Regional Metastatic Behavior of Nonfunctional Pancreatic Neuroendocrine Tumors: Impact of Lymph Node Positivity on Survival.

OBJECTIVES: Literature addressing the significance of lymph node positivity in the management of nonfunctional pancreatic neuroendocrine tumors (PNETs) is conflicting. METHODS: The National Cancer Data Base was queried for patients who underwent surgical resection of nonfunctional PNETs between 1998 and 2011. Clinical data and overall survival were analyzed using χ and Cox proportional hazards regression. Multiple imputation was used as a comparative analysis because of the high number of patients missing data on tumor grade. RESULTS: Two thousand seven hundred thirty-five patients were identified. The overall incidence of lymph node metastasis was 51%. In the subset of patients with grade 1 tumors less than 1 cm, 24% had positive lymph nodes. Overall median survival for patients with negative lymph nodes was 11 years compared with 8 years for lymph node-positive patients (P < 0.001). On multivariate survival analysis, tumor grade, distant metastases, regional lymph node involvement, positive surgical margins, male sex, and older age were predictive of decreased overall survival. CONCLUSIONS: Lymph node positivity was associated with decreased overall survival. The incidence of lymph node involvement in resected low-grade tumors less than 1 cm is higher than previously reported. Patients selected for resection of PNETs should be offered lymphadenectomy for staging.

Neoadjuvant radiation therapy and its impact on complications after pancreaticoduodenectomy for pancreatic cancer: analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP).

OBJECTIVES: This study investigated the impact of neoadjuvant radiation therapy (XRT) on postoperative outcomes following pancreaticoduodenectomy for pancreatic cancer. METHODS: The American College of Surgeons National Quality Improvement Program database was queried for the period 2005-2010 to assess complication rates following pancreaticoduodenectomy for pancreatic cancer. Two groups of patients were identified, comprising those who received neoadjuvant XRT and those who did not (control group). RESULTS: A total of 4416 patients were identified, including 200 in the XRT group and 4216 in the control group. There were differences in patient characteristics between the groups, including in age, hypertension and bilirubin level. Despite the fact that weight loss was more common, median operative time was longer (423 min versus 368 min; P < 0.001), and vascular reconstruction was more commonly required (20.5% versus 8.4%; P < 0.001) in the XRT group. In addition, the XRT group had a shorter median hospital stay than the control group (9 days versus 10 days; P = 0.005). Mortality (3.0% versus 2.7%; P = 0.818) and morbidity (40.5% versus 37.6%; P = 0.404) rates were not influenced by neoadjuvant XRT. Blood transfusion rates were increased in the XRT group (13.0% versus 7.4%; P = 0.003). Severe complications were influenced by age >70 years, American Society of Anesthesiologists (ASA) class >2, preoperative sepsis, dyspnoea, weight loss, impaired functional status, peripheral vascular disease and operative time of >8 h. CONCLUSIONS: Neoadjuvant XRT is not associated with an increase in complications after pancreaticoduodenectomy.

Umbilical hernia repair in patients with signs of portal hypertension: surgical outcome and predictors of mortality.

OBJECTIVES: To compare the outcomes of umbilical hernia repair in patients with and without signs of portal hypertension, such as esophageal varices or ascites; to assess the effect of emergency surgery on complication rates; and to identify predictors of postoperative mortality. DESIGN: Database search from January 1, 2005, through December 31, 2009. SETTING: North American hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program initiative. PATIENTS: We studied patients who underwent umbilical hernia repair. Those with congestive heart failure, disseminated malignant tumor, or chronic renal failure while undergoing dialysis were excluded. MAIN OUTCOME MEASURES: Preoperative variables and perioperative course were analyzed. Main outcome measures were morbidity and mortality after umbilical hernia repair. RESULTS: A total of 390 patients with ascites and/or esophageal varices formed the study group, and the remaining 22 952 patients formed the control group. The overall morbidity and mortality rates for the study group were 13.1% and 5.1%, whereas these rates were 3.9% and 0.1% for the control group, respectively (P < .001). For the study group, the mortality after elective repair among patients with a model for end-stage liver disease (MELD) score greater than 15 was 11.1% compared with 1.3% in patients with a MELD score of 15 or less. The patients with ascites and/or esophageal varices underwent emergency surgery more frequently than the control group (37.7% vs 4.9%; P < .001). Emergency surgery for the study group was associated with a higher morbidity than elective surgery (20.8% vs 8.3%; P < .001) but not a significantly higher mortality (7.4% vs 3.7%; P = .11). However, logistic regression analysis showed that age older than 65 years, MELD score higher than 15, albumin level less than 3.0 g/dL (to convert to grams per liter, multiply by 10), and sepsis at presentation were more predictive of postoperative mortality. CONCLUSIONS: Umbilical hernia repair in the presence of ascites and/or esophageal varices is associated with significant postoperative complication rates. Emergency surgery is associated with higher morbidity rates but not significantly higher mortality rates. Elective repair of umbilical hernia should be avoided for those with adverse predictors, such as age older than 65 years, MELD score higher than 15, and albumin level less than 3.0 g/dL.

Serum markers for necroinflammatory activity in patients with chronic viral hepatitis and normal or mildly elevated aminotransferase levels.

BACKGROUND: Reports on the usefulness of serum markers for predicting liver necroinflammation are limited. The aim of this study was to determine the serum markers that predict significant inflammation in patients with chronic hepatitis B (CHB) and C (CHC) and normal or mildly elevated serum aminotransferase levels. METHODS: Two hundred twenty-seven patients with CHB or CHC with normal or mildly elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (≤60 IU/L) were enrolled in this study. Significant inflammation was defined as inflammatory grade ≥3 activities using the Batt-Ludwig scoring system. The correlation between liver histology and serum markers of liver inflammation was analysed. RESULTS: Forty-eight (21.1%) and eight patients (3.5%) had grade 3 and 4 inflammation respectively. Univariate analysis revealed that age, platelet coun, and AST, ALT, γ-glutamyl transpeptidase, alkaline phosphatase, hyaluronic acid, haptoglobin, apolipoprotein A1 and procollagen III N-terminal peptide levels were significantly different between the patients with and without significant inflammation. There were no significant differences in the cytokeratin-18 fragment levels between the two groups. On the basis of multivariate analysis, the AST and apolipoprotein A1 levels and stage of fibrosis were highly predictive of significant inflammation. Using AST and apolipoprotein cut-off values ≥44 IU/L and ≤100 ng/ml, respectively, the presence of significant inflammation was predicted with high specificity (96.5%) and with a negative predictive value of 76.3%. CONCLUSION: The AST and apolipoprotein A1 levels were shown to be independent predictors of significant inflammatory activities in patients with CHB and CHC and normal or mildly elevated aminotransferase levels.

High mobility group box 1 release from hepatocytes during ischemia and reperfusion injury is mediated by decreased histone deacetylase activity.

The mobilization and extracellular release of nuclear high mobility group box-1 (HMGB1) by ischemic cells activates inflammatory pathways following liver ischemia/reperfusion (I/R) injury. In immune cells such as macrophages, post-translational modification by acetylation appears to be critical for active HMGB1 release. Hyperacetylation shifts its equilibrium from a predominant nuclear location toward cytosolic accumulation and subsequent release. However, mechanisms governing its release by parenchymal cells such as hepatocytes are unknown. In this study, we found that serum HMGB1 released following liver I/R in vivo is acetylated, and that hepatocytes exposed to oxidative stress in vitro also released acetylated HMGB1. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups and control the acetylation status of histones and various intracellular proteins. Levels of acetylated HMGB1 increased with a concomitant decrease in total nuclear HDAC activity, suggesting that suppression in HDAC activity contributes to the increase in acetylated HMGB1 release after oxidative stress in hepatocytes. We identified the isoforms HDAC1 and HDAC4 as critical in regulating acetylated HMGB1 release. Activation of HDAC1 was decreased in the nucleus of hepatocytes undergoing oxidative stress. In addition, HDAC1 knockdown with siRNA promoted HMGB1 translocation and release. Furthermore, we demonstrate that HDAC4 is shuttled from the nucleus to cytoplasm in response to oxidative stress, resulting in decreased HDAC activity in the nucleus. Together, these findings suggest that decreased nuclear HDAC1 and HDAC4 activities in hepatocytes following liver I/R is a mechanism that promotes the hyperacetylation and subsequent release of HMGB1.

Spontaneous rupture of hepatic artery aneurysm associated with polyarteritis nodosa.

Polyarteritis nodosa (PAN) is a vasculitis, which often involves small and medium sized visceral arteries. This condition may result in multifocal aneurismal formation and end-organ damage. Uncommonly, PAN may present with rupture of hepatic artery aneurysms. Here, we report a rare case of a ruptured intrahepatic aneurysm associated with PAN. A 79-year-old woman presenting with abdominal pain had CT scan of the abdomen, which revealed hematoma in the right hepatic lobe. Visceral angiogram confirmed pseudo-aneurysm of a right hepatic arterial branch, and this was managed with endovascular coil embolization. The diagnosis of PAN was made and corticosteroid therapy was initiated. We also performed a literature review to define this condition's demographics, clinical presentations, and appropriate management. The review revealed 17 published cases of ruptured PAN-related intrahepatic aneurysms. We conclude that unexplained findings of visceral arterial aneurysms should prompt investigations for vasculitis as the etiology.

Transcatheter arterial chemoembolization is a feasible palliative locoregional therapy for breast cancer liver metastases.

Background. Liver metastases are common in advanced breast cancer. We sought to evaluate the role of transcatheter arterial chemoembolization (TACE) in breast cancer patients with hepatic metastases. Methods. A retrospective review of ten patients with breast cancer who were treated with TACE for unresectable liver metastases (1998-2008). Results. All patients, median age 46.5, had received prior systemic chemotherapies. Adriamycin was administered for 6, cisplatin/gemcitabine for 2, cisplatin for one and oxaliplatin for one patient. Median number of TACE cycles was 4. Kaplan Meier survival analysis showed an increase in median survival for patients who responded to treatment when compared to those who did not respond (24 vs 7 months, P = .02). Conclusions. This is one of the largest series of breast cancer patients with liver metastases treated with TACE. It suggests that TACE is a feasible palliative option and warrants further investigations.

Postoperative management of Crohn disease.

Crohn disease often recurs after surgical resection. Despite extensive research in the prevention of postoperative Crohn disease, optimal management strategies have yet to be defined. Risk of disease recurrence needs to be carefully balanced against potential risks associated with treatment. Patients with low risk of postoperative recurrence may not require medication, whereas those at moderate risk may benefit from antibiotics or immunomodulators. Those at highest risk of recurrence may benefit from biologic therapy for maintenance of surgical remission. Postoperative colonoscopy within 1 year of resective surgery is important for identification of disease recurrence and modification of medications.

Postoperative management of crohn disease.

Crohn disease often recurs after surgical resection. Despite extensive research in the prevention of postoperative Crohn disease, optimal management strategies have yet to be defined. Risk of disease recurrence needs to be carefully balanced against potential risks associated with treatment. Patients with low risk of postoperative recurrence may not require medication, whereas those at moderate risk may benefit from antibiotics or immunomodulators. Those at highest risk of recurrence may benefit from biologic therapy for maintenance of surgical remission. Postoperative colonoscopy within 1 year of resective surgery is important for identification of disease recurrence and modification of medications.

Donor graft interferon regulatory factor-1 gene transfer worsens liver transplant ischemia/reperfusion injury.

BACKGROUND: Liver ischemia and reperfusion (IR) injury is a phenomenon that leads to graft dysfunction after liver transplantation. Understanding the molecular mechanisms behind this process is crucial to developing strategies to prevent short- and long-term graft dysfunction. The purpose of this study was to explore the role of the transcription factor interferon regulatory factor-1 (IRF-1) in a model of orthotopic rat liver transplantation. METHODS: Orthotopic syngeneic LEW rat liver transplantation (OLT) was performed after 18 or 3 hours preservation in cold University of Wisconsin solution. Adenovirus-expressing IRF-1 (AdIRF-1) or control gene vector (Adnull) was delivered to the liver by donor intravenous pretreatment 4 days before graft harvesting. Uninfected grafts also served as controls. Recipients were humanely killed 1-24 hours post-transplantation. RESULTS: Rats that underwent OLT with long-term preserved grafts (18 hours) displayed increased hepatic nuclear expression of IRF-1 protein at 1 and 3 hours. Rats pretreated with AdIRF-1 before transplantation had elevated alanine aminotransferase levels and increased expression of interferon (IFN)-beta, IFN-gamma, interleukin-12, and inducible nitric oxide synthase in the short-term period (3 hours) when compared with donor livers pretreated with Adnull. AdIRF-1 pretreated donor livers also exhibited increased susceptibility to early apoptosis in the transplanted grafts as shown by increased terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining and expression of cleaved caspase-3. Additionally, AdIRF-1 pretreated donor livers had increased activation of the MAP kinase Jun N-terminal kinase as compared with Adnull pretreated donor livers. CONCLUSION: IRF-1 is an important regulator of IR injury after OLT in rats. Targeting of IRF-1 may be a potential strategy to ameliorate ischemic liver injury after transplantation to minimize organ dysfunction.

Surgical management of hepatocellular adenoma: take it or leave it?

BACKGROUND: Hepatocellular adenoma (HA) is a rare benign tumor of the liver. Surgical resection is generally indicated to reduce risks of hemorrhage and malignant transformation. We sought to evaluate clinical presentation, surgical management, and outcomes of patients with HA at our institution. METHODS: We performed a retrospective review of 41 patients who underwent surgical resection for HA between 1988 and 2007. RESULTS: Thirty-eight patients were women, and the median age at presentation was 36 years (range, 19-65 years). The most common clinical presentation was abdominal pain (70%) followed by incidental radiological finding (17%). Twenty-two patients had a history of oral contraceptive use. Median number of HA was one (range, 1-3). There were 32 open cases (3 trisectionectomy, 15 hemihepatectomy, 7 sectionectomy, 4 segmentectomy, and 3 wedge resection), and 9 laparoscopic cases (1 hemihepatectomy, 5 sectionectomy, 1 segmentectomy, and 2 wedge resection). The median estimated blood loss was 225 mL (range, 0-3400 mL). The median length of stay was 6 days (range, 1-15 days). Surgical morbidities included pleural effusion requiring percutaneous drainage (n = 2), pneumonia (n = 1), and wound infection (n = 1). There was no perioperative mortality. Twelve patients had hemorrhage from HA. Hepatocellular carcinoma was observed in two patients with HA. Median follow-up was 23 months (range, 1-194 months), at which time all patients were alive. CONCLUSION: In view of 29% hemorrhagic and 5% malignant complication rates, we recommend surgical resection over observation if patient comorbidities and anatomic location of HA are favorable. A laparoscopic approach can be safely used in selected cases.

Extrahepatic portal vein aneurysm--report of six patients and review of the literature.

Extrahepatic portal vein aneurysm is a rare condition. We report six patients with extrahepatic portal vein aneurysm, four of whom were surgically treated. In addition, a review of the literature was performed to examine natural history, management, and outcomes regarding portal vein aneurysm. Patients seen at our institution with extrahepatic portal vein aneurysm greater than 1.9 cm in diameter were reviewed (1998 to 2006). There were five females and one male; median age was 66.5 (30-77). Computed tomography (CT) scan was utilized for diagnosis in all cases. The median diameter of the aneurysm was 4.7 cm (2.7-6.0). Indications for surgery included gallstone pancreatitis, mass effect on the adjacent duodenum, a peripancreatic mass, and liver cirrhosis. Three patients underwent aneurysm resection, and one patient had an orthotropic liver transplant. Two patients were managed with observation. The median follow-up from first presentation and surgery was 50 months (9-181) and 5 months (2-73), respectively. At last follow-up, five patients were alive with radiologically proven portal vein patency. One patient died 2 months after liver transplantation. There was no case of aneurysmal rupture. One patient had intramural thrombus at presentation that resolved with conservative treatment. This report suggests that symptomatic aneurysms can be safely resected with excellent patency.

Aggressive surgical management of peritoneal carcinomatosis with low mortality in a high-volume tertiary cancer center.

BACKGROUND: Cytoreductive surgery (CS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for treatment of peritoneal carcinomatosis (PC) traditionally involves high perioperative morbidity and mortality. We report our experience performing CS-HIPEC in a high-volume regional perfusion program designed to limit morbidity and mortality. METHODS: A total of 122 patients underwent 124 CS-HIPEC procedures. Common tumors treated with CS-HIPEC included appendiceal (38.5%), colorectal (24.6%), and ovarian cancers (13.1%), and peritoneal mesothelioma (12.3%). Complete cytoreduction was performed in all patients, with organ resections performed as necessary. RESULTS: R0 resection was achieved in 28.7% of cases, R1 in 54.9%, and R2 in 16.4%. Median operative time was 460 minutes (range, 250-840 minutes), and median blood loss was 1150 mL (range, 10-14,000 mL). Median hospital and intensive care unit stays were 12 days (range, 6-50 days) and 3 days (range, 0-41 days), respectively. Grade 3 or 4 morbidity by National Cancer Institute criteria (major morbidity) was seen in 29.8% of cases, with overall morbidity 56.5%. Independent prognostic variables for major morbidity included number of anastomoses and degree of cytoreduction. In-hospital and 30-day mortality rates were 0% and 1.6%, respectively. The most favorable diagnosis was appendiceal cancer, for which 2-year survival was 66.7%, with lower-grade histologic subtypes of appendiceal cancer reaching 85.7% 2-year survival. Colorectal cancer had 2-year survival of 36.7%. CONCLUSIONS: In a high-volume center with extensive experience treating peritoneal malignancies, perioperative mortality can be lowered to nearly zero, although morbidity remains high. CS-HIPEC procedures should be studied further in a controlled manner to help define their important role in the care of patients with PC.