Predicting early intrahepatic recurrence after curative resection of colorectal liver metastases with molecular markers.

BACKGROUND: The aim of this case-control study was to identify clinicopathological factors and test three relevant biomarkers for their ability to predict early intrahepatic recurrence after curative liver resection for colorectal liver metastases (CLM). METHODS: Of the 184 patients with CLM undergoing hepatectomy between January 2007 and December 2009, thirty patients had intrahepatic disease recurrence within 6 months. The control group was randomly selected from a cohort of patients between April 1997 and December 2005 who have survived without disease recurrence after CLM resection for over 5 years. Both groups were matched for size of metastasis greater than 5.0 cm, the presence of multiple metastases, and synchronous versus metachronous CLM. The final study population consisted of 60 patients with CLM undergoing R0 hepatectomy, 30 of whom had early intrahepatic-only recurrences (study group) and 30 patients without recurrence for more than 5 years (control group). Both groups were analyzed and compared for the presence of clinical factors and expression levels of CD133, survivin, and Bcl-2 within tumor tissue. RESULTS: Characteristics of patients were similar between the two groups except primary tumor location and administration of postoperative chemotherapy. Expression level of CD133 and survivin were significantly increased in tumors of patients with recurrence compared to patients without recurrence. On multivariate analysis high tumor expression levels of CD133 (odds ratio [OR] 14.7, confidence interval [CI] 1.8-121.3, p = 0.012) and survivin (OR 9.5, CI 2.1-44.3, p = 0.004) and postoperative chemotherapy (OR 4.8, CI 1.01-22.9, p = 0.049) were independent factors associated with early intrahepatic recurrence. CONCLUSIONS: Tumor expression levels of CD133 and survivin may be a useful predictor of early intrahepatic recurrence after hepatectomy for CLM. Administration of postoperative chemotherapy may prevent early intrahepatic recurrence.

Post-hepatectomy liver failure in patients with colorectal liver metastases.

Liver resection remains the standard treatment for colorectal liver metastases (CLM). Major hepatic resection is now performed frequently and with relative safety, but postoperative mortality is still reported to occur in up to 6 % of the patients with CLM undergoing liver resection even at high-volume centers. Post-hepatectomy liver failure (PHLF) is a key factor involved in mortality. The frequency of PHLF is reported to be 1-16 %, and has varied greatly among studies since a clear definition of PHLF has been lacking. Recently, the International Study Group of Liver Surgery (ISGLS) proposed a simple definition of PHLF, which includes the combination of the severity of PHLF and does not use an arbitrary cut-off value for the serum bilirubin concentration and INR. Hence, it may be the most useful definition in the clinical setting. Advanced age, a small future liver remnant volume, preoperative chemotherapy and chemotherapy-induced liver injury may all be associated with PHLF. Once PHLF occurs, it is difficult to reverse, and thus, strategies aimed at prevention are keys to reducing the mortality after liver surgery.

Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial.

BACKGROUND: Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. METHODS: This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m(2) (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. FINDINGS: Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6-9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68-1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0-83·4) in the perioperative chemotherapy group and 54·3 months (41·9-79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6-58·3) in the perioperative chemotherapy group versus 47·8% (40·3-55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. INTERPRETATION: We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients. FUNDING: Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.

Reoperative surgery after repair of postcholecystectomy bile duct injuries: is it worthwhile?

BACKGROUND: Repeat repair of bile duct injuries (BDIs) after cholecystectomy is technically challenging, and its success remains uncertain. We retrospectively evaluated the short- and long-term outcomes of patients requiring reoperative surgery for BDI at a major referral center for hepatobiliary surgery. METHODS: Between January 1991 and May 2011, we performed surgical BDI repairs in 46 patients. Among them, 22 patients had undergone a previous surgical repair elsewhere (group 1), and 24 patients had no previous repair (group 2). We compared the early and late outcomes in the two groups. RESULTS: The patients in group 1 were younger (48.6 vs. 54.8 years, p = 0.0001) and were referred after a longer interval (>1 month) from BDI (72.7 vs. 41.7%, p = 0.042). Intraoperative diagnosis of BDI (59.1 vs. 12.5%, p = 0.001), ongoing cholangitis (45.4 vs. 12.5%; p = 0.02), and delay of repair after referral to our institution (116 ± 34 days vs. 23 ± 9 days; p = 0.001) were significantly more frequent in group 1 than in group 2. No significant differences were found for postoperative mortality, morbidity, or length of stay between the groups. Patients with associated vascular injuries had a higher postoperative morbidity rate (p = 0.01) and associated hepatectomy rate (p = 0.045). After a mean follow-up of 96.6 ± 9.7 months (range 5-237.2 months, median 96 months), the rate of recurrent cholangitis (6.5%) was comparable in the two groups. CONCLUSIONS: This study demonstrates that short- and long-term outcomes after surgical repair of BDI are comparable regardless of whether the patient requires reoperative surgery for a failed primary repair. Associated vascular injuries increase postoperative morbidity and the need for liver resection.

What is a safe future liver remnant size in patients undergoing major hepatectomy for colorectal liver metastases and treated by intensive preoperative chemotherapy?

BACKGROUND: A multidisciplinary approach involving preoperative chemotherapy has become common practice in patients with colorectal liver metastases (CLM). The definition of a safe future liver remnant (FLR) volume based on preoperative clinical data in these patients is lacking. Our aim was to identify predictors of postoperative morbidities in patients undergoing major hepatectomy after intensive preoperative chemotherapy for CLM. METHODS: Between January 2000 and August 2010, a total of 101 consecutive patients with CLM underwent major hepatectomy after preoperative chemotherapy (≥6 cycles of oxaliplatin or irinotecan regimen with or without targeted therapies). The FLR ratio was calculated by two formulas: actual FLR (aFLR) ratio, and standardized FLR (sFLR) ratio. Predictors of postoperative overall morbidity, sepsis, and liver failure were identified by univariate and multivariate analyses. RESULTS: Fifty-eight patients (57.4%) had 95 postoperative complications. Sepsis and postoperative liver failure occurred in 23 (22.8%) and 16 patients (15.8%), respectively. On univariate analysis, small aFLR ratio was significantly associated with all complications, and sFLR ratio was associated with sepsis and liver failure. In receiver-operating characteristic analysis, the cutoff of aFLR ratio in predicting overall morbidity, sepsis, and liver failure was 44.8, 43.1, and 37.7%, respectively, and that of sFLR ratio in predicting sepsis and liver failure was 43.6 and 48.5%, respectively. On multivariate analysis, these aFLR and sFLR ratio cutoffs were independent predictors of all complications and of sepsis and liver failure, respectively. CONCLUSIONS: This study provides a cutoff FLR ratio for safe postoperative outcome after major hepatectomy in CLM patients receiving six or more cycles of preoperative chemotherapy.

Liver injury due to chemotherapy-induced sinusoidal obstruction syndrome is associated with sinusoidal capillarization.

BACKGROUND: Indocyanine green (ICG) retention is a validated test of hepatic function in patients with chronic liver disease. The underlying mechanism for the impairment of ICG retention in patients undergoing chemotherapy for colorectal liver metastases (CLM) remains unclear. We sought to elucidate the mechanism for impairment of ICG retention in patients with CLM. METHODS: Clinicopathologic data of 98 patients with CLM undergoing hepatectomy were analyzed. The archived nontumoral liver parenchyma bearing no CLM were immunostained with CD34 antibody to determine the sinusoidal capillarization. RESULTS: Of 98 patients, 80 received preoperative chemotherapy. Sinusoidal obstruction syndrome (SOS) occurred in 39 patients (39.8%). The development of SOS in patients receiving oxaliplatin-based chemotherapy was significantly higher compared to those receiving non-oxaliplatin-based chemotherapy (P=0.003). SOS was independently associated with abnormal ICG retention rate at 15 minutes (ICG-R15) (odds ratio 3.45, 95% confidence interval 1.31-9.04, P=0.012) and CD 34 overexpression (odds ratio 18.76, 95% confidence interval 4.58-76.81, P<0.001). ICG-R15 correlated with CD34 expression within the nontumoral liver parenchyma (r=0.707, P<0.001) and severity of SOS (r=0.423, P<0.001). CD34 positive areas were likely situated at the peripheral area of SOS, and both SOS score and number of cycles of oxaliplatin-based chemotherapy significantly correlated with CD34 expression (r=0.629, P<0.001 and r=0.522, P<0.001, respectively). CONCLUSIONS: These results suggest that the deterioration of hepatic functional reserve due to SOS is associated with sinusoidal capillarization, indicated by CD34 overexpression within nontumoral liver parenchyma adjacent to SOS.

Prolonged portal triad clamping increases postoperative sepsis after major hepatectomy in patients with sinusoidal obstruction syndrome and/or steatohepatitis.

BACKGROUND: Portal triad clamping (PTC) has been widely adopted in an attempt to decrease bleeding during liver parenchymal transection. As a larger proportion of patients are treated with chemotherapy prior to liver resection, the safety of PTC in patients with chemotherapy-associated liver injury remains poorly investigated. This study aims to evaluate the influence of PTC on early postoperative outcomes in patients with chemotherapy-associated liver injury undergoing major hepatectomy for colorectal liver metastases (CLM). PATIENTS AND METHODS: From January 2000 to October 2010, 53 patients with histologically proven chemotherapy-associated liver injuries [sinusoidal obstruction syndrome (SOS; n = 41), steatohepatitis (n = 5), and both SOS and steatohepatitis (n = 7)] who underwent major hepatectomy for CLM were divided into two groups; patients undergoing intermittent TPC (n = 20) and those who did not undergo TPC (n = 33). Perioperative clinicobiological factors, morbidity including septic complications, and mortality were analyzed and compared between the two groups. RESULTS: Intraoperative blood transfusions and postoperative liver function were comparable between the two groups. Sepsis and biloma occurred more often in patients undergoing PTC longer than 30 min than in those undergoing PTC ≤ 30 min (66.7 % versus 17.1 %, p = 0.002, and 33.3 versus 0 %, p = 0.002, respectively). A multiple logistic regression analysis showed that prolonged PTC (>30 min) and the ratio of future liver remnant volume to total liver volume ≤ 43 % were independent factors for predicting postoperative sepsis [odds ratio (OR): 32.68; 95 % confidence interval (95 % CI): 2.86-372.82; p = 0.005--and odds ratio: 9.70; 95 % CI: 1.04-90.86; p = 0.047, respectively]. CONCLUSIONS: Portal triad clamping can be safely used in patients with chemotherapy-associated liver injury who require major liver resection. Prolonged PTC can increase the occurrence of postoperative biliary and septic complications.

Predictive factors for the benefit of perioperative FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC Intergroup Trial 40983).

OBJECTIVE: In EORTC study 40983, perioperative FOLFOX increased progression-free survival (PFS) compared with surgery alone for patients with initially 1 to 4 resectable liver metastases from colorectal cancer (CRC). We conducted an exploratory retrospective analysis to identify baseline factors possibly predictive for a benefit of perioperative FOLFOX on PFS. METHODS: The analysis was based on 237 events from 342 eligible patients. Cox proportional hazards regression models with a significance level of 0.1 were used to build up univariate and multivariate models. RESULTS: After adjustment for identified prognostic factors, moderately (5.1-30 ng/mL) and highly (>30 ng/mL) elevated carcinoembryonic antigen (CEA) serum levels were both predictive for the benefit of perioperative chemotherapy (interaction P = 0.07; hazard ratio [HR] = 0.58 and HR = 0.52 for treatment benefit). For patients with moderately or highly elevated CEA (>5 ng/mL), the 3-year PFS was 35% with perioperative chemotherapy compared to 20% with surgery alone. Performance status (PS) 0 and BMI lower than 30 were also predictive for the benefit of perioperative chemotherapy (interaction P = 0.04 and P = 0.02). However, the number of patients with PS 1 and BMI 30 or higher were limited. The benefit of perioperative therapy was not influenced by the number of metastatic lesions (1 vs 2-4, interaction HR = 0.98). CONCLUSIONS: Perioperative FOLFOX seems to benefit in particular patients with resectable liver metastases from CRC when CEA is elevated and when PS is unaffected, regardless of the number of metastatic lesions.ClinicalTrials.gov number NCT00006479.

Multivariate analysis of risk factors for pulmonary complications after hepatic resection.

OBJECTIVE: To generate the first evaluation of risk factors for postoperative pulmonary complications (PPCs) after hepatectomy. BACKGROUND: Postoperative pulmonary complications (PPCs) after surgery are associated with significant morbidity and have been shown to increase the length of hospital stays. Several studies have been conducted to identify the risk factors for PPCs after abdominal surgery. METHODS: Between January 2006 and December 2009, 555 patients underwent elective hepatectomy. We prospectively collected and retrospectively analyzed demographic data, pathological variables, associated pathological conditions, and preoperative, intraoperative, and postoperative variables. The dependent variables studied were the occurrence of PPCs, pleural effusion, pneumonia, and pulmonary embolism. RESULTS: Multivariate analysis identified 5 independent risk factors for global PPCs: prolonged surgery [odds ratio (OR) = 1], presence of a nasogastric tube (OR = 1.6), intraoperative blood transfusion (OR = 1.7), diabetes mellitus (OR = 2.7), and a transverse subcostal bilateral muscle cutting incision (OR = 3.4). There were 4 independent risk factors for pleural effusion: prolonged surgery (OR = 1), surgery on the right lobe of the liver (OR = 1.6), neoadjuvant chemotherapy (OR = 2), and a transverse subcostal bilateral muscle cutting incision (OR = 2.5). There were 3 independent risk factors for pneumonia: intraoperative blood transfusion (OR = 1.9), diabetes mellitus (OR = 2.2), and atrial fibrillation (OR = 3). For pulmonary embolism, history of previous thromboembolic events was identified as the only risk factor (OR = 8.8). CONCLUSIONS: The correction of modifiable risk factors among the identified factors could reduce the incidence of PPCs and, as a consequence, improve patient outcomes and reduce the length of hospital stays.

Inferior vena cava graft-enteric fistula after extended hepatectomy with caval replacement.

A case of an inferior vena cava (IVC) graft-enteric fistula manifesting with recurrent sepsis 11 years after a right hepatectomy extending to segments I and IV, the extrahepatic bile duct, and IVC followed by chemotherapy and external-beam radiation therapy is described. A preoperative workup revealed graft thrombosis with air bubbles inside the lumen. Laparotomy found a chronic fistula between the graft and the enteric biliary loop. Removal of the graft without further vascular reconstruction, a take-down of the biliary loop, and a redo hepaticojejunostomy were performed successfully. The diagnostic challenges, possible etiology, and therapeutic implications of this case are discussed.

Impact of biomarkers expression before and after portal vein embolization on recurrence after two-stage hepatectomy for colorectal liver metastases.

BACKGROUND: The adverse oncological effect of portal vein embolization (PVE) in patients with colorectal liver metastases (CLM) remains controversial. This study was designed to evaluate the effect of PVE on change of tumor characteristics using tumor specimens obtained from sequential hepatectomy before and after PVE. METHODS: Between December 1996 and April 2009, among 55 patients who achieved two-stage hepatectomy (TSH) combined with PVE, 39 had available cancer tissue blocks from both the first- and second-stage hepatectomy and constituted the study population. The immunohistochemistry of Ki67 and Bcl-2 before and after PVE was performed. Biomarker expressions and clinicopathological variables were assessed and their impact on recurrence was analyzed. RESULTS: Whereas tumor volume and carcinoembryonic serum level significantly increased after PVE, the expression of Ki67 and Bcl-2 remained similar before and after PVE. The Bcl-2 ratio (expressed as Bcl-2 after PVE over Bcl-2 before PVE) was an independent prognostic factor for recurrence-free survival (P=0.030). Patients with Bcl-2 ratio ≤ 1 had a significantly longer median recurrence-free survival compared with those with Bcl-2 ratio >1 receiving or not receiving adjuvant chemotherapy (24.8 months versus 8.9 or 5.8 months, respectively). CONCLUSION: Bcl-2 ratio may predict early recurrence and identify patients who do not require postoperative chemotherapy in patients undergoing TSH with PVE for CLM.

Splenic vein-inferior mesenteric vein anastomosis to lessen left-sided portal hypertension after pancreaticoduodenectomy with concomitant vascular resection.

HYPOTHESIS: A splenic vein (SV)-inferior mesenteric vein (IMV) anastomosis reduces congestion of the stomach and spleen after pancreaticoduodenectomy with resection of the SV-mesenteric vein confluence but carries a risk of left-sided venous hypertension. DESIGN: Comparative retrospective study. SETTING: Department of Digestive Surgery and Transplantation, University of Strasbourg, Strasbourg, France. PATIENTS: From January 1, 2002, to February 28, 2010, 39 patients underwent pancreaticoduodenectomy with resection of the SV-mesenteric vein confluence for pancreatic adenocarcinoma. All patients had a terminoterminal portal vein-superior mesenteric vein anastomosis. The SV blood flow into the portal vein was preserved in 11 patients by reimplantation of the SV into the portal vein. Sixteen patients underwent surgical reconstruction of the SV-IMV confluence by anastomosis (group 1), and in 12 patients the natural SV-IMV confluence was preserved (group 2). MAIN OUTCOME MEASURES: Preoperative and postoperative spleen volume and platelet count. RESULTS: Demographic characteristics, preoperative tumor staging, pathological outcome, and postoperative complications were comparable in both groups. There was no difference in platelet count between groups 1 and 2 preoperatively (mean [SD], 293.13 [125.37] vs 241.09 [49.12] × 10(3)/µL [to convert to × 10(9)/L, multiply by 1.0], respectively; P = .21) or postoperatively (mean [SD], 231.75 [156.39] vs 164.31 [76.46] × 10(3)/µL, respectively; P = .32). Likewise, no difference was found in the spleen volume preoperatively (mean [SD], 258.96 [179.23] vs 237.31 [122.46] mL, respectively; P = .76) and on postoperative day 15 (mean [SD], 279.08 [158.10] vs 299.12 [153.11] mL, respectively; P = .78). CONCLUSION: Early assessment shows that SV-IMV anastomosis is as feasible and as safe as the preservation of a natural SV-IMV confluence in patients undergoing pancreaticoduodenectomy with vascular resection for pancreatic head adenocarcinoma.

Robotic central pancreatectomy with stented pancreaticogastrostomy: operative details.

BACKGROUND: Central pancreatectomy (CP) is increasingly being used to treat selected lesions of the central pancreatic segment. A step-by-step technique for robotic CP is described and a literature review provided for this minimally invasive approach. METHODS: A 55-year-old woman was referred to the authors' center for the treatment of a single 4 cm lesion located at the proximal part of the pancreatic body. The da Vinci Robotic surgical system® with a five trocar technique was used. The pancreatic neck was transected using an endoscopic stapler. The pancreatic body was progressively dissected from the splenic vessels right to left and sectioned with an appropriate oncologic margin. A pancreaticogastrostomy protected by a transanastomotic external stent was constructed to the distal pancreatic stump. RESULTS: Surgery lasted 450 min (8 min docking time) with minimal blood loss. Pathology showed a 28 mm well-differentiated neuroendocrine pancreatic tumor with tumor-free resection margins. The patient was discharged home on postoperative day 15 in good condition. CONCLUSIONS: Robotic surgery can be safely used for complex pancreatic resection requiring pancreaticoenteric reconstruction. The experience reported so far is still limited but the results are encouraging; robotics shows the potential to bridge the gap between minimally invasive surgery and advanced pancreatic surgery.

Two-stage hepatectomy procedure to treat initially unresectable multiple bilobar colorectal liver metastases: technical aspects.

A two-stage hepatectomy procedure is a therapeutic strategy for patients presenting with initially unresectable multiple and bilobar colorectal liver metastases in order to achieve a curative R0 resection. The main goal of this approach is to minimize the risk of postoperative liver failure resulting from a too small remnant liver after completing a curative resection. This procedure combines two sequential liver resections that involve perioperative chemotherapy and portal vein embolization. This article describes our standardized strategy of two-stage hepatectomy combined with portal vein embolization used over the last 15 years and discusses the alternative procedures as well as their respective advantages and drawbacks.

Gastroduodenal artery-preserving pancreaticoduodenectomy after subtotal esophagectomy and gastric pull-up.

PURPOSE: Division of the gastroduodenal artery is commonly performed during pancreaticoduodenectomy for both malignant and benign disease. We describe here a technical modification of pylorus preserving pancreaticoduodenectomy with gastroduodenal artery preservation performed in a patient who previously underwent subtotal esophagectomy with gastric pull-up discussing advantages and drawbacks of the technique. METHODS: A 73-year-old man with a previous history of right nephrectomy and lower esophagectomy for cancer was referred to our center for the treatment of a 5-cm tumor of the pancreatic head. Following the preliminary steps of a standard pancreaticoduodenectomy, the gastroduodenal artery was isolated at its origin from the common hepatic artery. The entire length of the gastroduodenal artery was dissected after having sectioned the posterior-superior pancreaticoduodenal artery. The right gastroepiploic vessels were preserved along with the gastroduodenal artery. Digestive reconstruction was completed just as for pylorus-preserving pancreaticoduodenectomy. RESULTS: The preservation of the gastroduodenal artery along with the gastroepiloic vessels was safely performed with an operative time of 300 min and minimal blood loss. Pathology showed a solitary 5-cm renal cell carcinoma metastasis. CONCLUSIONS: Gastroduodenal artery preserving pancreaticoduodenectomy can serve as an additional option in the armamentarium of a pancreatic surgeon. This technique constitutes an interesting technical option that ensures optimal vascular supply to the gastric remnant after previous esophagectomy. Its clinical application remains limited to selected indications and deserves further experience and comparison with standard techniques.