma. It is also associated with reduced efficacy of immunotherapy, which is the standard of care for advanced hepatocellular carcinoma. Herein, we show that non-alcoholic steatohepatitis is associated with impaired motility, metabolic function, and response to anti-PD-1 treatment in hepatic CD8+ T cells, which can be rescued by metformin treatment.

Steatohepatitis Impairs T-cell-Directed Immunotherapies Against Liver Tumors in Mice.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis causes loss of hepatic CD4+ T cells and promotes tumor growth. The liver is the most common site of distant metastases from a variety of malignancies, many of which respond to immunotherapy. We investigated the effects of steatohepatitis on the efficacy of immunotherapeutic agents against liver tumors in mice. METHODS: Steatohepatitis was induced by feeding C57BL/6NCrl or BALB/c AnNCr mice a methionine and choline-deficient diet or a choline-deficient l-amino acid-defined diet. Mice were given intrahepatic or subcutaneous injections of B16 melanoma and CT26 colon cancer cells, followed by intravenous injections of M30-RNA vaccine (M30) or intraperitoneal injections of an antibody against OX40 (aOX40) on days 3, 7, and 10 after injection of the tumor cells. We measured tumor growth and analyzed immune cells in tumor tissues by flow cytometry. Mice were given N-acetylcysteine to prevent loss of CD4+ T cells from liver. RESULTS: Administration of M30 and aOX40 inhibited growth of tumors from intrahepatic injections of B16 or CT26 cells in mice on regular diet. However, M30 and/or aOX40 did not slow growth of liver tumors from B16 or CT26 cells in mice with diet-induced steatohepatitis (methionine and choline-deficient diet or choline-deficient l-amino acid-defined diet). Steatohepatitis did not affect the ability of M30 to slow growth of subcutaneous B16 tumors. In mice with steatohepatitis given N-acetylcysteine, which prevents loss of CD4+ T cells, M30 and aOX40 were able slow growth of hepatic tumors. Flow cytometry analysis of liver tumors revealed reduced CD4+ T cells and effector memory cells in mice with vs without steatohepatitis. CONCLUSIONS: Steatohepatitis reduces the abilities of immunotherapeutic agents, such as M30 and aOX40, to inhibit tumor liver growth by reducing tumor infiltration by CD4+ T cells and effector memory cells. N-acetylcysteine restores T-cell numbers in tumors and increases the ability of M30 and aOX40 to slow tumor growth in mice.

CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: While cholangiocarcinomas (CCAs) commonly express programmed cell death 1 (PD-1) and its ligand (PD-L1), they respond poorly to immune checkpoint inhibitors (ICIs). We aimed to determine whether stimulating antigen-presenting cells, including macrophages and dendritic cells, using a CD40 agonist could improve this response. METHODS: We compared treatment responses in subcutaneous, orthotopic, and 2 plasmid-based murine intrahepatic CCA (iCCA) models. Mice were treated for 4 weeks with weekly IgG control, a CD40 agonistic antibody, anti-PD-1, or the combination of both (anti-CD40/PD-1). Flow cytometric (FACS) analysis of lymphocytes and myeloid cell populations (including activation status) was performed. We used dendritic cell knockout mice, and macrophage, CD4+ and CD8+ T cell depletion models to identify effector cells. Anti-CD40/PD-1 was combined with chemotherapy (gemcitabine/cisplatin) to test for improved therapeutic efficacy. RESULTS: In all 4 models, anti-PD-1 alone was minimally efficacious. Mice exhibited a moderate response to CD40 agonist monotherapy. Combination anti-CD40/PD-1 therapy led to a significantly greater reduction in tumor burden. FACS demonstrated increased number and activation of CD4+ and CD8+ T cells, natural killer cells, and myeloid cells in tumor and non-tumor liver tissue of tumor-bearing mice treated with anti-CD40/PD-1. Depletion of macrophages, dendritic cells, CD4+ T cells, or CD8+ T cells abrogated treatment efficacy. Combining anti-CD40/PD-1 with gemcitabine/cisplatin resulted in a significant survival benefit compared to gemcitabine/cisplatin alone. CONCLUSION: CD40-mediated activation of macrophages and dendritic cells in iCCA significantly enhances response to anti-PD-1 therapy. This regimen may enhance the efficacy of first-line chemotherapy. LAY SUMMARY: Checkpoint inhibition, a common form of immune therapy, is generally ineffective for the treatment of cholangiocarcinoma. These tumors suppress the infiltration and function of surrounding immune cells. Stimulating immune cells such as macrophages and dendritic cells via the CD40 receptor activates downstream immune cells and enhances the response to checkpoint inhibitors.

Prognostic impact of lymphovascular invasion in pT1-T3 gallbladder adenocarcinoma.

BACKGROUND: Most gallbladder cancers are diagnosed after cholecystectomy for presumed benign disease, and nodal staging to inform subsequent treatment is therefore often lacking. We evaluated the association of lymphovascular invasion (LVI) with regional lymph node involvement in gallbladder adenocarcinoma and its impact on survival. METHODS: The National Cancer Database was queried to identify patients with resected gallbladder adenocarcinoma and with available staging and LVI status. Patients with pT4 and M1 disease were excluded. Univariable and multivariable regression identified factors associated with positive lymph nodes. Cox proportional hazards model was used to evaluate overall survival (OS). RESULTS: Of 1649 patients with available LVI status, 1142 (69.7%) had at least one positive lymph node and 765 (46.4%) had LVI. On multivariable regression, presence of LVI was the strongest predictor of positive lymph nodes (odds ratio, 3.69; P < .001). The positive predictive value of LVI for positive lymph nodes in pT2 and pT3 tumors was 80.1% and 90.5%, respectively. LVI was independently associated with decreased OS (hazard ratio, 1.21; P = .001), as were node-positive disease and increasing T stage. CONCLUSION: In patients with gallbladder adenocarcinoma, LVI is independently associated with regional lymph node metastases and abbreviated OS. LVI status may help risk-stratify patients following initial cholecystectomy and inform subsequent treatment.

Gallbladder squamous cell carcinoma: An analysis of 1084 cases from the National Cancer Database.

BACKGROUND/OBJECTIVES: Gallbladder squamous cell carcinoma (SCC) is an uncommon malignancy whose rarity has made it particularly challenging to study. We utilized a national database to shed light on the clinicopathologic characteristics, management patterns, and survival associated with these tumors. METHODS: Patients with gallbladder SCC were identified in the National Cancer Database. Clinicopathologic and treatment characteristics were recorded and compared with adenocarcinoma for context. Univariate and multivariable survival analyses were completed for patients who underwent resection. RESULTS: Overall, 1084 patients with SCC and 23 958 patients with adenocarcinoma were identified. Compared with those with adenocarcinoma, patients with SCC had higher grade tumors (P < .001) and were diagnosed at a later stage (P < .001). Patients with SCC were more likely to undergo radical cholecystectomy (17% vs 9%; P < .001), but had a higher rate of margin positivity (36% vs 29%; P < .001). SCC histology was associated with worse survival compared with adenocarcinoma, even after adjusting for R0 resections (13 vs 29 months; P < .001). On multivariable analysis, SCC histology was independently associated with abbreviated survival (P = .003). CONCLUSIONS: Gallbladder SCCs are aggressive cancers that often present at an advanced stage. Complete surgical extirpation should be pursued when feasible. However, prognosis is worse than that of adenocarcinoma, even after R0 resection.

Tumor grade may be used to select patients with multifocal hepatocellular carcinoma for resection.

BACKGROUND: While resection is a recommended treatment for patients with stage 1 hepatocellular carcinoma (HCC), it remains controversial for multifocal disease. We sought to identify patients with multifocal HCC with survival after resection similar to patients with clinical stage 1 HCC. METHODS: The National Cancer Database was queried to identify patients that underwent resection for HCC. RESULTS: In this study, 2990 patients with a single tumor, and 1087 patients with multifocal disease confined to one lobe underwent resection. In the multifocal cohort, patients with clinical stage 3 (HR 1.54, CI 1.31-1.81, p < 0.0001) or 4 (HR 2.27, CI 1.57-3.29, p < 0.0001) disease, and those with moderately-differentiated (HR 1.32, CI 1.06-1.64, p = 0.012) or poorly differentiated/undifferentiated tumors (HR 1.53, CI 1.20-1.95, p = 0.0006) were associated with worse overall survival (OS). There was no difference in OS between patients with well-differentiated clinical stage 2 multifocal HCC and those with all grades of clinical stage 1 HCC (median of 84.8 (CI 66.3-107.2) vs 76.2 months (CI 71.2-81.3), respectively, p = 0.356). CONCLUSIONS: Patients with well-differentiated, clinical stage 2 multifocal HCC confined to one lobe experience similar OS following hepatic resection to patients with clinical stage 1 disease. These findings may impact the management of select patients with multifocal HCC.

Resection and chemotherapy is the optimal treatment approach for patients with clinically node positive intrahepatic cholangiocarcinoma.

BACKGROUND: Clinically lymph node positive (cLNP) intrahepatic cholangiocarcinoma (ICC) carries a poor prognosis, without clear management guidelines for the practicing clinician. We sought to evaluate current practice patterns for cLNP ICC, including associations with survival. METHODS: The National Cancer Database was queried for patients with cLNP ICC, without extrahepatic metastases. RESULTS: We identified 1023 patients with cLNP ICC, 77%% (n = 784) of whom received chemotherapy alone. Resection was undertaken in 23% (n = 239) of patients and was most commonly utilized in combination with chemotherapy (n = 150). Median survival for all patients was 13.6 months. Patients undergoing resection in combination with chemotherapy were associated with an improved survival (22.5 months) as compared to those patients receiving chemotherapy alone (11.9 months) or resection alone (12.4 months) (p < 0.01). Finally, we compared the survival of patients with cLNP ICC with that of patients with pathologically proved lymph node positive (pLNP) ICC, all of whom were treated with resection with chemotherapy, and found no difference in survival (22.5 months-19.3 months, p = 0.99, respectively). CONCLUSIONS: While the decision to pursue resection for ICC is multifactorial and patient specific, the presence of clinically positive LNs should not represent a contraindication.

Laparoscopic Approach to Intrahepatic Cholangiocarcinoma is Associated with an Exacerbation of Inadequate Nodal Staging.

INTRODUCTION: Laparoscopic approach to liver resection is feasible and safe, though its utilization with intrahepatic cholangiocarcinoma (ICC) remains poorly documented. We sought to evaluate the use laparoscopy for ICC, and to examine adherence to oncologic standards. METHODS: The National Cancer Database was queried for patients who underwent resection for ICC. Patients were stratified by laparoscopic (LLR) versus open liver resection (OLR). Clinicopathologic parameters and hospital volumes were recorded. RESULTS: In total, 2309 patients with ICC underwent hepatic resection (1997 OLR, 312 LLR) between 2010 and 2015. LLR increased from 12 to 16% during the study period and was utilized more commonly than OLR for wedge and segmental resections (56% vs. 33%, p < 0.001). Nodal evaluation was performed in 58% of all patients with ICC and was significantly more common in patients undergoing OLR (61%, n = 1210) versus LLR (39%, n = 120), p < 0.001. Of the 120 patients undergoing LLR with any nodal evaluation, 31% (n = 37) had a single node evaluated. Patients who underwent LLR were less likely to have ≥ 6 lymph nodes evaluated compared with those who underwent OLR (9% vs. 15%, respectively, p < 0.001). CONCLUSIONS: The use of laparoscopy for ICC is associated with an exacerbation of inadequate nodal evaluation compared with open resections.

Practice patterns of VTE chemoprophylaxis after discharge following hepatic and pancreatic resections for cancer: A survey of hepatopancreatobiliary surgeons.

Patients with hepatopancreatobiliary (HPB) malignancies undergoing resection are prone to venous thromboembolism (VTE), and current guidelines recommend up to 28 days of chemoprophylaxis after major surgery. We sought to determine the practice patterns among HPB surgeons for use of chemoprophylaxis after discharge. A survey on VTE chemoprophylaxis after oncologic HPB operations was distributed to attending surgeons at the 18 HPB fellowship training programs in the United States and Canada. Of the HPB surgeons surveyed, 44 (44%) responded. VTE prophylaxis is used by 93% of respondants in the inpatient postoperative setting. Chemoprophylaxis after discharge for pancreaticoduodenenctomy and distal pancreatectomy is utilized by 45% and 39% of respondants, respectively. Of those who prescribe chemoprophylaxis after discharge, 79% and 88% prescribe it for the recommended 28 days after pancreaticoduodenectomy and distal pancreatectomy, respectively. Chemoprophylaxis after discharge for major and minor hepatectomy is utilized by 39% and 26% of respondents, respectively. Of those who prescribe chemoprophylaxis after discharge, 67% and 55% provide it for the recommended 28 days after major and minor hepatectomy, respectively. Despite documented prolonged postoperative thrombogenic risk, the use of chemoprophylaxis following discharge after pancreatic and liver resections for cancer was moderate among surveyed HPB surgeons.

Tumor grade and sex should influence the utilization of portal lymphadenectomy for early stage intrahepatic cholangiocarcinoma.

BACKGROUND: Portal lymphadenectomy for intrahepatic cholangiocarcinoma (ICC) is encouraged for staging purposes, though it is under-utilized for clinically early-stage tumors. We sought to determine if any factor knowable prior to resection influences rates of portal lymph node metastases. METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program (1973-2014) database was queried to identify patients with T1/T2 ICC undergoing resection. Patients were stratified by lymph node (LN) status. Patients deemed LN negative required examination of six or more LNs (AJCC guidelines). RESULTS: One-hundred and fifty-two patients were included in the analysis (LN negative: 38, LN positive: 114). Patients with LN negative cancers experienced prolonged overall survival as compared to patients with positive LNs (median 77 months vs 19 months, respectively p < 0.001). Twelve patients had well-differentiated tumors (G1), 92 patients had moderately-differentiated tumors (G2) and 58 patients had poorly-differentiated tumors (G3). Tumor grade (OR 3.9, CI 1.1-13.7, p = 0.031) and male sex (OR 2.6, CI 1.1-6.1, p = 0.022) were associated with positive LNs on multivariable logistic regression analysis. CONCLUSION: Intermediate/High grade and male sex are associated with high rates of lymph node metastasis for patients with early-stage ICC, which portends abbreviated overall survival.

An Examination of Applicants and Factors Associated with Matriculation to Complex General Surgical Oncology Fellowship Training Programs.

BACKGROUND: The demand for training in complex general surgical oncology (CGSO) fellowships currently exceeds the number of positions offered; however, there are scarce data defining the applicant pool or characteristics associated with successful matriculation. Our study described the applicant population and to determine factors associated with acceptance into the fellowship. STUDY DESIGN: Data were extracted from the Electronic Residency Application System for applicants in 2015 and 2016 and stratified based on matriculation status. Applicant demographics, including medical education, residency, and research achievements, were analyzed. Academic productivity was quantified using the number of peer-reviewed publications as well as the journal with the highest impact factor in which an applicant's work was published. RESULTS: Data were gathered on a total of 283 applicants, of which 105 matriculated. The overall population was primarily male (63.2%), Caucasian (40.6%), educated at a U.S. allopathic medical school (53.4%), and trained at a university-based General Surgery residency (55.5%). Education at a U.S. allopathic school (OR = 5.63, p < 0.0001), university-based classification of the applicant's surgical residency (OR = 4.20, p < 0.0001), and a residency affiliation with a CGSO fellowship (OR = 2.61, p = 0.004) or National Cancer Institute designated Comprehensive Cancer Center (OR = 3.16, p < 0.001) were found to be associated with matriculation. Matriculants published a higher number of manuscripts than nonmatriculants (median of 10 vs. 4.5, p < 0.0001) and more frequently achieved publication in journals with higher impact factors (p < 0.0001). CONCLUSIONS: This study represents the first objective description of the CGSO fellowship applicant pool. Applicants' medical school, residency, and research data points correlated with successful matriculation.

Metabolomic and BH3 profiling of esophageal cancers: novel assessment methods for precision therapy.

BACKGROUND: Esophageal cancers accounted for nearly 16,000 deaths in 2016. The number of patients with esophageal cancers increases every year. Neoadjuvant chemoradiotherapy (nCRT) prior to esophagectomy is a standard treatment for esophageal cancers. The patients who have no residual tumor (pathological complete response (pCR)) at surgery are the most likely to experience long term survival. Accurately determining which patients will have a pCR will improve prognostic information for patients and families, confirm lack of response to nCRT, or avoid surgery if no residual tumor is present. Imaging, endoscopy, and liquid biomarkers have all failed to detect pCR without performing an esophagectomy. METHODS: In this study, we are enrolling patients with esophageal adenocarcinoma and squamous cell carcinoma. Patients will undergo standard evaluation including CT scans, laboratory tests, endoscopy with biopsies, and evaluation by a thoracic surgeon. Tissue biopsy is required for enrollment that will be sent for BH3 profiling and metabolomics. Patients will be treated with standard nCRT followed by surgery. Patients with metastatic disease are not eligible. Surgery at the National Cancer Institute will be minimally-invasive robotic surgery. Patients will remain on study indefinitely with regular clinic visits and imaging tests. DISCUSSION: The mitochondria are critically involved in the intrinsic pathway apoptosis. Bcl-2 homology domain 3 (BH3) profiling is a technique to measure a cell's susceptibility to apoptosis. BH3 profiling measures the relative interactions of proteins that induce or block apoptosis. The collective balance of these proteins determines whether a cell is near the threshold to undergo apoptosis. If the cell is near this threshold, then the tumor may be more likely to die when treated with nCRT. The mitochondria secrete metabolites that may be detectable as biomarkers. Metabolomics is a global assessment of all metabolite changes that has been performed for detection, monitoring, prognosis, and treatment response in cancers. Stratification of patients based on whether pCR occurs or not may elucidate metabolomic signatures that may be associated with response. We are asking whether BH3 profiling or a metabolomic signature will correlate with tumor death after nCRT for esophageal cancer. TRIAL REGISTRATION: NCT03223662 ; Clinicaltrials.gov. July 21, 2017.

Review of Traumatic Duodenal Injuries: Etiology, Diagnosis, and Management.

Traumatic duodenal injuries are rare and often challenging to diagnose and treat. Management of these injuries remains controversial and continues to evolve. Here, we performed a review of the literature and guidelines for the diagnosis and management of traumatic duodenal injuries.A common recommendation in more recent literature is primary, tension-free repair of duodenal injuries when possible if surgical repair is necessary. Conversely, if duodenal injuries are unamenable to primary repair, more complex procedures such as Roux-en-Y duodenojejunostomy or pancreaticoduodenectomy may be necessary. Regardless of injury grade or type of surgical repair, the literature continues to support wide extraluminal drainage. Over time, the management of complex duodenal injuries has evolved to favor simple primary repair whenever possible. According to recent studies, more complex procedures are associated with higher rates of post-operative complications and should be reserved for severe injuries when primary repair is not possible.

Early Immune Changes Support Signet Ring Cell Dormancy in CDH1-Driven Hereditary Diffuse Gastric Carcinogenesis.

Stage IA gastric adenocarcinoma, characterized by foci of intramucosal signet ring cells (SRC), is found in nearly all asymptomatic patients with germline pathogenic CDH1 variants and hereditary diffuse gastric cancer syndrome (HDGC). The molecular steps involved in initiating malignant transformation and promoting SRC dormancy in HDGC are unknown. Here, whole-exome bulk RNA sequencing (RNA-seq) of SRCs and adjacent non-SRC epithelium (NEP) was performed on laser-capture microdissected (LCM) regions of interest found in risk-reducing total gastrectomy specimens from patients with HDGC (Clinicaltrials.gov ID: NCT03030404). In total, 20 patients (6 male, 14 female) with confirmed HDGC were identified. Analysis of differentially expressed genes (DEG) demonstrated upregulation of certain individual EMT and proliferation genes. However, no oncogenic pathways were found to be upregulated in SRCs. Rather, SRC regions had significant enrichment in pathways involved in T-cell signaling. CIBERSORTx predicted significant increases in the presence of regulatory T cells (Treg) specific to SRC regions. IHC confirmed an increase in FOXP3+ cells in SRC foci, as well as elevations in CD4+ T cells and HLA-DR staining. In summary, the tumor immune microenvironment is microscopically inseparable from stage IA gastric SRCs using a granular isolation technique. An elevation in CD4+ T cells within SRC regions correlates with clinically observed SRC dormancy, while Treg upregulation represents a potential immune escape mechanism. IMPLICATIONS: Characterization of the tumor-immune microenvironment in HDGC underscores the potential for the immune system to shape the transcriptional profile of the earliest tumors, which suggests immune-directed therapy as a potential cancer interception strategy in diffuse-type gastric cancer.

NAFLD indirectly impairs antigen-specific CD8+ T cell immunity against liver cancer in mice.

Non-alcoholic fatty liver disease (NAFLD) has become an important etiology leading to liver cancer. NAFLD alters adaptive T cell immunity and has a profound influence on liver cancer development. However, it is unclear how NAFLD affects tumor antigen-specific T cell response. In this study, we generated a doxycycline-inducible MHC-I and -II antigen-expressing HCC cell line which allowed us to investigate tumor antigen-specific T cell response in two NAFLD mouse models. The system proved to be an effective and efficient way to study tumor antigen-specific T cells. Using this model, it was found that NAFLD impairs antigen-specific CD8+ T cell immunity against HCC. The effect was not due to reduced generation or intrinsic functional changes of tumor antigen-specific CD8+ T cells but caused by accumulated macrophages in the liver environment. The findings suggest that targeting macrophages in NAFLD-driven HCC may improve therapeutic outcomes.

Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD.

Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L-/- platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8+ T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD.

Video-assisted thoracoscopic surgery pleurectomy: a suitable alternative for treating malignant pleural effusions.

BACKGROUND: Malignant pleural effusions (MPEs) are common manifestations of metastatic cancers and are associated with a dismal prognosis. Talc pleurodesis has been proven to be effective in the management of MPEs, however, class-action lawsuits linking talc to ovarian adenocarcinoma have rendered it unavailable at many institutions. As a result, surgeons have resorted to less effective chemical pleurodesis as an alternative to indwelling pleural drainage catheters. Given the absence of talc, we explored the effectiveness of video-assisted thoracoscopic surgery (VATS) partial pleurectomy (VPP) for treating MPEs. METHODS: We performed a retrospective review of patients with MPEs managed after talc became unavailable at our institution. Between 2016 and 2018, we identified five patients who refused pleural drainage catheters and underwent VPP. Symptoms at presentation included fatigue, dyspnea, and pleuritic chest pain. All had unilateral MPEs (left n=3, right n=2). VPP included removal of parietal surfaces of the pleura other than the pleura overlying the subclavian vessels, the mediastinum, and the lung viscera. RESULTS: There were no significant perioperative adverse events and post-operative pain was well controlled. Chest tubes were removed between post-operative day (POD) 3 and 7. Follow-up time ranged from four to 36 weeks. All patients had symptomatic relief and radiographic evidence of improved MPEs. No patients required re-interventions. One patient expired six months after surgery while the remaining four were alive at last follow-up. CONCLUSIONS: VPP offers an effective alternative to chemical pleurodesis for managing MPEs in patients who prefer to avoid pleural drainage catheters.

Hydroxychloroquine can impair tumor response to anti-PD1 in subcutaneous mouse models.

Hydroxychloroquine (HCQ) is a well-known anti-inflammatory drug but is also known as an anti-inflammatory drug. Here, we evaluate the influence of HCQ treatment on the effect of anti-PD1 tumor immunotherapy. Anti-PD1 therapy-sensitive tumor lines MC38, CT26, and RIL-175 were used to investigate the impact of HCQ on anti-PD1 therapy efficacy. In vitro assays demonstrated that HCQ directly inhibited tumor cell growth in all the tested tumor cell lines. HCQ treatment impaired both antigen-specific and nonspecific T-cell production of TNFα and IFNγ in vitro and in vivo. Importantly, in all the three tumor models, HCQ treatment significantly impaired the response to anti-PD1 treatment, accompanying diminished in vivo T-cell activation and reduced tumor-infiltrating, antigen-specific CD8+ T cells. This study shows that HCQ treatment can result in immunotherapy failure due to its immunosuppressive effects that offset both increased MHC-I expression by tumor cell and direct cytotoxicity.