Epigenetic Regulation of Cancer Immune Cells.

The epigenetic regulation of immune response involves reversible and heritable changes that do not alter the DNA sequence. Though there have been extensive studies accomplished relating to epigenetic changes in cancer cells, recent focus has been shifted on epigenetic-mediated changes in the immune cells including T cells, Macrophages, Natural Killer cells and anti-tumor immune responses. This review compiles the most relevant and recent literature related to the role of epigenetic mechanisms including DNA methylation and histone modifications in immune cells of wide range of cancers. We also include recent research with respect to role of the most relevant transcription factors that epigenetically control the anti-tumor immune response. Finally, a statement of future direction that promises to look forward for strategies to improve immunotherapy in cancer.

Nanoliposome C6-Ceramide in combination with anti-CTLA4 antibody improves anti-tumor immunity in hepatocellular cancer.

Combination therapy represents an effective therapeutic approach to overcome hepatocellular cancer (HCC) resistance to immune checkpoint blockade (ICB). Based upon previous work demonstrating that nanoliposome C6-ceramide (LipC6) not only induces HCC apoptosis but also prevents HCC-induced immune tolerance, we now investigate the potential of LipC6 in combination with ICB in HCC treatment. We generated orthotopic HCC-bearing mice, which have typical features in common with human patients, and then treated them with LipC6 in combination with the antibodies (Abs) for programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte antigen 4 (CTLA4). The tumor growth was monitored by magnetic resonance imaging (MRI) and the intrahepatic immune profiles were checked by flow cytometry in response to the treatments. Realtime PCR (qPCR) was used to detect the expression of target genes. The results show that LipC6 in combination with anti-CTLA4 Ab, but not anti-PD-1 Ab, significantly slowed tumor growth, enhanced tumor-infiltrating CD8+ T cells, and suppressed tumor-resident CD4+ CD25+ FoxP3+ Tregs. Further molecular investigation indicates that the combinational treatment suppressed transcriptional factor Krüppel-like Factor 2 (KLF2), forkhead box protein P3 (FoxP3), and CTLA4. Our studies suggest that LipC6 in combination with anti-CTLA4 Ab represents a novel therapeutic approach with significant potential in activating anti-HCC immune response and suppressing HCC growth.

Tumorigenic circulating tumor cells from xenograft mouse models of non-metastatic NSCLC patients reveal distinct single cell heterogeneity and drug responses.

BACKGROUND: Circulating tumor cells (CTCs) are liquid biopsies that represent micrometastatic disease and may offer unique insights into future recurrences in non-small cell lung cancer (NSCLC). Due to CTC rarity and limited stability, no stable CTC-derived xenograft (CDX) models have ever been generated from non-metastatic NSCLC patients directly. Alternative strategies are needed to molecularly characterize CTCs and means of potential future metastases in this potentially curable patient group. METHODS: Surgically resected NSCLC primary tumor tissues from non-metastatic patients were implanted subcutaneously in immunodeficient mice to establish primary tumor patient-derived xenograft (ptPDX) models. CTCs were isolated as liquid biopsies from the blood of ptPDX mice and re-implanted subcutaneously into naïve immunodeficient mice to generate liquid biopsy CTC-derived xenograft (CDX) tumor models. Single cell RNA sequencing was performed and validated in an external dataset of non-xenografted human NSCLC primary tumor and metastases tissues. Drug response testing in CDX models was performed with standard of care chemotherapy (carboplatin/paclitaxel). Blockade of MYC, which has a known role in drug resistance, was performed with a MYC/MAX dimerization inhibitor (10058-F4). RESULTS: Out of ten ptPDX, two (20%) stable liquid biopsy CDX mouse models were generated. Single cell RNA sequencing analysis revealed an additional regenerative alveolar epithelial type II (AT2)-like cell population in CDX tumors that was also identified in non-xenografted NSCLC patients' metastases tissues. Drug testing using these CDX models revealed different treatment responses to carboplatin/paclitaxel. MYC target genes and c-MYC protein were upregulated in the chemoresistant CDX model, while MYC/MAX dimerization blocking could overcome chemoresistance to carboplatin/paclitaxel. CONCLUSIONS: To overcome the lack of liquid biopsy CDX models from non-metastatic NSCLC patients, CDX models can be generated with CTCs from ptPDX models that were originally established from patients' primary tumors. Single cell analyses can identify distinct drug responses and cell heterogeneities in CDX tumors that can be validated in NSCLC metastases tissues. CDX models deserve further development and study to discover personalized strategies against micrometastases in non-metastatic NSCLC patients.

Single Circulating-Tumor-Cell-Targeted Sequencing to Identify Somatic Variants in Liquid Biopsies in Non-Small-Cell Lung Cancer Patients.

Non-small-cell lung cancer (NSCLC) accounts for most cancer-related deaths worldwide. Liquid biopsy by a blood draw to detect circulating tumor cells (CTCs) is a tool for molecular profiling of cancer using single-cell and next-generation sequencing (NGS) technologies. The aim of the study was to identify somatic variants in single CTCs isolated from NSCLC patients by targeted NGS. Thirty-one subjects (20 NSCLC patients, 11 smokers without cancer) were enrolled for blood draws (7.5 mL). CTCs were identified by immunofluorescence, individually retrieved, and DNA-extracted. Targeted NGS was performed to detect somatic variants (single-nucleotide variants (SNVs) and insertions/deletions (Indels)) across 65 oncogenes and tumor suppressor genes. Cancer-associated variants were classified using OncoKB database. NSCLC patients had significantly higher CTC counts than control smokers (p = 0.0132; Mann-Whitney test). Analyzing 23 CTCs and 13 white blood cells across seven patients revealed a total of 644 somatic variants that occurred in all CTCs within the same subject, ranging from 1 to 137 per patient. The highest number of variants detected in ≥1 CTC within a patient was 441. A total of 18/65 (27.7%) genes were highly mutated. Mutations with oncogenic impact were identified in functional domains of seven oncogenes/tumor suppressor genes (NF1, PTCH1, TP53, SMARCB1, SMAD4, KRAS, and ERBB2). Single CTC-targeted NGS detects heterogeneous and shared mutational signatures within and between NSCLC patients. CTC single-cell genomics have potential for integration in NSCLC precision oncology.

Astaxanthin Prevents Diet-Induced NASH Progression by Shaping Intrahepatic Immunity.

Dietary change leads to a precipitous increase in non-alcoholic fatty liver disease (NAFLD) from simple steatosis to the advanced form of non-alcoholic steatohepatitis (NASH), affecting approximately 25% of the global population. Although significant efforts greatly advance progress in clarifying the pathogenesis of NAFLD and identifying therapeutic targets, no therapeutic agent has been approved. Astaxanthin (ASTN), a natural antioxidant product, exerts an anti-inflammation and anti-fibrotic effect in mice induced with carbon tetrachloride (CCl4) and bile duct ligation (BDL); thus, we proposed to further investigate the potential effect of ASTN on a diet-induced mouse NASH and liver fibrosis, as well as the underlying cellular and molecular mechanisms. By treating pre-development of NASH in mice induced with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), we have demonstrated that oral administration ASTN preventively ameliorated NASH development and liver fibrosis by modulating the hepatic immune response, liver inflammation, and oxidative stress. Specifically, ASTN treatment led to the reduction in liver infiltration of monocyte-derived macrophages, hepatic stellate cell (HSC) activation, oxidative stress response, and hepatocyte death, accompanied by the decreased hepatic gene expression of proinflammatory cytokines such as TNF-α, TGF-ß1, and IL-1ß. In vitro studies also demonstrated that ASTN significantly inhibited the expression of proinflammatory cytokines and chemokine CCL2 in macrophages in response to lipopolysaccharide (LPS) stimulation. Overall, in vivo and in vitro studies suggest that ASTN functions as a promising therapeutic agent to suppress NASH and liver fibrosis via modulating intrahepatic immunity.

LncRNA GAS5 attenuates fibroblast activation through inhibiting Smad3 signaling.

Transforming growth factor-ß (TGF-ß)-induced fibroblast activation is a key pathological event during tissue fibrosis. Long noncoding RNA (lncRNA) is a class of versatile gene regulators participating in various cellular and molecular processes. However, the function of lncRNA in fibroblast activation is still poorly understood. In this study, we identified growth arrest-specific transcript 5 (GAS5) as a novel regulator for TGF-ß-induced fibroblast activation. GAS5 expression was downregulated in cultured fibroblasts by TGF-ß and in resident fibroblasts from bleomycin-treated skin tissues. Overexpression of GAS5 suppressed TGF-ß-induced fibroblast to myofibroblast differentiation. Mechanistically, GAS5 directly bound mothers against decapentaplegic homolog 3 (Smad3) and promoted Smad3 binding to Protein phosphatase 1A (PPM1A), a Smad3 dephosphatase, and thus accelerated Smad3 dephosphorylation in TGF-ß-treated fibroblasts. In addition, GAS5 inhibited fibroblast proliferation. Importantly, local delivery of GAS5 via adenoviral vector suppressed bleomycin-induced skin fibrosis in mice. Collectively, our data revealed that GAS5 suppresses fibroblast activation and fibrogenesis through inhibiting TGF-ß/Smad3 signaling, which provides a rationale for an lncRNA-based therapy to treat fibrotic diseases.

Targeted and Immune-Based Therapies for Hepatocellular Carcinoma.

Treatment options for patients with hepatocellular carcinoma are rapidly changing based on positive results from phase 3 trials of targeted and immune-based therapies. More agents designed to target specific pathways and immune checkpoints are in clinical development. Some agents have already been shown to improve outcomes of patients with hepatocellular carcinoma, as first- and second-line therapies, and are awaiting approval by the Food and Drug Administration or have been recently approved. We summarize the targeted and immune-based agents in trials of patients with advanced hepatocellular carcinoma and discuss the future of these strategies for liver cancer.

Tumor-Cell-Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer.

Although molecular mechanisms driving tumor progression have been extensively studied, the biological nature of the various populations of circulating tumor cells (CTCs) within the blood is still not well understood. Tumor cell fusion with immune cells is a longstanding hypothesis that has caught more attention in recent times. Specifically, fusion of tumor cells with macrophages might lead to the development of metastasis by acquiring features such as genetic and epigenetic heterogeneity, chemotherapeutic resistance, and immune tolerance. In addition to the traditional FDA-approved definition of a CTC (CD45-, EpCAM+, cytokeratins 8+, 18+ or 19+, with a DAPI+ nucleus), an additional circulating cell population has been identified as being potential fusions cells, characterized by distinct, large, polymorphonuclear cancer-associated cells with a dual epithelial and macrophage/myeloid phenotype. Artificial fusion of tumor cells with macrophages leads to migratory, invasive, and metastatic phenotypes. Further studies might investigate whether these have a potential impact on the immune response towards the cancer. In this review, the background, evidence, and potential relevance of tumor cell fusions with macrophages is discussed, along with the potential role of intercellular connections in their formation. Such fusion cells could be a key component in cancer metastasis, and therefore, evolve as a diagnostic and therapeutic target in cancer precision medicine.

Overproduction of endothelin-1 impairs glucose tolerance but does not promote visceral adipose tissue inflammation or limit metabolic adaptations to exercise.

Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide that is upregulated in obesity. Herein, we tested the hypothesis that ET-1 signaling promotes visceral adipose tissue (AT) inflammation and disrupts glucose homeostasis. We also tested if reduced ET-1 is a required mechanism by which exercise ameliorates AT inflammation and improves glycemic control in obesity. We found that 1) diet-induced obesity, AT inflammation, and glycemic dysregulation were not accompanied by significantly increased levels of ET-1 in AT or circulation in wild-type mice and that endothelial overexpression of ET-1 and consequently increased ET-1 levels did not cause AT inflammation yet impaired glucose tolerance; 2) reduced AT inflammation and improved glucose tolerance with voluntary wheel running was not associated with decreased levels of ET-1 in AT or circulation in obese mice nor did endothelial overexpression of ET-1 impede such exercise-induced metabolic adaptations; 3) chronic pharmacological blockade of ET-1 receptors did not suppress AT inflammation in obese mice but improved glucose tolerance; and 4) in a cohort of human subjects with a wide range of body mass indexes, ET-1 levels in AT, or circulation were not correlated with markers of inflammation in AT. In aggregate, we conclude that ET-1 signaling is not implicated in the development of visceral AT inflammation but promotes glucose intolerance, thus representing an important therapeutic target for glycemic dysregulation in conditions characterized by hyperendothelinemia. Furthermore, we show that the salutary effects of exercise on AT and systemic metabolic function are not contingent on the suppression of ET-1 signaling.

Nanoliposome C6-Ceramide Increases the Anti-tumor Immune Response and Slows Growth of Liver Tumors in Mice.

BACKGROUND & AIMS: Ceramide, a sphingolipid metabolite, affects T-cell signaling, induces apoptosis of cancer cells, and slows tumor growth in mice. However, it has not been used as a chemotherapeutic agent because of its cell impermeability and precipitation in aqueous solution. We developed a nanoliposome-loaded C6-ceremide (LipC6) to overcome this limitation and investigated its effects in mice with liver tumors. METHODS: Immune competent C57BL/6 mice received intraperitoneal injections of carbon tetrachloride and intra-splenic injections of oncogenic hepatocytes. As a result, tumors resembling human hepatocellular carcinomas developed in a fibrotic liver setting. After tumors formed, mice were given an injection of LipC6 or vehicle via tail vein every other day for 2 weeks. This was followed by administration, also via tail vein, of tumor antigen-specific (TAS) CD8+ T cells isolated from the spleens of line 416 mice, and subsequent immunization by intraperitoneal injection of tumor antigen-expressing B6/WT-19 cells. Tumor growth was monitored with magnetic resonance imaging. Tumor apoptosis, proliferation, and AKT expression were analyzed using immunohistochemistry and immunoblots. Cytokine production, phenotype, and function of TAS CD8+ T cells and tumor-associated macrophages (TAMs) were studied with flow cytometry, real-time polymerase chain reaction (PCR), and ELISA. Reactive oxygen species (ROS) in TAMs and bone marrow-derived macrophages, induced by colony stimulating factor 2 (GMCSF or CSF2) or colony stimulating factor 1 (MCSF or CSF1), were detected using a luminescent assay. RESULTS: Injection of LipC6 slowed tumor growth by reducing tumor cell proliferation and phosphorylation of AKT, and increasing tumor cell apoptosis, compared with vehicle. Tumors grew more slowly in mice given the combination of LipC6 injection and TAS CD8+ T cells followed by immunization compared with mice given vehicle, LipC6, the T cells, or immunization alone. LipC6 injection also reduced numbers of TAMs and their production of ROS. LipC6 induced TAMs to differentiate into an M1 phenotype, which reduced immune suppression and increased activity of CD8+ T cells. These results were validated by experiments with bone marrow-derived macrophages induced by GMCSF or MCSF. CONCLUSIONS: In mice with liver tumors, injection of LipC6 reduces the number of TAMs and the ability of TAMs to suppress the anti-tumor immune response. LipC6 also increases the anti-tumor effects of TAS CD8+ T cells. LipC6 might therefore increase the efficacy of immune therapy in patients with hepatocellular carcinoma.

Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model.

BACKGROUND & AIMS: We have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible anti-tumor chemoimmunotherapeutic strategy. METHODS: Intraperitoneal injection of carbon tetrachloride and intrasplenic inoculation of oncogenic hepatocytes were combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. Immunization and adoptive cell transfer (ACT) were used to dissect the tumor antigen-specific immune response. The ability of the tyrosine kinase inhibitor sunitinib to enhance immunotherapy in the setting of HCC was evaluated. RESULTS: This new mouse model mimics human HCC and reflects its typical features. Tumor-antigen-specific CD8+ T cells maintained a naïve phenotype and remained responsive during early-stage tumor progression. Late tumor progression produced circulating tumor cells, tumor migration into draining lymph nodes, and profound exhaustion of tumor-antigen-specific CD8+ T cells associated with accumulation of programmed cell death protein 1 (PD-1)hi CD8+ T cells and regulatory T cells (Tregs). Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity. CONCLUSION: Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using Food and Drug Administration-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients. LAY SUMMARY: In the current study, we have established a clinically relevant mouse model which mimics human liver cancer. Using this unique model, we studied the response of the immune system to this aggressive cancer. Findings from this trial have led to the development of an innovative and clinically feasible chemoimmunotherapeutic strategy.

Qualities and characteristics of successfully matched North American HPB surgery fellowship candidates.

BACKGROUND: Hepato-pancreato-biliary (HPB) fellowships in North America are difficult to secure with an acceptance rate of 1 in 3 applicants. Desirable characteristics in an HPB surgery applicant have not been previously reported. This study examines the perceptions of trainees and HPB program directors with regards to positive attributes in applicants for HPB fellowships. METHODS: Parallel surveys were distributed by email with a web-link to current and recent HPB fellows in North America (from the past 5 years) with questions addressing the following domains: surgical training, research experience, and mentorship. A similar survey was distributed to HPB fellowship program directors in North America requesting their opinion as to the importance of these characteristics in potential applicants. RESULTS: 32 of 60 of surveyed fellows and 21 of 38 of surveyed program directors responded between November 2014-February 2015. Fellows overall came from fairly diverse backgrounds (13/32 were overseas medical graduates) about one third of respondents having had some prior research experience. Program directors gave priority to the applicant's interview, curriculum vitae, and their recommendation letters (in order of importance). Both the surveyed fellows and program directors felt that the characteristics most important in a successful HPB fellowship candidate include interpersonal skills, perceived operative skills, and perceived fund of knowledge. CONCLUSION: Results of this survey provide useful and practical information for trainees considering applying to an HPB fellowship program.

Pleural space infections after image-guided percutaneous drainage of infected intraabdominal fluid collections: a retrospective single institution analysis.

BACKGROUND: Percutaneous drainage of infected intraabdominal fluid collections is preferred over surgical drainage due to lower morbidity and costs. However, it can be a challenging procedure and catheter insertion carries the potential to contaminate the pleural space from the abdomen. This retrospective analysis demonstrates the clinical and radiographic correlation between percutaneous drainage of infected intraabdominal collections and the development of iatrogenic pleural space infections. METHODS: A retrospective single institution analysis of 550 consecutive percutaneous drainage procedures for intraabdominal fluid collections was performed over 24 months. Patient charts and imaging were reviewed with regard to pleural space infections that were attributed to percutaneous drain placements. Institutional review board approval was obtained for conduct of the study. RESULTS: 6/550 (1.1%) patients developed iatrogenic pleural space infections after percutaneous drainage of intraabdominal fluid collections. All 6 patients presented with respiratory symptoms and required pleural space drainage (either by needle aspiration or chest tube placement), 2 received intrapleural fibrinolytic therapy and 1 patient had to undergo surgical drainage. Pleural effusion cultures revealed same bacteria in both intraabdominal and pleural fluid in 3 (50%) cases. A video with a dynamic radiographic sequence demonstrating the contamination of the pleural space from percutaneous drainage of an infected intraabdominal collection is included. CONCLUSIONS: Iatrogenic pleural space infections after percutaneous drainage of intraabdominal fluid collections occur at a low incidence, but the pleural empyema can be progressive requiring prompt chest tube drainage, intrapleural fibrinolytic therapy or even surgery. Expertise in intraabdominal drain placements, awareness and early recognition of this complication is critical to minimize incidence, morbidity and mortality in these patients.

Morbidity of total pancreatectomy with islet cell auto-transplantation compared to total pancreatectomy alone.

BACKGROUND: In pancreatitis, total pancreatectomy (TP) is an effective treatment for refractory pain. Islet cell auto-transplantation (IAT) may mitigate resulting endocrinopathy. Short-term morbidity data for TP + IAT and comparisons with TP are limited. METHODS: This study, using 2005-2011 National Surgical Quality Improvement Program data, examined patients with pancreatitis or benign neoplasms. Morbidity after TP alone was compared with that after TP + IAT. RESULTS: In 126 patients (40%) undergoing TP and 191 (60%) patients undergoing TP + IAT, the most common diagnosis was chronic pancreatitis. Benign neoplasms were present in 46 (14%) patients, six of whom underwent TP + IAT. Patients in the TP + IAT group were younger and had fewer comorbidities than those in the TP group. Despite this, major morbidity was more frequent after TP + IAT than after TP [n = 79 (41%) versus n = 36 (29%); P = 0.020]. Transfusions were more common after TP + IAT [n = 39 (20%) versus n = 9 (7%); P = 0.001], as was longer hospitalization (13 days versus 9 days; P < 0.0001). There was no difference in mortality. CONCLUSIONS: This study is the only comparative, multicentre study of TP and TP + IAT. The TP + IAT group experienced higher rates of major morbidity and transfusion, and longer hospitalizations. Better data on the longterm benefits of TP + IAT are needed. In the interim, this study should inform physicians and patients regarding the perioperative risks of TP + IAT.

Gut microbiota and metabolite interface-mediated hepatic inflammation.

Immunologic and metabolic signals regulated by gut microbiota and relevant metabolites mediate bidirectional interaction between the gut and liver. Gut microbiota dysbiosis, due to diet, lifestyle, bile acids, and genetic and environmental factors, can advance the progression of chronic liver disease. Commensal gut bacteria have both pro- and anti-inflammatory effects depending on their species and relative abundance in the intestine. Components and metabolites derived from gut microbiota-diet interaction can regulate hepatic innate and adaptive immune cells, as well as liver parenchymal cells, significantly impacting liver inflammation. In this mini review, recent findings of specific bacterial species and metabolites with functions in regulating liver inflammation are first reviewed. In addition, socioeconomic and environmental factors, hormones, and genetics that shape the profile of gut microbiota and microbial metabolites and components with the function of priming or dampening liver inflammation are discussed. Finally, current clinical trials evaluating the factors that manipulate gut microbiota to treat liver inflammation and chronic liver disease are reviewed. Overall, the discussion of microbial and metabolic mediators contributing to liver inflammation will help direct our future studies on liver disease.

Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy.

Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack of early diagnoses and the high refractory response to the currently available treatments, PDAC has a very poor prognosis, with a 5-year overall survival rate of less than 10%. Targeted therapy and immunotherapy are highly effective and have been used for the treatment of many types of cancer; however, they offer limited benefits in pancreatic cancer patients due to tumor-intrinsic and extrinsic factors that culminate in drug resistance. The identification of key factors responsible for PDAC growth and resistance to different treatments is highly valuable in developing new effective therapeutic strategies. In this review, we discuss some molecules which promote PDAC initiation and progression, and their potential as targets for PDAC treatment. We also evaluate the challenges associated with patient outcomes in clinical trials and implications for future research.

Targeted Therapy for Highly Desmoplastic and Immunosuppressive Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a very poor prognosis. Despite advancements in treatment strategies, PDAC remains recalcitrant to therapies because patients are often diagnosed at an advanced stage. The advanced stage of PDAC is characterized by metastasis, which typically renders it unresectable by surgery or untreatable by chemotherapy. The tumor microenvironment (TME) of PDAC comprises highly proliferative myofibroblast-like cells and hosts the intense deposition of a extracellular matrix component that forms dense fibrous connective tissue, a process called the desmoplastic reaction. In desmoplastic TMEs, the incessant aberration of signaling pathways contributes to immunosuppression by suppressing antitumor immunity. This feature offers a protective barrier that impedes the targeted delivery of drugs. In addition, the efficacy of immunotherapy is compromised because of the immune cold TME of PDAC. Targeted therapy approaches towards stromal and immunosuppressive TMEs are challenging. In this review, we discuss cellular and non-cellular TME components that contain actionable targets for drug development. We also highlight findings from preclinical studies and provide updates about the efficacies of new investigational drugs in clinical trials.

Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model.

UNLABELLED: The high rate of mortality and frequent incidence of recurrence associated with hepatocellular carcinoma (HCC) reveal the need for new therapeutic approaches. In this study we evaluated the efficacy of a novel chemoimmunotherapeutic strategy to control HCC and investigated the underlying mechanism that increased the antitumor immune response. We developed a novel orthotopic mouse model of HCC through seeding of tumorigenic hepatocytes from SV40 T antigen (Tag) transgenic MTD2 mice into the livers of syngeneic C57BL/6 mice. These MTD2-derived hepatocytes form Tag-expressing HCC tumors specifically within the liver. This approach provides a platform to test therapeutic strategies and antigen-specific immune-directed therapy in an immunocompetent murine model. Using this model we tested the efficacy of a combination of oral sunitinib, a small molecule multitargeted receptor tyrosine kinase (RTK) inhibitor, and adoptive transfer of tumor antigen-specific CD8(+) T cells to eliminate HCC. Sunitinib treatment alone promoted a transient reduction in tumor size. Sunitinib treatment combined with adoptive transfer of tumor antigen-specific CD8(+) T cells led to elimination of established tumors without recurrence. In vitro studies revealed that HCC growth was inhibited through suppression of STAT3 signaling. In addition, sunitinib treatment of tumor-bearing mice was associated with suppression of STAT3 and a block in T-cell tolerance. CONCLUSION: These findings indicate that sunitinib inhibits HCC tumor growth directly through the STAT3 pathway and prevents tumor antigen-specific CD8(+) T-cell tolerance, thus defining a synergistic chemoimmunotherapeutic approach for HCC.

Scientific impact of Association for Academic Surgery and Society of University Surgeons plenary session abstracts increases in the era of the Academic Surgical Congress from 2006 to 2010.

BACKGROUND: The objective of our study was to analyze plenary abstracts since 2006, when the Association for Academic Surgery (AAS) and Society of University Surgeons (SUS) began hosting the combined annual Academic Surgical Congress (ASC). Plenary session abstracts from the separate AAS and SUS meetings from 2002 to 2004 had previously revealed no significant difference in the scientific impact of published manuscripts. MATERIALS AND METHODS: In total, 76 abstracts from the AAS (n = 40) and SUS (n = 36) plenary sessions at the annual ASC meetings (2006-2010) were reviewed. Publication rate, citation number, 2010 impact factor (IF), and 5-y IF were obtained. Statistical analysis was conducted using Fisher exact and Student t-tests. RESULTS: Overall, 60 (79%) of 76 ASC plenary abstracts presented between 2006 and 2010 were published in peer-reviewed journals. Analysis revealed a higher publication rate for AAS (90%) compared with SUS (67%) plenary abstracts (P = 0.02). Among the articles published, the overall mean number of total citations was 6.7, with no difference between AAS and SUS (5.9 versus 7.8, P = 0.46). The mean 2010 five-year IF for all publications was 4.6 (AAS, 4.3 versus SUS, 5.0; P = 0.54). Compared with a previous analysis from the separate meetings, the mean IF has increased for both societies at an equivalent rate of 0.4. CONCLUSIONS: After the initiation of the joint ASC meeting in 2006, the SUS and AAS plenary presentations continue to exhibit high-quality research. This study supports the benefit of a joint meeting for the AAS and SUS, as it has been associated with an increasing overall scientific impact for plenary abstracts.

Lymphoepithelial cysts of the pancreas. Can preoperative imaging distinguish this benign lesion from malignant or pre-malignant cystic pancreatic lesions?

CONTEXT: Lymphoepithelial cysts of the pancreas are rare true benign cystic tumors of the pancreas of uncertain etiology. Cystic neoplasms of the pancreas present a significant diagnostic dilemma in differentiating benign from premalignant or malignant variants. Since the first description of lymphoepithelial cysts in 1985, 109 cases have been reported in the literature. We describe 6 cases of this rare tumor, the preoperative imaging results, and a review the literature. PATIENTS: Five males and one female ranging in age from 47 to 76 years underwent resection for lymphoepithelial cysts. Five patients presented with abdominal pain related to the lesion and in one patient the lesion was discovered incidentally. Four patients had elevated serum CA 19-9 levels. Pre-operative imaging with a CT scan and MRI of the abdomen typically revealed a well defined hypodense mass with Hounsfield units (HU) in the range of 15 to 20. One patient had papillary projections into the lesion. The mean size was 3.3 cm (ranging from 1.8 cm to 4 cm). All lesions were exophytic off the pancreatic parenchyma (1 cyst was located in the head of the pancreas, 2 were in the body, and 3 were in the tail region). Pre-operative EUS-guided/CT-guided needle aspiration, when performed, was not diagnostic. All patients underwent resection (one pancreaticoduodenectomy, five left pancreatectomies) to remove these cystic neoplasms. Pathology revealed a cyst lined by non-dysplastic squamous cells surrounded by sheets of benign lymphocytes. No evidence of malignancy was found. CONCLUSION: Lymphoepithelial cysts of the pancreas are rare and are characteristically seen in men. While a hypodense mass (less than 20 HU) with papillary projections should be considered suspicious for lymphoepithelial cyst, a definitive diagnosis cannot be made solely based on preoperative imaging. EUS-guided biopsy coupled with biochemical/tumor marker studies are increasingly being used as a diagnostic tool to help differentiate between the various types of cystic pancreatic neoplasms. Imaging findings of lymphoepithelial cysts are non-specific and hence surgical resection is often required to rule out the presence of a malignant or pre-malignant cystic pancreatic lesion. In true lymphoepithelial cysts, malignant transformation is not seen and patients who have these cysts are not at increased risk of developing a pancreatic malignancy.