The Frequency of Germline BRCA and Non-BRCA HR-Gene-Variants in a Cohort of Pancreatic Cancer Patients.

Germline DNA alterations affecting homologous recombination pathway genes have been associated with pancreatic cancer (PC) risk. BRCA2 is the most studied gene and affects the management of PC patients and their families. Even though recent reports have suggested a similar role of germline ATM pathogenic variants (PV) in familial PC, there is still a disagreement between experts on how it could affect patient management given the lack of proper PC risk estimates. We retrospectively analyzed the germline data of 257 PC patients among whom nearly 50% were sporadic cases. We showed similar frequencies of BRCA2 (4.9%) and ATM (4.4%) PV or likely pathogenic variants, which were not related to familial history. Based on our findings and that of the literature, we suggest including ATM gene among the panel of genes analyzed in PC patients pending the publication of prospective studies.

Fully covered self-expanding metal stents for benign colonic strictures.

BACKGROUND AND STUDY AIMS: Uncovered self-expanding metal stents offer effective relief for colonic obstruction. The aim of this study was to determine the effectiveness of fully covered self-expanding metal stents (FCSEMSs) in the treatment of benign colonic strictures. PATIENTS AND METHODS: All patients presenting with a symptomatic benign colonic stricture (occlusion or subocclusion) during a 6-year study period were treated with FCSEMSs. The stents were placed and removed 4 - 6 weeks later at one of 10 endoscopy centers. The efficacy of the stent (clinical and radiological signs of colonic decompression within 48 hours), technical success, stent retrieval, safety, and recurrence of symptoms were evaluated during follow-up. Univariate and multivariate analyses were performed to identify variables associated with clinical success, stent migration, and symptom recurrence. RESULTS: The study included 43 patients (24 men, 19 women; mean age 67.6 ± 10.4) with occlusive (n = 18) or subocclusive symptoms (n = 25) due to anastomotic (n = 40), post-ischemic (n = 2), or post-radiation (n = 1) strictures. Insertion was successful in all patients. Clinical success was obtained in 35 patients (81 %). Migration was observed in 27 patients (63 %). The median duration of stenting was 21 days (95 %CI 17.8 - 35.4 days). Multivariate analysis showed that stents more than 20 mm wide migrated significantly less often. Recurrence of obstructive symptoms was observed in 23 patients (53 %), irrespective of migration. No predictive factors for recurrence or clinical efficacy were found. CONCLUSIONS: FCSEMSs for treatment of symptomatic benign colonic strictures are safe and effective, despite a high rate of spontaneous migration.

Macroscopic and histologic regression of duodenal polyposis with FOLFOX4 chemotherapy for an ileal pouch adenocarcinoma in a patient with familial adenomatous polyposis.

Severe (stage IV) duodenal polyposis is difficult to manage in patients with familial adenomatous polyposis (FAP), with no effective medical treatment, complex endoscopic treatment modalities, and a high morbidity and mortality from pancreaticoduodenectomy. We present the case of a 44-year-old woman with FAP, stage IV duodenal polyposis, and with an ileal pouch adenocarcinoma that required surgery and adjuvant chemotherapy. Her duodenal polyposis regressed to stage II after four sessions of FOLFOX4 adjuvant chemotherapy, which avoided the need for aggressive endoscopic therapy or pancreatoduodenectomy in this patient.

Prospective multicenter evaluation of colon capsule examination indicated by colonoscopy failure or anesthesia contraindication.

BACKGROUND AND STUDY AIMS: In France, in about 5% of cases colonoscopies are incomplete or temporarily contraindicated.We tested the diagnostic yield of colon capsule endoscopy (CCE) in these patients. PATIENTS AND METHODS: In a prospective study, in 17 French centers, inclusion criteria were colonoscopy failure or general disease that excluded colonoscopy with anesthesia. Patients underwent CCE using the first-generation PillCam Colon capsule. The main end point was CCE diagnostic yield, defined as identification of a colorectal lesion that directly explained symptoms or necessitated a diagnostic or therapeutic examination. A secondary objective was to test a simplified Movi-Prep colon cleansing. Follow-up to identify missed symptomatic cancer was scheduled. RESULTS: CCE showed positive findings in 36 patients (diagnostic yield 33.6 %), among whom 23 subsequently underwent therapeutic intervention. Among 64 patients with negative capsule findings, 9 had a complementary procedure showing adenomas in only 1 case. CCE was incomplete in 7/107 patients. Colonoscopy was done in one patient to retrieve a capsule retained in the left colon, and sigmoidoscopy in 11 because the rectum was not reached. No colorectal cancer was diagnosed during the follow-up period. Colon cleansing with MoviPrep was rated good or excellent in 75.9% of cases. CONCLUSION: This study shows the feasibility and the usefulness of CCE in the situation of colonoscopy failure or contraindication. The colon capsule modality should be tested against other available approaches, such as virtual colonoscopy or repeat colonoscopy by an expert.

Cost effectiveness and projected national impact of colorectal cancer screening in France.

BACKGROUND: Colorectal cancer (CRC) is a major cause of morbidity and mortality in France. Only scanty data on cost-effectiveness of CRC screening in Europe are available, generating uncertainty over its efficiency. Although immunochemical fecal tests (FIT) and guaiac-based fecal occult blood tests (g-FOBT) have been shown to be cost-effective in France, cost-effectiveness of endoscopic screening has not yet been addressed. METHODS: Cost-effectiveness of screening strategies using colonoscopy, flexible sigmoidoscopy, second-generation colon capsule endoscopy (CCE), FIT and g-FOBT were compared using a Markov model. A 40 % adherence rate was assumed for all strategies. Colonoscopy costs included anesthesiologist assistance. Incremental cost-effectiveness ratios (ICERs) were calculated. Probabilistic and value-of-information analyses were used to estimate the expected benefit of future research. A third-payer perspective was adopted. RESULTS: In the reference case analysis, FIT repeated every year was the most cost-effective strategy, with an ICER of €48165 per life-year gained vs. FIT every 2 years, which was the next most cost-effective strategy. Although CCE every 5 years was as effective as FIT 1-year, it was not a cost-effective alternative. Colonoscopy repeated every 10 years was substantially more costly, and slightly less effective than FIT 1-year. When projecting the model outputs onto the French population, the least (g-FOBT 2-years) and most (FIT 1-year) effective strategies reduced the absolute number of annual CRC deaths from 16037 to 12916 and 11217, respectively, resulting in an annual additional cost of €26 million and €347 million, respectively. Probabilistic sensitivity analysis demonstrated that FIT 1-year was the optimal choice in 20% of the simulated scenarios, whereas sigmoidoscopy 5-years, colonoscopy, and FIT 2-years were the optimal choices in 40%, 26%, and 14%, respectively. CONCLUSIONS: A screening program based on FIT 1-year appeared to be the most cost-effective approach for CRC screening in France. However, a substantial uncertainty over this choice is still present.

A guide for assessing the clinical relevance of findings in small bowel capsule endoscopy: analysis of 8064 answers of international experts to an illustrated script questionnaire.

BACKGROUND AND AIM: Although recommended, the P-score used for assessing the pertinence / relevance of findings seen in small bowel (SB) capsule endoscopy (CE) is based on a low level of knowledge. The aim of this study was to evaluate the clinical relevance of the most frequent SBCE findings through an illustrated script questionnaire. MATERIALS AND METHODS: Sixteen types of SBCE findings were illustrated four times each in three different settings (occult and overt obscure gastrointestinal bleeding and suspected Crohn's disease), and with a variable number (n = 1/n = 2-5/n ≥ 6), thus providing a questionnaire with 192 scenarios and 576 illustrated questions. Fifteen international experts were asked to rate the finding's relevance for each question as very unlikely (-2) / unlikely (-1) / doubtful (0) / likely (+1) / very likely (+2). The median score (≤-0.75, between -0.75 and 0.75, or ≥0.75) obtained for each scenario determined a low (P0), intermediate (P1) or high (P2) relevance, respectively. RESULTS: 8064 answers were analyzed. Participation and completion rates were 93% and 100%, respectively. In overt or occult OGIB, resultant P2 findings were 'typical angiectasia', 'deep ulceration', 'stenosis', and'blood', whatever their numbers, and 'superficial ulcerations' when multiple. While in suspected CD, consensus P2 lesions were 'deep ulceration' and 'stenosis' whatever their numbers, and 'aphthoid erosions' and 'superficial ulcerations' when multiple. CONCLUSION: This study establishes a guide for the evaluation of relevance of SBCE findings. It represents a step forward for SB-CE interpretation and is intended to be used as a tool for teaching and academic research.

Small-bowel capsule endoscopy diagnoses early and advanced neoplasms in asymptomatic patients with Lynch syndrome.

BACKGROUND AND STUDY AIMS: Patients with Lynch syndrome are at increased risk of developing small-bowel adenocarcinoma, which usually has a bad prognosis and needs to be diagnosed early. Our aim was to evaluate the yield of capsule endoscopy and CT enteroclysis in this situation. PATIENTS AND METHODS: We performed a prospective, blinded, comparative study of capsule endoscopy and CT enteroclysis in five academic centers. Thirty-five consecutive asymptomatic patients with Lynch syndrome, all with one proven deleterious mutation, were included. A double reading was performed blind for both types of examination. RESULTS: Histologically confirmed small-bowel neoplasms were diagnosed in three patients (8.6 %): one adenocarcinoma (T3N0M0) and two adenomas with low-grade dysplasia. Capsule endoscopy identified all neoplasms. CT enteroclysis raised suspicion of one neoplasm (adenocarcinoma) but missed the two others. Concordance between the two capsule readings was high with a κ value of 0.78 (95 %CI 0.55 to 1.0), which was not the case for CT enteroclysis, where the κ value was 0.15 (95 %CI -0.27 to 0.58). CONCLUSION: Curable early or advanced neoplasms in asymptomatic patients with Lynch syndrome using capsule endoscopy can be detected with a better reproducibility than with CT enteroclysis. The clinical usefulness of systematic small-bowel screening in these patients should be confirmed through large prospective studies.

Diagnostic accuracy of esophageal capsule endoscopy versus conventional upper digestive endoscopy for suspected esophageal squamous cell carcinoma.

BACKGROUND AND STUDY AIM: A video capsule similar to that used in small-bowel capsule endoscopy is now available for esophageal exploration. The aim of our study was to compare the accuracy of upper endoscopy (esophageal gastroduodenoscopy [EGE]) with esophageal capsule endoscopy (ECE) in patients at risk of esophageal squamous cell cancer (SCC). PATIENTS AND METHODS: 68 patients at risk of SCC secondary to a history of head and neck neoplasia were included in this comparison of techniques for detecting SCC and dysplasia. ECE was done using the first generation Pillcam ESO and EGE was performed in accordance with the usual practice of each center, followed by examination with 2 % Lugol staining and biopsy of unstained areas (39 neoplasia comprising 5 low grade dysplasia, 8 high grade dysplasia and 26 SCC). RESULTS: Compared with EGE with and without Lugol staining, the sensitivities of ECE for neoplasia diagnosis were 46 % and 54 %, respectively. On a per-patient basis, the sensitivity, specificity, and positive and negative predictive value of ECE were 63 %, 86 %, 77 % and 76 %, respectively, compared with EGE without staining, and 61 %, 86 %, 77 % and 73 % compared with EGE with iodine staining. Neither the ECE transit time nor the distance between the esopharyngeal line and the neoplastic lesion differed between the 21 false-negative and 18 true-positive cases diagnosed by ECE; the only difference was a smaller median diameter among false negatives ( P < 0.001). CONCLUSION: In a cohort at high risk for esophageal SCC, ECE is not sensitive enough to diagnose neoplastic lesions.

Esophageal capsule endoscopy vs. EGD for the evaluation of portal hypertension: a French prospective multicenter comparative study.

OBJECTIVES: Esophagogastroduodenoscopy (EGD) is the standard method for the diagnosis of esophago-gastric varices. The aim of this prospective multicenter study was to evaluate the PillCam esophageal capsule endoscopy (ECE) for this indication. METHODS: Patients presenting with cirrhotic or noncirrhotic portal hypertension underwent ECEfollowed by EGD at the time of diagnosis. Capsule recordings were blindly read by two endoscopists. RESULTS: A total of 120 patients (72 males, mean age: 58 years; mean Child-Pugh score: 7.2) were included. Esophageal varices were detected in 74 patients. No adverse event was observed after either EGD or ECE. Seven (6%) patients were unable to swallow the capsule. The mean recording time was 204 s (range 1-876). Sensitivity, specificity, negative predictive value, and positive predictive value of ECE for the detection of esophageal varices were 77%, 86%, 69%, and 90%, respectively. Sensitivity, specificity, negative and positive predictive values of ECE for the indication of primary prophylaxis (esophageal varices > or = grade 2 and/or red signs) were 77, 88, 90, and 75%, respectively, and 85% of the patients were adequately classified for the indication (or not) of prophylaxis. Interobserver concordance for ECE readings was 79.4% for the diagnosis of varices, 66.4% for the grading of varices, and 89.7% for the indication of prophylaxis. CONCLUSIONS: This large multicenter study confirms the safety and acceptable accuracy of ECE for the evaluation of esophageal varices. ECE might be proposed as an alternative to EGD for the screening of portal hypertension, especially in patients unable or unwilling to undergo EGD.

[Role of chromoendoscopy for the management of colorectal neoplasia]. / Place des colorations dans la prise en charge des néoplasies colorectales.

Early detection of colorectal neoplasia is a major aim for gastroenterologists, much more than diagnosing advanced cancer. Chromoscopy using mostly indigo-carmine dye at 0.2% is an important tool in this setting, with proven interest for the detection of flat neoplasia in specific at risk patients including Lynch syndrome and inflammatory bowel disease. No other diagnostic tool has demonstrated its superiority, or even its equivalence, to chromoscopy in these situations. With less scientific evidences, chromoscopy helps the endoscopist to delimitate neoplasia before and after endoscopic treatment, and in the specific situation of digestive polyposes. In contrast, there is no proven interest of systematic chromoscopy in the usual situation of coloscopy for cancer screening in moderate or high-risk patients. However, a frequent use of chromoscopy is probably associated with higher ability of the endoscopist, even in usual colonoscopy indications, to identify difficult colorectal lesions.

Endoscopic resection of sporadic duodenal adenomas: an efficient technique with a substantial risk of delayed bleeding.

INTRODUCTION: Data on endoscopic resection of sporadic duodenal adenoma (SDA) are sparse; we present our results concerning safety and efficacy in a retrospective analysis of saline-assisted endoscopic resection of SDA. PATIENTS AND METHODS: The cases of all patients who underwent endoscopic resection for SDA between May 1998 and May 2006 were analyzed. Endoscopic resection was carried out using standard injection and cut methods. In some patients hemoclips and argon plasma coagulation were used, either for prophylaxis or for the treatment of procedure-related bleeding. RESULTS: Thirty-six patients with a total of 37 lesions (mean size 19 mm, range 4 - 50 mm) were analyzed. Lesions larger than 20 mm were more frequently resected piecemeal ( P = 0.022). Intraprocedural bleeding occurred in 14 % of cases, without any significant association with lesion size or the resection technique. One fatal perforation occurred. Macroscopically complete resection was achieved in 97 % of cases, as confirmed by at least one negative control endoscopy with biopsies after a mean follow-up of 15 months. Although clipping and argon plasma coagulation were not applied in any systematic way, it was noticeable that in the 20 cases in which they were used for hemostasis or prevention, no delayed bleeding was observed after the procedures. In contrast, bleeding occurred in 22 % of the 23 procedures performed without these additional techniques. CONCLUSION: Endoscopic resection is an efficient and acceptably safe technique for treating SDA. Further studies need to assess whether systematic bleeding prophylaxis will reduce the incidence of delayed hemorrhage after endoscopic resection.

Frequency and severity of ileal adenomas in familial adenomatous polyposis after colectomy.

BACKGROUND AND STUDY AIMS: The high cumulative risk of colorectal cancer in patients with familial adenomatous polyposis (FAP) justifies prophylactic colectomy with either ileorectal (IRA) or ileal-pouch-anal anastomosis (IPAA). Our aim was to evaluate retrospectively the frequency of and time interval to adenoma development in the ileal mucosa of patients with both types of surgery. PATIENTS AND METHODS: Retrospective study of 44 FAP patients with IRA (n = 21) and IPAA (n = 23). All patients were followed with a standardized procedure including chromoscopy and biopsies of visible polyps. In patients with IRA, specific attention was paid to the ileal mucosa above the anastomosis. RESULTS: In the IPAA group, 18/23 patients (78 %) presented with visible polyps [histology: 16 (70 %) had adenoma with low-grade dysplasia; 1 (4 %) had adenoma with high-grade dysplasia; 1 had normal mucosa]. The mean interval between colectomy and the diagnosis of adenoma was 4.7 +/- 3.3 years. In the IRA group, 16/21 patients (77 %) presented visible polyps in the ileal mucosa [adenoma with low-grade dysplasia in 8 patients (38 %), with high-grade dysplasia in 2 (10 %), and lymphoid nodular hyperplasia in 6]. The mean interval between colectomy and adenoma diagnosis was significantly shorter in the IPAA than in the IRA group (4.76 +/- 3.3 vs. 16.4 +/- 8.5 years, P< 0.0001). CONCLUSION: Our results show a high frequency of adenomas in the ileal mucosa of patients with IPAA and IRA (74 % and 48 % respectively), with evolution into high-grade dysplasia in 6.7 % of cases.

Management of desmoid tumours: A large national database of familial adenomatous patients shows a link to colectomy modalities and low efficacy of medical treatments.

BACKGROUND: Desmoid tumours represent a major complication of familial adenomatous polyposis. Our aims were to study the factors associated with the development of desmoid tumours in familial adenomatous polyposis patients, and to describe presentation and management of desmoid tumours. METHODS AND PATIENTS: We reviewed all patients with familial adenomatous polyposis followed at our institution between 1965-2013, with either identified adenomatous polyposis coli gene mutation, or a personal and family history suggesting adenomatous polyposis coli-related polyposis. Response to treatment of desmoid tumours was assessed by Response Evaluation Criteria In Solid Tumor (RECIST) criteria. RESULTS: A total of 180 patients with familial adenomatous polyposis were included with a median follow-up of 19 years since diagnosis. Thirty-one (17%) patients developed 58 desmoid tumours, a median (range) 4.7 (0.8-41.6) years after their diagnosis of familial adenomatous polyposis. The only factor significantly associated with occurrence of desmoid tumours was the type of surgery: 12 (12%) desmoid tumours in 104 patients treated by colectomy, versus 19 (25%) desmoid tumours in 76 patients treated by proctocolectomy, p = 0.027. The localisation of desmoid tumours was: mesenteric (n = 25), abdominal wall (n = 30) or extra-abdominal (n = 3). Nineteen patients underwent 36 surgical procedures for desmoid tumours. Recurrence occurred in 26 (72%) cases and the recurrence-free survival was 2.6 (95% confidence interval (CI), 0.2-5.9) years. Thirteen patients received 27 medical treatments over a median 14 months. Objective response was observed in four (15%) patients and the median progression-free survival was nine (95% CI, 1.1-16.9) months. CONCLUSION: If confirmed, colectomy (versus proctocolectomy) should be performed in adenomatous polyposis coli-related familial adenomatous polyposis patients to avoid desmoid tumours. We show that there is a high prevalence of post-surgical recurrence and the low efficacy of available medical treatments for desmoid tumours.

Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments.

Large genomic deletions within the mismatch repair MLH1 and MSH2 genes have been identified in families with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, and their detection represents a technical problem. To facilitate their detection, we developed a simple semiquantitative procedure based on the multiplex PCR of short fluorescent fragments. This method allowed us to confirm in HNPCC families three known deletions of MLH1 or MSH2 and to detect in 19 HNPCC families, in which analysis of mismatch repair genes using classical methods had revealed no alteration, a deletion of exon 5 and a duplication of MSH2 involving exons 9 and 10. The presence of such duplications, the frequency of which is probably underestimated, must be considered in HNPCC families in which conventional screening methods have failed to detect mutations.

Bombesin stimulates adhesion, spreading, lamellipodia formation, and proliferation in the human colon carcinoma Isreco1 cell line.

The neuropeptide bombesin and its mammalian homologue, gastrin-releasing peptide (GRP), enhance proliferation in some but not all human tumor cell lines. The pathophysiological relevance of the bombesin/GRP receptor (GRP-R), which is expressed in 30% of human colon tumor cell lines and in 24-40% of native tumors, has not been clearly assessed at this time. We studied the effects of bombesin in the recently characterized human colon carcinoma Isreco1 cell line. Competitive reverse transcription-PCR showed a high GRP-R mRNA level in Isreco1 cells, and binding studies confirmed the expression of bombesin/GRP-subtype receptors (Kd = 0.42 nM; Bmax = 18,000 sites/cell). Exposure to bombesin resulted in an increase of intracellular calcium concentrations. Bombesin (1 nM) induced cell spreading at 24 h (21.7+/-1.6% versus 6.4+/-0.8% in control cells; P<0.01) and markedly increased the formation of lamellipodia. In addition, adhesion of Isreco1 cells to collagen I-coated culture dishes was stimulated in the presence of 1 nM bombesin (69+/-6% versus 42+/-1% in control cells; P<0.01). Finally, bombesin significantly increased [3H]thymidine uptake by Isreco1 cells in a dose-dependent manner, with a first significant response at 0.1 nM and a maximal effect at 100 nM bombesin (192.2+/-9.7% of control). These results clearly indicate that bombesin exerts morphological, adhesive, and proliferative effects on Isreco1 cells, suggesting that expression of the bombesin/GRP-R may contribute to the malignant properties of colon carcinoma cells.

Rab3a controls exocytosis in cholecystokinin-secreting cells.

The expression of rab3A and rab3D isoforms in the enteroendocrine, cholecystokinin-secreting, cell lines STC-1 and GLUTag is here demonstrated. In contrast, rab3B is undetectable in these two cell lines, and rab3C is only slightly expressed in GLUTag cells. Using a transient co-transfection system with human growth hormone as reporter protein, we show that overexpression of the GTPase-deficient mutant rab3AQ81L, but not rab3DQ81L, significantly decreases human growth hormone secretory responses to various agonists in STC-1 cells. These results indicate that endocrine cell lines of intestinal origin express rab3A and rab3D proteins, but the GTP-bound form of rab3A only acts as a negative modulator in the control of cholecystokinin secretion from STC-1 cells.

High gastrin releasing peptide receptor mRNA level is related to tumour dedifferentiation and lymphatic vessel invasion in human colon cancer.

The neuropeptide bombesin stimulates tumour cell proliferation in vitro. Through pharmacological testing, 20-40% of human colorectal tumours have been shown to be equipped with bombesin/gastrin releasing peptide receptor (GRP-R). The aim of the present study was to test whether GRP-R expression is correlated with tumour characteristics and usual prognostic factors in colorectal adenocarcinomas. A sensitive reverse transcription (RT)-competitive polymerase chain reaction (PCR) method was validated by studying GRP-R mRNA in separated layers of normal colonic wall, and GRP-R mRNA levels (in parallel with binding studies) in colon cancer cell lines LoVo and Caco-2. GRP-R mRNA levels were then determined in 29 surgical tumour specimens and the results compared with tumour histology and, using histochemistry, with the accumulation of p53 protein and a Ki-67 cell proliferation index. The mRNA was not detected in normal colonic epithelium, whereas a distinct signal was observed after amplification in 27/29 (93%) tumour specimens. Estimates of mRNA levels in the 27 positive tumours ranged from 52 to 8000 amol/0.25 microgram total RNA, and were significantly higher in poorly/moderately differentiated tumours (P < 0.05) and in tumours with lymphatic vessel invasion (P < 0.01). There was no relationship with p53 accumulation or to the proliferation index. Our results show that GRP-R mRNA can be detected in most colorectal tumour specimens, and suggest a link between high mRNA levels and both tumour dedifferentiation and lymph vessel invasion, but not proliferation.

[Locally advanced adenocarcinoma of the pancreas: current therapeutic modalities]. / Adénocarcinomes du pancréas localement évolués: modalités thérapeutiques actuelles.

Pancreatic cancer still have bad prognosis. At the time of diagnosis, less than 10% of patients can undergo surgery with an overall 5-year survival rate of less than 2%. For patients with localized pancreatic adenocarcinoma, the combination of radiation therapy and chemotherapy has been shown to control symptoms and to enhance patient survival. This treatment should be proposed to all the patients with good performance status and without icterus. Pain management should be optimized and often need morphinic and co-antalgic (anticonvulsivants, steroids) consumption. The celiac plexus block with alcohol gives an excellent pain relief and should be more frequently used.