Future liver remnant function as a predictor of postoperative morbidity following liver resection for hepatocellular carcinoma - A risk factor analysis.

BACKGROUND: Advances in anaesthesia and surgical technique have considerably reduced mortality in hepatocellular carcinoma (HCC) patients undergoing liver resection. However, extended resections in patients with liver cirrhosis still represent a challenge. The aim of this study was to investigate the predictive value of volume/function analysis for the prediction of morbidity in HCC patients following liver resection. METHODS: Between 2001 and 2014, a total of 261 patients who underwent open hepatectomy for HCC were enrolled in this study. Future liver remnant volume (FLRV) and future liver remnant function (FLRF) based on LiMAx testing were obtained retrospectively. Uni- and multivariable analyses were performed to identify predictors for postoperative ascites, post-hepatectomy haemorrhage (PHH), and wound healing disorders (WHD) within the total cohort and in a subgroup of cirrhotic patients. RESULTS: The most commonly observed complication was ascites (57.1%), followed by liver failure (25.3%), PHH (19.5%), and WHD (19.2%). FLRF was a major predictor of postoperative ascites (AUC 0.776; OR 0.987, p = 0.001), PHH (AUC 0.717; OR 0.984, p = 0.001), and WHD (AUC 0.660; OR 0.994, p = 0.032) in total cohort. Multivariable analysis of the cirrhosis subgroup showed FLRF to be an independent predictor of ascites (AUC 0.814; OR 0.989, p = 0.021), PHH (AUC 0.677; OR 0.991, p = 0.040), and WHD (AUC 0.615; OR 0.989, p = 0.033). CONCLUSIONS: FLRF is a major predictor of postoperative ascites, haemorrhage, and wound healing disorders in cirrhotic and non-cirrhotic patients whereas FLRV failed to show significant correlations. Preoperative calculation of FLRF may augment surgical decision-making in high-risk patients and thereby improve perioperative outcome.

The predictive value of future liver remnant function after liver resection for HCC in noncirrhotic and cirrhotic patients.

BACKGROUND: Surgical procedures in patients with underlying liver disease are still burdened by a high rate of postoperative morbidity, especially posthepatectomy liver failure (PHLF), ranging from 1.2 to 33.8%. The aim of this study was to investigate the prognostic value of volume/function analysis for the prediction of hepatectomy-related morbidity in patients with hepatocellular carcinoma. METHODS: Clinicopathological data were analysed in 261 patients who underwent liver resection for HCC between 2001 and 2014. Future liver remnant volume (FLRV) and future liver remnant function (FLRF) based on LiMAx test were obtained retrospectively. A subgroup analysis for high-risk patients with impaired liver function was conducted. Univariate and multivariate regression analysis was performed to identify risk factors for major complications, defined by Dindo ≥ IIIb and PHLF grade ≥ B. RESULTS: In the total cohort, FLRF was independently associated with major complications. FLRV, resected liver volume, and FLRF were independent risk factors for PHLF. In a subgroup analysis of high-risk patients, FLRF was identified as the only independent risk factor for major complications and PHLF development. DISCUSSION: These results suggest the superior value of FLRF to FLRV in predicting postoperative complications as well as PHLF in patients with chronic liver disease.

DNA Cytometry for Differentiation Between Low- and Medium-grade Dysplasia in Intraductal Papillary Mucinous Neoplasms.

BACKGROUND/AIM: The indication for resection of cystic pancreatic lesions is usually performed by sectional imaging criteria, such as the Sendai criteria. The aim of this study was to analyze a possible correlation between DNA cytometry and Sendai criteria for the differentiation between low-grade intraductal papillary mucinous neoplasms (IPMN-A) and medium-grade dysplasia (IPMN-B). MATERIALS AND METHODS: Histopathological analysis, DNA index and preoperative Sendai criteria were determined in 16 patients who underwent pancreatic resection for IPMN. RESULTS: All patients with IPMN-B showed aneuploid histograms with DNA indices ≥1.3, whereas three out of four patients with IPMN-A had diploid DNA indices ≤1.3. All 11 patients with one or more high-risk stigmata and aneuploid histograms had IPMN-Bs, whereas both patients who were Sendai-negative and diploid in the DNA analysis had an IPMN-A. CONCLUSION: DNA index may be an important diagnostic tool for the differentiation of different IPMN types beyond the traditional Sendai criteria.

Secondary Sclerosing Cholangitis in Critically Ill Patients: Clinical Presentation, Cholangiographic Features, Natural History, and Outcome: A Series of 16 Cases.

Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is an important differential diagnosis in patients presenting with cholestasis and PSC-like cholangiographic changes in endoscopic retrograde cholangiography (ERC). As a relatively newly described entity, SSC-CIP is still underdiagnosed, and the diagnosis is often delayed. The present study aims to improve the early detection of SSC-CIP and the identification of its complications.A total of 2633 records of patients who underwent or were listed for orthotopic liver transplantation at the University Hospital Charité, Berlin, were analyzed retrospectively. The clinical presentation and outcome (mean follow-up 62.7 months) of the 16 identified SSC-CIP cases were reviewed.Cholestasis was the first sign of SSC-CIP. GGT was the predominant enzyme of cholestasis. Hypercholesterolemia occurred in at least 75% of the patients. SSC-CIP provoked a profound weight loss (mean 18 kg) in 94% of our patients. SSC-CIP was diagnosed by ERC in all patients. The 3 different cholangiographic features detected correspond roughly to the following stages: (I) evidence of biliary casts, (II) progressive destruction of intrahepatic bile ducts, and (III) picture of pruned tree. Biliary cast formation is a hallmark of SSC-CIP and was seen in 87% of our cases. In 75% of the patients, the clinical course was complicated by cholangiosepsis, cholangitic liver abscesses, acalculous cholecystitis, or gallbladder perforation. SSC-CIP was associated with worse prognosis; transplant-free survival was ∼40 months (mean).Because of its high rate of serious complications and unfavorable prognosis, it is imperative to diagnose SSC-CIP early and to differentiate SSC-CIP from other types of sclerosing cholangitis. Specific characteristics enable identification of SSC-CIP. Early cooperation with a transplant center and special attention to biliary complications are required after diagnosis of SSC-CIP.

Implications of imaging criteria for the management and treatment of intraductal papillary mucinous neoplasms - benign versus malignant findings.

OBJECTIVES: Evaluation of computed tomography (CT) and magnetic resonance imaging (MRI) for differentiation of pancreatic intraductal papillary mucinous neoplasm (IPMN) subtypes based on objective imaging criteria. METHODS: Fifty-eight patients with 60 histologically confirmed IPMNs were included in this retrospective study. Eighty-three imaging studies (CT,n = 42; MRI,n = 41) were analysed by three independent blinded observers (O1-O3), using established imaging criteria to assess likelihood of malignancy (-5, very likely benign; 5, very likely malignant) and histological subtype (i.e., low-grade (LGD), moderate-grade (MGD), high-grade dysplasia (HGD), early invasive carcinoma (IPMC), solid carcinoma (CA) arising from IPMN). RESULTS: Forty-one benign (LGD IPMN,n = 20; MGD IPMN,n = 21) and 19 malignant (HGD IPMN,n = 3; IPMC,n = 6; solid CA,n = 10) IPMNs located in the main duct (n = 6), branch duct (n = 37), or both (n = 17) were evaluated. Overall accuracy of differentiation between benign and malignant IPMNs was 86/92 % (CT/MRI). Exclusion of overtly malignant cases (solid CA) resulted in overall accuracy of 83/90 % (CT/MRI). The presence of mural nodules and ductal lesion size ≥30 mm were significant indicators of malignancy (p = 0.02 and p < 0.001, respectively). CONCLUSIONS: Invasive IPMN can be identified with high confidence and sensitivity using CT and MRI. The diagnostic problem that remains is the accurate radiological differentiation of premalignant and non-invasive subtypes. KEY POINTS: • CT and MRI can differentiate benign from malignant forms of IPMN. • Identifying (pre)malignant histological IPMN subtypes by CT and MRI is difficult. • Overall, diagnostic performance with MRI was slightly (not significantly) superior to CT.

Implication of microscopic and macroscopic vascular invasion for liver resection in patients with hepatocellular carcinoma.

BACKGROUND AND AIM: Long-term data after liver resection for hepatocellular carcinoma (HCC) with vascular invasion are rare for non-Asian patients. The aim of the present study was to analyze the long-term outcome of liver resection for HCC with vascular invasion and to compare the results of subgroups with micro- and macrovascular invasion. METHODS: From January 2000 to September 2010, 288 patients without extrahepatic metastases underwent liver resection for HCC. In 107 out of 288 patients (37%), vascular invasion was found in the final pathological analysis. The long-term outcome as well as the perioperative course of these patients was analyzed using a prospective database. RESULTS: The 1-, 3- and 5-year cumulative survival rate of HCC patients with vascular invasion was 64.3, 41.4 and 23.9%, respectively. The median survival was 19 months. In the multivariate analysis, the overall survival was not influenced by the type of vascular invasion (micro- vs. macrovascular invasion), however overall survival was significantly impaired in case of lymphatic vessel invasion, intraoperative blood transfusions, need of fresh frozen plasma application, prolonged ICU stay and elevated preoperative bilirubin levels. CONCLUSIONS: Acceptable survival rates can be achieved in selected patients with macrovascular invasion after surgical resection, which is not markedly different from those with microvascular invasion. In view of an otherwise poor prognosis, liver resection seems to be justified for selected HCC patients with macrovascular invasion, although this stands in contrast with the BCLC recommendations. However, it is in accordance for example with the guidelines of the Asia-Pacific Association for the Study of the Liver.

Patient age and extent of liver resection influence outcome of liver resection for hepatocellular carcinoma in non-cirrhotic liver.

BACKGROUND/AIMS: Data about the clinical course after liver resection for HCC in non-cirrhotic liver (NCL) is rare in western countries. Although the patients with HCC in NCL tolerate major liver resections, it is less clear if an underlying steatosis or NASH increase the perioperative and postoperative risk. The purpose of this study was to characterize the clinical course after hepatic resection in patients with HCC in the absence of liver cirrhosis and in the absence of viral hepatitis. METHODOLOGY: The data of 148 patients with HCC in non-cirrhotic liver, who underwent curatively intented liver resection, were analyzed. Patients with hepatitis B or C infection were excluded. Patients with fibrolamellar HCC or liver cirrhosis or fibrosis higher than grade 2 according to the Desmet-Scheuer score were also excluded. RESULTS: The overall 1-, 3- and 5-year survival rates were 75.4%, 54.7% and 38.9%. Increased patient age (elder than 70 years) influenced the cumulative survival significantly. Especially the combination of increased patient age and major resection (>2 segments) at once influenced the cumulative survival. The overall postoperative morbidity was 37.8 %. No intraoperative death was observed. Postoperative increased leucocytes, urea and creatinin increased the postoperative complications. In the subgroup with major resection increased GGT correlated with steatosis, and raised AST correlated with elevated patient age. CONCLUSIONS: In Western countries HCC in non-cirrhotic liver is rare. Liver resection is safe and is the only curative therapy option for the time by HCC without liver cirrhosis. Further studies are necessary for identification of more prognostic factors and optionally special treatment

Long-term results of liver resection for hepatocellular carcinoma in noncirrhotic liver.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the most common malignant neoplasms worldwide. Only few data on HCC in noncirrhotic livers without viral hepatitis in Western countries are available. The purpose of this study was to define the outcomes and potential prognostic factors associated with survival after hepatic resection in patients with HCC in the absence of liver cirrhosis and hepatitis B or C infection. PATIENTS AND METHODS: From January 2000 to September 2010, 148 patients without liver cirrhosis and without extrahepatic metastases underwent curative hepatic resection for HCC at the Surgical Department of the Charité, Campus Virchow Klinikum. The outcomes of these patients were retrospectively reviewed. Patients with cirrhosis or severe fibrosis, fibrolamellar HCC, and those positive for hepatitis B or C were excluded. RESULTS: The cumulative 1-, 3-, 5-, and 7-year survival rates were 75.4%, 54.7%, 38.9%, and 31.8%, respectively. The 1-, 3-, 5-, and 7-year disease-free survival rates were 60.3%, 38.0%, 29.1%, and 18.1%, respectively. In the multivariate analysis, cumulative survival was decreased by patient age, increased operative time, increased preoperative serum gamma-glutamyl transferase (GGT), and tumor stage. In the subgroup with unifocal neoplasms, N0 and R0 status, tumor size >10 cm, and tumor differentiation were highly predictive of lesser survival. Unfavorable survival was observed in patients with multifocal neoplasms, tumor size >10 cm, and/or poor tumor differentiation. CONCLUSION: The current TNM staging system is stratified for survival and recurrence. Extension of the current TNM staging system by grading and more exact differentiation of tumor size may increase its prognostic accuracy for predicting outcome. Preoperative increased serum GGT level could be a new poor prognostic factor.

Pancreatoenteral anastomosis or direct closure of the pancreatic remnant after a distal pancreatectomy: a single-centre experience.

BACKGROUND: A major complication of a distal pancreatectomy (DP) is the formation of a post-operative pancreatic fistula (POPF). In spite of the utilization of numerous surgical techniques no consensus on an appropriate technique for closure of the pancreatic remnant after DP has been established yet. The aim of this study was to analyse the impact of pancreatoenteral anastomosis (PE) vs. direct closure (DC) of the pancreatic remnant on POPF. METHODS: A total of 198 consecutive patients who underwent a distal pancreatectomy between 2002 and 2010 at our institution were retrospectively analysed for post-operative morbidity and mortality. RESULTS: One hundred and fifty-one patients (76.3%) received DC whereas PE was performed in 47 patients (23.7%). The incidence of POPF was higher in the DC group (22% vs. 11%), whereas the rate of post-operative haemorrhage was higher in the PE group (11% vs. 7%). However, these differences were not significant. Additionally, there were no significant differences in overall post-operative morbidity and mortality between the groups. CONCLUSIONS: The performance of PE instead of DC may be considered as a safe alternative in individual patients, but it does not significantly lead to a general improvement in post-operative outcome after DP. An interdisciplinary collaboration in the prevention and treatment of POPF therefore remains essential.

Matched-pair analysis of postoperative morbidity and mortality for pancreaticogastrostomy and pancreaticojejunostomy using mattress sutures in soft pancreatic tissue remnants.

BACKGROUND: After pancreaticoduodenectomy, the incidence of postoperative pancreatic fistula remains high, especially in patients with "soft" pancreatic tissue remnants. No "gold standard" surgical technique for pancreaticoenteric anastomosis has been established. This study aimed to compare the postoperative morbidity and mortality of pancreaticogastrostomy and pancreaticojejunostomy for "soft" pancreatic tissue remnants using modified mattress sutures. METHODS: Seventy-five patients who had undergone pancreaticogastrostomy and 75 who had undergone pancreaticojejunostomy after pancreaticoduodenectomy between 2002 and 2008 were retrospectively compared using matched-pair analysis. A modified mattress suture technique was used for the pancreaticoenteric anastomosis. Patients with an underlying "hard" pancreatic tissue remnant, as in chronic pancreatitis, were excluded. Both groups were homogeneous for age, gender, and underlying disease. Postoperative morbidity, mortality, and preoperative and operative data were analyzed. RESULTS: There were no significant differences between the groups for the incidence of postoperative pancreatic fistula (10.7% in both). Postoperative morbidity and mortality, median operation time, median length of hospital stay, intraoperative blood loss, and the amount of intraoperatively transfused erythrocyte concentrates also did not significantly differ between the groups. Patient age >65 years (P=0.017), operation time >350 minutes (P=0.001), and intraoperative transfusion of erythrocyte concentrates (P=0.038) were identified as risk factors for postoperative morbidity. CONCLUSIONS: Our results showed no significant differences between the groups in the pancreaticogastrostomy and pancreaticojejunostomy anastomosis techniques using mattress sutures for "soft" pancreatic tissue remnants. In our experience, the mattress sutures are safe and simple to use, and pancreaticogastrostomy in particular is feasible and easy to learn, with good endoscopic accessibility to the anastomosis region. However, the location of the anastomosis and the surgical technique need to be individually evaluated to further reduce the incidence of postoperative pancreatic fistula.

Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma.

Abberrant DNA methylation is one of the hallmarks of cancerogenesis. Our study aims to delineate differential DNA methylation in cirrhosis and hepatic cancerogenesis. Patterns of methylation of 27,578 individual CpG loci in 12 hepatocellular carcinomas (HCCs), 15 cirrhotic controls and 12 normal liver samples were investigated using an array-based technology. A supervised principal component analysis (PCA) revealed 167 hypomethylated loci and 100 hypermethylated loci in cirrhosis and HCC as compared to normal controls. Thus, these loci show a "cirrhotic" methylation pattern that is maintained in HCC. In pairwise supervised PCAs between normal liver, cirrhosis and HCC, eight loci were significantly changed in all analyses differentiating the three groups (p < 0.0001). Of these, five loci showed highest methylation levels in HCC and lowest in control tissue (LOC55908, CELSR1, CRMP1, GNRH2, ALOX12 and ANGPTL7), whereas two loci showed the opposite direction of change (SPRR3 and TNFSF15). Genes hypermethylated between normal liver to cirrhosis, which maintain this methylation pattern during the development of HCC, are depleted for CpG islands, high CpG content promoters and polycomb repressive complex 2 (PRC2) targets in embryonic stem cells. In contrast, genes selectively hypermethylated in HCC as compared to nonmalignant samples showed an enrichment of CpG islands, high CpG content promoters and PRC2 target genes (p < 0.0001). Cirrhosis and HCC show distinct patterns of differential methylation with regards to promoter structure, PRC2 targets and CpG islands.

Repeated liver resection for recurrent hepatocellular carcinoma.

BACKGROUND AND AIM: Tumor recurrence after liver resection occurs in the majority of patients with hepatocellular carcinoma (HCC). This study was conducted to clarify the safety and effectiveness of repeated liver resection as a curative option for intrahepatic HCC recurrence. METHODS: Between July 1990 and January 2009, 483 patients underwent 514 curative hepatic resections for HCC in our institution. Among this collective, 27 patients underwent 31 repeated resections due to recurrent HCC (27 s resections, three third resections and one forth resection). The outcome of these patients was retrospectively reviewed using a prospective database. RESULTS: Perioperative morbidity and mortality was 11% (three of 27) and 0%. Six patients showed multiple liver lesions, 23 underwent minor liver resections (fewer than three segments) and five patients underwent major resections (three or more segments). The majority of the patients showed no signs of chronic liver disease (16 of 27). The median tumor free margin was 1.5 mm (range: 0 to 20 mm). The median tumor diameter was 40 mm (range: 10 to 165 mm). Tumor dedifferentiations at time of tumor recurrence were not observed. The 1-, 3- and 5-year overall survival rates after second liver resection were 96%, 70% and 42%. CONCLUSIONS: Repeated liver resection is a valid and safe curative therapy option for recurrent HCC and results in significant prolongation of survival in comparison to interventional treatment strategies in selected patients. However, due to impaired liver function, multifocal intrahepatic or extrahepatic recurrence repeated resection is only feasible in a minority of patients.

Donor brain death significantly interferes with tolerance induction protocols.

Studies in rodents showed that antibodies are able to induce tolerance of allografts. As clinical results are unsatisfactory and deceased donors are still the main source of organ transplants, we investigated whether donor brain-death impacts on tolerance induction after experimental kidney transplantation. Anti-CD4 monoclonal antibodies (RIB 5/2; 2.5 mg/kg x 5 days) treated and untreated recipients of brain-dead donor grafts were compared with RIB 5/2 treated and untreated recipients of living donor grafts (F344-to-Lewis). All recipients received low-dose CsA (1.5 mg/kg x 10 days). Kidneys were recovered 4, 16 and 40 weeks after transplantation and examined by morphology, immunohistology and flow cytometry. Renal function was monitored monthly. RIB 5/2 treatment significantly decreased proteinuria in recipients of living donor allografts when compared with living donor controls. After 40 weeks, inflammatory cell infiltration and MHC class II expression were reduced while morphologic alterations were minimal. In contrast, treatment of brain-dead graft recipients had no impact on graft function. Structural changes and graft infiltration were comparable to brain-dead donor controls at all time points. RIB 5/2 treatment significantly improved graft function in recipients of living donor grafts; however, it was not effective in recipients of brain-dead donor organs.