David M. Nagorney

The International Position on Laparoscopic Liver Surgery: The Louisville Statement, 2008

Objective:To summarize the current world position on laparoscopic liver surgery. Summary Background Data:Multiple series have reported on the safety and efficacy of laparoscopic liver surgery. Small and medium sized procedures have become commonplace in many centers, while major laparoscopic liver resections have been performed with efficacy and safety equaling open surgery in highly specialized centers. Although the field has begun to expand rapidly, no consensus meeting has been convened to discuss the evolving field of laparoscopic liver surgery. Methods:On November 7 to 8, 2008, 45 experts in hepatobiliary surgery were invited to participate in a consensus conference convened in Louisville, KY, US. In addition, over 300 attendees were present from 5 continents. The conference was divided into sessions, with 2 moderators assigned to each, so as to stimulate discussion and highlight controversies. The format of the meeting varied from formal presentation of experiential data to expert opinion debates. Written and video records of the presentations were produced. Specific areas of discussion included indications for surgery, patient selection, surgical techniques, complications, patient safety, and surgeon training. Results:The consensus conference used the terms pure laparoscopy, hand-assisted laparoscopy, and the hybrid technique to define laparoscopic liver procedures. Currently acceptable indications for laparoscopic liver resection are patients with solitary lesions, 5 cm or less, located in liver segments 2 to 6. The laparoscopic approach to left lateral sectionectomy should be considered standard practice. Although all types of liver resection can be performed laparoscopically, major liver resections (eg, right or left hepatectomies) should be reserved for experienced surgeons facile with more advanced laparoscopic hepatic resections. Conversion should be performed for difficult resections requiring extended operating times, and for patient safety, and should be considered prudent surgical practice rather than failure. In emergent situations, efforts should be made to control bleeding before converting to a formal open approach. Utilization of a hand assist or hybrid technique may be faster, safer, and more efficacious. Indications for surgery for benign hepatic lesions should not be widened simply because the surgery can be done laparoscopically. Although data presented on colorectal metastases did not reveal an adverse effect of the laparoscopic approach on oncological outcomes in terms of margins or survival, adequacy of margins and ability to detect occult lesions are concerns. The pure laparoscopic technique of left lateral sectionectomy was used for adult to child donation while the hybrid approach has been the only one reported to date in the case of adult to adult right lobe donation. Laparoscopic liver surgery has not been tested by controlled trials for efficacy or safety. A prospective randomized trial appears to be logistically prohibitive; however, an international registry should be initiated to document the role and safety of laparoscopic liver resection. Conclusions:Laparoscopic liver surgery is a safe and effective approach to the management of surgical liver disease in the hands of trained surgeons with experience in hepatobiliary and laparoscopic surgery. National and international societies, as well as governing boards, should become involved in the goal of establishing training standards and credentialing, to ensure consistent standards and clinical outcomes.

Improved Survival in Metastatic Colorectal Cancer Is Associated With Adoption of Hepatic Resection and Improved Chemotherapy

PURPOSE Fluorouracil/leucovorin as the sole therapy for metastatic colorectal cancer (CRC) provides an overall survival of 8 to 12 months. With an increase in surgical resections of metastatic disease and development of new chemotherapies, indirect evidence suggests that outcomes for patients are improving in the general population, although the incremental gain has not yet been quantified. METHODS We performed a retrospective review of patients newly diagnosed with metastatic CRC treated at two academic centers from 1990 through 2006. Landmark analysis evaluated the association of diagnosis year and liver resection with overall survival. Additional survival analysis of the Surveillance Epidemiology and End Results (SEER) database evaluated a similar population from 1990 through 2005. RESULTS Two thousand four hundred seventy patients with metastatic CRC at diagnosis received their primary treatment at the two institutions during this time period. Median overall survival for those patients diagnosed from 1990 to 1997 was 14.2 months, which increased to 18.0, 18.6, and 29.3 months for patients diagnosed in 1998 to 2000, 2001 to 2003, and 2004 to 2006, respectively. Likewise, 5-year overall survival increased from 9.1% in the earliest time period to 19.2% in 2001 to 2003. Improved outcomes from 1998 to 2004 were a result of an increase in hepatic resection, which was performed in 20% of the patients. Improvements from 2004 to 2006 were temporally associated with increased utilization of new chemotherapeutics. In the SEER registry, overall survival for the 49,459 identified patients also increased in the most recent time period. CONCLUSION Profound improvements in outcome in metastatic CRC seem to be associated with the sequential increase in the use of hepatic resection in selected patients (1998 to 2006) and advancements in medical therapy (2004 to 2006).

Diagnosis and management of primary sclerosing cholangitis

Preamble This guideline has been approved by the American Association for the Study of Liver Diseases and represents the position of the Association. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recentlypublished world literature on the topic (Medline search); (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines2; and (4) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventative aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1).3 The strength of recommendations in the GRADE system are classified as strong (class 1) or weak (class 2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (level A), moderate (level B), or low-quality (level C).

Surgical treatment of neuroendocrine metastases to the liver: : a plea for resection to increase survival

BACKGROUND Hepatic metastases from neuroendocrine tumors have a protracted natural history and are associated with endocrinopathies. Resection is indicated for symptom control. Previous reports have suggested improvement in survival for patients undergoing debulking procedures. STUDY DESIGN The records of all consecutive patients undergoing resection of hepatic metastases from neuroendocrine tumors between 1977 and 1998 were reviewed. Tumors were classified according to histology, endocrine activity, and primary location. Patients lost to followup before 1 year were excluded. Followups were based on outpatient evaluations and were updated by correspondence. The Kaplan-Meier method was used to generate survival and recurrence curves, and the log-rank test was used for comparison. RESULTS A total of 170 patients fulfilled the inclusion criteria, of whom 73 were men. Mean age (+/-SD) was 57 (+/-11.5) years. Carcinoid (n = 120) and nonfunctioning islet cell tumors (n = 18) predominated; the ileum (n = 85) and the pancreas (n = 52) were the most common primary sites. Major hepatectomy (one or more lobes) was performed in 91 patients (54%). The postoperative complication rate was 14%, and two patients died (1.2%). Operation controlled symptoms in 104 of 108 patients, but the recurrence rate at 5 years was 59%. Operation decreased 5-hydroxyindoleacetic acid levels considerably, and no patient experienced carcinoid heart disease postoperatively. Recurrence rate was 84% at 5 years. Overall survival was 61% and 35% at 5 and 10 years, respectively, with no difference between carcinoid and islet cell tumors. CONCLUSIONS Hepatic resection for metastatic neuroendocrine tumors is safe and achieves symptom control in most patients. Debulking extends survival, although recurrence is expected. Hepatic resection is justified by its effects on survival and quality of life.

Association of MicroRNA Expression in Hepatocellular Carcinomas with Hepatitis Infection, Cirrhosis, and Patient Survival

Purpose: MicroRNA (miRNA) is a new class of small, noncoding RNA. The purpose of this study was to determine if miRNAs are differentially expressed in hepatocellular carcinoma (HCC). Experimental Design: More than 200 precursor and mature miRNAs were profiled by real-time PCR in 43 and 28 pairs of HCC and adjacent benign liver, respectively, and in normal liver specimens. Results: Several miRNAs including miR-199a, miR-21, and miR-301 were differentially expressed in the tumor compared with adjacent benign liver. A large number of mature and precursor miRNAs were up-regulated in the adjacent benign liver specimens that were both cirrhotic and hepatitis-positive compared with the uninfected, noncirrhotic specimens (P < 0.01). Interestingly, all of the miRNAs in this comparison had increased expression and none were decreased. The expression of 95 randomly selected mRNAs was not significantly altered in the cirrhotic and hepatitis-positive specimens, suggesting a preferential increase in the transcription of miRNA. Comparing the miRNA expression in the HCC tumors with patients survival time revealed two groups of patients; those with predominantly lower miRNA expression and poor survival and those with predominantly higher miRNA expression and good survival (P < 0.05). A set of 19 miRNAs significantly correlated with disease outcome. A number of biological processes including cell division, mitosis, and G1-S transition were predicted to be targets of the 19 miRNAs in this group. Conclusion: We show that a global increase in the transcription of miRNA genes occurs in cirrhotic and hepatitis-positive livers and that miRNA expression may prognosticate disease outcome in HCC.

Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma.

The authors reviewed their institutional experience with liver resection for metastatic colorectal carcinoma to (1) determine whether perioperative blood transfusion affects survival; (2) identify prognostic determinants; and (3) estimate the patient requirement for a prospective randomized trial designed to demonstrate efficacy of liver resection. Two hundred eighty consecutive patients treated by potentially curative liver resection between 1960 and 1987 were included. Data were obtained for all but 10 patients for at least 5 years after operation or through 1990. Actuarial survival curves related to potential prognostic determinants were analyzed with the log-rank test. Overall, survival was 47 ± 3% at 3 years and 25 ± 3% at 5 years, including 4% 60-day operative mortality rate. Eighty-one patients who did not receive blood 7 days before to 14 days after operation had 60 ± 6% 3-year and 32 ± 6% 5-year survival compared with 40 ± 4% and 21 ± 3% survival rates for 183 patients who received at least one unit (p = 0.03, operative deaths excluded). Extra-hepatic disease (p = 0.015), extrahepatic lymph node involvement (p = 0.002), satellite configuration of multiple metastases (p = 0.0052), and initial detection by abnormal liver enzymes (p = 0.0005) were associated with poor survival rates. Synchronous presentation of metastatic and stage B primary disease was associated with a favorable prognosis (p = 0.003). The requirement for a prospective randomized trial estimated by an exponential survival model would be 36, 74, 168, or 428 patients if 5-year survival without resection were 1, 5, 10, or 15%. We conclude that (1) perioperative blood transfusion may be adversely associated with survival; (2) extrahepatic disease, extrahepatic lymph node involvement, satellite configuration, and initial detection by clinical examination or a liver enzyme abnormality portend a poor prognosis; and (3) a prospective randomized trial of liver resection is impractical because of the large patient requirement, at least by a single institution.

Liver Transplantation with Neoadjuvant Chemoradiation is More Effective than Resection for Hilar Cholangiocarcinoma

Objective:Compare survival after neoadjuvant therapy and liver transplantation with survival after resection for patients with hilar CCA. Summary Background Data:We developed a protocol combining neoadjuvant radiotherapy, chemosensitization, and orthotopic liver transplantation for patients with operatively confirmed stage I and II hilar CCA in 1993. Since then, patients with unresectable CCA or CCA arising in the setting of PSC have been enrolled in the transplant protocol. Patients with tumors amenable to resection have undergone excision of the extrahepatic duct with lymphadenectomy and liver resection. Methods:We reviewed our experience between January 1993 and August 2004 and compared patient survival between the treatment groups. Results:Seventy-one patients entered the transplant treatment protocol and 38 underwent liver transplantation. Fifty-four patients were explored for resection. Twenty-six (48%) underwent resection, and 28 (52%) had unresectable disease. One-, 3-, and 5-year patient survival were 92%, 82%, and 82% after transplantation and 82%, 48%, and 21% after resection (P = 0.022). There were fewer recurrences in the transplant patients (13% versus 27%). Conclusions:Liver transplantation with neoadjuvant chemoradiation achieved better survival with less recurrence than conventional resection and should be considered as an alternative to resection for patients with localized, node-negative hilar CCA.

Hepatic resection for metastatic neuroendocrine carcinomas

BACKGROUND Metastatic neuroendocrine malignancies frequently cause incapacitating endocrinopathies, and metastases predominant in the liver. Hepatic resection of metastases from such tumors is attractive because the natural history of neuroendocrine tumors is protracted, clinical severity of the endocrinopathy correlates with tumor volume, and local and intrahepatic growth characteristics often allow complete resection. PATIENTS AND METHODS To define the role of hepatic resection for metastatic neuroendocrine tumors, the records of 74 patients who underwent hepatic resection for such tumors between 1984 and 1992 were reviewed. Neuroendocrine tumors were classified by site of origin and clinical endocrinopathy. Survival, and type and duration of symptomatic response, were assessed as the major outcomes of this study. RESULTS There were 50 carcinoid, 23 islet-cell, and 1 atypical neuroendocrine tumors. Resections included 36 hemihepatectomies or extended hepatectomies and 38 nonanatomic resections. Thirty-eight primary tumors were resected concomitantly. Perioperative mortality was 2.7% and morbidity was 24%. Four-year survival was 73%. Overall postoperative symptomatic response rate was 90% with a mean duration of response of 19.3 months. CONCLUSIONS Hepatic resection for metastatic neuroendocrine malignancies is safe, provides effective palliation, and probably prolongs survival.

Mutational spectrum of β-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas

Activation of Wnt signaling through β-catenin mutations contributes to the development of hepatocellular carcinoma (HCC) and hepatoblastoma (HB). To explore the contribution of additional Wnt pathway molecules to hepatocarcinogenesis, we examined β-catenin, AXIN1 and AXIN2 mutations in 73 HCCs and 27 HBs. β-catenin mutations were detected in 19.2% (14 out of 73) HCCs and 70.4% (19 out of 27) HBs. β-catenin mutations in HCCs were primarily point mutations, whereas more than half of the HBs had deletions. AXIN1 mutations occurred in seven (9.6%) HCCs and two (7.4%) HBs. The AXIN1 mutations included seven missense mutations, a 1 bp deletion, and a 12 bp insertion. The predominance of missense mutations found in the AXIN1 gene is different from the small deletions or nonsense mutations described previously. Loss of heterozygosity at the AXIN1 locus was present in four of five informative HCCs with AXIN1 mutations, suggesting a tumor suppressor function of this gene. AXIN2 mutations were found in two (2.7%) HCCs but not in HBs. Two HCCs had both AXIN1 and β-catenin mutations, and one HCC had both AXIN2 and β-catenin mutations. About half the HCCs with AXIN1 or AXIN2 mutations showed β-catenin accumulation in the nucleus, cytoplasm or membrane. Overall, these data indicate that besides the approximately 20% of HCCs and 80% of HBs with β-catenin mutations contributing to hepatocarcinogenesis, AXIN1 and AXIN2 mutations appear to be important in an additional 10% of HCCs and HBs.

Hepatic steatosis as a potential risk factor for major hepatic resection

Hepatic steatosis is a recognized risk factor for primary nonfunction of hepatic allografts, but the effect of steatosis on postoperative recovery after major liver resection is unknown. Our aim was to determine if hepatic steatosis is associated with increased perioperative morbidity and mortality in patients undergoing major resection. A retrospective review of medical records of 13 5 patients who had undergone major hepatic resection from 1990 to 1993 was performed. Histopathology of the hepatic parenchyma at the resection margin was reviewed for the presence of macroor microvesicular steatosis. The extent of steatosis was graded as none (group l), mild with less than 30% hepatocytes involved (group 2), or moderate-to-severe with 30% or more hepatocytes involved (group 3). Outcome of patients was correlated with extent of steatosis. Patients with moderate-to-severe steatosis were obese (body mass index = 25.8 +-2 0.5 vs. 26.5 t 1.0+-. 33.4 +2.9; P <0.05 groups 1,2, and 3, respectively) and had an increased serum bilirubin concentration preoperatively. Hepatectomy required a longer operative time for group 3 (290 +-2 9 minutes vs. 287 +13 minutes vs. 35.5 +24 minutes; P <0.05 groups 1,2, and 3, respectively). Likelihood of blood transfusion was 5 1% in group l,S2 % in group 2, and 7 1% in group 3. Mortality was 14% in group 3 vs. 3% in group 1, and 7% in group 2; and liver failure occurred in 14% of patients in group 3 compared to 4% and 9% in groups 1 and 2, respectively. Patients in group 3 also had increased post-operative bilirubin levels compared to preoperative values. Moderate-to-severe hepatic steatosis may be associated with increased perioperative morbidity and mortality, and preoperative identification of steatosis warrants caution prior to major resection.