Sherilyn Gordon Burroughs

Hepatocellular carcinoma: a review

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the United States, HCC is the ninth leading cause of cancer deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. Cirrhosis remains the most important risk factor for the development of HCC regardless of etiology. Hepatitis B and C are independent risk factors for the development of cirrhosis. Alcohol consumption remains an important additional risk factor in the United States as alcohol abuse is five times higher than hepatitis C. Diagnosis is confirmed without pathologic confirmation. Screening includes both radiologic tests, such as ultrasound, computerized tomography, and magnetic resonance imaging, and serological markers such as α-fetoprotein at 6-month intervals. Multiple treatment modalities exist; however, only orthotopic liver transplantation (OLT) or surgical resection is curative. OLT is available for patients who meet or are downstaged into the Milan or University of San Francisco criteria. Additional treatment modalities include transarterial chemoembolization, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, cryoablation, radiation therapy, systemic chemotherapy, and molecularly targeted therapies. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function. HCC is an aggressive cancer that occurs in the setting of cirrhosis and commonly presents in advanced stages. HCC can be prevented if there are appropriate measures taken, including hepatitis B virus vaccination, universal screening of blood products, use of safe injection practices, treatment and education of alcoholics and intravenous drug users, and initiation of antiviral therapy. Continued improvement in both surgical and nonsurgical approaches has demonstrated significant benefits in overall survival. While OLT remains the only curative surgical procedure, the shortage of available organs precludes this therapy for many patients with HCC.

Combined lung and liver transplantation: Analysis of a single-center experience

Patients with end‐stage lung disease complicated by cirrhosis are not expected to survive lung transplantation alone. Such patients are potential candidates for combined lung‐liver transplantation (CLLT), however few reports document the indications and outcomes after CLLT. This is a review of a large single‐center CLLT series. Eight consecutive CLLT performed during 2009‐2012 were retrospectively reviewed. One patient received a third simultaneous heart transplant. Mean age was 42.5 ± 11.5 years. Pulmonary indications included cystic fibrosis (CF) (n = 3), idiopathic pulmonary fibrosis (n = 2), α1‐antitrypsin deficiency (AATD) (n = 1) and pulmonary hypertension (n = 2). Liver indications were CF (n = 3), hepatitis C (n = 2), AATD (n = 1), cryptogenic (n = 1), and cardiac/congestive (n = 1). Urgency was reflected by median lung allocation score (LAS) of 41 (36.0‐89.0) and median predicted FEV1 of 25.7%. Median donor age was 25 (20‐58) years with median cold ischemia times of 147 minutes and 6.1 hours for lung and liver, respectively. Overall patient survival at 30 days, 90 days and 1 year was 87.5%, 75.0% and 71.4% respectively. One patient had evidence of acute lung rejection, and no patients had liver allograft rejection. Early postoperative mortalities (90 days) were caused by sepsis in 2 recipients who exhibited the highest LAS of 69.9 and 89.0. The remaining recipients had a median LAS of 39.5 and 100% survival at 1‐year. Median length of stay was 25 days (7‐181). Complications requiring operative intervention included bile duct ischemia (n = 1) and bile leak (n = 1), ischemia of the bronchial anastomosis (n = 1), and necrotizing pancreatitis with duodenal perforation (n = 1). This series reflects a large single‐center CLLT experience. Sepsis is the most common cause of death. The procedure should be considered for candidates with LAS < 50. Liver Transpl 20:46–53, 2014.

Combined lung and liver transplantation

Patients with end‐stage lung disease complicated by cirrhosis are not expected to survive lung transplantation alone. Such patients are potential candidates for combined lung‐liver transplantation (CLLT), however few reports document the indications and outcomes after CLLT. This is a review of a large single‐center CLLT series. Eight consecutive CLLT performed during 2009‐2012 were retrospectively reviewed. One patient received a third simultaneous heart transplant. Mean age was 42.5 ± 11.5 years. Pulmonary indications included cystic fibrosis (CF) (n = 3), idiopathic pulmonary fibrosis (n = 2), α1‐antitrypsin deficiency (AATD) (n = 1) and pulmonary hypertension (n = 2). Liver indications were CF (n = 3), hepatitis C (n = 2), AATD (n = 1), cryptogenic (n = 1), and cardiac/congestive (n = 1). Urgency was reflected by median lung allocation score (LAS) of 41 (36.0‐89.0) and median predicted FEV1 of 25.7%. Median donor age was 25 (20‐58) years with median cold ischemia times of 147 minutes and 6.1 hours for lung and liver, respectively. Overall patient survival at 30 days, 90 days and 1 year was 87.5%, 75.0% and 71.4% respectively. One patient had evidence of acute lung rejection, and no patients had liver allograft rejection. Early postoperative mortalities (90 days) were caused by sepsis in 2 recipients who exhibited the highest LAS of 69.9 and 89.0. The remaining recipients had a median LAS of 39.5 and 100% survival at 1‐year. Median length of stay was 25 days (7‐181). Complications requiring operative intervention included bile duct ischemia (n = 1) and bile leak (n = 1), ischemia of the bronchial anastomosis (n = 1), and necrotizing pancreatitis with duodenal perforation (n = 1). This series reflects a large single‐center CLLT experience. Sepsis is the most common cause of death. The procedure should be considered for candidates with LAS < 50. Liver Transpl 20:46–53, 2014.

Pre-transplant utilization of sorafenib is not associated with increased complications after liver transplantation

Hepatocellular carcinoma (HCC) is increasing in incidence, resulting in approximately 35% of orthotopic liver transplantation (OLT) performed each year. Sorafenib (SOR) is a multi‐kinase inhibitor that is approved for the treatment of unresectable HCC. Concerns have been raised regarding the safety of SOR in patients undergoing major surgery. We retrospectively reviewed 79 consecutive patients with HCC receiving OLT. Patient data were compared for those who received SOR pre‐OLT with those who did not. SOR was continued until time of transplant. During this time period, 15 patients received SOR pre‐OLT and 64 did not. The two groups were similar with regards to demographic and clinical data. SOR patients were more likely to have larger tumors, more tumor nodules, and be outside of Milan criteria. The rate of recurrence of HCC was not different between the groups (13% in SOR group, 11% in no‐SOR group). Surgical complications were not increased in patients receiving SOR prior to OLT. Survival rate was also similar between the two groups (median follow‐up 19.7 months). In this small cohort of patients, use of SOR prior to liver transplantation does not confer an increased risk of surgical complications, even when continued until the day of surgery.

Efficacy and cost‐effectiveness of voriconazole prophylaxis for prevention of invasive aspergillosis in high‐risk liver transplant recipients

Aspergillus infection remains a significant and deadly complication after liver transplantation (LT). We sought to determine whether the antifungal prophylactic use of voriconazole reduces the incidence of invasive aspergillosis (IA) in high‐risk LT recipients without prohibitively increasing cost. During the study era (April 2008 to April 2014), 339 deceased donor LTs were performed. Of those patients, 174 high‐risk recipients were administered antifungal prophylaxis with voriconazole. The median biological Model for End‐Stage Liver Disease score at the time of LT was 33 (range, 18‐49) with 56% requiring continuous renal replacement therapy and 50% requiring ventilatory support immediately before transplantation. Diagnosis of IA was stratified as proven, probable, or possible according to previously published definitions. No IA was documented in patients receiving voriconazole prophylaxis. At 90 days after LT, the institutional cost of prophylaxis was

Utility of an immune cell function assay to differentiate rejection from infectious enteritis in pediatric intestinal transplant recipients

5324 or 5.6% of the predicted cost associated with post‐LT aspergillosis. There was no documentation of resistant strains isolated from any recipient who received voriconazole. In conclusion, these data suggest that voriconazole prophylaxis is safe, clinically effective, and cost‐effective in high‐risk LT recipients. Liver Transpl 22:163–170, 2016.

Recruited metastasis suppressor NM23-H2 attenuates expression and activity of peroxisome proliferator-activated receptor δ (PPARδ) in human cholangiocarcinoma.

The Cylex Immune Cell Function Assay measures cell‐mediated immunity based on ATP production by stimulated CD4 + cells. We hypothesized that this test would discriminate acute cellular rejection (ACR) from infectious enteritis (IE) in pediatric intestinal transplant (ITx) recipients with allograft dysfunction. We retrospectively analyzed 224 Cylex assays drawn in 47 children who received 53 ITx. Samples were classified as stable, ACR, or IE based on clinical status. ATP values were analyzed using Kruskal–Wallis and t‐tests. Overall, there was a statistically significant difference in ATP values based on clinical status (p = 0.03); however, overlap was observed between groups. The median ATP value during ACR was significantly greater than during stable periods (p = 0.02). No difference was seen in IE vs. stability (p = 0.8). The difference in median ATP value in ACR vs. IE approached significance (p = 0.1). Relative to previous levels, ACR episodes were associated with a median ATP increase of 101 ng/mL and IE episodes with a decrease of 3 ng/mL (p = 0.3). These data indicate that the Cylex assay has limited utility in differentiating ACR from IE, largely due to interpatient variability. Following longitudinal intrapatient trends may be an adjunctive tool in discriminating IE from ACR and guiding immunosuppression adjustments in select patients.

2013: SUBTOTAL BOWEL INFARCTION ASSOCIATED WITH ANTIPHOSPHOLIPID SYNDROME

BACKGROUND Peroxisome proliferator-activated receptor δ (PPARδ) is a versatile regulator of distinct biological processes and overexpression of PPARδ in cancer may be partially related to its suppression of its own co-regulators. AIMS To determine whether recruited suppressor proteins bind to and regulate PPARδ expression, activity and PPARδ-dependent cholangiocarcinoma proliferation. METHODS Yeast two-hybrid assays were done using murine PPARδ as bait. PPARδ mRNA expression was determined by qPCR. Protein expression was measured by western blot. Immunohistochemistry and fluorescence microscopy were used to determine PPARδ expression and co-localization with NDP Kinase alpha (NM23-H2). Cell proliferation assays were performed to determine cell numbers. RESULTS Yeast two-hybrid screening identified NM23-H2 as a PPARδ binding protein and their interaction was confirmed. Overexpressed PPARδ or treatment with the agonist GW501516 resulted in increased cell proliferation. NM23-H2 siRNA activated PPARδ luciferase promoter activity, upregulated PPARδ RNA and protein expression and increased GW501516-stimulated CCA growth. Overexpression of NM23-H2 inhibited PPARδ luciferase promoter activity, downregulated PPARδ expression and AKT phosphorylation and reduced GW501516-stimulated CCA growth. CONCLUSIONS We report the novel association of NM23-H2 with PPARδ and the negative regulation of PPARδ expression by NM23-H2 binding to the C-terminal region of PPARδ. These findings provide evidence that the metastasis suppressor NM23-H2 is involved in the regulation of PPARδ-mediated proliferation.