Michael D. Kluger

Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria.

BACKGROUND & AIMS The aim of this study was to generate an improved prognostic model for predicting recurrence in liver transplant candidates with hepatocellular carcinoma (HCC). METHODS Predictors of recurrence were tested by a Cox model analysis in a training cohort of 537 patients transplanted for HCC. A prognostic score was developed and validated in a national cohort of 435 patients followed up prospectively. RESULTS α-Fetoprotein (AFP) independently predicted tumor recurrence and correlated with vascular invasion and differentiation. At a Cox score threshold of 0.7 (area under the receiver operating characteristic curve, 0.701; 95% confidence interval, 0.63-0.76; accuracy, 75.8%), a model combining log(10) AFP, tumor size, and number was highly predictive of tumor recurrence and death. By using a simplified version of the model, with untransformed AFP values, a cut-off value of 2 was identified. In the validation cohort, a score greater than 2 predicted a marked increase in 5-year risk of recurrence (50.6% ± 10.2% vs 8.8% ± 1.7%; P < .001) and decreased survival (47.5% ± 8.1% vs 67.8% ± 3.4%; P = .002) as compared with others. Among patients exceeding Milan criteria, a score of 2 or lower identified a subgroup of patients with AFP levels less than 100 ng/mL with a low 5-year risk of recurrence (14.4% ± 5.3% vs 47.6% ± 11.1%; P = .006). Among patients within Milan criteria, a score greater than 2 identified a subgroup of patients with AFP levels greater than 1000 ng/mL at high risk of recurrence (37.1% ± 8.9% vs 13.3% ± 2.0%; P < .001). Net reclassification improvement showed that predictability of the AFP model was superior to Milan criteria. CONCLUSIONS Prediction of tumor recurrence is improved significantly by a model that incorporates AFP. We propose the adoption of new selection criteria for HCC transplant candidates, taking into account AFP.

Hepatic resection for hepatocellular carcinoma in patients with Child–Pugh's A cirrhosis: is clinical evidence of portal hypertension a contraindication?

BACKGROUND According to international guidelines [European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD)], portal hypertension (PHTN) is considered a contraindication for liver resection for hepatocellular carcinoma (HCC), and patients should be referred for other treatments. However, this statement remains controversial. The aim of this study was to elucidate surgical outcomes of minor hepatectomies in patients with PHTN (defined by the presence of esophageal varices or a platelet count of <100,000 in association with splenomegaly) and well-compensated liver disease. METHODS Between 1997 and 2012, a total of 223 cirrhotic patients [stage A according to the Barcelona Clinic Liver Cancer (BCLC) classification] were eligible for this analysis and were divided into two groups according to the presence (n = 63) or absence (n = 160) of PHTN. The demographic data were comparable in the two patient groups. RESULTS Operative mortality was not different (only one patient died in the PHTN group). However, patients with PHTN had higher liver-related morbidity (29% versus 14%; P = 0.009), without differences in hospital stay (8.8 versus 9.8 days, respectively). The PHTN group showed a worse survival rate only if biochemical signs of liver decompensation existed. Multivariate analysis identified albumin levels as an independent predictive factor for survival. CONCLUSIONS PHTN should not be considered an absolute contraindication to a hepatectomy in cirrhotic patients. Patients with PHTN have short- and long-term results similar to patients with normal portal pressure. A limited hepatic resection for early-stage tumours is an option for Child-Pugh class A5 patients with PHTN.

The learning curve in laparoscopic major liver resection

Laparoscopic major hepatectomy remains a relatively rare operation because it is a difficult and technically demanding procedure, and a standard, safe, reproducible technique has not been widely adopted. This is compounded by “major hepatectomy” encompassing multiple different operations each with their own anatomic and procedural considerations. In 2010, we investigated our learning curve for laparoscopic liver resection. We found a significant increase in the number of major hepatectomies performed over a 12-year period, with concurrent reductions in the use of hand-assistance, pedicle clamping, median clamping time, median operative time, blood loss and morbidity. This learning curve was confirmed by a subsequent multinational study. Both hospital and surgeon volume have been shown to affect outcomes, and defining a sufficient number of repetitions before the learning curve plateaus is not easy for laparoscopic major hepatectomy. We recommend that laparoscopic competencies be developed upon a foundation of open liver surgery and that laparoscopic major hepatectomy should only be attempted after competency with less technically complex laparoscopic resections. A center advanced along its institutional learning curve provides the collective expertise necessary for safe patient selection and management. An environment with colleagues willing to share their acquired proficiency allows the surgeon to observe and critique his or her performance against colleagues. Also, the guidance of like-minded surgeons supports technical development and improved outcomes. In conclusion, steady progress can be made along the learning curve through committed practice of increasingly complex tasks and with proper coaching in a high-volume environment.

Liver resection for hepatocellular carcinoma in 313 Western patients: Tumor biology and underlying liver rather than tumor size drive prognosis

BACKGROUND & AIMS Treatment decisions for hepatocellular carcinoma are mostly guided by tumor size. The aim of this study was to analyze resection outcomes according to tumor size and characterize prognostic factors. METHODS Patients resected at a Western center between 1989 and 2010 were grouped by largest tumor size: <50mm, 50-100mm, and >100mm. The primary end points were overall- and recurrence-free survival. Univariate associations with primary endpoints were entered into a Cox proportional hazard regression model. RESULTS Three hundred thirteen patients underwent resection: 111 (36%) had tumors <50mm, 113 (36%) had tumors between 50 and 100mm, and 89 (28%) had tumors >100mm. Five-year overall and disease-free survival rates for the three groups were 67%, 46%, and 34%, and 32%, 27%, and 27%, respectively. Thirty-five patients, mostly from <50mm group, underwent transplantation which was associated with a 91% 5 year survival rate. Tumor size was not an independent predictor of overall or recurrence-free survival on multivariate analyses. Independent predictors of decreased overall survival were: intraoperative transfusion (HR=2.60), cirrhosis (HR=2.42), poorly differentiated tumor (HR=2.04), satellite lesions (HR=1.69), alpha-fetoprotein >200 (HR=1.53), and microvascular invasion (HR=1.48). The use of salvage transplantation was an independent predictor of improved survival (HR=0.21). Recurrence-free survival was predicted by intraoperative transfusion (HR=2.15), poorly differentiated tumor (HR=1.87), microvascular invasion (HR=1.71) and cirrhosis (HR=1.69). CONCLUSION By studying a large group of patients across a distribution of tumor sizes and background liver diseases, it is demonstrated that size alone is a limited prognostic factor. Tumor biology and condition of the underlying liver are better prognosticators and should be given closer attention. Although hampered by recurrence rates, resection is safe and offers good overall survival. In addition, it may allow for better selection for salvage transplantation after consideration of histopathological risk factors.

A tumor-penetrating peptide enhances circulation-independent targeting of peritoneal carcinomatosis

Peritoneal carcinomatosis is a major source of morbidity and mortality in patients with advanced abdominal neoplasms. Intraperitoneal chemotherapy (IPC) is an area of intense interest given its efficacy in ovarian cancer. However, IPC suffers from poor drug penetration into peritoneal tumors. As such, extensive cytoreductive surgery is required prior to IPC. Here, we explore the utility of iRGD, a tumor-penetrating peptide, for improved tumor-specific penetration of intraperitoneal compounds and enhanced IPC in mice. Intraperitoneally administered iRGD significantly enhanced penetration of an attached fluorescein into disseminated peritoneal tumor nodules. The penetration was tumor-specific, circulation-independent, and mediated by the neuropilin-binding RXXK tissue-penetration peptide motif of iRGD. Q-iRGD, which fluoresces upon cleavage, including the one that leads to RXXK activation, specifically labeled peritoneal metastases displaying different growth patterns in mice. Importantly, iRGD enhanced intratumoral entry of intraperitoneally co-injected dextran to approximately 300% and doxorubicin to 250%. Intraperitoneal iRGD/doxorubicin combination therapy inhibited the growth of bulky peritoneal tumors and reduced systemic drug toxicity. iRGD delivered attached fluorescein and co-applied nanoparticles deep into fresh human peritoneal metastasis explants. These results indicate that intraperitoneal iRGD co-administration serves as a simple and effective strategy to facilitate tumor detection and improve the therapeutic index of IPC for peritoneal carcinomatosis.

Liver resection in obese patients: results of a case–control study

OBJECTIVES Obesity has been associated with worse postoperative outcomes. No data are available regarding short-term results after liver resection (LR). The aim of this study was to analyse outcomes in obese patients (body mass index [BMI] > 30 kg/m(2) ) undergoing LR. METHODS 85 consecutive obese patients undergoing LR between 1998 and 2008 were matched on a ratio of 1:2 with 170 non-obese patients. Matching criteria were diagnosis, ASA score, METAVIR fibrosis score, extent of LR, and Child-Pugh score in patients with cirrhosis. RESULTS Operative time, blood loss and blood transfusions were similar in the two groups. Mortality was 2.4% in both groups. Morbidity was significantly higher in the obese group (32.9% vs. 21.2%; P= 0.041). However, only grade II morbidity was increased in obese patients (14.1% vs. 1.8%; P < 0.001) and this was mainly related to abdominal wall complications (8.2% vs. 2.4%; P= 0.046). No differences were encountered in terms of grade III or IV morbidity. The same results were observed in major LR and cirrhotic patients. When patients were stratified by BMI (<20, 20-25, 25-30 and >30 kg/m(2) ), progressive increases in overall and infectious morbidity were observed (5.6%, 22.4%, 23.7%, 32.9%, and 5.6%, 11.8%, 14.5%, 18.8%, respectively). Rates of grade III and IV morbidity did not change. DISCUSSION Obese patients have increased postoperative morbidity after LR in comparison with non-obese patients, but this is mainly related to minor abdominal wall complications. Severe morbidity rates and mortality are similar to those in non-obese patients, even in cirrhosis or after major LR.

Transplantation for liver failure in patients with sickle cell disease: Challenging but feasible

Sickle cell disease (SCD) frequently affects the liver; if acute liver failure (ALF) develops, the only potentially effective therapeutic option is liver transplantation (LT). Only 12 patients for whom LT was performed for SCD‐related ALF have been described so far. We report a retrospective series of 6 adult patients with SCD (3 men and 3 women, median age = 40.1 years) who underwent emergency LT. The indication for LT was ALF complicating cirrhosis in 5 patients (hepatitis C/iron overload–induced cirrhosis in 3 and iron overload–induced cirrhosis in 2); one patient had autoimmune hepatitis. The median follow‐up was 52.7 months (0.5‐123 months). The 1‐, 3‐, 5‐, and 10‐year survival rates were 83.3%, 66.7%, 44.4%, and 44.4%, respectively. One patient died of hepatocellular failure precipitated by hyperacute allograft rejection on post‐LT day 10. Soon after LT, 2 patients developed seizures; in 1 case, the seizures were a complication of early calcineurin inhibitor–induced leukoencephalopathy. Four long‐term survivors benefited from specific management of SCD; specifically, the hemoglobin S fraction was maintained below 30% and the total hemoglobin level was maintained between 8 and 10 g/dL. Two patients had mild vaso‐occlusive crises. Three patients experienced a recurrence of hepatitis C virus (HCV) infection; 2 of these patients experienced reversible neurological complications while they were receiving antiviral treatment. Carefully selected patients with SCD may benefit from emergency LT. However, such patients seem to be particularly susceptible to neurological complications after LT. In contrast, severe SCD‐related crises do not seem to recur if specific management is provided. Outcomes may be improved if the neurological complications can be minimized; for example, the administration of a calcineurin inhibitor can be delayed, and the management of HCV infection recurrence can be improved. Liver Transpl, 2011.

Liver resection for colorectal liver metastases with peri-operative chemotherapy: oncological results of R1 resections

BACKGROUND Retrospective analysis of outcomes of R0 (negative margin) versus R1 (positive margin) liver resections for colorectal metastases (CLM) in the context of peri-operative chemotherapy. METHODS All CLM resections between 2000 and 2006 were reviewed. Exclusion criteria included: macroscopically incomplete (R2) resections, the use of local treatment modalities, the presence of extra-hepatic disease and no peri-operative chemotherapy. R0/R1 status was based on pathological examination. RESULTS Of 86 eligible patients, 63 (73%) had R0 and 23 (27%) had R1 resections. The two groups were comparable for the number, size of metastases and type of hepatectomy. The R1 group had more bilobar CLM (52% versus 24%, P = 0.018). The median follow-up was 3.1 years. Five-year overall and disease-free survival were 54% and 21% for the R0 group and 49% and 22% for the R1 group (P = 0.55 and P = 0.39, respectively). An intra-hepatic recurrence was more frequent in the R1 group (52% versus 27%, P = 0.02) and occurred more frequently at the surgical margin (22% versus 3%, P = 0.01). DISCUSSION R1 resections were associated with a higher risk of intra-hepatic and surgical margin recurrence but did not negatively impact survival suggesting that in the era of efficient chemotherapy, the risk of an R1 resection should not be considered as a contraindication to surgery.

Bland embolization versus chemoembolization of hepatocellular carcinoma before transplantation

There is conflicting literature regarding the superiority of transarterial chemoembolization (TACE) versus bland transarterial embolization (TAE), and this has not been well studied before transplantation. Twenty‐five TAE patients were matched in a 1:2 ratio with TACE patients by the initial radiographic tumor size and number in a retrospective, case‐controlled study. The patients were otherwise treated according to the same protocols. The method of embolization was chosen on the basis of interventionalist practices at 2 sites within the program. Kaplan‐Meier survival analyses at 1 and 3 years were the primary endpoints. There were no significant demographic differences between the groups. The mean adjusted Model for End‐Stage Liver Disease scores at transplantation and waiting times were not significantly different between the TAE and TACE patients (MELD scores: 26 ± 3 versus 24 ± 3 points, P = 0.12; waiting times: 13 ± 8 versus 11 ± 10 months, P = 0.43). TAE patients (16%) were less likely than TACE patients (40%) to require 2 procedures (P = 0.04). Explant tumors were completely necrotic for 36% of the TAE patients and for 26% of the TACE patients. The 3‐year overall survival rates were 78% for the TAE patients and 74% for the TACE patients (P = 0.66), and the 3‐year recurrence‐free survival rates were 72% for the TAE patients and 68% for the TACE patients (P = 0.67). On an intention‐to‐treat basis, there was no significant risk of wait‐list dropout associated with TAE or TACE (P = 0.83). In conclusion, there were no significant differences in wait‐list dropout or in overall or recurrence‐free survival between HCC patients undergoing TAE and HCC patients undergoing TACE before transplantation. Liver Transpl 20:536–543, 2014.

Pancreatic cancer surgery and nutrition management: a review of the current literature.

Surgery remains the only curative treatment for pancreaticobiliary tumors. These patients typically present in a malnourished state. Various screening tools have been employed to help with preoperative risk stratification. Examples include the subjective global assessment (SGA), malnutrition universal screening tool (MUST), and nutritional risk index (NRI). Adequate studies have not been performed to determine if perioperative interventions, based on nutrition risk assessment, result in less morbidity and mortality. The routine use of gastric decompression with nasogastric sump tubes may be unnecessary following elective pancreatic resections. Instead, placement should be selective and employed on a case-by-case basis. A wide variety of feeding modalities are available, oral nutrition being the most effective. Artificial nutrition may be provided by temporary nasal tube (nasogastric, nasojejunal, or combined nasogastrojejunal tube) or surgically placed tube [gastrostomy (GT), jejunostomy (JT), gastrojejunostomy tubes (GJT)], and intravenously (parenteral nutrition, PN). The optimal tube for enteral feeding cannot be determined based on current data. Each is associated with a specific set of complications. Dual lumen tubes may be useful in the presence of delayed gastric emptying (DGE) as the stomach may be decompressed while feeds are delivered to the jejunum. However, all feeding tubes placed in the small intestine, except direct jejunostomies, commonly dislodge and retroflex into the stomach. Jejunostomies are associated with less frequent, but more serious complications. These include intestinal torsion and bowel necrosis. PN is associated with septic, metabolic, and access-related complications and should be the feeding strategy of last-resort. Enteral feeds are clearly preferred over parental nutrition. A sound understanding of perioperative nutrition may improve patient outcomes. Patients undergoing pancreatic cancer surgery should undergo multidisciplinary nutrition screening and intervention, and the surgical/oncological team should include nutrition professionals in managing these patients in the perioperative period.