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Endosonography, ultrasonography, and computed tomography (CT) were carried out prospectively in 52 patients with extrahepatic cholestasis. 35 patients had extrahepatic biliary obstructions (21 tumorous, 14 non-tumorous) and 17, with recent gallstone migration within the bile duct, had no extrahepatic obstruction at the time of investigation. The definitive diagnosis was established by surgery (in 39 patients), by transendoscopic sphincterotomy (11 patients), or by retrograde biliary opacification (2 patients). Endosonography was significantly more sensitive than ultrasonography or CT (100% vs 80% and 83%, respectively) in making a positive diagnosis of obstruction. Endosonography was also significantly more accurate than ultrasonography or CT (97% vs 49% and 66%) in diagnosing the cause of the obstruction and more effective in the assessment of the locoregional spread of tumorous obstructions (75% vs 38% and 62%). Thus, endosonography was superior to ultrasonography and CT in the diagnosis and staging of biliary obstructions.

// Mohamad Younes 1, * , Zherui Wu 1 , 2, * , Sandra Dupouy 1, * , Audrey Mansuet Lupo 3 , Najat Mourra 1 , 4 , Takashi Takahashi 5 , Jean Francois Flejou 4 , Jean Tredaniel 2 , 6 , Jean Francois Regnard 7 , Diane Damotte 3 , Marco Alifano 2 , 7 , Patricia Forgez 2 1 UMRS U938, Hopital Saint-Antoine 75012 Paris, France. 2 UMRS 1007 Universite Paris Descartes 45, rue des Saints-Peres 75270 Paris cedex 06. 3 Pathology Department, Universite Paris Descartes, Hopitaux Universitaires Cochin Hotel-Dieu Broca, 75014 Paris, France. 4 Pathology Department Hopital Saint-Antoine 75012 Paris, France. 5 Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya 466-8550, Japan. 6 Thoracic Oncology Department Hopital Saint-Joseph and Universite Paris Descartes 75014 Paris, France. 7 Thoracic Surgery Department, Universite Paris Descartes, Hopitaux Universitaires Cochin Hotel-Dieu Broca, 75014 Paris, France. * MY, ZW, and SD contributed equally to this work. Correspondence to: Patricia Forgez, e-mail: Patricia.forgez@inserm.fr Key words: Cancer growth and metastasis, neurotensin, EGFR, HER2, HER3, EGF like ligands. Received: November 28, 2013 Accepted: May 07, 2014, Published: September 26, 2014 ABSTRACT Alterations in the signaling pathways of epidermal growth factor receptors (HERs) are associated with tumor aggressiveness. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 60% of lung cancers. In a previous clinical study, NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in a selected population of stage I lung adenocarcinomas treated by surgery alone. In a second study, shown here, the frequent and high expression of NTSR1 was correlated with a pejorative prognosis in 389 patients with stage I to III lung adenocarcinoma, and was an independent prognosis marker. Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here we highlight the cellular mechanisms activated by Neurotensin (NTS) and its high affinity receptor (NTSR1) contributing to lung cancer cell aggressiveness. We show that the NTS autocrine and/or paracrine regulation causes EGFR, HER2, and HER3 over-expression and activation in lung tumor cells. The EGFR and HER3 autocrine activation is mediated by MMP1 activation and EGF “like” ligands (HB-EGF, Neuregulin 1) release. By establishing autocrine and/or paracrine NTS regulation, we show that tumor growth is modulated according to NTS expression, with a low growth rate in those tumors that do not express NTS. Accordingly, xenografted tumors expressing NTS and NTSR1 showed a positive response to erlotinib, whereas tumors void of NTSR1 expression had no detectable response. This is consistent with the presence of a NTS autocrine loop, leading to the sustained activation of EGFR and responsible for cancer aggressiveness. We propose the use of NTS/NTSR1 tumor expression, as a biomarker for the use of EGFR tyrosine kinase inhibitors in patients lacking EGFR mutation.

We analyzed the results of an aggressive surgical approach to intrahepatic cholangiocarcinoma. Between 1990 and 1997, 30 of 42 patients with intrahepatic cholangiocarcinoma underwent resection with curative intent. Mean tumor size was 10 +/- 5 cm, and the tumors were classified as TNM type III, IVa, and IVb in 63%, 34%, and 3% of the patients, respectively. All patients underwent hepaticoduodenal lymphadenectomy. Fifteen patients received adjuvant radio- and chemotherapy. The overall survival rates at 1, 2, and 3 years were 86%, 63%, and 22%, respectively, and the median survival time was 28 months. Tumor recurrence was the main cause of death. Three patients survived for more than 5 years, including 2 patients with no evidence of recurrence. Factors influencing survival were: presence of satellite nodules (P = 0.007) and lymph node invasion (P = 0.05). The width of the resection margin and the use of an adjuvant therapy had no impact on survival. Complete surgical resection may offer a chance for long-term survival in selected patients and may improve the quality of life of patients with more advanced disease.

Background—The development of endocrine tumours of the duodenopancreatic area (ETDP) is thought to be slow, but their natural history is not well known. The aim of this study was to determine the factors that influence survival of patients with ETDP.Patients/Methods—Eighty two patients with ETDP (44 non-functioning tumours, 23 gastrinomas, seven calcitonin-secreting tumours, four glucagonomas, three insulinomas, one somatostatinoma) followed from October 1991 to June 1997 were included in the study. The following factors were investigated: primary tumour size, hormonal clinical syndrome, liver metastases, lymph node metastases, extranodular/extrahepatic metastases, progression of liver metastases, local invasion, complete resection of the primary tumour, and degree of tumoral differentiation. The prognostic significance of these factors was investigated by uni- and multi-variate analysis.Results—Twenty eight patients (34%) died within a median of 17 months (range 1–110) from diagnosis. Liver metastases (p = 0.001), lymph node metastases (p = 0.001), progression of liver metastases (pConclusion—Liver metastases are a major prognostic factor in patients with ETDP. Progression of liver metastases is also an important factor which must be taken into account when deciding on the therapeutic approach. The only other independent prognostic factors are tumoral cell differentiation and complete resection of the primary tumour.

Cutaneous metastases arising along the exit site of an abdominal drain in one patient and within the operative wound in two others after resection of a hepatocellular carcinoma (HCC) are reported. All patients underwent curative hepatic resection, and cutaneous metastases occurred 9, 12, and 22 months after surgery respectively. Cutaneous metastases were not associated with intrahepatic recurrence and were treated by local excision. Two patients are alive and disease-free 48 and 49 months after hepatic resection, respectively; the third patient died from recurrence 39 months later. These observations suggest that cutaneous malignant seeding may occur, and the authors recommend the observance of special care during liver surgery to prevent occurrence of this complication, including the use of wound protection and avoiding the opening of the specimen by the surgeon. The follow-up of patients who have undergone liver resection for an HCC should include the examination of all operative wounds including the exit site of abdominal drains. These subcutaneous nodules should be resected as an appreciable survival can be expected.

The spectrum of tumors showing microsatellite instability (MSI) has recently been enlarged to sporadic neoplasms whose incidence is favored in the context of chronic immunosuppression. We investigated the biological, therapeutic and clinical features associated with MSI in immunodeficiency-related non-Hodgkin lymphomas (ID-RL). MSI screening was performed in 275 ID-RL. MSI ID-RL were further analyzed for MMR gene expression and for BRAF/KRAS mutations since these genes are frequently altered in MSI cancers. We also assessed the expression of O(6)-methylguanine-DNA methyltransferase (MGMT), an enzyme whose inactivation has been reported in lymphomas and may help in the selection of MMR deficient clones. Unlike other sporadic MSI neoplasms, MSI ID-RL (N = 17) presented with heterogeneous MMR defects and no MLH1 promoter methylation. About one third of these tumors presented with normal expression of MLH1, MSH2, MSH6 and PMS2. They accumulated BRAF activating mutations (33%). Unlike other ID-RL, MSI ID-RL were primarily EBV-negative NHL of T-cell origin, and arose after long-term immunosuppression in patients who received azathioprine as part of their immunosuppressive regimen (p = 0.05) and/or who exhibited methylation-induced loss of expression of MGMT in tumor cells (p= 0.02). Overall, these results highlight that, in the context of deficient immune status, some MSI neoplasms arise through alternative mechanism when compared to other sporadic MSI neoplasms. They give the exact way how to make the diagnosis of MSI in these tumors and may help to define biological and clinicalrisk factors associated with their emergence in such a clinicalcontext.

AIMS--To establish the prevalence of c-erbB-2 protein expression in a surgical series of Barrett's adenocarcinomas; and to correlate this expression with clinicopathological data and prognosis. METHODS--Sixty six surgical specimens of Barrett's adenocarcinomas were included in this retrospective study. Blocks of the tumour and of non-dysplastic Barrett's mucosa were stained with a polyclonal antibody specific for the intracytoplasmic domain of the c-erbB-2 protein. RESULTS--Seven of 66 tumours showed membrane staining for the c-erbB-2 protein. The non-dysplastic Barrett's mucosa was negative in all cases. There was no difference between c-erbB-2 positive and negative tumours with regard to mean age, sex ratio, percentage of alcohol misusers, percentage of smokers, tumour differentiation, depth of invasion, lymph node response, and proliferative activity, assessed by the percentage of tumour cells positive with the MIB-1 antibody directed against the Ki-67 antigen. All c-erb B2 positive tumours were of Lauren's intestinal type compared with negative c-erbB-2 tumours. Patients with c-erbB-2 positive tumours had a significantly poorer prognosis than patients with negative tumours. CONCLUSIONS--The prevalence of Barrett's adenocarcinomas expressing c-erbB-2 found in this study (11%) was similar to that observed in published series of gastric adenocarcinomas. c-erbB-2 protein expression could be an important prognostic indicator in Barrett's adenocarcinoma.

International audience; Background & AimsThere is consensus on the criteria used to define acute severe ulcerative colitis (ASUC) and on patient management, but it has been a challenge to identify patients at risk for colectomy based on data collected at hospital admission. We aimed to develop a system to determine patients’ risk of colectomy within 1 y of hospital admission for ASUC based on clinical, biomarker, and endoscopy data.MethodsWe performed a retrospective analysis of consecutive patients with ASUC treated with corticosteroids, ciclosporin, or tumor necrosis factor (TNF) antagonists and admitted to 2 hospitals in France from 2002 through 2017. Patients were followed until colectomy or loss of follow up. A total of 270 patients with ASUC were included in the final analysis, with a median follow-up time of 30 months (derivation cohort). Independent risk factors identified by Cox multivariate analysis were used to develop a system to identify patients at risk for colectomy 1 y after ASUC. We developed a scoring system based on these 4 factors (1 point for each item) to identify high-risk (score 3 or 4) vs low-risk (score 0) patients. We validated this system using data from an independent cohort of 185 patients with ASUC treated from 2006 through 2017 at 2 centers in France.ResultsIn the derivation cohort, the cumulative risk of colectomy was 12.3% (95% CI, 8.6–16.8). Based on multivariate analysis, previous treatment with TNF antagonists or thiopurines (hazard ratio [HR], 3.86; 95% CI, 1.82–8.18), Clostridioides difficile infection (HR, 3.73; 95% CI, 1.11–12.55), serum level of C-reactive protein above 30 mg/L (HR, 3.06; 95% CI, 1.11–8.43), and serum level of albumin below 30 g/L (HR, 2.67; 95% CI, 1.20–5.92) were associated with increased risk of colectomy. In the derivation cohort, the cumulative risks of colectomy within 1 y in patients with scores of 0, 1, 2, 3, or 4 were 0.0%, 9.4% (95% CI, 4.3%–16.7%), 10.6% (95% CI, 5.6%–17.4%), 51.2% (95% CI, 26.6%–71.3%), and 100%. Negative predictive values ranged from 87% (95% CI, 82%–91%) to 92% (95% CI, 88%–95.0%). Findings from the validation cohort were consistent with findings from the derivation cohort.ConclusionsWe developed a scoring system to identify patients at low-risk vs high-risk for colectomy within 1 y of hospitalization for ASUC, based on previous treatment with TNF antagonists or thiopurines, C difficile infection, and serum levels of CRP and albumin. The system was validated in an external cohort.