Alberto Larghi

Indications, results, and clinical impact of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline

This article is part of a combined publication that expresses the current view of the European Society of Gastrointestinal Endoscopy (ESGE) about endoscopic ultrasound (EUS)-guided sampling in gastroenterology, including EUS-guided fine needle aspiration (EUS-FNA) and EUS-guided trucut biopsy (EUS-TCB), of submucosal tumors, diffuse esophageal/gastric wall thickening, pancreatic solid masses and cystic-appearing lesions, mediastinal lesions unrelated to lung or esophageal cancer, cancer of the esophagus, stomach, and rectum, lymph nodes of unknown origin, adrenal gland masses, and focal liver lesions. False-positive cytopathological results and needle tract seeding are also discussed. The present Clinical Guideline describes the results of EUS-guided sampling in the different clinical settings, considers the role of this technique in patient management, and makes recommendations on circumstances that warrant its use. A two-page executive summary of evidence statements and recommendations is provided. A separate Technical Guideline describes the general technique of EUS-guided sampling, particular techniques to maximize the diagnostic yield depending on the nature of the target lesion, and sample processing. The target readership for the Clinical Guideline mostly includes gastroenterologists, oncologists, internists, and surgeons while the Technical Guideline should be most useful to endoscopists who perform EUS-guided sampling.

Feasibility and yield of a new EUS histology needle: results from a multicenter, pooled, cohort study

BACKGROUND EUS-guided FNA is an efficacious technique for sampling intraintestinal and extraintestinal mass lesions. However, cytology has limitations to its final yield and accuracy, which may be overcome if histological specimens are provided to the pathologist. OBJECTIVE To evaluate feasibility, yield, and diagnostic accuracy of a newly developed 19-gauge, fine-needle biopsy (FNB) device. DESIGN Multicenter, pooled, cohort study. SETTING Five medical centers. PATIENTS This study involved 109 consecutive patients with 114 intraintestinal or extraintestinal mass lesions and/or peri-intestinal lymph nodes. INTERVENTION EUS-guided FNB (EUS-FNB) with a newly developed, 19-gauge, FNB device. MAIN OUTCOME MEASUREMENTS Percentage of cases in which pathologists classified the sample quality as optimal for histological evaluation and the overall diagnostic accuracy compared with a composite criterion-standard diagnosis. RESULTS We evaluated 114 lesions (mean [± standard deviation] size 35.1 ± 18.7 mm; 84 malignant [73.7%] and 30 [26.3%] benign). EUS-FNB was technically feasible in 112 lesions (98.24%). Sample quality was adequate for full histological assessment in 102 lesions (89.47%). In 98 cases (85.96%), diagnosis proved to be correct according to criterion-standard diagnosis. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy for diagnosis of malignancy were 90.2%, 100%, 100%, 78.9%, and 92.9%, respectively. LIMITATIONS Use of a surrogate criterion-standard diagnosis, including clinical follow-up when no surgical specimens were available, mainly in benign diagnoses. CONCLUSION Performing an EUS-FNB with a new 19-gauge histology needle is feasible for histopathology diagnosis of intraintestinal and extraintestinal mass lesions, offering the possibility of obtaining a core sample for histological evaluation in the majority of cases, with an overall diagnostic accuracy of over 85%.

Learning, techniques, and complications of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Technical Guideline

This article is the second of a two-part publication that expresses the current view of the European Society of Gastrointestinal Endoscopy (ESGE) about endoscopic ultrasound (EUS)-guided sampling, including EUS-guided fine needle aspiration (EUS-FNA) and EUS-guided Trucut biopsy. The first part (the Clinical Guideline) focused on the results obtained with EUS-guided sampling, and the role of this technique in patient management, and made recommendations on circumstances that warrant its use. The current Technical Guideline discusses issues related to learning, techniques, and complications of EUS-guided sampling, and to processing of specimens. Technical issues related to maximizing the diagnostic yield (e.g., rapid on-site cytopathological evaluation, needle diameter, microcore isolation for histopathological examination, and adequate number of needle passes) are discussed and recommendations are made for various settings, including solid and cystic pancreatic lesions, submucosal tumors, and lymph nodes. The target readership for the Clinical Guideline mostly includes gastroenterologists, oncologists, internists, and surgeons while the Technical Guideline should be most useful to endoscopists who perform EUS-guided sampling. A two-page executive summary of evidence statements and recommendations is provided.

Ki-67 grading of nonfunctioning pancreatic neuroendocrine tumors on histologic samples obtained by EUS-guided fine-needle tissue acquisition: a prospective study

BACKGROUND Preoperative determination of Ki-67 expression, an important prognostic factor for grading nonfunctioning pancreatic endocrine tumors (NF-PETs), remains an important clinical challenge. OBJECTIVE To prospectively evaluate the feasibility, yield, and clinical impact of EUS-guided fine-needle tissue acquisition (EUS-FNTA) with a large-gauge needle to obtain tissue samples for histologic diagnosis and Ki-67 analysis in patients with suspected NF-PETs. DESIGN Prospective cohort study. SETTING Tertiary-care academic medical center. PATIENTS Consecutive patients with a single pancreatic lesion suspicious for NF-PET on imaging. INTERVENTION EUS-FNTA with a 19-gauge needle. MAIN OUTCOME MEASUREMENTS Feasibility and yield of EUS-FNTA for diagnosis and Ki-67 expression determination. RESULTS Thirty patients (mean [± SD] age 55.7 ± 14.9 years), with a mean (± SD) lesion size of 16.9 ± 6.1 mm were enrolled. EUS-FNTA was successfully performed without complications in all patients, with a mean (± SD) of 2.7 ± 0.5 passes per patient. Adequate samples for histologic examination were obtained in 28 of the 30 patients (93.3%). Ki-67 determination could be performed in 26 of these 28 patients (92.9%, 86.6% overall), 12 of whom underwent surgical resection. Preoperative and postoperative Ki-67 proliferation indexes were concordant in 10 patients (83.3%), whereas 2 patients were upstaged from G1 to G2 or downstaged from G2 to G1, respectively. LIMITATIONS Single center study with a single operator. CONCLUSION In patients with suspected nonfunctioning low-grade to intermediate-grade pancreatic neuroendocrine tumors (p-NETs), retrieval of tissue specimens with EUS-FNTA by using a 19-gauge needle is safe, feasible, and highly accurate for both diagnosis and Ki-67 determination. A Ki-67 proliferative index acquired through this technique might be of great help for further therapeutic decisions.

Management of Hilar Biliary Strictures

Biliary strictures at the liver hilum are caused by a heterogeneous group of benign and malignant conditions. In the absence of a clear-cut benign etiology, i.e. bile duct damage during surgery, hilar biliary strictures remain a diagnostic and therapeutic challenge for which a multidisciplinary approach is often necessary. A definitive diagnosis can be achieved in only 40–60% of the patients, while in all the other cases strictures are treated as though they are malignant until surgical pathology determines otherwise. Surgical resection is the only treatment that prolongs survival in patients with malignant strictures. Because these tumors frequently extend longitudinally via the hepatic ducts into the liver parenchyma, partial hepatic resection has been gradually added to biliary resection to ensure tumor-free surgical margins. For unresectable cases, endoscopic stenting of biliary obstruction is considered the preferred palliation modality to relieve pruritus, cholangitis, pain and jaundice, while the percutaneous approach has been reserved for cases of failure. Other modalities of treatment such as radiotherapy, chemotherapy, and photodynamic therapy currently remain investigational. For benign post surgical hilar strictures, surgical repair can be difficult and requires specific skills and experience. As an alternative, a multi-stent technique with endoscopic placement of an increasing number of stents over time until complete resolution of the stricture has been proposed.

Clinical Pharmacokinetics of Therapeutic Bile Acids

SummaryThe pharmacokinetics of chenodeoxycholic and ursodeoxycholic acids are reviewed in this article. Chenodeoxycholic acid is well absorbed by the intestine, whereas the absorption of ursodeoxycholic acid is incomplete. They are extracted efficiently by the liver, conjugated with glycerine and taurine, secreted in bile, and then undergo enterohepatic circulation with the endogenous bile acids. Therapeutic bile acids are metabolised by intestinal bacteria to lithocholic acid which is mainly excreted with faeces.Since the large majority of bile acid is confined within the enterohepatic circulation (resulting in low serum concentrations) their volume of distribution is relatively high. Despite the high hepatic extraction, the clearance of therapeutic bile acids is relatively low because of the highly efficient enterohepatic recirculation. Elimination of therapeutic bile acids mainly occurs in the faeces either unmodified or after biotransformation.At present the main clinical indication for therapeutic bile acids is ursodeoxycholic acid treatment for chronic cholestatic liver disease. In these patients, urso-deoxycholic acid is efficiently absorbed but its hepatic uptake and biliary secretion are impaired, thus leading to reduced biliary enrichment and high serum concentrations of this exogenous bile acid. In patients with cystic fibrosis-associated liver disease, bile acid malabsorption also occurs, thus indicating the need for higher dosages.The volume of distribution and clearance of ursodeoxycholic acid reduced in the presence of liver disease, Also in this case, elimination mainly occurs with the faeces but, in the presence of severe cholestasis, renal clearance may become relevant. Sulphation or conjugation with glucose and N-acetylglucosamine facilitate urinary excretion.

Combined endobronchial and esophageal endosonography for the diagnosis and staging of lung cancer: European Society of Gastrointestinal Endoscopy (ESGE) Guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS)

This is an official guideline of the European Society of Gastrointestinal Endoscopy (ESGE), produced in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS). It addresses the benefit and burden associated with combined endobronchial and esophageal mediastinal nodal staging of lung cancer. The Scottish Intercollegiate Guidelines Network (SIGN) approach was adopted to define the strength of recommendations and the quality of evidence.The article has been co-published with permission in the European Journal of Cardio-Thoracic Surgery and the European Respiratory Journal. Recommendations 1 For mediastinal nodal staging in patients with suspected or proven non-small-cell lung cancer (NSCLC) with abnormal mediastinal and/or hilar nodes at computed tomography (CT) and/or positron emission tomography (PET), endosonography is recommended over surgical staging as the initial procedure (Recommendation grade A). The combination of endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic (esophageal) ultrasound with fine needle aspiration, with use of a gastrointestinal (EUS-FNA) or EBUS (EUS-B-FNA) scope, is preferred over either test alone (Recommendation grade C). If the combination of EBUS and EUS-(B) is not available, we suggest that EBUS alone is acceptable (Recommendation grade C).Subsequent surgical staging is recommended, when endosonography does not show malignant nodal involvement (Recommendation grade B). 2 For mediastinal nodal staging in patients with suspected or proven non-small-cell peripheral lung cancer without mediastinal involvement at CT or CT-PET, we suggest that EBUS-TBNA and/or EUS-(B)-FNA should be performed before therapy, provided that one or more of the following conditions is present: (i) enlarged or fluorodeoxyglucose (FDG)-PET-avid ipsilateral hilar nodes; (ii) primary tumor without FDG uptake; (iii) tumor size ≥ 3 cm (Fig. 3a - c) (Recommendation grade C). If endosonography does not show malignant nodal involvement, we suggest that mediastinoscopy is considered, especially in suspected N1 disease (Recommendation grade C).If PET is not available and CT does not reveal enlarged hilar or mediastinal lymph nodes, we suggest performance of EBUS-TBNA and/or EUS-(B)-FNA and/or surgical staging (Recommendation grade C). 3 In patients with suspected or proven < 3 cm peripheral NSCLC with normal mediastinal and hilar nodes at CT and/or PET, we suggest initiation of therapy without further mediastinal staging (Recommendation grade C). 4 For mediastinal staging in patients with centrally located suspected or proven NSCLC without mediastinal or hilar involvement at CT and/or CT-PET, we suggest performance of EBUS-TBNA, with or without EUS-(B)-FNA, in preference to surgical staging (Fig. 4) (Recommendation grade D). If endosonography does not show malignant nodal involvement, mediastinoscopy may be considered (Recommendation grade D). 5 For mediastinal nodal restaging following neoadjuvant therapy, EBUS-TBNA and/or EUS-(B)-FNA is suggested for detection of persistent nodal disease, but, if this is negative, subsequent surgical staging is indicated (Recommendation grade C). 6 A complete assessment of mediastinal and hilar nodal stations, and sampling of at least three different mediastinal nodal stations (4 R, 4 L, 7) (Fig. 1, Fig. 5) is suggested in patients with NSCLC and an abnormal mediastinum by CT or CT-PET (Recommendation grade D). 7 For diagnostic purposes, in patients with a centrally located lung tumor that is not visible at conventional bronchoscopy, endosonography is suggested, provided the tumor is located immediately adjacent to the larger airways (EBUS) or esophagus (EUS-(B)) (Recommendation grade D). 8 In patients with a left adrenal gland suspected for distant metastasis we suggest performance of endoscopic ultrasound fine needle aspiration (EUS-FNA) (Recommendation grade C), while the use of EUS-B with a transgastric approach is at present experimental (Recommendation grade D). 9 For optimal endosonographic staging of lung cancer, we suggest that individual endoscopists should be trained in both EBUS and EUS-B in order to perform complete endoscopic staging in one session (Recommendation grade D). 10 We suggest that new trainees in endosonography should follow a structured training curriculum consisting of simulation-based training followed by supervised practice on patients (Recommendation grade D). 11 We suggest that competency in EBUS-TBNA and EUS-(B)-FNA for staging lung cancer be assessed using available validated assessment tools (Recommendation Grade D).

Risk factors for intraductal papillary mucinous neoplasm (ipmn) of the pancreas: A multicentre case-control study

OBJECTIVES:To investigate environmental, personal, and hereditary risk factors associated with the occurrence of intraductal papillary mucinous neoplasms of the pancreas (IPMNs).METHODS:Multicentre case–control study. Risk factors were identified from a questionnaire collecting data on family and medical history, and environmental factors. Cases were prevalent IPMNs seen at the participating units within an 18-month timeframe. Matched controls were enrolled alongside patients seen at outpatient clinics.RESULTS:Three-hundred and ninety patients with IPMN and 390 matched controls (166 males, mean age 65 in each group) were enrolled. Of the IPMNs, 310 had branch-duct involvement and 80 main-duct involvement. The only cancer with a 1st degree family history significantly higher in IPMN was pancreatic ductal adenocarcinoma (PDAC) (5.4% vs. 1.5%). Previous history of diabetes (13.6% vs. 7.5%), chronic pancreatitis (CP) (3.1% vs. 0.3%), peptic ulcer (7.2% vs. 4.3%), and insulin use (4.9% vs. 1.1%) were all more frequent with IPMNs. Logistic regression multivariate analysis revealed that history of diabetes (odds ratio (OR): 1.79, confidence interval (CI) 95%: 1.08–2.98), CP (OR: 10.10, CI 95%: 1.30–78.32), and family histories of PDAC (OR: 2.94, CI 95%: 1.17–7.39) were all independent risk factors. However, when analysis was restricted to diabetics who had taken insulin, risk of IPMN became stronger (OR: 6.03, CI 95%: 1.74–20.84). The association with all these risk factors seemed stronger for the subgroup with main duct involvement.CONCLUSIONS:A previous history of diabetes, especially with insulin use, CP, and family history of PDAC are all relevant risk factors for the development of IPMN. These results suggest an overlap between certain risk factors for PDAC and IPMN.

EUS-guided gall bladder drainage with a lumen-apposing metal stent: a prospective long-term evaluation

Endoscopic ultrasound-guided gall bladder drainage (EUS-GBD) has been shown to be comparable with percutaneous gall bladder drainage (PTGBD) in terms of technical feasibility and clinical efficacy for the treatment of acute cholecystitis in high-risk surgical patients.1 However, a potential serious complication of this technique is air or bile leakage into the peritoneal cavity, since insertion of a drain or plastic stent requires a fistula tract with a diameter larger than the diameter of the inserted drain or stent. Therefore, a specifically designed lumen-apposing metal stents (LAMSs) has been developed for transenteric drainage and successfully tested in animal models.2 ,3 Preliminary clinical experience with LAMSs for drainage of peri-pancreatic fluid collections (PFCs) appears to be consistent with anchoring features tested in animal models.4–6 However, reports on the use of LAMSs for gall bladder drainage are limited to case reports and small case series without long-term follow-up.3 ,5 ,7–12 We performed a multicentre, prospective study to determine the feasibility and safety of the use of LAMS for EUS-GBD in high-risk surgical patients with acute cholecystitis. A total of 30 patients were included. Technical success was achieved in 27 of 30 patients (90%) (figure 1) and clinical success in 26 of 27 patients (96%). Two of 27 patients (7%) developed recurrent cholecystitis due to LAMS obstruction. Successful LAMS removal was performed in 15 of 30 patients (50%) after a mean of 91 days (SD±24 days). In 15 patients (50%), no LAMS removal was performed because of death (n=5), significant tissue overgrowth (n=2) or other causes (n=8). Mean follow-up was 298 days (SD±82 days) for all patients and 364 days (SD±82 days) for the patients alive at the end of the study. A total of 15 serious adverse events (SAEs) (50%) were …

The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies

BACKGROUND Differential diagnosis of pancreatic solid masses with EUS-guided FNA (EUS-FNA) is still challenging in about 15% of cases. Mutation of the K-ras gene is present in over 75% of pancreatic adenocarcinomas (PADC). OBJECTIVE To assess the accuracy of K-ras gene mutation analysis for diagnosing PADC. DESIGN We systematically searched the electronic databases for relevant studies published. Data from selected studies underwent meta-analysis by use of a bivariate model providing a pooled value for sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve. SETTING Meta-analysis of 8 prospective studies. PATIENTS Total of 931 patients undergoing EUS-FNA for diagnosis of pancreatic solid masses. INTERVENTION K-ras mutation analysis. MAIN OUTCOME MEASUREMENTS Diagnostic accuracy of K-ras mutation analysis and of combined diagnostic strategy by using EUS-FNA and K-ras mutation analysis in the diagnosis of PADC. RESULTS The pooled sensitivity of EUS-FNA for the differential diagnosis of PADC was 80.6%, and the specificity was 97%. Estimated sensitivity and specificity were 76.8% and 93.3% for K-ras gene analysis, respectively, and 88.7% and 92% for combined EUS-FNA plus K-ras mutation analysis. Overall, K-ras mutation testing applied to cases that were inconclusive by EUS-FNA reduced the false-negative rate by 55.6%, with a false-positive rate of 10.7%. Not repeating EUS-FNA in cases in which mutation testing of the K-ras gene is inconclusive would reduce the repeat-biopsy rate from 12.5% to 6.8%. LIMITATIONS Small number of studies and between-study heterogeneity. CONCLUSION K-ras mutation analysis can be useful in the diagnostic work-up of pancreatic masses, in particular when tissue obtained by EUS-FNA is insufficient, and the diagnosis inconclusive.