Michel Rayar

Treatment of recurrent intrahepatic cholangiocarcinoma.

The aims of this study were to evaluate risk factors for recurrence following hepatectomy with curative intent for intrahepatic cholangiocarcinoma (ICC), and predictors of survival after intrahepatic recurrence.

Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well‐established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling, we demonstrate that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 nonredundant genes that significantly discriminate the tumor stroma from nontumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up‐regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix, and transforming growth factor beta (TGFβ) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increased expression of collagen 4A1/COL4A1, laminin gamma 2/LAMC2, osteopontin/SPP1, KIAA0101, and TGFβ2 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of osteopontin, TGFβ2, and laminin in the stroma of ICC was significantly correlated with overall patient survival. More important, multivariate analysis demonstrated that the stromal expression of osteopontin was an independent prognostic marker for overall and disease‐free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidate biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression. (Hepatology 2013; 58:1992–2000)

Epithelial cell adhesion molecule is a prognosis marker for intrahepatic cholangiocarcinoma.

BACKGROUND Recently, we identified a gene signature of intrahepatic cholangiocarcinoma (ICC) stroma and demonstrated its clinical relevance for prognosis. The most upregulated genes included epithelial cell adhesion molecule (EpCAM), a biomarker of cancer stem cells (CSC). We hypothesized that CSC biomarkers could predict recurrence of resected ICC. METHODS Both functional analysis of the stroma signature previously obtained and immunohistochemistry of 40 resected ICC were performed. The relationships between the expression of CSC markers and clinicopathologic factors including survival were assessed by univariate and multivariable analyzes. RESULTS Gene expression profile of the stroma of ICC highlighted embryonic stem cells signature. Immunohistochemistry on tissue microarray showed at a protein level the increased expression of CSC biomarkers in the stroma of ICC compared with nontumor fibrous liver tissue. The overexpression of EpCAM in the stroma of ICC is an independent risk factor for overall (hazard ratio = 2.6; 95% confidence interval, 1.3-5.1; P = 0.005) and disease-free survival (hazard ratio = 2.2; 95% confidence interval, 1.2-4.2; P = 0.012). In addition, the overexpression of EpCAM in nontumor fibrous liver tissue is closely correlated with a worst disease-free survival (P = 0.035). CONCLUSIONS Our findings provide new arguments for a potential role of CSC on ICC progression supporting the idea that targeting CSC biomarkers might represent a promise personalized treatment.

Conservative surgical management of Boerhaave's syndrome: Experience of two tertiary referral centers

BACKGROUND Surgery is generally proposed for Boerhaaves syndrome, spontaneous rupture of the esophagus. But diagnosis can be difficult, delaying appropriate management. The purpose of the present study was to evaluate outcome of conservative surgery for primary or T-tube repair performed in two tertiary referral centers. METHODS From June 1985 to November 2010, among 53 patients presenting with Boerhaaves syndrome treated surgically, 39 underwent a conservative procedure. These patients were retrospectively divided into two groups by type of repair: primary suture (group 1, n = 25) or suture on a T-tube (group 2, n = 14). Patients in group 1 were further stratified into two subgroups depending on whether the primary suture was made with reinforcement (subgroup rS) or not (subgroup S). RESULTS Length of stays in hospital and intensive care were shorter in patients in group 1 (p = 0.037), but after a shorter delay before therapeutic management (p = 0.003) compared with group 2. For the other variables studied, outcome was more favorable in group 1, but the differences were not significant. Comparing subgroups rS and S showed that the rate of persistent leakage was significantly lower after reinforced suture (p = 0.021). CONCLUSIONS These findings from the largest reported cohort of Boerhaaves syndrome patients undergoing conservative surgery showed that primary and T-tube repair provide at least equivalent results. Reinforced sutures appear to provide better outcomes by reducing postoperative leakage.

Impact of age over 75 years on outcomes after pancreaticoduodenectomy

BACKGROUND The risks associated with pancreaticoduodenectomy (PD) in elderly patients continue to be debated. The aim of our study was to assess the incidence of death and postoperative complications following PD and identify the risk factors in patients >75 y. STUDY DESIGN All patients who underwent PD between January 2000 and September 2009 were analyzed retrospectively. Patients were divided into two groups according to age (Group 1: patients aged <75 y, and Group 2: patients aged ≥ 75 y). Morbidity and perioperative mortality risk factors were analyzed using univariate and multivariate analyses. RESULTS Among the 314 patients, 273 were included in Group 1 (sex ratio 1.4) and 41 in Group 2 (sex ratio 1). In multivariate analysis, postoperative hemorrhage (PH) (OR 6.61, IC95% [1.96; 22.31], P = 0.002) and age >75 y proved to be predictive factors for mortality (OR 11.04, IC95% [2.57; 47.49], P = 0.001). When compared with Group 1, Group 2 was associated with increased postoperative deaths (24.4% versus 3.66%, P < 0.001) and pancreatic fistulas (26.8% versus 13.2%, P = 0.041), in particular, Grade C fistulas (14.6% versus 4.4%, P = 0.023). In multivariate analysis, only PH proved to be an independent predictive factor for mortality (OR 12.9, IC95% [1.07; 155.5], P = 0.04). CONCLUSIONS PD in elderly patients aged over 75 y appears to be associated with an increased risk of postoperative death and pancreatic fistula. No single preoperative factor made it possible to predict this risk.

Glass Microspheres 90Y Selective Internal Radiation Therapy and Chemotherapy as First-Line Treatment of Intrahepatic Cholangiocarcinoma.

Purpose of the Report Intrahepatic cholangiocarcinomas incidence is increasing. We studied the efficacy of 90Y selective internal radiation therapy (SIRT) as first-line treatment, with chemotherapy, and compared with the results of chemotherapy alone. Patients and Methods We retrospectively studied data from patients treated at our institution with glass microspheres SIRT for intrahepatic cholangiocarcinoma as part of first-line treatment in combination with chemotherapy. We compared results with those of similar patients treated in the ABC-02 study (a study in advanced biliary tract cancer that defined the current standard chemotherapy), assessed as not progressing after the first evaluation. We assessed progression-free survival (PFS) and overall survival (OS). Results Twenty-four patients were treated with SIRT. Chemotherapy was given concomitantly in 10 (42%), as induction before SIRT in 13 (54%) or after SIRT in 1 (4%). Grade 3 adverse events were reported in 1 (4%). Median PFS after SIRT was 10.3 months. Longer PFS was observed when chemotherapy was given concomitantly than when chemotherapy was given before SIRT, with respective median of 20.0 versus 8.8 months (P = 0.001). Median OS after SIRT was not reached. Eleven patients went to surgery (46%). Thirty-three patients in ABC-02 had locally advanced nonextrahepatic cholangiocarcinoma, not progressing after first evaluation. From the start of any treatment, the median PFS was 16.0 months in our cohort versus 11.3 months in ABC-02 (P = 0.25), whereas the median OS was significantly higher in our cohort, not reached versus 17.9 months, respectively (P = 0.026). Conclusions Selective internal radiation therapy combined with concomitant chemotherapy seems a promising strategy as first-line treatment for unresectable intrahepatic cholangiocarcinoma.

Extended liver resections for intrahepatic cholangiocarcinoma: Friend or foe?

BACKGROUND In patients with intrahepatic cholangiocarcinoma (ICC), extended liver resections (ELRs) increase the rate of resectability. The aims of the present study were to evaluate the morbidity and oncologic outcomes of ELR compared with other liver resections (LR) for ICC. METHODS All LR for ICC that were performed in our center between January 1997 and September 2013 and conducted with curative intent were included in this retrospective analysis. ELRs were defined by resections of ≥5 liver segments. The factors that influenced the occurrence of major complications (Clavien ≥ 3) and overall survival (OS) were tested with univariate and multivariate analyses. RESULTS One hundred seven patients (82 men and 25 women) were resected, and 27 (25.3%) underwent ELRs. Compared with the LRs, the ELRs were performed in larger tumors (P = .003) and were significantly associated with more complex surgeries such as vascular (P < .001) or biliary reconstructions (P < .001). Multivariate analysis revealed that ELR was an independent risk factor for major complications (odds ratio [OR], 6.2; 95% CI, 2.11-19.62; P < .001). Compared with the other LRs, ELRs had no effects on OS or disease-free survival (P = .881 and P = .228, respectively). Perioperative blood transfusion (Hazard ratio (HR), 2.51; 95% CI, 1.49-4.23; P < .001), the presence of >1 nodule (HR, 3.17; 95% CI, 1.67-5.97; P < .001), and age ≥65 years (HR, 1.72; 95% CI, 1.03-2.86; P = .036) were independent prognostic factors for OS. CONCLUSION This study suggests that ELRs performed for large ICCs do not affect negatively oncologic outcomes, despite the increased risk of major complications.

Intrahepatic cholangiocarcinoma: impact of genetic hemochromatosis on outcome and overall survival after surgical resection.

BACKGROUND The influence of genetic hemochromatosis (GH) on outcomes following surgical resections for intrahepatic cholangiocarcinoma (ICC) has not been evaluated. METHODS All patients with ICC who underwent a surgical resection between January 1997 and August 2011 were analyzed retrospectively. Risk factors were assessed by univariate and multivariate analyses. RESULTS Eighty-seven patients were analyzed; 16 of these patients (18.4%) had GH. Among the 71 non-GH patients, 52 (73.2%) and 19 (26.8%) had normal or cirrhotic parenchyma, respectively. There was no significant difference in survival between the GH and non-GH patients. A univariate analysis showed that major hepatectomy (P = 0.012), intraoperative blood transfusion (P = 0.007), tumor size >5 cm (P = 0.006), several nodules (P < 0.001), and microvascular invasion (P = 0.04) were significantly associated with poor survival. A multivariate analysis showed that intraoperative blood infusion (HR 0.37; CI 95% [0.19; 0.71]) and more than one nodule (HR 2.5; CI 95% [1.06; 5.8]) were associated with a lower survival rate. CONCLUSION Although the incidence of GH was high in our series, the presence of GH did not affect the outcomes after a liver hepatectomy for ICC. GH does not appear to increase recurrences or worsen the overall and disease-free survival.

Pancreatic head cancer in patients with chronic pancreatitis

BACKGROUND Chronic pancreatitis (CP) is a risk factor of pancreatic adenocarcinoma (PA). The discovery of a pancreatic head lesion in CP frequently leads to a pancreaticoduodenectomy (PD) which preceded by a multidisciplinary meeting (MM). The aim of this study was to evaluate the relevance between this indication of PD and the definitive pathological results. METHODS Between 2000 and 2010, all patients with CP who underwent PD for suspicion of PA without any histological proof were retrospectively analyzed. The operative decision has always been made at an MM. The definitive pathological finding was retrospectively confronted with the decision made at an MM, and patients were classified in two groups according to this concordance (group 1) or not (group 2). Clinical and biological parameters were analyzed, preoperative imaging were reread, and confronted to pathological findings in order to identify predictive factors of malignant degeneration. RESULTS During the study period, five of 18 (group 1) patients with CP had PD were histologically confirmed to have PA, and the other 13 (group 2) did not have PA. The median age was 52.5+/-8.2 years (gender ratio 3.5). The main symptoms were pain (94.4%) and weight loss (72.2%). There was no patients death. Six (33.3%) patients had a major complication (Clavien-Dindo classification ≥ 3). There was no statistical difference in clinical and biological parameters between the two groups. The rereading of imaging data could not detect efficiently all patients with PA. CONCLUSIONS Our results confirmed the difficulty in detecting malignant transformation in patients with CP before surgery and therefore an elevated rate of unnecessary PD was found. A uniform imaging protocol is necessary to avoid PD as a less invasive treatment could be proposed.

Defining Benchmarks in Liver Transplantation: A Multicenter Outcome Analysis Determining Best Achievable Results.

&NA; This multicentric study of 17 high-volume centers presents 12 benchmark values for liver transplantation. Those values, mostly targeting markers of morbidity, were gathered from 2024 “low risk” cases, and may serve as reference to assess outcome of single or any groups of patients. Objective: To propose benchmark outcome values in liver transplantation, serving as reference for assessing individual patients or any other patient groups. Background: Best achievable results in liver transplantation, that is, benchmarks, are unknown. Consequently, outcome comparisons within or across centers over time remain speculative. Methods: Out of 7492 liver transplantation performed in 17 international centers from 3 continents, we identified 2024 low risk adult cases with a laboratory model for end-stage liver disease score ⩽20 points, a balance of risk score ⩽9, and receiving a primary graft by donation after brain death. We chose clinically relevant endpoints covering intra- and postoperative course, with a focus on complications graded by severity including the complication comprehensive index (CCI®). Respective benchmarks were derived from the median value in each center, and the 75 percentile was considered the benchmark cutoff. Results: Benchmark cases represented 8% to 49% of cases per center. One-year patient-survival was 91.6% with 3.5% retransplantations. Eighty-two percent of patients developed at least 1 complication during 1-year follow-up. Biliary complications occurred in one-fifth of the patients up to 6 months after surgery. Benchmark cutoffs were ⩽4 days for ICU stay, ⩽18 days for hospital stay, ⩽59% for patients with severe complications (≥ Grade III) and ⩽42.1 for 1-year CCI®. Comparisons with the next higher risk group (model for end stage liver disease 21–30) disclosed an increase in morbidity but within benchmark cutoffs for most, but not all indicators, while in patients receiving a second graft from 1 center (n = 50) outcome values were all outside of benchmark values. Conclusions: Despite excellent 1-year survival, morbidity in benchmark cases remains high with half of patients developing severe complications during 1-year follow-up. Benchmark cutoffs targeting morbidity parameters offer a valid tool to assess higher risk groups.