Emilie Gregoire

Predictors of Long-Term Survival After Liver Transplantation for Metastatic Endocrine Tumors: An 85-Case French Multicentric Report

Liver transplantation (LTx) for metastatic endocrine tumors (MET) remains controversial due to the lack of clear selection criteria. From 1989 to 2005, 85 patients underwent LTx for MET. The primary tumor was located in the pancreas or duodenum in 40 cases, digestive tract in 26 and bronchial tree in five. In the remaining 14 cases, primary location was undetermined at the time of LTx. Hepatomegaly (explanted liver ≥120% of estimated standard liver volume) was observed in 53 patients (62%). Extrahepatic resection was performed concomitantly with LTx in 34 patients (40%), including upper abdominal exenteration (UAE) in seven.

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.

Resection of hepatocellular carcinoma with tumor thrombus in the major vasculature. A European case-control series

Tumor thrombus in major vasculature is a frequent finding with a poor long-term prognosis in patients with hepatocellular carcinoma (HCC). The utility of surgical resection is still controversial. This study compared morbidity and survival after resection for HCC with and without tumor thrombus. Data of 108 patients who underwent major hepatic resection for HCC were prospectively recorded. Patients were divided into two groups. The venous thrombectomy (VT) group included 26 patients who had HCC with tumor thrombus in the portal or hepatic veins. The matched control group included 82 patients who had HCC without tumor thrombus. Surgical technique, early outcome, and late survival were analyzed in each group. Multivariate analysis was performed to assess the prognostic value of this feature. Surgical technique was comparable in the VT and control group with regard to extent of hepatectomy, procedure duration, and transfusion requirements. Early postoperative outcome was also comparable. Actuarial survival at 1, 3, and 5 years was 38%, 20%, and 13%, respectively, in the VT group (median: 9 months) versus 74%, 56%, and 33%, respectively, in the control group (median: 41 months). In the subgroup of patients with tumor thrombus limited to the portal vein, actuarial survival at 1, 3, and 5 years was 50%, 26%, and 17%, respectively, (median: 12 months) and two patients lived longer than 5 years. Multivariate analysis showed that incomplete resection, alphafetoprotein level greater than 100 N, more than two tumor nodules, and tumor thrombus in major vasculature were independent factors of poor prognosis. Survival after resection for HCC with tumor thrombus in the major vasculature is poorer than after resection for HCC without tumor thrombus. However, an aggressive surgical strategy can provide significant survival with comparable morbidity in selected cases, that is, tumor thrombus located in the portal vein only and expected complete resection of the lesions.

Mapping of NKp46+ cells in healthy human lymphoid and non-lymphoid tissues

Understanding Natural Killer (NK) cell anatomical distribution is key to dissect the role of these unconventional lymphocytes in physiological and disease conditions. In mouse, NK cells have been detected in various lymphoid and non-lymphoid organs, while in humans the current knowledge of NK cell distribution at steady state is mainly restricted to lymphoid tissues. The translation to humans of findings obtained in mice is facilitated by the identification of NK cell markers conserved between these two species. The Natural Cytotoxicity Receptor (NCR) NKp46 is a marker of the NK cell lineage evolutionary conserved in mammals. In mice, NKp46 is also present on rare T cell subsets and on a subset of gut Innate Lymphoid Cells (ILCs) expressing the retinoic acid receptor-related orphan receptor γt (RORγt) transcription factor. Here, we documented the distribution and the phenotype of human NKp46+ cells in lymphoid and non-lymphoid tissues isolated from healthy donors. Human NKp46+ cells were found in splenic red pulp, in lymph nodes, in lungs, and gut lamina propria, thus mirroring mouse NKp46+ cell distribution. We also identified a novel cell subset of CD56dimNKp46low cells that includes RORγt+ ILCs with a lineage−CD94−CD117brightCD127bright phenotype. The use of NKp46 thus contributes to establish the basis for analyzing quantitative and qualitative changes of NK cell and ILC subsets in human diseases.

Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression

It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)(+) memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation-induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)(+) precursors and shapes the systemic presentation of FL patients.

Pancreatic head resectable adenocarcinoma: preoperative chemoradiation improves local control but does not affect survival

BACKGROUND This study assesses the impact of preoperative chemoradiation on recurrence, surgical morbidity, histopathological data and survival in resectable adenocarcinoma of the pancreatic head. METHODS We carried out a retrospective study with an intention-to-treat analysis. From 1997 to 2006, 173 patients with resectable pancreas head carcinoma were treated in two reference centres in France using different treatment strategies. RESULTS Sixty-seven of 85 (79%) patients in the surgery-first (SF) group and 38 of 88 (43%) patients in the chemoradiation (CR) group underwent surgical resection (P < 0.001). Overall morbidity was 40% (15/38) in the CR group and 43% (29/67) in the SF group (P= 0.837). In the CR group, median tumour size was smaller (1.5 cm vs. 3.0 cm; P < 0.001) and fewer patients were node-positive (29% vs. 64%; P= 0.001) than in the SF group. There was less perineural (43% vs. 93%; P < 0.001), lymphatic and vascular (21% vs. 92%; P < 0.001) invasion in the CR group than in the SF group. In both groups, 89% of patients had recurrence (31/35 in the CR group and 57/64 in the SF group; P= 1.000), predominantly involving metastasis and carcinomatosis in the CR group (30/31 vs. 35/57; P < 0.001) and locoregional recurrence in the SF group (24/57 vs. 3/31; P= 0.002). Median survival for all patients and for resected patients in the CR and SF groups was, respectively, 15 months vs. 17 months, and 21 months vs. 18 months (P= non-significant). CONCLUSIONS Preoperative chemoradiation allows for good local control of the disease but does not increase survival, mainly for reasons of metastatic spread. Other options should be developed to improve both local and distant control of the disease.

Liver transplantation for primary or secondary endocrine tumors.

Endocrine tumors comprise a heterogeneous group of rare neoplasms. Liver metastatic endocrine tumors (MET) are amenable to various therapeutic modalities including liver transplantation (LT). However, LT for MET remains controversial because of the lack of clear selection criteria. The purpose of this study based on thorough perusal of English and French literature since 1989 was to identify prognostic factors and propose recommendations for selecting patients most likely to benefit LT for primary and secondary endocrine tumors.

Lymphoepithelial cyst of the pancreas: an analysis of 117 patients.

Objectives Lymphoepithelial cyst (LEC) of the pancreas is an unusual and benign cystic tumor. Accurate preoperative diagnosis is difficult; hence, most of pancreatic LECs are resected. The aim was to describe clinicopathological features of pancreatic LEC to guide appropriate management. Methods We retrospectively collected data about LEC patients treated in our department between 1987 and 2012 and added cases from review of the literature during the same period. Results One hundred seventeen cases (3 from our institution and 114 from literature review) were identified. Most patients were men (78%). The discovery was generally fortuitous. Serum CA19-9 was elevated in half of the cases. No specific radiological feature was identified. Fine needle aspiration and cytologic analysis allowed a correct preoperative diagnosis in 21% of the patients, showing presence of squamous cells, lymphocytes, and keratinous debris. Half of them were treated conservatively, whereas other patients underwent surgery. Neither malignant transformation nor recurrence after resection was observed. Conclusions The LEC of the pancreas is a rare benign tumor that could be treated conservatively. Fine needle aspiration is the only tool that can achieve a diagnosis without resection. If no certain diagnosis can be made, surgery is warranted to rule out a malignant differential diagnosis.

Which Treatment to Choose for Portal Biliopathy with Extensive Portal Thrombosis

Background: Portal biliopathy refers to abnormalities of the biliary tract developing in relation to portal hypertension. Portosystemic splenorenal or mesenterico-caval shunting is a safe and effective method to relieve biliary obstruction in symptomatic patients but is unfeasible in cases of extensive thrombosis of the splenic and superior mesenteric veins. In such cases, a makeshift portosystemic shunt between a suitable portal varix and the caval system can be an interesting alternative. Methods: This study describes 3 patients admitted for symptomatic portal biliopathy caused by idiopathic portal cavernoma associated with extensive portal thrombosis. A makeshift portosystemic shunt was carried out after preoperative portal imaging had demonstrated the presence of a suitable splanchnic varix. Results: The makeshift portosystemic shunt was performed by direct anastomosis in 2 patients and by prosthetic interposition in 1 case. Shunting was between a splanchnic varix and the inferior vena cava in 2 cases and the left renal vein in 1 case. Postoperative morbidity was nil and follow-up ranging from 2 to 12 years showed good results with no recurrence of biliary obstruction. Conclusion: In patients presenting symptomatic portal biliopathy associated with extensive thrombosis of the portal system, a makeshift portosystemic shunt is preferable to repeated endoscopic procedures or intrahepatic biliodigestive bypass, provided that a suitable varix is available.

Successful treatment with sofosbuvir of fibrosing cholestatic hepatitis C after liver transplantation in an HIV-HCV-coinfected patient.

Fibrosing cholestatic hepatitis is a severe form of post-liver transplantation HCV recurrence. Fibrosing cholestatic hepatitis is characterized by its early onset and severe prognosis in HIV-infected patients. We report the case of an HIV-HCV genotype-4 coinfected patient successfully treated with a combination of sofosbuvir and ribavirin. After 4 weeks of treatment we observed a resolution of HCV recurrence related symptoms associated with a normalization of liver biochemistry and dramatic decrease of HCV viral load. This case illustrates the efficiency and tolerance of a sofosbuvir-based anti-HCV interferon-free regimen in post-liver HCV recurrence. Because of the absence of drug interactions between sofosbuvir and antiretroviral treatment or calcineurin inhibitors, its administration in HIV-HCV-coinfected liver transplanted patients is very promising.