Relevance of biopsy-derived pancreatic organoids in the development of efficient transcriptomic signatures to predict adjuvant chemosensitivity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients are frequently treated by chemotherapy. Even if personalized therapy based on molecular analysis can be performed for some tumors, PDAC regimens selection is still mainly based on patients' performance status and expected efficacy. Therefore, the establishment of molecular predictors of chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. We have recently developed an RNA-based signature that predicts the efficacy of adjuvant gemcitabine using 38 PDAC primary cell cultures. While demonstrated its efficiency, a significant association with the classical/basal-like PDAC spectrum was observed. We hypothesized that this flaw was due to the basal-like biased phenotype of cellular models used in our strategy. To overcome this limitation, we generated a prospective cohort of 27 consecutive biopsied derived pancreatic organoids (BDPO) and include them in the signature identification strategy. As BDPO's do not have the same biased phenotype as primary cell cultures we expect they can compensate one with each other and cover a broader range of molecular phenotypes. We then obtained an improved signature predicting gemcitabine sensibility that was validated in a cohort of 300 resected PDAC patients that have or have not received adjuvant gemcitabine. We demonstrated a significant association between the improved signature and the overall and disease-free survival in patients predicted as sensitive and treated with adjuvant gemcitabine. We propose then that including BDPO along primary cell cultures represent a powerful strategy that helps to overcome primary cell cultures limitations producing unbiased RNA-based signatures predictive of adjuvant treatments in PDAC.

A transcriptomic signature to predict adjuvant gemcitabine sensitivity in pancreatic adenocarcinoma.

BACKGROUND: Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. PATIENTS AND METHODS: Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated. RESULTS: The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred- (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months [95% confidence interval (CI): 61.2-not reached] versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value. CONCLUSION: The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.

Interest of submucosal dissection knife for endoscopic treatment of Zenker's diverticulum.

BACKGROUND: Dual-Knife(®) (Olympus) and Hydride-Knife(®) are new needle knives frequently used for submucosal dissection because of their safety and precision. In this study we aimed to evaluate the efficacy and safety of such devices in the diverticulopexy by flexible endoscopy. METHODS: From February 2009 to March 2013, 42 patients (25 men), mean age 74.5, with symptomatic Zenker's diverticulum, were included in a non-randomized prospective multicenter study. The symptoms described by all patients include dysphagia, regurgitation and/or swallowing disorders. The diverticulopexy was performed with the Dual-Knife(®) or Hydrid-Knife(®), after septum exposure with the diverticuloscope, and terminated with distal tip clips positioning. All complications were noted. Patients' symptoms were regularly assessed during follow-up visits or telephone interviews. RESULTS: The first endoscopy treatment was successful for all patients. Thirty-seven patients (88%) had symptoms improvement after the first treatment. The recurrence rate was 14% (6 patients); a second endoscopic treatment was required 12 months on average after the first treatment, with 100% efficiency. Mid-term (16 months) efficiency was 91.67% after 1 to 3 endoscopic treatments. A total of 55 procedures were performed without perforation or significant bleeding and 3 patients underwent surgery. In multivariate analysis, the diverticulum size and the type of dissection knife were not risks factors for recurrence. CONCLUSIONS: Endoscopic diverticuloscope-assisted diverticulotomy with submucosal dissection knives is a safe and effective alternative treatment for patients with a symptomatic Zenker's diverticulum measuring between 2 and 10 cm.

Self-expanding plastic stent removed after radiochemotherapy for advanced esophageal cancer.

Endoscopic evaluation after chemoradiotherapy (CR) is impossible with an esophageal stent in place. The main study objective was to evaluate self-expanding plastic stent (SEPS) removal post-CR. Secondary end-points were the improvement of dysphagia and patients' quality of life. From October 2008 to March 2011, 20 dysphagic patients who suffered from advanced esophageal cancer were enrolled in a multicenter, prospective study. SEPS was inserted prior to CR and then removed endoscopically. SEPS efficiency (dysphagia score) and tolerance, as well as the patients' quality of life (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire validated for the esophagus), were monitored. Continuous variables were compared using a paired t-test analysis for matched data. A P-value of less than 0.05 was considered statistically significant. Twenty patients (15 men and 5 women), aged 61.5 years (±9.88) (range 43-82 years), with adenocarcinoma (n = 12) and squamous cell carcinoma (n = 8), were enrolled. SEPS were successfully inserted in all patients (100%). There was one perforation and three episodes of migration. All of these complications were medically treated. The mean dysphagia score at the time of stent placement was 2.79 (0.6). Mean dysphagia scores obtained on day 1 and day 30 post-SEPS placement were 0.7 (0.9) (P < 0.0001) and 0.45 (0.8) (P < 0.0001), respectively. Quality of Life Questionnaire validated for the esophagus score showed an improvement in dysphagia (P = 0.01) and quality of oral feeding (P = 0.003). All SEPS were removed endoscopically without complications. In two patients, the stent was left in place due to metastatic disease. SEPS are extractable after CR of esophageal cancer. Early stenting by SEPS prior to and during CR may reduce dysphagia and improve quality of oral alimentation.

Evaluation of a storage cabinet for heat-sensitive endoscopes in a clinical setting.

BACKGROUND: In most countries, endoscopes must be disinfected or fully reprocessed before the beginning of each session, even if they were cleaned and disinfected after their last use. Several storage cabinets for heat-sensitive endoscopes (SCHE) are commercially available. They are designed to maintain the microbiological quality of reprocessed endoscopes for a predefined period of time validated by the SCHE manufacturer. Use of an SCHE increases the acceptable storage time before it is necessary to re-disinfect the endoscope. AIM: To evaluate the efficacy of an SCHE (DSC8000, Soluscope, SAS Marseilles, France) in a clinical setting. METHOD: The microbiological quality of endoscopes was assessed after 72 h of storage in an SCHE (Group I), and compared with the microbiological quality of endoscopes stored for 72 h in a clean, dry, dedicated cupboard without morning disinfection (Group II) and the microbiological quality of endoscopes stored for 72 h in a clean, dry, dedicated cupboard with morning disinfection (Group III). Forty-one endoscopes in each group were sampled for microbiological quality. Endoscope contamination levels were analysed according to guidelines published by the National Technical Committee on Nosocomial Infection in 2007. FINDINGS/CONCLUSION: Use of an SCHE helps to maintain the microbiological quality of endoscopes, provided that staff members are well trained and all practices are framed by a proven quality assurance process.

[Ischemic cholangitis in intensive care unit: favourable outcome with ursodesoxycholic acid and fenofibrate]. / Cholangite sclérosante de réanimation : évolution favorable sous acide ursodésoxycholique et fénofibrate.

INTRODUCTION: Ischemic cholangitis in intensive care unit is a recently reported liver disease in patients who have had a prolonged mechanical ventilation and vasopressive drug support for multiple organ deficiency. Prognosis is usually poor and the only life-saving therapy is liver transplantation despite ursodesoxycholic acid treatment. CASE REPORT: We report a 63-year-old man who presented with a sclerosis cholangitis after a month in intensive care unit, effectively treated with fenofibrate and ursodesoxycholic acid. Recent reports underline fenofibrate efficacy in the treatment of primary biliary cirrhosis, especially in association with ursodesoxycholic acid. This treatment has prevented liver transplantation for our patient with a correct quality of life. CONCLUSION: The addition of fibrate to ursodesoxycholic acid improves persistent cholestasis in sclerosing cholangitis.

Fully covered self-expanding metal stents for refractory pancreatic duct strictures in chronic pancreatitis.

Fully covered self-expanding metal stents (FC-SEMSs), which can be removed from the bile duct, have recently been used in the main pancreatic duct (MPD) in chronic pancreatitis. The aim of this study was to investigate the feasibility, safety, and efficacy of FC-SEMSs in painful chronic pancreatitis with refractory pancreatic strictures. The primary endpoints were technical success and procedure-related morbidity. Secondary endpoints were pain relief at the end of follow-up and resolution of the dominant pancreatic stricture at endoscopic retrograde pancreatography. Over 5 months, 10 patients with painful chronic pancreatitis and refractory dominant pancreatic duct strictures were treated with FC-SEMSs. All FC-SEMSs were successfully released and removed, although two stents were embedded in the MPD at their distal end and treated endoscopically without complications. Mild abdominal pain was noted in three patients after stent release. During treatment, pain relief was achieved in nine patients, but one continued to take morphine, because of addiction. Cholestasis developed in two patients and was treated endoscopically; no patient developed acute pancreatitis or pancreatic sepsis. After stent removal, the diameter of the narrowest MPD stricture had increased significantly from 3.5 mm to 5.8 mm. Patients were followed up for a mean of 19.8 months: two patients who continued drinking alcohol presented with mild acute pancreatitis; one patient developed further chronic pancreatic pain; and one had a transient pain episode. At the end of the study, nine patients no longer had chronic pain and no patients had required surgery. Endoscopic treatment of refractory MPD stricture in chronic pancreatitis by placement of an FC-SEMS appears feasible, safe, and potentially effective.

Advantage of expressing the variations in some digestive parameters as a function of gastric emptying instead of time.

BACKGROUND/AIM: Gastric emptying is a major cause of variability when studying gastrointestinal parameters as a function of time. Here, we investigate whether the parametric variability could be reduced by running experiments on a gastric emptying basis rather than on a time basis. METHODS: Healthy volunteers were intubated with gastric and duodenal tubes and were given a liquid meal containing polyethylene glycol to monitor gastric emptying. Gastric pH and human gastric lipase (HGL) concentrations were measured. Their variations were plotted as a function of either time or gastric emptying (%). In both cases, mean curves of variation were established by polynomial regression. RESULTS: When time was the variable used, the overall deviation of the experimental values from the values given by the best-fitting curve was high (chi2 = 33 for gastric pH; chi2 = 1,744 for HGL), and the individual deviations increased with time. When gastric emptying was the variable used, the overall deviation of the experimental values from the values given by the best-fitting curve was much lower (chi2 = 10 for gastric pH; chi2 = 642 for HGL). CONCLUSIONS: Expressing gastric pH or HGL concentration as a function of gastric emptying instead of time makes it possible to reduce the individual variability. This new type of data analysis may be of a general interest to observe specific variations of gastrointestinal parameters induced by drugs, hormones, and meals, and that might be masked by the large intrinsic variability induced by gastric emptying.

Effects of lansoprazole on human gastric lipase secretion and intragastric lipolysis in healthy human volunteers.

BACKGROUND: Lansoprazole is a potent proton-pump inhibitor (PPI) of parietal cells, which reduces the secretion of gastric acid. Although human gastric lipase (HGL) is produced only by the chief cells of the stomach, the possibility that interactions may occur between lansoprazole and HGL has never been addressed so far in humans. The aim of this study was therefore to quantify the effects of lansoprazole on HGL secretion and intragastric lipolysis during the ingestion of test meals by healthy human volunteers. METHODS: Six healthy volunteers were intubated twice with a gastric and a duodenal tube, before ingesting a standard liquid test meal alone (-PPI experiments) and after 7 days of lansoprazole treatment (+PPI experiments). The HGL concentration was assessed in gastric and duodenal samples by measuring the lipase activity using a pH-stat, and the lipolysis products were quantified by performing thin layer chromatography. The level of intragastric lipolysis was defined as the percentage acyl chains released from the meal triglycerides. The pyloric outputs of HGL and lipolysis products were calculated, based on the use of a non-absorbable marker added to the meal. RESULTS: The pH of the gastric contents was significantly higher in the +PPI experiments than in the -PPI experiments (p < 0.05), since mean values of 4.3 +/- 2.5 and 2.2 +/- 1.6, respectively, were recorded at the end of the gastric emptying of the meal. The HGL concentrations recorded during the meal were found to be higher in the experiments with lansoprazole (p < 0.05) than in those without lansopra- zole, but the HGL secretion levels (-PPI: 15.4 +/- 8.0 mg; +PPI: 19.0 +/- 7.4 mg) and the intragastric lipolysis (-PPI: 24.0 +/- 8.0%; +PPI: 23.6 +/- 6.8%) were not significantly affected by lansoprazole (p > 0.05 in both cases). CONCLUSION: Lansoprazole affected neither the HGL secretion nor the intragastric lipolysis levels, although an increase was observed in the intragastric pH at the end of the gastric emptying of the meal. The HGL concentration increased, however, due to the decrease in the acid secretion process, resulting in less diluted gastric contents.

[Maldigestion during chronic pancreatitis]. / Maldigestion au cours des pancréatites chroniques.

During chronic pancreatitis exocrine pancreatic insufficiency develops leading to a loss of pancreatic enzymes in the duodenum, especially pancreatic lipase. As a result, lipid maldigestion occurs (on a clinical standpoint it is more serious than proteic maldigestion) responsible for greasy diarrhoea with steatorrhoea and abdominal discomfort. Stearorrhoea is diagnosed thanks to a direct measurement of the total lipid content in the stool rather than indirect test. The pancreatic origin of the steatorrhoea is demonstrated in view of the clinical history of the disease, the normal duodenal biopsy specimen or by imaging or biological testing. Steatorrhoea is treated by pancreatic extract given as a form of enteric coated microcapsules (which are protected from proteolitic and acidic digestion) together with some dietary advises.

Pseudotumorous chronic pancreatitis associated with inflammatory bowel disease.

Chronic pancreatitis associated with inflammatory bowel disease is now considered as extraintestinal manifestation of that disease. The clinical and radiological features of the new entity are markedly different from those of chronic calcifying pancreatitis. We report the case of a 68-year-old man presenting with a pseudotumorous chronic pancreatitis associated with ulcerative colitis. Diagnosis was made after endoscopic retrograde cholangiopancreatography (ERCP) and cytological analysis of stenosis brushings and was confirmed by the clinical evolution. Existence of IBD-associated pancreatitis with pseudotumorous features has to be taken into account in order to avoid inappropriate pancreatic resection.

Endoscopic treatment of the main pancreatic duct: correlations among morphology, manometry, and clinical follow-up.

BACKGROUND AND AIM: During the course of chronic pancreatitis, the gradual increase in the main pancreatic duct pressure is the main pathophysiological factor responsible for pain, but up to now, the intra ductal pressure has never been measured during and after endoscopic stenting and correlated with clinical results. Pressure measurements of this kind could thus provide objective information about the useful duration of stenting period. METHODS: Main pancreatic duct pressure was measured by performing endoscopic manometry on 13 chronic pancreatitis symptomatic patients (10 men, 3 women, mean age: 45.1+/-7.9 yr); clinical follow-up was carried out for a period of 29.0+/-16.1 mo. Before treatment, the main anatomical alteration present was a localized stenosis of the main pancreatic duct, i.e., one with a diameter of less than 2 mm (chronic pancreatitis alone), 10 cases; chronic pancreatitis associated with pancreas divisum, 3 cases). Stenosis was treated by endoscopic stenting: 7 F stent (7 cases) and 12 F stent (6 cases). The pressure was measured simultaneously in the duodenum (zero level) and within the main pancreatic duct, using an electronic device, The pancreatico-duodenal gradient was taken to be the difference between the pressure in the main pancreatic duct and the duodenum. RESULTS: The endoscopic stenting induced a nonsignificant decrease in the intraductal pressure (p = 0.16). Among the 9 patients with a normal pressure at the end of the stenting and a successful anatomical outcome, 6 were painless during the follow-up period whereas 3 presented with recurrent pancreatic-type pain. The remaining 4 patients were symptom-free during the entire follow-up period, although the main pancreatic duct pressure was high at the end of the stenting and the stenosis was not completely cured. CONCLUSION: The intraductal pressure at the end of the stenting period was perfectly correlated with the anatomical result, whether or not it was successful, but was not an accurate predictor of a favorable clinical outcome in patients with a poor anatomical result.

[Infection of submucosal tumor after endosonography-guided needle biopsy]. / Infection d'une tumeur sous-muqueuse après ponction sous écho-endoscopie.

Endosonography fine needle guided aspiration (EUS-FNA) biopsy is an interesting technique for the diagnosis of suspected gastrointestinal lesions, and is rarely complicated by infection. We report one case of severe infection after EUS-FNA of benign oesophageal leiomyoma, leading to an oesophagectomy. Recent studies about this technique described only infectious complications after biopsy of cystic lesions. They also show that EUS-FNA may misdiagnose leiomyosarcoma. Our report confirms these data, and relates a hitherto non-reported complication, i.e. the infection of a non-cystic lesion.