Anne Couvelard

Relationship between vascular development and vascular differentiation during liver organogenesis in humans.

BACKGROUNDS/AIMSnThe complex vascular architecture characteristic of the normal adult liver is progressively acquired during the fetal life. In this study, we aimed to evaluate the relationship between angiogenesis and vascular differentiation during liver organogenesis.nnnMETHODSnWe studied, in 51 fetuses of different gestational ages, the expression of markers of endothelial cell differentiation, integrins, pro- and anti-angiogenic extracellular matrix components, vascular endothelial growth factor (VEGF) and its receptors.nnnRESULTSnThree main stages in the development of the vascular architecture of the liver were identified: (a) from 5 to 10 gestation weeks (GW), no evidence of de novo angiogenesis was detected; the vessels present in the liver primordium were the precursors of portal veins and sinusoids, deriving from preexisting vessels; (b) from 10 to 25 GW, angiogenesis and vasculogenesis resulted in the development of, respectively, arteries and intra-portal capillaries, while portal veins and hepatic sinusoids followed a differentiation process; (c) after 25 GW, little changes were detected in the various vascular compartments. The maximal expression of VEGF and its receptors was from 5 to 25 GW.nnnCONCLUSIONSnThe development of the hepatic vascular architecture is a multistep process combining angiogenesis, vasculogenesis and vascular differentiation, regulated by specific growth and differentiation factors including VEGF.

Reappraisal of Central Pancreatectomy A 12-Year Single-Center Experience

IMPORTANCEnCentral pancreatectomy, as an alternative to standard resection for benign and low-grade pancreatic neoplasms, has been described in mainly small retrospective series.nnnOBJECTIVEnTo describe a large single-center experience with central pancreatectomy.nnnDESIGN, SETTING, AND PARTICIPANTSnA retrospective case series in a tertiary referral center included 100 consecutive patients undergoing central pancreatectomy with pancreaticogastrostomy from January 1, 2000, to March 1, 2012.nnnMAIN OUTCOMES AND MEASURESnSurgical indications, postoperative morbidity, mortality, and long-term outcomes regarding pancreatic function and recurrence.nnnRESULTSnCentral pancreatectomies were performed mainly for neuroendocrine tumors (35%), intraductal papillary mucinous neoplasms (33%), solid pseudopapillary neoplasms(12%), and mucinous cystadenomas (6%). The postoperative mortality rate was 3% (due to pulmonary embolisms in 2 patients and hemorrhage after pancreatic fistula in 1 patient). Clavien-Dindo III or IV complications occurred in 15%of patients and were due mainly to pancreatic fistula, requiring 10 radiologic drainage procedures, 7 endoscopic procedures, and 6 reoperations overall. After a median follow-up of 36 months, the rates of new-onset exocrine and endocrine insufficiency were 6%and 2%, respectively. Overall, 7 lesions could be considered undertreated, including 3 node-negative R0 microinvasive intraductal papillary mucinous neoplasms (without recurrence at 27, 29, and 34 months) and 4 node-positive neuroendocrine tumors (with 1 hepatic recurrence at 66 months). Among the 25 patients with a doubtful preoperative diagnosis, 9 could be considered over treated (ie, operated on for benign non evolutive asymptomatic lesions).nnnCONCLUSIONS AND RELEVANCEnCentral pancreatectomy is associated with an excellent pancreatic function at the expense of a significant morbidity and a non-nil mortality rate,underestimated by the published literature. The procedure is best indicated for benign or low-grade lesions in young and fit patients who can sustain a significant postoperative morbidity and could benefit from the excellent long-term results.

Integrin up-regulation in chronic liver disease: relationship with inflammation and fibrosis in chronic hepatitis C.

In 94 patients with chronic hepatitis C, the pattern of integrin expression was correlated with firstly, the histological activity index, necro‐inflammatory grade, and stage of fibrosis; secondly, the expression of inflammatory markers including ICAM‐1; and thirdly, the extent and intensity of laminin deposition in the perisinusoidal matrix. Immunohistochemical results were evaluated according to a semi‐quantitative scoring system or by image analysis. Increased β1 expression was observed in 88.2% of cases. The expression of α1 and α5 was increased in 55% and 58.5% of cases, respectively. α6 chain was detected in 78.7% of cases. There were no statistically significant differences in integrin expression level according to Knodells score, inflammatory grade, or stage of fibrosis. ICAM‐1 expression was higher in patients with high scores for β1 expression, but the differences were not statistically significant. There were significantly more patients with high scores for β1 expression among those with continuous perisinusoidal deposition of laminin. Moreover, a close statistical correlation was observed between α6 induction and perisinusoidal laminin deposition (p<0.001). The results suggest that integrin up‐regulation in chronic hepatitis C is more closely related to the fibrotic process than to the inflammatory lesions. This reinforces the idea that integrin induction in chronic liver disease is part of a coordinated process involved in the progression of liver fibrosis. Copyright

State of the art and future directions of pancreatic ductal adenocarcinoma therapy

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second cause of cancer-related death in 2030. PDAC is the poorest prognostic tumor of the digestive tract, with 80% of patients having advanced disease at diagnosis and 5-year survival rate not exceeding 7%. Until 2010, gemcitabine was the only validated therapy for advanced PDAC with a modest improvement in median overall survival as compared to best supportive care (5-6 vs 3 months). Multiple phase II-III studies have used various combinations of gemcitabine with other cytotoxics or targeted agents, most in vain, in attempt to improve this outcome. Over the past few years, the landscape of PDAC management has undergone major and rapid changes with the approval of the FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens in patients with metastatic disease. These two active combination chemotherapy options yield an improved median overall survival (11.1 vs 8.5 months, respectively) thus making longer survival a reasonably achievable goal. This breakthrough raises some new clinical questions about the management of PDAC. Moreover, better knowledge of the environmental and genetic events that underpin multistep carcinogenesis and of the microenvironment surrounding cancer cells in PDAC has open new perspectives and therapeutic opportunities. In this new dynamic context of deep transformation in basic research and clinical management aspects of the disease, we gathered updated preclinical and clinical data in a multifaceted review encompassing the lessons learned from the past, the yet unanswered questions, and the most promising research priorities to be addressed for the next 5 years.

Sporadic nonfunctioning pancreatic neuroendocrine tumors: Prognostic significance of incidental diagnosis

BACKGROUNDnSporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are increasingly diagnosed as incidentalomas, and their resection is usually recommended. The prognostic significance of this diagnosis feature is poorly studied, and management of these tumors remains controversial. Clinical, pathologic characteristics and outcome of resected incidentally diagnosed NF-PNET (Inc) were compared with resected symptomatic NF-PNET (Symp) to better assess their biologic behavior and tailor their management.nnnMETHODSnFrom 1994 to 2010, 108 patients underwent resection for sporadic nonmetastatic NF-PNET. Diagnosis was considered as incidental in patients with no abdominal symptoms or symptoms unlikely to be related to tumor mass. Patients with Inc were compared with patients with Symp, regarding demographics, postoperative course, pathology, and disease-free survival (DFS).nnnRESULTSnOf the 108 patients, 65 (61%) had incidentally diagnosed tumors. Pancreas-sparing pancreatectomies (enucleation/central pancreatectomy) were performed more frequently in Inc (62%xa0vsxa030%, P = .001). Inc tumors were more frequently <20 mm (65% vs 42%, P = .019), staged T1 (62% vs 33%, P = .0001), node negative (85% vs 60%; P = .005), and grade 1 (66% vs 33%, P = .0001). One postoperative death occurred in the Inc group, and postoperative morbidity was similar between the two groups (60% vs 65%, P = .59). DFS was substantially better in the Inc group (5-yearxa0DFS = 92% vs 82%, P = .0016).nnnCONCLUSIONnIncidentally diagnosed NF-PNETs are associated with less aggressive features compared with symptomatic lesions but cannot always be considered to be benign. Operative resection remains recommended for most. Incidentally diagnosed NF-PNET may be good candidates for pancreas-sparing pancreatectomies.

Pathology Analysis Reveals That Dysplastic Pancreatic Ductal Lesions Are Frequent in Patients With Hereditary Pancreatitis

BACKGROUND & AIMSnHereditary pancreatitis (HP) is a risk factor for pancreatic adenocarcinoma. We performed a retrospective, multicenter study to characterize and evaluate the frequency of pancreatic intraepithelial neoplasia (PanIN) and to describe the characteristics of fibrosis in pancreatic surgical specimens from patients with HP.nnnMETHODSnSamples from partial pancreatectomies (n = 13) of patients with HP complications (n = 12; 7 males; mean age, 24 y; 1 patient underwent 2 surgeries over 16 years) were analyzed by histologic and immunohistologic analyses; patients with suspected or proven pancreatic adenocarcinoma were excluded. HP diagnosis was confirmed by analysis of PRSS1 mutations. Dysplastic lesions were described according to the PanIN classification.nnnRESULTSnEleven patients were found to have the R122H mutation in PRSS1 and 1 patient was found to have the N29I mutation in PRSS1. Fifty-one PanIN lesions were observed in 10 specimens (77%): PanIN lesions 1a, 1b, 2, and 3 were observed in 8, 5, 8, and 5 specimens, respectively. The median number of PanIN lesions was 3.5 for each specimen. The density of the lesions was 2.6 per 10 cm(2). The size of lesions was greater than 0.5 mm in 55% of the samples. Two patients with PanIN-3 developed pancreatic cancer, 18 months and 44 years after surgery.nnnCONCLUSIONSnPanIN lesions are frequent, severe, and occur early in the course of HP. Among patients with PanINs, 50% had PanIN-3 lesions. Pancreatectomy could be considered as a prophylactic against pancreatic cancer in patients with high-grade dysplasia.

Human pancreatic mucinous cystadenoma is characterized by distinct mucin, cytokeratin and CD10 expression compared with intraductal papillary-mucinous adenoma

Aims :u2002To examine cytokeratin, epithelial glycoprotein (mucin) and glycoprotein CD10 expression in benign mucinous cystdenomas (MCAs) in comparison with intraductal papillary mucinous adenomas (IPMAs).

Lessons From McCune-Albright Syndrome-Associated Intraductal Papillary Mucinous Neoplasms GNAS-Activating Mutations in Pancreatic Carcinogenesis

GNAS-activating mutations are reported in intraductal papillary mucinous neoplasms (IPMNs) and in McCune-Albright syndrome, characterized by fibrous dysplasia, precocious puberty, and café au lait spots. Recently, IPMNs have been described as a McCune-Albright syndrome-associated tumor, present in about 15% of patients. The aim of the present work was to assess the prevalence of polyostotic fibrous dysplasia and McCune-Albright syndrome among patients operated on for presumptive sporadic IPMNs. All patients operated on for IPMNs between January 1, 2007, and December 31, 2012, with available imaging were retrospectively screened for polyostotic fibrous dysplasia based on their preoperative abdominal or thoracoabdominal spiral computed tomography images. Systematic screening of 272 patients operated on for IPMNs revealed 1 patient with axial and peripheral polyostotic fibrous dysplasia and café au lait spots on clinical examination suggestive of McCune-Albright syndrome. This patient had been operated on for an unusually large invasive colloid adenocarcinoma (pT3N0M0 R0) derived from an intestinal subtype GNAS-mutated IPMN. The patient underwent adjuvant chemotherapy with gemcitabine for 6 months and was alive without recurrence 6 years later. Besides providing additional evidence of a syndromic IPMN as a feature of McCune-Albright syndrome, this observation is further evidence of the functional oncogenic consequences of GNAS mutations in the pancreas.

High c-Met expression in stage I-II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis.

AIMSnc-Met is an emerging biomarker in pancreatic ductal adenocarcinoma (PDAC); there is no consensus regarding the immunostaining scoring method for this marker. We aimed to assess the prognostic value of c-Met overexpression in resected PDAC, and to elaborate a robust and reproducible scoring method for c-Met immunostaining in this setting.nnnMETHODS AND RESULTSnc-Met immunostaining was graded according to the validated MetMab score, a classic visual scale combining surface and intensity (SI score), or a simplified score (high c-Met: ≥ 20% of tumour cells with strong membranous staining), in stage I-II PDAC. A computer-assisted classification method (Aperio software) was developed. Clinicopathological parameters were correlated with disease-free survival (DFS) and overall survival(OS). One hundred and forty-nine patients were analysed retrospectively in a two-step process. Thirty-seven samples (whole slides) were analysed as a pre-run test. Reproducibility values were optimal with the simplified score (kappa = 0.773); high c-Met expression (7/37) was associated with shorter DFS [hazard ratio (HR) 3.456, P = 0.0036] and OS (HR 4.257, P = 0.0004). c-Met expression was concordant on whole slides and tissue microarrays in 87.9% of samples, and quantifiable with a specific computer-assisted algorithm. In the whole cohort (n = 131), patients with c-Met(high) tumours (36/131) had significantly shorter DFS (9.3 versus 20.0 months, HR 2.165, P = 0.0005) and OS (18.2 versus 35.0 months, HR 1.832, P = 0.0098) in univariate and multivariate analysis.nnnCONCLUSIONSnSimplified c-Met expression is an independent prognostic marker in stage I-II PDAC that may help to identify patients with a high risk of tumour relapse and poor survival.

EGFR expression in pancreatic adenocarcinoma. Relationship to tumour morphology and cell adhesion proteins

Aims We aimed to study epidermal growth factor receptor (EGFR) expression in surgically resected pancreatic ductal adenocarcinomas (PDACs) by immunohistochemistry and their relationship to clinicopathological features, cell proliferation and cell adhesion protein expression. Methods A total of 99 PDACs were analysed on tissue microarrays for EGFR, E-cadherin and β-catenin expression patterns in tumour cells. The percentage of cells expressing the three proteins (membrane, cytoplasm or nuclear pattern) and of Ki67-positive tumour cells was assessed. Tumour protein expression was studied with regard to clinicomorphological features, Ki67 index and for postsurgical survival. Results Membrane tumour EGFR correlated with histological poor differentiation (dedifferentiation), increased number of mitoses and severe tumour cell atypia (pleiomorphism) as well as with aberrant adhesion protein expression such as nuclear β-catenin and cytoplasmic E-cadherin. Cytoplasmic tumour E-cadherin correlated with an increased Ki67-positive tumour cell component, whereas nuclear E-cadherin correlated with a shorter postsurgical overall survival, as well as with tumour necrosis and an abundant clear cell component. Conclusions In conclusion, the results of our study suggest a complex role for EGFR in PDAC carcinogenesis, tumour expression of this protein being associated with tumour dedifferentiation, mitotic activity or pleiomorphism, as well as with aberrant tumour cell adhesion protein expression.