Oral anticoagulants but not antiplatelet agents increase the risk of delayed bleeding after endoscopic papillectomy: a large study in a tertiary referral center.

BACKGROUND: Endoscopic papillectomy (EP) is an effective curative treatment in patients with ampullary adenomas. However, EP is burdened by a not-negligible risk of bleeding. The aim of this study was to determine risk factors for delayed bleeding after EP. METHODS: A retrospective analysis of a prospectively-collected database was performed, retrieving all EP performed over a 20-year period. Anti-thrombotic treatments were managed according to guidelines. Delayed bleeding was defined as overt gastrointestinal bleeding or drop in haemoglobin level. Multivariate logistic regression was used to identify variables related to delayed bleeding. RESULTS: Three-hundred-seven patients (48.5% male, median age 68-year-old) entered the study; of them, 51 (16.6%) received anti-thrombotic treatments. Delayed bleeding occurred in 44 (14.3%) patients. No difference was observed in patients receiving antiplatelet agents. Multivariate analysis identified oral anticoagulant agents (odd Ratio 4.37 [2.86-5.95]) and procedural bleeding (OR 2.22 [1.10-4.40]) as independently related to delayed bleeding; in patients with no procedural bleeding, oral anticoagulant agents (OR 5.63 [2.25-9.83]) and ampullary tumor size (OR 1.07 [1.01-1.13]) were independently related to delayed bleeding. Patients on anticoagulant agents presented significantly higher need for blood transfusion (16.7 vs. 1.5%); no difference in intensive care unit admission, surgery or mortality was observed. CONCLUSIONS: This study demonstrates that patients on oral antiplatelet agents do not present increased risk for post-EP delayed bleeding. EP represents a valid alternative to surgery even in patients on anticoagulant agents, despite significantly increased risk of delayed bleeding. A tailored approach to those cases should be planned.

22G Acquire vs. 20G Procore needle for endoscopic ultrasound-guided biopsy of pancreatic masses: a randomized study comparing histologic sample quantity and diagnostic accuracy.

BACKGROUND : Endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) has been suggested for obtaining high quality tissue samples from pancreatic tumors. We performed a multicenter randomized crossover trial comparing EUS-FNB with a 20G Procore needle vs. a 22G Acquire needle. The aims were to compare the quantity of targeted tissue (pancreas) and diagnostic accuracy for the two needles. METHODS : 60 patients admitted for EUS-FNB in three endoscopy units were included. One pass was performed consecutively with each needle, in a randomized order. Histologic material was studied in a blinded manner with respect to the needle. The primary end point was mean cumulative length of tissue core biopsies per needle pass. RESULTS : Final diagnosis was adenocarcinoma (n = 46; 77 %), neuroendocrine neoplasm (n = 11; 18 %), autoimmune pancreatitis (n = 2), and mass-forming chronic pancreatitis (n = 1). The mean cumulative length of tissue core biopsies per needle pass was significantly higher with the 22G Acquire needle at 11.4 mm (95 % confidence interval [CI] 9.0 - 13.8] vs. 5.4 mm (95 %CI 3.8 - 7.0) for the 20G Procore needle (P < 0.001), as was the mean surface area (3.5 mm2 [95 %CI 2.7 - 4.3] vs. 1.8 mm2 [95 %CI 1.2 - 2.3]; P < 0.001). Diagnostic adequacy and accuracy were 100 % and 87 % with the 22G Acquire needle, and 82 % and 67 % with the 20G Procore needle (P = 0.001 and P = 0.02, respectively). CONCLUSIONS : EUS-guided biopsy of pancreatic masses with the 22G Acquire needle provided more tissue for histologic evaluation and better diagnostic accuracy than the 20G Procore needle.

Impact of needle-based confocal laser endomicroscopy on the therapeutic management of single pancreatic cystic lesions.

BACKGROUND AND AIM: The diagnosis and therapeutic management of large single pancreatic cystic lesions (PCLs) represent major issues for clinicians and essentially rely on endoscopic ultrasound fine-needle aspiration (EUS-FNA) findings. Needle-based confocal laser endomicroscopy (nCLE) has high diagnostic performance for PCLs. This study aimed to evaluate the impact of nCLE on the therapeutic management of patients with single PCLs. METHODS: Retrospective and comparative study. Five independent pancreatic disease experts from tertiary hospitals independently reviewed data from a prospective database of 206 patients with single PCL, larger than 2 cm and who underwent EUS-FNA and nCLE. Two evaluations were performed. The first one included the sequential review of clinical information, EUS report and FNA results. The second one included the same data + nCLE report. Participants had to propose a therapeutic management for each case. RESULTS: The addition of nCLE to EUS-FNA led to significant changes in therapeutic management for 28% of the patients (p < 0.001). nCLE significantly increased the interobserver agreement of 0.28 (p < 0.0001), from 0.36 (CI 95% 0.33-0.49) to 0.64 (CI 95% 0.61-0.67). nCLE improved the rates of full agreement among the five experts of 24% (p < 0.0001), from 30 to 54%. With nCLE, the surveillance rate of benign SCAs fell by 35%, from 40 (28/70) to 5% (4/76). CONCLUSION: The addition of nCLE to EUS-FNA significantly improves reliability of PCL diagnosis and could impact the therapeutic management of patients with single PCLs. ClinicalTrials.gov number, NCT01563133.

Macroscopic onsite evaluation using endoscopic ultrasound fine needle biopsy as an alternative to rapid onsite evaluation.

Background and aims This study aimed to evaluate the performance of Macroscopic On-site Evaluation (MOSE) using a novel endoscopic ultrasound (EUS) fine needle biopsy (FNB) needle (22-G Franseen-tip needle, Acquire, Boston Scientific Incorporated, Boston, Massachusetts, United States), and without using Rapid On-Site Evaluation (ROSE). Method Between May 2016 and August 2016, all consecutive patients referred to our center for EUS tissue acquisition (TA) for solid lesions underwent EUS-FNB with the 22-G Franseen-tip needle unless contra-indicated. The operator performed MOSE. If no macroscopic core was visualized, a second pass was performed. The final diagnosis was defined as unequivocal histology from EUS-TA with compatible 18 months follow-up, surgical resection, or both. We retrospectively analyzed the performance of MOSE. Results A total of 46 consecutive patients was included, and 54 solid lesions were biopsied. The endosonographer visualized core tissue in 93 % (50/54) of targets with a single pass, of which the pathologist confirmed histologic core fragments in 94 % (47/50). Four lesions required two passes, and the overall correlation between MOSE and histologic core fragments was 94 % (48/51). Diagnostic adequacy was 98 % (53/54) with one biliary target biopsied without significant material. The overall diagnostic accuracy was 94 %. Sensitivity, specificity, positive predictive value, and negative predictive value for malignancy were 92 %, 100 %, 100 %, and 81 %, respectively. No adverse events were reported. Conclusion Our study demonstrated that MOSE using the 22-G Franseen-tip needle could limit needle passes by accurately estimating histologic core fragments. It also demonstrated that high diagnostic adequacy and accuracy of > 90 % could be achieved without ROSE.

Needle-based confocal laser endomicroscopy of pancreatic cystic lesions: a prospective multicenter validation study in patients with definite diagnosis.

BACKGROUND: Needle-based confocal laser endomicroscopy (nCLE) enables observation of the inner wall of pancreatic cystic lesions (PCLs) during an endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). This study prospectively evaluated the diagnostic performance of nCLE for large, single, noncommunicating PCLs using surgical histopathology or EUS-FNA cytohistopathology as a reference diagnosis. METHODS: From April 2013 to March 2016, consecutive patients referred for EUS-FNA of indeterminate PCLs without evidence of malignancy or chronic pancreatitis were prospectively enrolled at five centers. EUS-FNA and nCLE were performed and cystic fluid was aspirated for cytohistopathological and carcinoembryonic antigen (CEA) analysis. The diagnostic performance of nCLE was assessed against the reference standard and compared with that of EUS and CEA. This study was registered on ClinicalTrials.gov (NCT01563133). RESULTS: 206 patients underwent nCLE and 78 PCLs (mean size 40 mm, range 20 - 110 mm) had reference diagnoses (53 premalignant and 25 benign PCLs). Post-procedure pancreatitis occurred in 1.3 % of the patients. nCLE was conclusive in 71 of the 78 cases (91 %). The sensitivies and specifities of nCLE for the diagnosis of serous cystadenoma, mucinous PCL, and premalignant PCL were all ≥ 0.95 (with 95 % confidence interval from 0.85 to 1.0). The AUROC was significantly larger for nCLE than for CEA or EUS. CONCLUSIONS: nCLE had excellent diagnostic performance that surpassed that of CEA and EUS for the diagnosis of large, single, noncommunicating PCLs. The nCLE procedure should be considered in patients with indeterminate PCLs to ensure a more specific diagnosis.

Can endoscopic papillectomy be curative for early ampullary adenocarcinoma of the ampulla of Vater?

BACKGROUND: The therapeutic role of endoscopic papillectomy (EP) for early ampullary cancer (AC) is still controversial. The aim of the present study was to evaluate the curative potential of EP for early AC and to identify predictors of lymph node metastases (LNMs). METHODS: We retrospectively reviewed 173 patients who were prospectively included in a database and who underwent EP between 1999 and 2013. Adenocarcinoma was present in 28 resected specimens. An additional surgery was proposed in cases of duodenal submucosal infiltration, duct ingrowth, R1 resection or lymphovascular invasion. Clinicopathological information and outcomes were collected, and predictors of LNMs were evaluated. RESULTS: Duodenal submucosal invasion was present in 16/28 cases and LNMs, in 9/28 cases. ACs of the biliopancreatic subtype were smaller (NS); 100 % had submucosal invasion, and 71 % had LNMs. Smaller tumour size, biliopancreatic subtype and submucosal invasion were significantly correlated with LNMs (p < 0.028, p < 0.028 and p < 0.014). Predictive factors of LNMs in the multivariate analysis were submucosal invasion and tumour size (OR 0.032, p < 0.023 and OR 0.711, p < 0.035). EP was curative in 100 % of cancers with R0 resection and no evidence of submucosal or lymphovascular invasion. CONCLUSION: EP may be curative for patients with AC limited to the duodenal mucosa or the sphincter of Oddi without lymphovascular invasion. Due to the presence of more invasive stages at diagnosis, EP may not be curative for ACs of the biliopancreatic subtype. The significance of tumour size is limited by other confounders, such as the histological subtype.

Endoscopic ultrasound-guided needle-based confocal laser endomicroscopy in solid pancreatic masses.

BACKGROUND AND STUDY AIMS: The differential diagnosis of solid pancreatic masses by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is currently suboptimal in centers that are not equipped with rapid on-site evaluation. Needle-based confocal laser endomicroscopy (nCLE) enables real-time in vivo microscopic imaging during endoscopy. This study aimed to describe nCLE interpretation criteria for the characterization of pancreatic masses, with histopathological correlation, and to perform the first validation of these criteria. PATIENTS AND METHODS: A total of 40 patients were evaluated by EUS-FNA combined with nCLE for the diagnosis of pancreatic masses. Final diagnosis was based on EUS-FNA histology and follow-up at 1 year. Five unblinded examiners defined nCLE criteria for adenocarcinoma, chronic pancreatitis, and neuroendocrine tumor (NET) using a set of video sequences from 14 patients with confirmed pathology (Step 1). These criteria were retrospectively validated by four independent, blinded examiners using sequences from 32 patients (Step 2). RESULTS: nCLE criteria were described for adenocarcinoma (dark cell aggregates, irregular vessels with leakages of fluorescein), chronic pancreatitis (residual regular glandular pancreatic structures), and NET (black cell aggregates surrounded by vessels and fibrotic areas). These criteria correlated with the histological features of the corresponding lesions. In the validation review, a conclusive nCLE result was obtained in 75 % of cases (96 % correct). Statistical evaluation provided promising results, with high specificity, and negative and positive predictive values for all types of pancreatic masses. CONCLUSION: Considering the low negative predictive value of EUS-FNA, nCLE could help to rule out malignancy after a previous inconclusive EUS-FNA. Larger studies are required to confirm these findings and to establish the role of nCLE in the diagnosis of pancreatic masses. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01563133).

In vivo characterization of pancreatic cystic lesions by needle-based confocal laser endomicroscopy (nCLE): proposition of a comprehensive nCLE classification confirmed by an external retrospective evaluation.

BACKGROUND AND AIMS: The differential diagnosis of solitary pancreatic cystic lesions is sometimes difficult. Needle-based confocal laser endomicroscopy (nCLE) performed during endoscopic ultrasound-fine-needle aspiration (EUS-FNA) enables real-time imaging of the internal structure of such cysts. Criteria have already been described for serous cystadenoma and intraductal papillary mucinous neoplasm (IPMN). The aims of the study were to determine new nCLE criteria for the diagnosis of pancreatic cystic lesions, to propose a comprehensive nCLE classification for the characterization of those lesions, and to carry out a first external retrospective validation . METHODS: Thirty-three patients with a lone pancreatic cystic lesion were included (CONTACT 1 study). EUS-FNA was combined with nCLE. Diagnosis was based on either pathology result (Group 1, n = 20) or an adjudication committee consensus (Group 2, n = 13). Six investigators, unblinded, studied cases from Group 1 and identified nCLE criteria for mucinous cystic neoplasm (MCN), pseudocyst (PC), and cystic neuroendocrine neoplasm (NEN). Four external reviewers assessed, blinded, the yield and interobserver agreement for the newly identified (MCN, PC) and previously described (IPMN, SC) criteria in a subset of 31 cases. RESULTS: New nCLE criteria were described for MCN (thick gray line), PC (field of bright particles), and cystic NEN (black neoplastic cells clusters with white fibrous areas). These criteria correlated with the histological features of the corresponding lesions. In the retrospective validation, a conclusive nCLE result was obtained for 74 % of the cases (87 % "true" and 13 % "false" with respect to the final diagnosis). On this limited case series, the nCLE criteria showed a trend for high diagnostic specificity (>90 % for mucinous cysts, 100 % for non-mucinous cysts). CONCLUSIONS: Based on this newly completed atlas of interpretation criteria, nCLE could facilitate the diagnosis of pancreatic cystic lesion types.

A novel approach to the diagnosis of pancreatic serous cystadenoma: needle-based confocal laser endomicroscopy.

BACKGROUND AND STUDY AIMS: The differential diagnosis of solitary pancreatic cystic lesions is frequently difficult. Needle-based confocal laser endomicroscopy (nCLE) performed during endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a new technology enabling real-time imaging of the internal structure of such cysts. The aim of this pilot study was to identify and validate new diagnostic criteria on nCLE for pancreatic cystic lesions. PATIENTS AND METHODS: A total of 31 patients with a solitary pancreatic cystic lesion of unknown diagnosis were prospectively included at three centers. EUS-FNA was combined with nCLE. The final diagnosis was based on either a stringent gold standard (surgical specimen and/or positive cytopathology) or a committee consensus. Six nonblinded investigators reviewed nCLE sequences from patients with the most stringent final diagnosis, and identified a single feature that was only present in serous cystadenoma (SCA). The findings were correlated with the pathology of archived specimens. After a training session, four blinded independent observers reviewed a separate independent video set, and the yield and interobserver agreement for the criterion were assessed. RESULTS: A superficial vascular network pattern visualized on nCLE was identified as the criterion. It corresponded on pathological specimen to a dense and subepithelial capillary vascularization only seen in SCA. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of this sign for the diagnosis of SCA were 87 %, 69 %, 100 %, 100 %, and 82 %, respectively. Interobserver agreement was substantial (κ = 0.77). CONCLUSION: This new nCLE criterion seems highly specific for the diagnosis of SCA. The visualization of this criterion could have a direct impact on the management of patients by avoiding unnecessary surgery or follow-up.Clinicaltrials.gov NCT01563133.

Multicenter validation study of pathologic response and tumor thickness at the tumor-normal liver interface as independent predictors of disease-free survival after preoperative chemotherapy and surgery for colorectal liver metastases.

BACKGROUND: To validate pathologic markers of response to preoperative chemotherapy as predictors of disease-free survival (DFS) after resection of colorectal liver metastases (CLM). METHODS: One hundred seventy-one patients who underwent resection of CLM after preoperative chemotherapy at 4 centers were studied. Pathologic response-defined as the proportion of tumor cells remaining (complete, 0%; major, <50%; minor, ≥50%) and tumor thickness at the tumor-normal liver interface (TNI) (<0.5 mm, 0.5 to <5 mm, ≥5 mm)-was assessed by a central pathology reviewer and local pathologists. RESULTS: Pathologic response was complete in 8% of patients, major in 49% of patients, and minor in 43% of patients. Tumor thickness at the TNI was <0.5 mm in 21% of patients, 0.5 to <5 mm in 56% of patients, and ≥5 mm in 23% of patients. On multivariate analyses, using either pathologic response or tumor thickness at TNI, pathologic response (P = .002, .009), tumor thickness at TNI (P = 0.015, <.001), duration of preoperative chemotherapy (P = .028, .043), number of CLM (P = .038, . 037), and margin (P = .011, .016) were associated with DFS. In a multivariate analysis using both parameters, tumor thickness at TNI (P = .004, .015), duration of preoperative chemotherapy (P = .025), number of nodules (P = .027), and margin (P = .014) were associated with DFS. Tumor size by pathology examination was the predictor of pathologic response. Predictors of tumor thickness at the TNI were tumor size and chemotherapy regimen. There was near perfect agreement for pathologic response (κ = .82) and substantial agreement (κ = .76) for tumor thickness between the central reviewer and local pathologists. CONCLUSIONS: Pathologic response and tumor thickness at the TNI are valid predictors of DFS after preoperative chemotherapy and surgery for CLM.

Impact of KRAS, BRAF and PI3KCA mutations in rectal carcinomas treated with neoadjuvant radiochemotherapy and surgery.

BACKGROUND: Conventional treatment for locally advanced rectal cancer usually combines neoadjuvant radiochemotherapy and surgery. Until recently, there have been limited predictive factors (clinical or biological) for rectal tumor response to conventional treatment. KRAS, BRAF and PIK3CA mutations are commonly found in colon cancers. In this study, we aimed to determine the mutation frequencies of KRAS, BRAF and PIK3CA and to establish whether such mutations may be used as prognostic and/or predictive factors in rectal cancer patients. METHODS: We retrospectively reviewed the clinical and biological data of 98 consecutive operated patients between May 2006 and September 2009. We focused in patients who received surgery in our center after radiochemotherapy and in which tumor samples were available. RESULTS: In the 98 patients with a rectal cancer, the median follow-up time was 28.3 months (4-74). Eight out of ninety-eight patients experienced a local recurrence (8%) and 17/98 developed distant metastasis (17%). KRAS, BRAF and PIK3CA were identified respectively in 23 (23.5%), 2 (2%) and 4 (4%) patients. As described in previous studies, mutations in KRAS and BRAF were mutually exclusive. No patient with local recurrence exhibited KRAS or PIK3CA mutation and one harbored BRAF mutation (12.5%). Of the seventeen patients with distant metastasis (17%), 5 were presenting KRAS mutation (29%), one BRAF (5%) and one PIK3CA mutation (5%). No relationship was seen between PIK3CA, KRAS or BRAF mutation and local or distant recurrences. CONCLUSION: The frequencies of KRAS, BRAF and PIK3CA mutations in our study were lower than the average frequencies reported in colorectal cancers and no significant correlation was found between local/distant recurrences and KRAS, BRAF or PIK3CA mutations. Future studies with greater number of patients, longer follow-up time and greater power to predict associations are necessary to fully understand this relationship.

Predictive factors of positive circumferential resection margin after radiochemotherapy for rectal cancer: the French randomised trial ACCORD12/0405 PRODIGE 2.

Circumferential resection margin (CRM) appears as a new powerful prognostic factor of survival after surgery for rectal cancer. We aimed to evaluate predictive factors of positive CRM following preoperative radiochemotherapy in a French trial. Patients with rectal cancer were randomised in long course preoperative radiotherapy 45 Gy plus capecitabine versus 50 Gy plus capecitabine and oxaliplatin. Mesorectal excision was performed 6 weeks after treatment. Impact of clinical, pathological and surgical variables on positive CRM (≤1 mm) were analysed by multivariate analysis. Of 565 randomised patients, CRM was recorded in 390 cases and was positive in 8% (30/390). Patients with 50 Gy plus capecitabine and oxaliplatin had a 6% rate of positive CRM while those treated by 45 Gy plus capecitabine had a 10% rate (p=0.128). Three independent predictive factors of positive CRM were identified: abdominoperineal resection (APR) (odds ratio OR=3.24; p=0.004), vascular tumour invasion (OR=2.78; p=0.026) and poor histological response (modified Dworak 0-2) (OR=9.01; p=0.003). Significant predictive factors of positive CRM are related to type of surgery, especially APR, and poor histological prognostic factors. Intensification of neoadjuvant radiochemotherapy does not seem to have a major role in this study.