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Whilst endoscopic retrograde cholangiopancreatography (ERCP) is being practiced on increasingly older patients, its benefits have not been well studied. This study assessed the clinical benefit of ERCP for subjects aged 75 and over, including follow-up at 3 months of geriatric functional parameters and lifestyle. This is a prospective mono-centric, cohort study. All patients aged 75 and over receiving ERCP were enrolled and monitored for a period of 3 months. We recorded 53 inclusions between November 1st 2014 to 31 May 2015. Our "ill-type" was a fragile polypathology woman of 85 years, living at home, with loss of autonomy for instrumental activities of daily living (IADL). Lithiasis was diagnosed in 56.6% of cases, and malignant stenosis in 35.8% of cases. The success rate was 88.7% with a 5.7% complication rate. At 3 months, we observed no clinically significant change in ADL parameters, IADL and lifestyle. Our follow-up data support the practice of ERCP in geriatric populations.

International audience; Colorectal cancer lethality usually results from post-treatment relapse in the majority of stage II-IV patients, due to the enhanced resistance of Cancer Stem Cells (CSCs). Here, we show that the nuclear receptor Pregnane X Receptor (PXR, NR1I2), behaves as a key driver of CSC-mediated tumor recurrence. First, PXR is specifically expressed in CSCs, where it drives the expression of genes involved in self-renewal and chemoresistance. Clinically, high levels of PXR correlate with poor recurrence-free survival in a cohort of >200 stage II/III colorectal cancer patients treated with chemotherapy, for whom finding biomarkers of treatment outcome is an urgent clinical need. shRNA silencing of PXR increased the chemo-sensitivity of human colon CSCs, reduced their self-renewal and tumor-initiating potential, and drastically delayed tumor recurrence in mice following chemotherapy. This study uncovers PXR as a key factor for CSC self-renewal and chemoresistance and targeting PXR thus represents a promising strategy to minimize colorectal cancer relapse by selectively sensitizing CSCs to chemotherapy.

Purpose: Patients with metastatic colorectal cancer suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for the self-renewal of colon CSCs, which is also a direct β-catenin/TCF4 target gene. In this study, we aimed to develop a novel targeted therapy to neutralize secreted progastrin to inhibit Wnt signaling, CSCs, and reduce relapses. Experimental Design: Antibodies (monoclonal and humanized) directed against progastrin were produced and selected for target specificity and affinity. After validation of their effectiveness on survival of colorectal cancer cell lines harboring B-RAF or K-RAS mutations, their efficacy was assessed in vitro and in vivo, alone or concomitantly with chemotherapy, on CSC self-renewal capacity, tumor recurrence, and Wnt signaling. Results: We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo, either alone or in combination with chemotherapy. Furthermore, migration and invasion of colorectal cancer cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and posttreatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity in vitro is decreased, and, in transgenic mice developing Wnt-driven intestinal neoplasia, the tumor burden is alleviated, with an amplification of cell differentiation in the remaining tumors. Conclusions: Altogether, these data show that humanized anti-progastrin antibodies might represent a potential new treatment for K-RAS–mutated colorectal patients, for which there is a crucial unmet medical need. Clin Cancer Res; 23(17); 5267–80. ©2017 AACR.

Background and study aims: A new core biopsy needle for endoscopic ultrasound (EUS)-guided sampling has recently been developed. The aim of this prospective multicenter study was to compare this needle with a standard needle in patients with solid pancreatic masses. Patients and methods: Consecutive patients with solid pancreatic masses referred to 17 centers for EUS-guided sampling were included. Each patient had two passes with a standard 22G needle and a single pass with a 22G core needle performed in a randomized order. Samples from both needles were separately processed for liquid-based cytology and cell-block preparation and were assessed independently by two blinded expert pathologists. The primary endpoint was the accuracy of the detection of malignancy. The reference standard was based on further cytohistological analysis obtained under ultrasound or computed tomography scanning, endoscopic or surgical guidance, and/or by clinical follow-up with repeated imaging examinations for at least 12 months. The secondary endpoints were the rate of technical failure and the quality of the cytohistological samples obtained. Results: Of the 80 patients included (49 men; mean age 67.1 ± 11.1), 87.5 % had final malignant diagnoses (adenocarcinoma n = 62, 77.5 %). There was no difference between the needles in diagnostic accuracy (standard needle 92.5 % vs. core needle 90 %; P = 0.68) or technical failure. Both pathologists found the overall sample quality significantly better for the standard needle (expert 1, P = 0.009; expert 2, P = 0.002). Conclusions: The diagnostic accuracy of EUS sampling for solid pancreatic masses using standard and core needles seems comparable but with a better overall histological sample quality for the former. ClinicalTrial.gov identifier: NCT01479803.

Background and study aims: The hemostatic powder TC-325 (Hemospray; Cook Medical, Winston-Salem, North Carolina, USA) has shown promising results in the treatment of upper gastrointestinal bleeding (UGIB) in expert centers in pilot studies. The aim of this study was to evaluate the feasibility and efficacy of TC-325 in a large prospective registry of use in routine practice. Patients and methods: The data of all patients treated with TC-325 were prospectively collected through a national registry. Outcomes were the immediate feasibility and efficacy of TC-325 application, as well as the rates of rebleeding at Day 8 and Day 30. Multivariate analysis was performed to determine predictive factors of rebleeding. Results: A total of 202 patients were enrolled and 64 endoscopists participated from 20 centers. TC-325 was used as salvage therapy in 108 patients (53.5 %). The etiology of bleeding was an ulcer in 75 patients (37.1 %), tumor in 61 (30.2 %), postendoscopic therapy in 35 (17.3 %), or other in 31 (15.3 %). Application of the hemostatic powder was found to be very easy or easy in 31.7 % and 55.4 %, respectively. The immediate efficacy rate was 96.5 %. Recurrence of UGIB was noted at Day 8 and Day 30 in 26.7 % and 33.5 %, respectively. Predictive factors of recurrence at Day 8 were melena at initial presentation and use of TC-325 as salvage therapy. Conclusion: These multicenter data confirmed the high rate of immediate hemostasis, excellent feasibility, and good safety profile of TC-325, which could become the treatment of choice in bleeding tumors or postendoscopic bleeding but not in bleeding ulcers where randomized studies are needed. Trial registration: ClinicalTrials.gov (NCT02595853)

Summary Aim Acute pancreatitis is an important cause of morbidity and mortality, mainly due to sepsis. The aim of this study was to determine the incidence of infectious complications and their impact on mortality in patients hospitalized for acute pancreatitis. Patients and Methods Patients admitted for acute pancreatitis were restropectively included within a period between 1995 and 2000. Incidence of abdominal and extra-abdominal sepsis and specific care were specifically analyzed. Risk factors for death were evaluated by uni- and multivariated analysis. Results Two hundreds and twelve consecutive patients (128 males, median age 54 years) were included. Mortality was 10.8%. At least one infectious episode was collected in 25% of the patients with an abdominal sepsis (26.8%), bacteriemia (24.4%), respiratory (24.4%) and urinary tracts (19.5%) infections. Infection was polymicrobial in 37.5%. An antibiotic prophylaxis was administered in 10.8%, more often in patients with severe pancreatitis. It did not alter mortality or incidence of infections but significantly delayed occurrence of sepsis. Mortality of patients treated with more than one line of antibiotics was higher. However in this study infectious complications were not an independent factor for mortality. Conclusion Infections are frequent and polymicrobial but are not an independent prognostic factor during acute pancreatitis.

International audience; BACKGROUND:This last decade, a lot of emphasis has been placed on developing new cancer cell culture models, closer to in vivo condition, in order to test new drugs and therapies. In the case of colorectal cancer, the use of patient biopsies to seed 3D primary cultures and mimic tumor initiation necessitates the use of antibiotics to prevent microbial intestinal contamination. However, not only long term use of antibiotics may mask the presence of low levels of microbial contamination, it may also impact cancer cell phenotype.METHODS:In this study we tested the impact of penicillin-streptomycin cocktail addition in both monolayer and suspension culture. To ensure the reliability of our observations we used six different cell lines and each experiment was performed in triplicate. Results were analyzed with Student's t test.RESULTS:We show that penicillin-streptomycin cocktail inhibits the sphere-forming ability of six cancer cell lines in suspension culture though it has no impact in monolayer culture. We correlate this effect with a significant decrease of cancer stem cells pool which holds self-renewal potential.CONCLUSIONS:Overall, this study warns against systematic addition of antibiotics in growth medium and raises the interesting possibility of using antibiotics to target cancer stem cells.

The Wnt and Notch signaling pathways are both abnormally activated in colorectal cancer (CRC). We recently showed that progastrin depletion inhibited Wnt signaling and increased goblet cell differentiation of CRC cells. Here, we show that progastrin down-regulation restores the expression by CRC cells of the early secretory lineage marker Math-1/Hath-1 due to an inhibition of Notch signaling. This effect is mediated by a decreased transcription of the Notch ligand Jagged-1, downstream of β-catenin/Tcf-4. Accordingly, recombinant progastrin sequentially activated the transcription of Wnt and Notch target genes in progastrin-depleted cells. In addition, restoration of Jagged-1 levels in these cells is sufficient to activate Tcf-4 activity, demonstrating the occurrence of a feedback regulation from Notch toward Wnt signaling. These results suggest that progastrin could be instrumental in maintaining the concomitant activation of Wnt and Notch pathways in CRC cells, further highlighting the interest of progastrin targeting for the clinical management of CRC. [Cancer Res 2009;69(15):6065–73]

A Novel Hemostatic Powder for the Endoscopic Treatment of Gastrointestinal Bleeding: Results From a Multicenter Prospective Study Performed in Routine Practice (the ‘Graphe' Registry) Sami Haddara, Julien Branche, Stephane Lecleire, Jeremie Jacques, Laurent Heyries, Jocelyn Privat, Philippe Bichard, Philippe Grandval, Yann Lebaleur, Ulriikka Chaput, Stephane Koch, Jonathan Levy, Bruno Godart, Antoine Charachon, Jean-Francois Bourgaux, Emmanuel Coron

Background : The cytoplasmic tyrosine kinase Src is frequently deregulated in colorectal cancer (CRC) and this deregulation is implicated in tumour growth and in the induction of metastasis. How Src is activated in this cancer has not been clearly established. In contrast to Ras, Src activating mutations are rare events, suggesting the existence of alternative mechanisms for the induction of Src oncogenic activity. Here, we addressed whether Src deregulation involves inhibition of its negative regulators, including the Src-Like Adaptor Protein (SLAP). Experimental procedures : SLAP expression was analyzed in colon cancer cells and in microdissected tissue samples of patients with CRC. The effect of SLAP was analyzed on the capacity of CRC cells to grow in soft agar and to induce tumours once engrafted in nude mice. The effect of SLAP on the invasive properties of CRC cells was investigated in vitro using Matrigel Boyden chamber assays, as well as in vivo following injection in the spleen of Balb-c mice. Results : We found that SLAP is expressed in the healthy colon and that its expression is reduced in 60% of CRC biopsies tested. Moreover, we showed that SLAP overexpression dramatically reduced the capacity of CRC cells to induce primary tumours and liver metastases in vivo. Conversely, SLAP knock-down in early-stage CRC cells led to a remarkable induction of liver metastasis in mice. This novel function of SLAP required its myristoylation site as well as intact SH3 and SH2 domains. A proteomic approach is under way to identify SLAP partners involved in this tumor suppressor activity. Conclusions: Our results suggest that, in addition to lymphocytes, SLAP also regulates transforming properties of CRC cells. We hypothesize that SLAP negatively regulates oncogenic signalling initiated by tyrosine kinases including Src. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1981. doi:10.1158/1538-7445.AM2011-1981