Andrea Ruzzenente

Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas

Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.

Surgical resection versus percutaneous radiofrequency ablation in the treatment of hepatocellular carcinoma on cirrhotic liver

Objective:We sought to compare the experience of 2 different surgical units in the treatment of hepatocellular carcinoma (HCC) on cirrhosis with resection or percutaneous radiofrequency ablation (RFA), respectively. Summary Background Data:When allowed by the hepatic functional reserve, surgery is the therapy for HCC on cirrhosis; alternative treatments are proposed because of the high tumor recurrence rate after resection. RFA is being widely adopted to treat HCC. Methods:Over a 4-year period, 79 cirrhotics with HCC underwent resection in 1 surgical unit (group A) and another 79 had RFA at a different unit (group B). Patient selection, operative mortality, hospital stay, and 1- and 3-year overall and disease-free survival were analyzed. Results:Group A (surgery): mean follow-up was 28.9 ± 17.9 months; operative mortality was 3.8%, mean hospital stay 9 days; 1- and 3-year survival were, respectively, 83 and 65%. One- and 3-year disease-free survival were 79 and 50%. Group B (RFA): mean follow-up was 15.6 ± 11.7 months. Mean hospital stay was 1 day (range 1–8). One- and 3-year survival were 78 and 33%; 1- and 3-year disease-free survival were 60 and 20%. Overall and disease-free survival were significantly higher in group A (P = 0.002 and 0.001). The advantage of surgery was more evident for Child-Pugh class A patients and for single tumors of more than 3 cm in diameter. Results were similar in 2 groups for Child-Pugh class B patients Conclusions:RFA has still to be confirmed as an alternative to surgery for potentially-resectable HCCs.

How much remnant is enough in liver resection

Background: Liver resection represents the first choice of treatment for primary and secondary liver malignancies, offering the patient the best chance of long-term survival. The extensive use of major hepatectomy increases the risk of post-hepatectomy liver failure (PHLF), which is associated with a high frequency of postoperative complications, mortality and increased length of hospital stay. Aims: The aim of this review is to investigate the different risk factors related to the occurrence of PHLF and to identify the limits for a safe liver resection in patients with normal liver and injured liver (cirrhosis, cholestasis, steatosis and post-chemotherapy liver injury). Methods: A literature search was undertaken in PubMed and related search engines, looking for articles relating to hepatic failure following hepatectomy in normal liver or injured liver. Results: In spite of improvements in surgical and postoperative management, the parameters determining how much liver can be resected are still largely undefined. A number of preoperative, intraoperative and postoperative factors all contribute to the likelihood of liver failure after surgery. The safe limits for liver resection can be estimated from the data of the literature for patients with normal liver and for those with different types of liver injury. Conclusions: Preoperative assessment that includes evaluation of liver volume and function of the remnant liver is a mandatory prerequisite before major hepatectomy. The critical residual liver volume for patients able to predict PHLF is mainly related to the presence of pre-existing liver disease and liver function. Among patients with normal liver, the limit for safe resection ranges from 20 to 30% future remnant liver of total liver volume. In patients with injured liver (cirrhosis, cholestasis or steatosis), preoperative assessment of the risk of PHLF should include future remnant liver volumetry and accurate liver function evaluation, including different dynamic liver function tests.

Role of preoperative biliary drainage in jaundiced patients who are candidates for pancreatoduodenectomy or hepatic resection: highlights and drawbacks.

Introduction: In this review of the literature, we analyze the indications for preoperative drainage in jaundiced patients who are candidates for pancreaticoduodenectomy (PD) or major hepatectomy due to periampullary or proximal bile duct neoplasms. Objective: The aim of this study is to review the literature and to report on the current management of jaundiced patients with periampullary or proximal bile duct neoplasms who are candidates for PD or major liver resection. Background: Jaundiced patients represent a major challenge for surgeons. Alterations and functional impairment caused by jaundice increase the risk of surgery; therefore, preoperative biliary decompression has been suggested. Methods: A literature review was performed in the MEDLINE database to identify studies on the management of jaundice in patients undergoing PD or liver resection. Papers considering palliative drainage in jaundiced patients were excluded. Results: The first group of papers considered patients affected by middle-distal obstruction from periampullary neoplasms, in which preoperative drainage was applied selectively. The second group of papers evaluated patients with biliary obstructions from proximal biliary neoplasms. In these cases, Asian authors and a few European authors considered it mandatory to drain the future liver remnant (FLR) in all patients, while American and most European authors indicated preoperative drainage only in selected cases (in malnourished patients and in those with hypoalbuminemia, cholangitis or long-term jaundice; with an FLR < 30% or 40%) given the high risk of complications of drainage (choleperitoneum, cholangitis, bleeding, and seeding). The optimal type of biliary drainage is still a matter of debate; recent studies have indicated that endoscopy is preferable to percutaneous drainage. Although the type of endoscopic biliary drainage has not been clearly established, the choice is made between plastic stents and short, covered, metallic stents, while other authors suggest the use of nasobiliary drainage. Conclusions: A multidisciplinary evaluation (made by a surgeon, biliary endoscopist, gastroenterologist, and radiologist) of jaundiced neoplastic patients should be performed before deciding to perform biliary drainage. Middle-distal obstruction in patients who are candidates for PD does not usually require routine biliary drainage. Proximal obstruction in patients who are candidates for major hepatic resection in the majority of cases requires a drain; however, the type, site, number, and approach must be defined and tailored according to the planned hepatic resection. Recently, the use of preoperative biliary drainage limited to the FLR has been a suggested strategy. However, multicenter, randomized, controlled trials should be conducted to clarify this issue.

Comparison of seven staging systems in cirrhotic patients with hepatocellular carcinoma in a cohort of patients who underwent radiofrequency ablation with complete response.

BACKGROUND AND AIMS:Many staging systems for hepatocellular carcinoma (HCC) have been proposed but the best tool for staging of HCC remains controversial. The aim of the present study was to identify the best staging system evaluating the predictive ability for outcome for each of the seven different staging systems applied in a homogeneous group of patients who underwent percutaneous radiofrequency ablation (RFA).METHODS:We analyzed retrospectively 112 patients with HCC and cirrhosis treated with percutaneous RFA from January, 1998 to April, 2005. Response to treatment after 30 days and for long-term follow-up was evaluated with computed tomography (CT) or magnetic resonance imaging (MRI) and serum alpha-fetoprotein level (AFP). All of the 112 patients were grouped according to each one of the seven different staging systems: Okuda, TNM, BCLC, CLIP, GRETCH, CUPI, JIS.RESULTS:The mean follow-up time of the 112 patients submitted to RFA was 24 months (range 3–92 months) with survival rates at 1, 3, and 5 yr of 82%, 40%, and 18%, respectively. Univariate and multivariate analyses showed that factors related to survival were Child-Pugh score (P ≤ 0.01), serum AFP (P ≤ 0.01), and the response to treatment (P ≤ 0.01) with hazard ratios of 2.09 (95% CI 1.21–3.61), 2.79 (95% CI 1.59–4.90), and 2.76 (95% CI 1.25–6.09), respectively. The comparison of the results of the different staging systems in all of the 112 patients and in a subgroup of 96 patients with complete response to treatment showed that BCLC had the best discrimination ability, monotonicity of gradient (linear trend χ2 6.07, P = 0.01), and homogeneity ability (LR χ2 test 10.00, P = 0.008).CONCLUSIONS:The BCLC staging system shows a superior discriminatory power in our cohort of HCC patients who underwent RFA; moreover, it can give important prognostic information after complete response to treatment. Our study confirms the validity of the BCLC staging system in patients with HCC in cirrhosis.

Systematic review of central pancreatectomy and meta-analysis of central versus distal pancreatectomy.

Central pancreatectomy (CP) is a parenchyma‐sparing surgical procedure that enables the removal of benign and/or low‐grade malignant lesions from the neck and proximal body of the pancreas. The aim of this review was to evaluate the short‐ and long‐term surgical results of CP from all published studies, and the results of comparative studies of CP versus distal pancreatectomy (DP).

Prognostic significance of lymph node ratio after resection of peri-hilar cholangiocarcinoma

BACKGROUND Lymph node (LN) metastases are a major negative prognostic factor for peri-hilar cholangiocarcinoma (PCC). Prognostic significance of the extent of LN dissection, number of metastatic LN and the lymph node ratio (LNR) are still under debate. AIMS The aims of the present study were to evaluate the prognostic value of the LN status, the total number of LNs evaluated and LNR in PCC. METHODS Between 1990 and 2008, 62 patients with PCC submitted to surgical resection with curative intent were retrospectively evaluated. Number and status of harvested LN were recorded. RESULTS In 53 patients (85.4%) regional lymphadenectomy was performed. Median number of LNs examined was 7 (range 1-25). Median survival was 41.9 months in patients with N0 compared with 22.7 months in 21 patients (39.6%) with N+ (P= 0.03). Median survival was 3, 18.5 and 29 months for patients with 0, 1-3 and >3 LN retrieved, respectively (P < 0.01). Five-year survival for patients above and below the LNR cut-off value of 0.25 was 0% and 22.5%, respectively (P= 0.03). CONCLUSIONS LN metastases are a major prognostic factor for survival after surgical resection of PCC. The number of LN harvested and LNR showed high prognostic value.

Hepatocellular carcinoma in cirrhotic patients with portal hypertension: Is liver resection always contraindicated?

AIM To analyze the outcome of hepatocellular carcinoma (HCC) resection in cirrhosis patients, related to presence of portal hypertension (PH) and extent of hepatectomy. METHODS A retrospective analysis of 135 patients with HCC on a background of cirrhosis was submitted to curative liver resection. RESULTS PH was present in 44 (32.5%) patients. Overall mortality and morbidity were 2.2% and 33.7%, respectively. Median survival time in patients with or without PH was 31.6 and 65.1 mo, respectively (P = 0.047); in the subgroup with Child-Pugh class A cirrhosis, median survival was 65.1 mo and 60.5 mo, respectively (P = 0.257). Survival for patients submitted to limited liver resection was not significantly different in presence or absence of PH. Conversely, median survival for patients after resection of 2 or more segments with or without PH was 64.4 mo and 163.9 mo, respectively (P = 0.035). CONCLUSION PH is not an absolute contraindication to liver resection in Child-Pugh class A cirrhotic patients, but resection of 2 or more segments should not be recommended in patients with PH.

Hepatocellular carcinoma: Surgical perspectives beyond the barcelona clinic liver cancer recommendations

The barcelona clinic liver cancer (BCLC) staging system has been approved as guidance for hepatocellular carcinoma (HCC) treatment guidelines by the main Western clinical liver associations. According to the BCLC classification, only patients with a small single HCC nodule without signs of portal hypertension or hyperbilirubinemia should undergo liver resection. In contrast, patients with intermediate-advanced HCC should be scheduled for palliative therapies, even if the lesion is resectable. Recent studies report good short-term and long-term outcomes in patients with intermediate-advanced HCC treated by liver resection. Therefore, this classification has been criticised because it excludes many patients who could benefit from curative resection. The aim of this review was to evaluate the role of surgery beyond the BCLC recommendations. Safe liver resection can be performed in patients with portal hypertension and well-compensated liver function with a 5-year survival rate of 50%. Surgery also offers good long-term result in selected patients with multiple or large HCCs with a reported 5-year survival rate of over 50% and 40%, respectively. Although macrovascular invasion is associated with a poor prognosis, liver resection provides better long-term results than palliative therapies or best supportive care. Recently, researchers have identified several genes whose altered expression influences the prognosis of patients with HCC. These genes may be useful for classifying the biological behaviour of different tumours. A revision of the BCLC classification should be introduced to provide the best treatment strategy and to ensure the best prognosis in patients with HCC.

Liver Resection for Hepatocellular Carcinoma ≤3 cm: Results of an Italian Multicenter Study on 588 Patients

BACKGROUND The best treatment for patients with small hepatocellular carcinoma (S-HCC) is still controversial. The aim of this study was to evaluate operative and long-term results after liver resection (LR) for S-HCC, defined as tumor ≤3 cm. STUDY DESIGN Retrospective multicenter study of 588 LRs for S-HCC from 8 Italian hepatobiliary surgery units (years 1992 to 2008). Primary outcomes included operative risk. Logistic regression analysis was used to evaluate risk factors for postoperative mortality. Secondary outcomes were overall survival (OS) and disease-free survival (DFS), estimated by the Kaplan-Meier method. RESULTS Postoperative mortality was 1.9%, morbidity was 35.7% (major morbidity 7.3%), and blood transfusion rate was 13.8%. Child-Pugh class B and blood transfusions were associated with higher postoperative mortality. Rates of microvascular invasion and microsatellite nodules were 37.0% and 23.1%. After a median follow-up of 38.4 months, 5- and 10-year OS rates were 52.8% and 20.3%, with DFS of 32.4% and 21.7%. Local recurrence rate was 1.4%. Between the years 2000 and 2008, 5-year OS was significantly higher than that between the years 1992 and 1999 (61.9% vs 42.6%; p < 0.001). In multivariable analysis, Child-Pugh class B, portal hypertension, and microsatellite lesions were independently associated with poor OS. Microsatellite lesion was the only variable independently associated with poor DFS. CONCLUSIONS Liver resection for S-HCC has improved over the years, with decreased operative risk. Long-term survival after LR has increased. Despite small tumor size, rates of microsatellite nodules and microvascular invasion are not negligible. Presence of microsatellite lesions was the only variable identified as being associated with poor both OS and DFS.