J. Peter A. Lodge

Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation

Patients undergoing orthotopic liver transplantation (OLT) have excessive blood loss during surgery that requires blood transfusions, leading to increased postoperative morbidity and mortality. We studied the efficacy and safety of activated recombinant factor VII (rFVIIa) in reducing transfusion requirements in OLT. This multicenter, randomized, double‐blind, placebo‐controlled trial enrolled patients undergoing OLT because of cirrhosis (Child‐Turcotte‐Pugh class B or C). Patients received a repeated intravenous bolus regimen of rFVIIa 60 or 120 μg/kg or placebo. The primary efficacy endpoint was the total number of red blood cell (RBC) units transfused during the perioperative period. A total of 182 patients were analyzed for efficacy and 183 for safety. No significant effect of rFVIIa was observed on the number of RBC units transfused or intraoperative blood loss compared with the placebo group. A significantly higher number of patients in the rFVIIa study groups avoided RBC transfusion. Administration of rFVIIa but not placebo restored the preoperative prolonged prothrombin time to normal value during surgery. Patients receiving rFVIIa and placebo did not experience a significant difference in rate of thromboembolic events. Additionally, there was no statistically significant effect of rFVIIa treatment on hospitalization rate, total surgery time, and the proportion of patients undergoing retransplantation. In conclusion, use of rFVIIa during OLT significantly reduced the number of patients requiring RBC transfusion. There was no increase in thromboembolic events with rFVIIa administration compared with placebo. (Liver Transpl 2005;11:973–979.)

Recombinant coagulation factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial.

Background:Prevention of bleeding episodes in noncirrhotic patients undergoing partial hepatectomy remains unsatisfactory in spite of improved surgical techniques. The authors conducted a randomized, placebo-controlled, double-blind trial to evaluate the hemostatic effect and safety of recombinant factor VIIa (rFVIIa) in major partial hepatectomy. Methods:Two hundred four noncirrhotic patients were equally randomized to receive either 20 or 80 &mgr;g/kg rFVIIa or placebo. Partial hepatectomy was performed according to local practice at the participating centers. Patients were monitored for 7 days after surgery. Key efficacy parameters were perioperative erythrocyte requirements (using hematocrit as the transfusion trigger) and blood loss. Safety assessments included monitoring of coagulation-related parameters and Doppler examination of hepatic vessels and lower extremities. Results:The proportion of patients who required perioperative red blood cell transfusion (the primary endpoint) was 37% (23 of 63) in the placebo group, 41% (26of 63) in the 20-&mgr;g/kg group, and 25% (15 of 59) in the 80-&mgr;g/kg dose group (logistic regression model; P = 0.09). Mean erythrocyte requirements for patients receiving erythrocytes were 1,024 ml with placebo, 1,354 ml with 20 &mgr;g/kg rFVIIa, and 1,036 ml with 80 &mgr;g/kg rFVIIa (P = 0.78). Mean intraoperative blood loss was 1,422 ml with placebo, 1,372 ml with 20 &mgr;g/kg rFVIIa, and 1,073 ml with 80 &mgr;g/kg rFVIIa (P = 0.07). The reduction in hematocrit during surgery was smallest in the 80-&mgr;g/kg group, with a significant overall effect of treatment (P = 0.04). Conclusions:Recombinant factor VIIa dosing did not result in a statistically significant reduction in either the number of patients transfused or the volume of blood products administered. No safety issues were identified.

Preoperative prognostic score for predicting survival after hepatic resection for colorectal liver metastases

Background:Despite indications for resection of colorectal liver metastases having expanded, debate continues about identifying patients that may benefit from surgery. Methods:Clinicopathologic data from a total of 700 patients was gathered between January 1993 and January 2006 from a prospectively maintained dataset. Of these, 687 patients underwent resection for colorectal liver metastases. Results:The median age of patient was 64 years and 36.8% of patients had synchronous disease. The overall 5-year survival was 45%. The presence of an inflammatory response to tumor (IRT), defined by an elevated C-reactive protein (>10 mg/L) or a neutrophil/lymphocyte ratio of >5:1, was noted in 24.5% of cases. Only the number of metastases and the presence or absence of an IRT influenced both overall and disease-free survival on multivariable analysis. A preoperative prognostic score was derived: 0 = less than 8 metastases and absence of IRT; 1 = 8 or more metastases or IRT, and 2 = 8 or more metastases and IRT—from the results of the multivariable analysis. The 5-year survival of those scoring 0 was 49% compared with 34% for those scoring 1. None of the patients that scored 2 were alive at 5 years. Conclusion:The preoperative prognostic score is a simple and effective system allowing preoperative stratification.

Correlation between postoperative infective complications and long-term outcomes after hepatic resection for colorectal liver metastasis.

Background:The impact of postoperative morbidity, and in particular infective complications on long-term outcomes, following hepatic resection for colorectal liver metastasis (CRLM) is not widely published. Objective:To evaluate the effect of postoperative complications on disease recurrence and overall survival in patients undergoing hepatic resection for CRLM. Methods:All patients undergoing hepatic resection for CRLM from January 1993 and March 2007 were identified, and postoperative complications analyzed. Patients who died of postoperative complications within 30 days of surgery were excluded form the study. Postoperative complications were graded using a validated system of classification. Complications were further classified into infective and noninfective complication groups and the primary end points of the study were disease free survival (DFS) and overall survival (OS) at 5 years. Result:A total of 705 patients underwent hepatic resection in the study period. Median follow-up was 38 months. Operative morbidity and mortality were 28% and 3.6%, respectively. The total number of patients was 197 (28%) with complications, and 508 (72%) without complications. The 5 year DFS and OS for those with and without complications were: 13% versus 26% (P < 0.001) and 24% versus 37% (P < 0.001), respectively. Multivariate analysis showed inflammatory response to tumor score, blood transfusion, tumor number >8, and postoperative sepsis to be independent factors associated with DFS, and inflammatory response to tumor, tumor number >8, and postoperative sepsis to be independent predictors for OS. Intra-abdominal and respiratory infection but not wound infections were associated with poorer long-term outcomes. Conclusions:Postoperative complications influence long-term outcomes in hepatic resection for CRLM. Specifically, postoperative sepsis is an independent predictor of disease free and overall survival. Thorough preoperative optimization, meticulous surgical technique and careful management in the postoperative period may reduce the incidence of these complications and influence long-term outcomes.

The value of intraoperative ultrasound during hepatic resection compared with improved preoperative magnetic resonance imaging

BACKGROUND Patients with colorectal metastases confined to the liver may be cured by resection. Combined bimanual palpation and intraoperative ultrasound (IOUS) augment the detection of colorectal hepatic metastases. The importance of IOUS in the surgical management of hepatic tumors has been demonstrated and should arguably be considered the final diagnostic procedure. OBJECTIVE To determine the relevance of routine IOUS prior to hepatic resection compared with improved preoperative Magnetic resonance imaging (MRI). PATIENTS AND METHODS Eighty patients with metastatic colorectal adenocarcinoma underwent hepatic resection between 1998 and 2001. The IOUS results were compared with preoperative MRI, bimanual palpation, and resection histopathology. The preoperative surgical plan was compared with the surgical procedure performed. Data were retrospectively analyzed. RESULTS IOUS provided additional useful information not available preoperatively for 37 (47%) patients, including the identification of subcentimetre metastatic lesions, characterization of the lesion, and the anatomy of the hepatic vasculature. The preoperative surgical plan was changed secondary to the IOUS findings alone in 14/80 (18%) patients. IOUS did not provide any additional useful information for 43 (53%) patients. A correlation was demonstrated between the preoperative diagnosis, intraoperative findings, and resection histopathology. CONCLUSION Accurate diagnostic studies facilitate critically decisive actions during planned hepatic resection(s). The current findings suggest that IOUS provide the most useful additional information for hepatic lesions, despite recent improvements in preoperative MRI scanning. Furthermore, routine IOUS should be employed during hepatic resection for colorectal metastases.

Impact of systemic inflammation on outcome following resection for intrahepatic cholangiocarcinoma

To analyse the results and prognostic factors affecting disease‐free and overall survival following potentially curative resection for intrahepatic cholangiocarcinoma (IHCC).

Surgical Strategy for Cystic Diseases of the Liver in a Western Hepatobiliary Center

The aim of this study was to define the indications and evaluate the results of various management options in patients with cystic liver disease. Between 1992 and 1999 we managed 60 consecutive patients with cystic liver disease. Diagnoses included a simple cyst (solitary 12, multiple 10), adult polycystic liver disease (APLD 17), Caroli’s disease (8), hydatid cysts (4), and neoplastic cysts (9). Half of the patients with simple cysts had mild or no symptoms and required no treatment. Percutaneous drainage in eight patients (simple cyst 4, APLD 4) was followed by symptomatic recurrence in three. Laparoscopic deroofing in three patients (multiple simple cysts 2, APLD 1) was followed by symptomatic enlargement of the remaining cysts that required further intervention (laparoscopic deroofing 2, transplantation 1). Laparoscopic hepatectomy was successful in three patients with solitary simple cysts. Of 18 patients who underwent open hepatic resection (neoplastic 8, Caroli’s 4, simple cysts 3, hydatid cysts 2, APLD 1), 2 patients with Caroli’s disease required liver transplantation for disease progression. Nine patients (Caroli’s 5, APLD 4) underwent liver transplantation, and three had a concomitant renal transplant. Seven patients developed complications, and three died (5%). Cholangiocarcinoma developed in three patients with bilateral Caroli’s disease, and all died. Radiologic treatment has a limited role in the management of patients with simple cysts or APLD. Laparoscopic deroofing of simple cysts may have to be repeated, whereas resection minimizes cyst recurrence. Unilobar Caroli’s disease may be resected, whereas bilateral disease requires early liver transplantation owing to the high risk of malignancy. Transplantation is a reserved option in patients with extensive APLD.

Liver Transplantation for Neuroendocrine Tumors in Europe—Results and Trends in Patient Selection A 213-Case European Liver Transplant Registry Study

Objective:The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period. Background:LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases. Methods:This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1–149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures. Results:Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT. Conclusions:LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.

Hepatic resection and transplantation for primary carcinoid tumors of the liver.

Objective:To discuss the diagnosis and management of primary carcinoid tumors of the liver in light of our experience and a literature review. Summary Background Data:Carcinoid tumors of the liver are rare and pose a diagnostic and management dilemma. This series is the largest reported and the only one to include liver transplantation as a treatment option. Methods:Between March 1994 and May 2002, we treated 8 patients (4 male, 4 female) with primary hepatic carcinoid tumors. Carcinoid syndrome complicated only 1 of the cases. Treatment was by liver resection in 6 patients and orthotopic liver transplantation in 2. Results:The diagnosis was confirmed histologically with light microscopy and immunohistochemistry in the absence of an alternative primary site. Six patients remain alive and disease free after follow-up of more than 3 years: 39, 43, 45, 50, 50, and 95 months. Two patients are recently postoperative. Conclusions:Active exclusion of an extrahepatic primary site is essential for the diagnosis of primary carcinoid of the liver. The mainstay of treatment should be liver resection, although liver transplantation may be considered in patients with widespread hepatic involvement. A radical surgical approach is warranted as this disease carries a better prognosis than for other primary hepatic tumors and for secondary hepatic carcinoids.

The effect of the selective cyclooxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases

BACKGROUND & AIMS Cyclooxygenase-2 (COX-2) is a potential target for chemotherapy of colorectal cancer (CRC). We tested the antineoplastic activity of the selective COX-2 inhibitor rofecoxib on human CRC liver metastases by measuring surrogate markers of tumor growth and angiogenesis in a randomized, double-blind, placebo-controlled trial. METHODS Patients undergoing liver resection surgery for metastatic disease were randomized to receive rofecoxib 25 mg daily or placebo before surgery (duration, >14 days). The apoptosis index (AI; neocytokeratin 18), proliferation index (PI; Ki-67), and microvessel density (MVD; CD31) were measured in metastases by immunohistochemistry. The effect of rofecoxib on COX-2-positive HCA-7 human CRC cell PGE(2) synthesis, proliferation, and apoptosis in vitro was also investigated. RESULTS Patients who received rofecoxib (n = 23) and placebo (n = 21) were well matched regarding clinical and metastasis characteristics. The mean (range) duration of rofecoxib therapy was 26 (14-46) days. Rofecoxib-treated metastases had a 29% decrease in MVD (mean, 25.1 [SEM, 2.7] per hpf) compared with placebo-treated tissue (32.5 [SEM, 4.5] per hpf; P = 0.15). There was little difference in AI (rofecoxib mean, 2.03% [SEM, 0.43%] vs. placebo 1.39% [SEM, 0.39%]) or PI (rofecoxib 54.7% [SEM, 5.1%] vs. placebo 52.6% [SEM, 5.6%]). Rofecoxib-induced growth arrest and apoptosis of HCA-7 cells occurred only at concentrations (>10 micromol/L), which were significantly higher than the IC(50) for COX-2 inhibition. CONCLUSIONS Rofecoxib may negatively regulate angiogenesis in human CRC liver metastases. The absence of a significant, direct effect of rofecoxib on epithelial cells in liver metastases in vivo mirrors the lack of activity on human CRC cells at pharmacologically relevant concentrations in vitro.