Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner.

Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2+ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.

[THE MULTIDISCIPLINARY APPROACH TO ACUTE NECROTIZING PANCREATITIS].

INTRODUCTION: Acute pancreatitis is among the most common gastrointestinal diseases, and a major cause of hospitalization and morbidity. Gallstones and alcohol abuse are the most common causes of acute pancreatitis. Other etiologies include hypertriglyceridemia, medications, post- endoscopic retrograde cholangiopancreatography (ERCP), trauma, hypercalcemia, infections and toxins, anatomic anomalies, etc. In most cases acute pancreatitis is a mild self-limiting disease. However, up to 20% of patients develop severe pancreatitis with pancreatic necrosis, which possess high rates of multi-organ failure and mortality. Conservative management of acute necrotizing pancreatitis includes fluid resuscitation, nutritional support, and broad spectrum antibiotics for infected necrotic peripancreatic fluid collection (PFC). Indications for further invasive interventions include infected necrotic PFC and/or persistent severe symptoms due to mass effect. Current clinical management algorithms favor endoscopic ultrasound (EUS)-guided drainage of PFCs. In case of a large collection or extension to the paracolic gutters, a percutaneous drainage is indicated. Dual modalities (percutaneous together with endoscopic drainage) possess lower rates of pancreatic-cutaneous fistulas, shorter length of hospitalization and less endoscopic interventions. Direct endoscopic necrosectomy should be considered when the patient fails to improve despite endoscopic and percutaneous drainage. A multidisciplinary approach, which involves advanced endoscopists, interventional radiologists, pancreaticobiliary surgeons as well as nutrition and infectious disease specialists, is needed for the optimal management of severe necrotizing pancreatitis.

Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients.

BACKGROUND & AIMS: Two SARS-CoV-2 mRNA vaccines were approved to prevent COVID-19 infection, with reported vaccine efficacy of 95%. Liver transplant (LT) recipients are at risk of lower vaccine immunogenicity and were not included in the registration trials. We assessed vaccine immunogenicity and safety in this special population. METHODS: LT recipients followed at the Tel-Aviv Sourasky Medical Center and healthy volunteers were tested for SARS-CoV-2 IgG antibodies directed against the Spike-protein (S) and Nucleocapsid-protein (N) 10-20 days after receiving the second Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine dose. Information regarding vaccine side effects and clinical data was collected from patients and medical records. RESULTS: Eighty LT recipients were enrolled. Mean age was 60 years and 30% were female. Twenty-five healthy volunteer controls were younger (mean age 52.7 years, p = 0.013) and mostly female (68%, p = 0.002). All participants were negative for IgG N-protein serology, indicating immunity did not result from prior COVID-19 infection. All controls were positive for IgG S-protein serology. Immunogenicity among LT recipients was significantly lower with positive serology in only 47.5% (p <0.001). Antibody titer was also significantly lower in this group (mean 95.41 AU/ml vs. 200.5 AU/ml in controls, p <0.001). Predictors for negative response among LT recipients were older age, lower estimated glomerular filtration rate, and treatment with high dose steroids and mycophenolate mofetil. No serious adverse events were reported in either group. CONCLUSION: LT recipients developed substantially lower immunological response to the Pfizer-BioNTech SARS-CoV-2 mRNA-based vaccine. Factors influencing serological antibody responses include age, renal function and immunosuppressive medications. The findings require re-evaluation of vaccine regimens in this population. LAY SUMMARY: The Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine elicited substantially inferior immunity in liver transplant recipients. Less than half of the patients developed sufficient levels of antibodies against the virus, and in those who were positive, average antibody levels were 2x less compared to healthy controls. Factors predicting non-response were older age, renal function and immunosuppressive medications.

Increased Rate of Complete Pathologic Response After Neoadjuvant FOLFIRINOX for BRCA Mutation Carriers with Borderline Resectable Pancreatic Cancer.

BACKGROUND: Neoadjuvant FOLFIRINOX is a standard-of-care treatment for BRPC patients. Patients with gBRCAm who have demonstrated improved response to platinum-based chemotherapy may have impaired homologous repair deficiency. This study aimed to describe the pathologic complete response rate and long-term survival for patients with germline BRCA1 or BRCA2 mutation (gBRCAm) and borderline resectable pancreatic cancer (BRPC) treated with neoadjuvant FOLFIRINOX. METHODS: A dual-center retrospective analysis was performed. Patients who had BRPC treated with neoadjuvant FOLFIRINOX followed by curative resection were identified from clinical databases. Pathologic complete response was defined as no viable tumor cells present in the specimen. Common founder Jewish germline BRCA1 or BRCA2 mutation was determined for available patients. RESULTS: The 61 BRPC patients in this study underwent resection after neoadjuvant FOLFIRINOX. Analysis of BRCA mutation was performed for 39 patients, and 9 patients were found to be BRCA2 germline mutation carriers. The pathologic complete response rate was 44.4% for the gBRCAm patients and 10% for the BRCA non-carriers (p = 0.009). The median disease-free survival was not reached for the gBRCAm patients and was 7 months for the BRCA non-carriers (p = 0.03). The median overall survival was not reached for the gBRCAm patients and was 32 months for the BRCA non-carriers (p = 0.2). After a mean follow-up period of 33.7 months, all eight patients with pathologic complete response were disease-free. CONCLUSIONS: The study showed that gBRCAm patients with BRPC have an increased chance for pathologic complete response and prolonged survival after neoadjuvant FOLFIRINOX. The results support the benefit of exposing gBRCAm patients to platinum-based chemotherapy early in the course of the disease. Neoadjuvant FOLFIRINOX should be considered for BRCA carriers who have resectable pancreatic cancer.

Prognostic significance of pancreatic fistula and postoperative complications after pancreaticoduodenectomy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The influence of postoperative complications, specifically, pancreatic fistula (PF), on long-term oncologic outcome in patients with pancreatic ductal adenocarcinoma (PDAC) is unclear. METHODS: Prospectively collected data of patients who underwent pancreaticoduodenectomy (PD) for PDAC between 2008 and 2016 were retrospectively reviewed and analyzed. Deaths within 90 days were excluded. Median follow-up time was 22 months for the entire cohort (range 2-102 months). PF was graded as biochemical leak, grade B, or grade C according to the criteria of the International Study Group on Pancreatic Fistula. Postoperative complications were graded according to the Clavien-Dindo classification (CDC). Data on clinical and pathological characteristics as well as on recurrence and survival were collected. RESULTS: Twenty-nine of the 148 identified patients (19%) developed PF, of whom 17 (11.4%) had a PF grade B or C. 29 patients developed a postoperative complication CDC grade 3 or 4. The respective 3-year disease-free survival was 15.5% and 19.2% (P = 0.725), and the 5-year overall survival was 20% and 16% (P = 0.914) in patients with and without PF. On multivariate analysis, the use of adjuvant chemotherapy, lymph node involvement, surgical margin involvement, and tumor grade were associated with patient survival. PF and postoperative complications CDC grade 3 or 4 were not associated with decreased long-term survival, disease-free survival or local recurrence rate. CONCLUSIONS: While acknowledging the limited sample size, no association was seen between PF or postoperative complications and overall or disease-free survival in patients undergoing PD for PDAC.

Surgical Approach to Abdominal Tumors Involving the Inferior Vena Cava.

BACKGROUND: Abdominal tumors invading the inferior vena cava (IVC) present significant challenges to surgeons and oncologists. OBJECTIVES: To describe a surgical approach and patient outcomes. METHODS: The authors conducted a retrospective analysis of surgically resected tumors with IVC involvement by direct tumor encasement or intravascular tumor growth. Patients were classified according to level of IVC involvement, presence of intravascular tumor thrombus, and presence of hepatic parenchymal involvement. RESULTS: Study patients presented with leiomyosarcomas (n=5), renal cell carcinoma (n=7), hepatocellular carcinoma (n=1), cholangiocarcinoma (n=2), Wilms tumor (n=1), neuroblastoma (n=1), endometrial leiomyomatosis (n=1), adrenocortical carcinoma (n=1), and paraganglioma (n=1). The surgeries were conducted between 2010 and 2019. Extension of tumor thrombus above the hepatic veins required a venovenous bypass (n=3) or a full cardiac bypass (n=1). Hepatic parenchymal involvement required total hepatic vascular isolation with in situ hepatic perfusion and cooling (n=3). Circular resection of IVC was performed in five cases. Six patients had early postoperative complications, and the 90-day mortality rate was 10%. Twelve patients were alive, and six were disease-free after a mean follow-up of 1.6 years. CONCLUSIONS: Surgical resection of abdominal tumors with IVC involvement can be performed in selected patients with acceptable morbidity and mortality. Careful patient selection, and multidisciplinary involvement in preoperative planning are key for optimal outcome.

The transcriptional profile of circulating myeloid derived suppressor cells correlates with tumor development and progression in mouse.

Myeloid derived suppressor cells (MDSCs) play key roles in cancer development. Accumulation of peripheral-blood MDSCs (PB-MDSCs) corresponds to the progression of various cancers, but provides only a crude indicator. We aimed toward identifying changes in the transcriptional profile of PB-MDSCs in response to tumor growth. CT26 colon cancer cells and B16 melanoma cells (106) were inoculated into peritoneal cavities of BALB/c mice and subcutaneously to C57-black mice, respectively. The circulating levels and global transcriptional patterns of PB CD11b+Ly6g+ MDSCs were assessed in control mice, and 4, 8, and 11 days following tumor cell inoculation. Although a significant accumulation of PB-MDSCs was demonstrated only 11 days following tumor induction, a pronounced transcriptional response was identified already on day 4 while the tumor was ~1 mm in size. Further transcriptional changes correlated with different stages of tumor growth. Key MDSC genes and canonical signaling pathways were activated along tumor progression. This phenomenon was demonstrated in both cancer models, and a consensus set of 817 genes, involved in myeloid cell recruitment and angiogenesis, was identified. The data suggest that the transcriptional signatures of PB-MDSC may serve as markers for tumor progression, as well as providing potential targets for future therapies.

R1 resection of colorectal liver metastasis - What is the cost of marginal resection?

BACKGROUND AND OBJECTIVES: The impact of resection margins on the outcome of patients with colorectal liver metastasis (CRLM) remains controversial. We evaluated the short and long-term results of R1 resection. METHODS: Between 2006 and 2016, 202 patients underwent liver resection for CRLM. R1 resection was defined as a distance of less than 1 mm between tumor cells and the transection plain. Patient and tumor characteristics, perioperative, and long-term outcomes were assessed. RESULTS: In 161 (79.7%) and 41 (20.3%) patients, an R0 and R1 resections were achieved, respectively. Patients that underwent an R1 resection had higher rates of disease progression while on chemotherapy (12.1% vs 5.5%, P = 0.001), need for second-line chemotherapy (17% vs 6.2%, P < 0.001), increased use of preoperative volume manipulation (14.6% vs 5.5%, P = 0.001), and inferior vena-cava involvement (21.9% vs 8.7%, P < 0.001). These patients had higher rates of major postoperative complications (19.5% vs 6.8%, P < 0.001) and reoperations (7.3% vs 2.4%, P < 0.001). Multivariate analysis demonstrated that R1 resections were not associated with decreased recurrence-free survival or overall survival. CONCLUSIONS: Although R1 resection is associated with worse disease behavior and postoperative complications, the long-term outcome of patients following an R1 resection is non-inferior to those who underwent an R0 resection.

Kidney transplantation in patients with inflammatory bowel diseases (IBD): analysis of transplantation outcome and IBD activity.

Inflammatory bowel diseases (IBD) is a systemic disorder with possible renal involvement, yet data regarding the outcome of kidney transplantation (KT) in those patients, and IBD course post KT, are scarce. In this retrospective analysis, we studied the outcome of 12 IBD kidney recipients (seven Crohn's disease, five ulcerative colitis; primary kidney disease was IgA nephropathy in five, polycystic disease in four), compared to two control groups: matched controls and a cohort of recipients with similar kidney disease. During a follow-up period of 60.1 (11.0-76.6) months (median, interquartile range), estimated 5-year survival was 80.8 vs. 96.8%, with and without IBD, respectively (P = 0.001). Risk of death with a functioning graft was higher with IBD (HR = 1.441, P = 0.048), and with increased age (HR = 1.109, P = 0.05). Late rehospitalization rate was higher in IBD [incidence rate ratio = 1.168, P = 0.030], as well as rate of hospitalization related to infection [1.42, P = 0.037]. All patients that were in remission before KT, remission was maintained. Patients that were transplanted with mild or moderate disease remained stable or improved with Infliximab or Adalimumab treatment. In conclusion, IBD is associated with an increased risk of mortality, hospitalization because of infection and late rehospitalization after KT. Clinical course of IBD is stable after KT.

In sickness and in health: Living HIV positive kidney donation from a wife to her husband, with 7 years' post-transplant follow-up.

Human immunodeficiency virus (HIV) infection was traditionally considered an absolute contraindication for kidney transplantation. After the introduction of ART, several studies have demonstrated comparable patient and graft outcomes between HIV-negative and HIV-positive kidney recipients. The US Congress passed the HIV Organ Policy Equity (HOPE) Act in 2013, which permits research in the area of HIV-positive to HIV-positive transplantation. HIV-infected living donation is also permitted under the HOPE Act. However, there is a concern regarding the safety of kidney donation in an HIV-infected person, given the risk of renal disease associated with HIV infection. We report here the case of successful kidney transplantation from HIV-positive living donor to HIV-positive recipient performed in our center on July 2012. To the best of our knowledge, this is the earliest case done in this medical context to be reported in the literature, therefore, potentially carrying several important messages to the transplantation community. In the present case, the living-donor kidney transplant was performed between a married couple infected with same strain of HIV-1, both on effective ART with efficiently suppressed viral replication and satisfactory pre-transplantation immune status.

Long term metabolic and renal outcomes of kidney donors compared to controls with excellent kidney function.

BACKGROUND: Only few studies of living kidney donors have included controls that were similarly healthy, including excellent kidney function. METHODS: In this study, we aimed to estimate long term metabolic and renal outcome in a cohort of 211 living donors compared to two control groups: paired-matched controls, and another control group of 2534 healthy individuals with excellent kidney function. RESULTS: Donors presented with higher estimated Glomerular Filtration Rate (eGFR): (97.6 ± 15.2 vs 96.1 ± 12.2 vs 94.5 ± 12.4 ml/min/1.73m2) and lower urine albumin to creatinine ratio (UACR) (4.3 ± 5.9 vs 5.9 ± 6.1 vs 6.1 ± 6.9 mg/g) for donors, matched controls and healthy controls, respectively (p <  0.001). In a mean follow up period of 5.5 for donors, donors presented with positive eGFR slopes during the first 3 years post donation, followed by negative slopes, compared to constantly negative slopes presented in the control group (p <  0.05). The variables related to the slope were being a donor, baseline eGFR, Body Mass Index (BMI) and age but not eGFR on the last day of follow-up or increased delta UACR. There was a significant increase in UACR in donors, as well as a higher rate of albuminuria, associated with a longer time since donation, higher pre-donation UACR and higher pre-donation BMI. Healthy controls had a lower BMI at baseline and gained less weight during the follow up period. Donors and controls had similar incidence of new onset diabetes mellitus and hypertension, as well as similar delta systolic and diastolic blood pressure. Donors were more likely to develop new onset metabolic syndrome, even after adjustment for age, gender and BMI. The higher incidence of metabolic syndrome resulted mainly from increased triglycerides and impaired fasting glucose criteria. However, prevalence of major cardiovascular events was not higher in this group. CONCLUSIONS: Donors are at increased risk to develop features of the metabolic syndrome in addition to the expected mild reduction of GFR and increased urine albumin excretion. Future studies are needed to explore whether addressing those issues will impact post donation morbidity and mortality.

Early reoperation following pancreaticoduodenectomy: impact on morbidity, mortality, and long-term survival.

BACKGROUND: Reoperation following PD is a surrogate marker for a complex post-operative course and may lead to devastating consequences. We evaluate the indications for early reoperation following PD and analyze its effect on short- and long-term outcome. METHODS: Four hundred and thirty-three patients that underwent PD between August 2006 and June 2016 were retrospectively analyzed. RESULTS: Forty-eight patients (11%; ROp group) underwent 60 reoperations within 60 days from PD. Forty-two patients underwent 1 reoperation, and 6 had up to 6 reoperations. The average time to first reoperation was 10.1 ± 13.4 days. The most common indications were anastomotic leaks (22 operations in 18 patients; 37.5% of ROp), followed by post-pancreatectomy hemorrhage (PPH) (14 reoperations in 12 patients; 25%), and wound complications in 10 (20.8%). Patients with cholangiocarcinoma had the highest reoperation rate (25%) followed by ductal adenocarcinoma (12.3%). Reoperation was associated with increased length of hospital stay and a high post-operative mortality of 18.7%, compared to 2.6% for the non-reoperated group. For those who survived the post-operative period, the overall and disease-free survival were not affected by reoperation. CONCLUSIONS: Early reoperations following PD carries a dramatically increased mortality rate, but has no impact on long-term survival.

The impact of donor liver allograft fibrosis on patients undergoing liver transplantation.

BACKGROUND: The utilization of extended criteria liver allografts (ECD) shortens time to transplantation. OBJECTIVE: To characterize the effect of liver allograft fibrosis on graft and patient survival after liver transplantation (LT), with particular attention to fibrosis progression. METHODS: Retrospective database search of donor and recipient liver allograft histology of liver transplants performed between 2007 and 2011. Donor and patient characteristics were analyzed. RESULTS: One hundred and one patients underwent LT with donor liver allografts with early-stage fibrosis (stage 1 fibrosis and stage 2 fibrosis). The level of liver fibrosis did not progress in 40% of the patients tested, and there was a regression of fibrosis in 30%. At a median follow-up of 71 months, of 101 patients transplanted with fibrotic livers, 63 patients (63%) were alive with functioning initial grafts, six patients (6%) were retransplanted, and 35 patients expired. The graft survival rates were 82% and 69% at 1 and 5 years, respectively. Graft survival differences were not found to be statistically significant between the degrees of liver allograft fibrosis: 5-year graft survival (73% for stage 1 fibrosis and 62% for stage 2 fibrosis, P = .24). The entire fibrosis group was further compared with a control group of 208 consecutive primary liver transplant patients with allografts having no fibrosis. The 5-year graft survival was not significantly different between the groups (69% for the fibrosis group vs 75% for the nonfibrosis group, P = .19). Survival was also not statistically different between the groups (5-year survival of 73% for the fibrosis group vs 79% for the nonfibrosis group, P = .2). In patients with HCV, graft survival differences were not found to be statistically significant with the use of early-stage fibrotic livers: 5-year graft survival of 60% for fibrosis group vs 70% for the nonfibrosis group, P = .22). CONCLUSION: This study demonstrates that allografts with early-stage fibrosis achieve acceptable long-term survival after liver transplantation. Given these preliminary results, the use of organs with early-stage fibrosis warrants further studies at a larger scale to validate these results.

Upper midline incision for living donor right hepatectomy.

BACKGROUND: Living donor liver transplantation is a viable option to increase access to transplantation and techniques to limit the operative incision is one way to increase donation by decreasing donor morbidity. We describe our experience with a limited upper midline incision (UMI) for living donor right hepatectomy. STUDY DESIGN: Prospective data were collected on 58 consecutive living liver donors who underwent right hepatectomy via a UMI. RESULTS: Donor median age was 32 years, with median body mass index of 24.6. The mean incision length was 11.7 cm. Ten liver grafts included middle hepatic vein. The mean graft volume by preoperative imaging was 940 cc. The mean operative time was 407 minutes; cellsaver was utilized in 35 patients with median of 1 unit. Mean peak aspartate transaminase (AST) and alanine transaminase (ALT) were 492 and 469, and peak bilirubin and international normalized ratio (INR) were 3.3 and 1.8. The average length of stay was 6 days. There were 10 Clavien grade I and 11 Clavien grade II complications. Three patients developed an incisional hernia requiring surgical repair. CONCLUSION: Living liver donor hepatectomy can be safely performed through a UMI. This approach consolidates the steps of liver mobilization, hilar dissection, and parenchymal transection in a single-exposure technique, with incision comparable to the laparoscopic-assisted modality.

Resection of colorectal liver metastases in the elderly-Is it justified?

BACKGROUND AND OBJECTIVES: Liver resection of colorectal liver metastasis (CRLM) may necessitate large metabolic and physiologic reserve. As the population ages, resection of CRLM is increasingly required in the elderly. We assessed the safety and efficacy of these operations. METHODS: Between February 2010 and 2015, 174 patients underwent liver resection of CRLM. Fifty-four and 120 patients were over and under the age of 70 at the time of surgery, respectively (mean ages: 76 ± 4 and 56.5 ± 9 years). Patient and tumor characteristics, perioperative, and long-term outcomes were compared. RESULTS: Elderly patients had increased rates of IHD (18.5% versus 6.6%, P = 0.0002), COPD (9.2% versus 4.1%, P = 0.01), and DM (30% versus 14%, P = 0.02). Operative time was shorter in elderly patients (222 ± 109 versus 261 ± 110 min; P = 0.04). Intraoperative blood loss was comparable. The rate of minor postoperative complications was similar between groups, but elderly patients had higher rate of major complications (11.1% versus 2.5%, P < 0.0001). One elderly patient died following surgery (1.8%). Length of hospital stay was similar between groups. No difference in 3-year survival was demonstrated. CONCLUSIONS: Although associated with a small increase in postoperative morbidity and mortality, liver resection may be performed safely and effectively in carefully selected elderly patients. J. Surg. Oncol. 2016;113:485-488. © 2016 Wiley Periodicals, Inc.

Visceral Fat Content Correlates with Retroperitoneal Soft Tissue Sarcoma (STS) Local Recurrence and Survival.

BACKGROUND: Our aim was to evaluate the association between visceral fat content with soft tissue sarcoma (STS) local recurrence and survival. METHODS: One hundred and one computed tomography imaging studies of primary STS patients who had complete macroscopic resection at our institution between 2002 and 2012 were reviewed, and retroperitoneal and circumferential fat contents were measured. Correlations between imaging findings and clinical data were analyzed. RESULTS: Fifty-seven STS tumors (56.4%) were retroperitoneal; of them, 65% were high grade, median size was 15 cm (range 3-49), and the most common histological subtype was high grade liposarcoma (31.6%). Median follow-up length for the entire cohort was 64 months (range 6-95). High visceral fat (VF) content≥15 versus <15 mm was identified as a risk factor for retroperitoneal STS local recurrence; 65.1 versus 26.7%, respectively (p=0.04); VF content did not correlate with distant metastasis. Median overall survival (OS) length of patients with VF≥15 versus <15 mm was 57 months (range 2-144) versus not reached, respectively (p=0.007). Multivariable analysis identified VF≥15 mm as an independent risk factor for decreased OS (HR: 4.2, 95% CI 1.07-16.67). In contrast, circumferential fat content did not correlate with retroperitoneal STS patient outcomes. CONCLUSION: High VF content is an independent adverse prognosticator associated with significantly higher rates of retroperitoneal STS local recurrence and decreased patients survival. Local tumor biology may be affected by the presence of adipose cells. Further clinical and molecular research is needed to establish this premise.

Segment 4 and the left lateral segment regeneration pattern after resection of the middle hepatic vein in a living donor right hepatectomy.

BACKGROUND: Inclusion of the middle hepatic vein (MHV) with a right hepatectomy (RH) in live donor liver transplantation improves venous drainage of the anterior sector of the graft. Its long-term effects on donor left liver (LL) regeneration are not well described. METHODS: Donors who underwent RH with MHV (MHV+, n = 12) were compared with donors who underwent RH with preservation of the MHV (MHV-, n = 24). Peri-operative complications and volume of the entire liver and individual segments were evaluated at 1 year post-donation. RESULTS: There was a trend towards a higher complication rate in the MHV+ group (41% versus 25%), without reaching statistical significance (P = 0.3). Males, high body mass index (BMI) and a smaller residual liver volume (RLV) were predictors for greater LL regeneration. MHV+ donors had impaired regeneration of segment 4 (S4) at 1 year, and compensatory greater left lateral segment regeneration. The absence of venous drainage of S4 (V4) to left hepatic vein (LHV) was a predictor of impaired S4 regeneration. CONCLUSIONS: Regeneration of S4 is impaired in MHV+ donors. Caution should be taken when considering MHV removal on donors with dominant S4, especially on those with potential increased demand for liver regeneration, such as males, higher BMI and a smaller RLV.

Differences in surgical outcomes between hepatitis B- and hepatitis C-related hepatocellular carcinoma: a retrospective analysis of a single North American center.

OBJECTIVE: Compare surgical outcomes for hepatitis B virus (HBV)-hepatocellular carcinoma (HCC) versus hepatitis C virus (HCV)-hepatocellular carcinoma (HCC). BACKGROUND: HCC is the second leading cause of death from cancer worldwide and is associated with hepatitis virus infection in 80% of cases. METHODS: Between 1997 and 2011, 1008 patients with hepatitis B (HBV, n = 431) or hepatitis C (HCV, n = 577) underwent resection (n = 567) or transplantation (n = 441). Resection was indicated for Child's A patients with single HCC; transplantation was indicated for patients within Milan criteria. Univariate and multivariate analyses were performed as well as survival and recurrence analysis using log-rank test. RESULTS: Based on uniform application of these criteria, resection: transplantation ratio was 3.6 for patients with HBV and 0.67 for patients with HCV. Resection: Patients with HBV had larger tumors and higher α-fetoprotein but less satellites and macrovascular invasion; 68% of HBV versus 89% of HCV were cirrhotic. Survival was better (P < 0.001) and recurrence was lower (P = 0.009) for HBV. Independent predictors of death included HCV (P = 0.024), transfusion (P = 0.013), and HCC of greater than 5 cm (P = 0.013). Limiting analysis to patients with cirrhosis, survival with HBV remained superior (P = 0.020) but recurrence did not. Transplantation: Tumors were similar in HBV and HCV. Survival was better (P = 0.002) for HBV; recurrence was similar. Independent predictors of death were HCV (P < 0.001), poor differentiation (P = 0.049), vascular invasion (P = 0.002), and outside Milan (P = 0.032). Limiting analysis to patients within Milan, HBV survival remained better for both resection (P = 0.030) and transplantation (P = 0.002). CONCLUSIONS: Survival after both resection and transplantation for HCC was better in HBV- than in HCV-related HCC whereas recurrence was also lower for HBV-HCC in the resection group, these differences are influenced by both liver and tumor factors.

Epithelial-to-mesenchymal transition (EMT) in intraductal papillary mucinous neoplasm (IPMN) is associated with high tumor grade and adverse outcomes.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is generally associated with increased tumor aggressiveness and poor prognosis. We evaluated EMT characteristics in intraductal papillary mucinous neoplasm (IPMN) tumor specimens and their potential role as biomarkers for malignancy, metastasis, and adverse patient outcomes. METHODS: IPMN surgical specimens were identified and reviewed by two gastrointestinal pathologists. Immunohistochemical analysis of E-cadherin, vimentin, and ZEB-1 was performed. Samples were linked to clinicopathologic and outcome data for these patients. Western blot test was used to evaluate ZEB-1 expression in IPMN samples; 846 human miRNAs were profiled, and EMT-related differentially expressed miRNAs were validated using quantitative real-time polymerase chain reaction. RESULTS: Fifty-eight IPMN specimens and five normal pancreatic tissue samples were immunohistochemically stained and scored. E-cadherin expression was significantly lower in malignant versus low-grade IPMN (p < 0.05). Vimentin expression was increased in malignant IPMN tumor samples (p < 0.05). EMT was associated with increased lymph node metastasis and decreased survival of malignant IPMN patients (p < 0.05). ZEB-1, an imperative EMT regulator, was exclusively expressed by malignant IPMN tumors. miRNA hierarchical clustering demonstrated grouping of two main IPMN subgroups: low-grade IPMN versus high-grade IPMN and carcinoma. Twenty-four miRNAs were differentially expressed (14 up-regulated, 10 down-regulated). The EMT-regulatory miRNAs, miR-200c and miR-141, were down-regulated (twofold and 1.8-fold decrease, respectively) in malignant versus low-grade IPMN (p < 0.05). CONCLUSIONS: EMT may play a role in IPMN tumorigenesis and metastasis. EMT molecular deregulations could be utilized as potential novel biomarkers for the identification of high-risk IPMN patients.