Therapeutic Challenges for Gastric Neuroendocrine Neoplasms: Take It or Leave It?

Background and Objectives: Gastric neuroendocrine neoplasms (gNENs) represent rare but increasingly recognized tumors. They are distinguished into three main clinical types (type-1, type-2, and type-3) according to gastrin level and at histological evaluation in well-differentiated G1, G2, or G3 lesions, as well as poorly-differentiated lesions. Small type-1 and type-2 neoplasms with low proliferation indices demonstrated excellent survival without progression during an extended follow-up period, and for these reasons, active endoscopic observation or endoscopic resection are feasible options. On the other hand, surgery is the treatment of choice for more aggressive type-3, G3, or infiltrating neoplasms. The present study aims to comprehensively review and compare the available therapeutic strategies for gNENs. Materials and Methods: A computerized literature search was performed using relevant keywords to identify all of the pertinent articles with particular attention to gNEN endoscopic treatment. Results: In recent years, different endoscopic resective techniques (such as endoscopic mucosal dissection, modified endoscopic mucosal resection, and endoscopic full-thickness resection) have been developed, showing a high rate of complete resection for advanced and more aggressive lesions. Conclusions: Overall, gNENs represent a heterogeneous group of lesions with varying behavior which require personalized management. The non-operative approach for small type-1 gNENs seems to be feasible and should be promoted. A step-up approach with minimally invasive endoscopic therapies might be proposed, particularly for type-1 gNEN. On the other hand, it is important to recognize the negative prognostic factors in order to identify those rare cases requiring more aggressive approaches. A possible therapeutic algorithm for localized gNEN management is provided.

Impact of Indocyanine Green Fluorescence Imaging on Lymphadenectomy Quality During Laparoscopic Distal Gastrectomy for Gastric Cancer (Greeneye): An Adaptative, Phase 2, Clinical Trial.

BACKGROUND: Indocyanine green (ICG)-guided lymphadenectomy using near-infrared visualization (NIR) may increase nodal yield during gastrectomy. The purpose of this study was to evaluate the clinical benefit of NIR visualization on the quality of D2 lymphadenectomy during laparoscopic distal gastrectomy. METHODS: This single-arm, open-label, Simon's two-stage, adaptive, phase 2 trial included patients who underwent laparoscopic distal gastrectomy for gastric adenocarcinoma. Endoscopic peritumoral injection of ICG was performed 24 ± 6 h before surgery. Intraoperatively, after standard D2 lymphadenectomy and specimen extraction, NIR was used for eventual completion lymphadenectomy. The primary endpoint was clinical benefit of NIR (i.e., at least one additional harvested station containing lymph nodes, with negative points for every harvested station with no lymph nodes at final pathology). RESULTS: We enrolled 18 patients (61% female, median age 69 years). With NIR, an extra 23 stations were harvested: 9 contained no lymph nodes, 12 contained nonmetastatic lymph nodes, and 2 contained metastatic lymph nodes. The most commonly visualized station with NIR were station 6 (8 patients) and 1 (4 patients). The total number of harvested nodes per patient was 32 (interquartile range [IQR] 26-41), with a median of 1 (IQR 0-1) additional lymph node after NIR. Overall, seven (39%) patients had a clinical benefit from NIR, of which two (11%) had one metastatic lymph node harvested with NIR. CONCLUSIONS: NIR visualization improves the quality of D2 lymphadenectomy in distal gastrectomy for gastric cancer. Considering the limited improve in the number of harvested lymph nodes, its real oncological benefit is still questionable.

Effectiveness of double-balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (DBE-ERCP): A multicenter real-world study.

BACKGROUND AND AIMS: To investigate the effectiveness of double-balloon enteroscope-assisted retrograde cholangiopancreatography (DBE-ERCP) in patients with gastrointestinal surgically altered anatomy (SAA). METHODS: From May 2013 to October 2021, all consecutive patients undergoing DBE-ERCP in three gastroenterological referral centers in Northern Italy were enrolled in the study. Patients were assessed regarding their medical history, previous surgery, time from previous surgery to the DBE-ERCP procedure, and the success or failure of DBE-ERCP. RESULTS: Fifty-three patients (60% men, median age 65 (23-89) years) undergoing 67 DBE-ERCP procedures (1-3 DBE-ERCP per patient) were enrolled. Reasons for SAA included orthotopic liver transplantation (23%), ulcers (15%), malignancies (43%), difficult cholecystectomy (17%), and other causes (2%). Types of surgery included Roux-en-Y biliodigestive anastomosis (45%), Roux-en-Y gastrectomy (32%), pancreaticoduodenectomy (17%), and Billroth II gastrectomy (6%). The overall DBE-ERCP success rate was 86%. The type of surgery, indications, and the length of time between previous surgery and DBE-ERCP were not statistically associated with DBE-ERCP success. The DBE-ERCP success rate increased from 2018 to 2021. CONCLUSIONS: DBE-ERCP is a successful procedure in challenging patients with SAA. The improvement in results over time indicates the necessity of adequate training and of centralizing patients in referral centers.

Flavonoid Intake in Relation to Colorectal Cancer Risk and Blood Bacterial DNA.

Flavonoids have been inversely associated to colorectal cancer (CRC) and are plausible intermediaries for the relation among gut microbiome, intestinal permeability and CRC. We analyzed the relation of flavonoid intake with CRC and blood bacterial DNA. We conducted a case-control study in Italy involving 100 incident CRC cases and 200 controls. A valid and reproducible food-frequency questionnaire was used to assess dietary habits and to estimate six flavonoid subclass intakes. We applied qPCR and 16S rRNA gene profiling to assess blood bacterial DNA. We used multiple logistic regression to derive odds ratios (ORs) of CRC and Mann-Whitney and chi--square tests to evaluate abundance and prevalence of operational taxonomic units (OTUs) according to flavonoid intakes. Inverse associations with CRC were found for anthocyanidins (OR for the highest versus the lowest tertile = 0.24, 95% confidence interval, CI = 0.11-0.52) and flavanones (OR = 0.18, 95% CI = 0.08-0.42). We found different abundance and prevalence according to anthocyanidin and flavanone intake for OTUs referring to Oligoflexales order, Diplorickettsiaceae family, Staphylococcus, Brevundimonas, Pelomonas and Escherischia-Shigella genera, and Flavobacterium and Legionella species. The study provides evidence to a protective effect of dietary anthocyanidins and flavanones on CRC and suggests an influence of flavonoids on blood bacterial DNA, possibly through intestinal permeability changes.

Digital single-operator cholangioscopy in diagnostic and therapeutic bilio-pancreatic diseases: A prospective, multicenter study.

BACKGROUND AND AIM: Digital single-operator cholangioscopy (D-SOC) is an endoscopic procedure that is increasingly used for the management of bilio-pancreatic diseases. We aimed to investigate the efficacy and safety of D-SOC for diagnostic and therapeutic indications. METHODS: This is a multicenter, prospective study(January 2016-June 2019) across eighteen tertiary centers. The primary outcome was procedural success of D-SOC. Secondary outcomes were: D-SOC visual assessment and diagnostic yield of SpyBite biopsy in cases of biliary strictures, stone clearance rate in cases of difficult biliary stones, rate of adverse events(AEs) for all indications. RESULTS: D-SOC was performed in 369 patients (201(54,5%) diagnostic and 168(45,5%)therapeutic). Overall, procedural success rate was achieved in 360(97,6%) patients. The sensitivity, specificity, PPV, NPV and accuracy in biliary strictures were: 88,5%, 77,3%, 83,3%, 84,1% and 83,6% for D-SOC visual impression; 80,2%, 92,6%, 95,1%, 72,5% and 84,7% for the SpyBite biopsy, respectively. For difficult biliary stones, complete duct clearance was obtained in 92,1% patients (82,1% in a single session). Overall, AEs occurred in 37(10%) cases.The grade of AEs was mild or moderate for all cases, except one which was fatal. CONCLUSION: D-SOC is effective for diagnostic and therapeutic indications.Most of the AEs were minor and managed conservatively, even though a fatal event has happened that is not negligible and should be considered before using D-SOC.

Migration rate using fully covered metal stent in anastomotic strictures after liver transplantation: Results from the BASALT study group.

BACKGROUND AND STUDY AIM: The traditional endoscopic therapy of anastomotic strictures (AS) after orthotopic liver transplantation (OLT) is multiple ERCPs with the insertion of an increasing number of plastic stents side-by-side. Fully covered self-expanding metal stents (cSEMS) could be a valuable option to decrease the number of procedures needed or non-responders to plastic stents. This study aims to retrospectively analyse the results of AS endoscopic treatment by cSEMS and to identify any factors associated with its success. PATIENTS AND METHODS: Ninety-one patients (mean age 55.9 ± 7.6 SD; 73 males) from nine Italian transplantation centres, had a cSEMS positioned for post-OLT-AS between 2007 and 2017. Forty-nine (54%) patients were treated with cSEMS as a second-line treatment. RESULTS: All the procedures were successfully performed without immediate complications. After ERCP, adverse events occurred in 11% of cases (2 moderate pancreatitis and 8 cholangitis). In 49 patients (54%), cSEMSs migrated. After cSEMS removal, 46 patients (51%) needed further endoscopic (45 patients) or radiological (1 patient) treatments to solve the AS. Lastly, seven patients underwent surgery. Multivariable stepwise logistic regression showed that cSEMS migration was the only factor associated with further treatments (OR 2.6, 95% CI 1.0-6.6; p value 0.03); cSEMS implantation before 12 months from OLT was associated with stent migration (OR 5.2, 95% CI 1.7-16.0; p value 0.004). CONCLUSIONS: cSEMS appears to be a safe tool to treat AS. cSEMS migration is the main limitation to its routinary implantation and needs to be prevented, probably with the use of new generation anti-migration stents.

The role of endoscopy in eosinophilic esophagitis: from diagnosis to therapy.

Endoscopy plays an important role in the management of eosinophilic esophagitis (EoE), since it is involved in the diagnosis, follow-up and treatment of this condition. In patients presenting with food impaction, dysphagia and other symptoms of suspected EoE, esophago-gastric-duodenoscopy (EGD) with multiple esophageal biopsies should be performed to confirm or rule out the diagnosis of EoE. The EREFS system, a validated instrument for assessment of the endoscopically-identified esophageal features in EoE (edema, rings, exudates, longitudinal furrows and strictures), is currently used in the clinical practice for the evaluation of the macroscopic aspects of esophageal mucosa during EGD. Multiple esophageal biopsies are mandatory to further confirm EoE diagnosis and subsequent response to treatment, since symptoms reported by patients do not always correlate with histological activity, and considering the low sensitivity of endoscopic assessment; a cut-off of ≥15 eosinophils in at least one high power field is the density threshold considered the standard for diagnosis (sensitivity 100%, specificity 96%). Other histological features, included in the EoE histologic scoring system (EoEHSS), are supportive for the diagnosis and for the assessment of inflammatory activity during follow-up. Esophageal dilation, performed either with Savary dilators/bougie or hydrostatic balloon, is an effective and safe treatment in both adult and pediatric EoE patients with fibrostenotic features, mainly in association with other therapeutic strategies which can control eosinophilic inflammation.

Blood Bacterial DNA Load and Profiling Differ in Colorectal Cancer Patients Compared to Tumor-Free Controls.

Inflammation and immunity are linked to intestinal adenoma (IA) and colorectal cancer (CRC) development. The gut microbiota is associated with CRC risk. Epithelial barrier dysfunction can occur, possibly leading to increased intestinal permeability in CRC patients. We conducted a case-control study including 100 incident histologically confirmed CRC cases, and 100 IA and 100 healthy subjects, matched to cases by center, sex and age. We performed 16S rRNA gene analysis of blood and applied conditional logistic regression. Further analyses were based on negative binomial distribution normalization and Random Forest algorithm. We found an overrepresentation of blood 16S rRNA gene copies in colon cancer as compared to tumor-free controls. For high levels of gene copies, community diversity was higher in colon cancer cases than controls. Bacterial taxa and operational taxonomic unit abundances were different between groups and were able to predict CRC with an accuracy of 0.70. Our data support the hypothesis of a higher passage of bacteria from gastrointestinal tract to bloodstream in colon cancer. This result can be applied on non-invasive diagnostic tests for colon cancer control.

Unusual Mesenchymal Tumors of the Lower Gastrointestinal Tract: When You Hear Hoofbeats in the Night, Do Not Forget the Zebras.

INTRODUCTION: Little information about clinical presentation of mesenchymal tumors of the lower gastrointestinal (GI) tract due to their extreme heterogeneity is available for clinical management. Usually, small solitary asymptomatic polyps are accidently found during a screening colonoscopy performed for hematochezia, abdominal pain, constipation, diarrhea, and bowel obstruction. In this case series, we illustrate our experience with mesenchymal tumors of the lower GI tract, which are a group of unusual and quite challenging lesions. CASE PRESENTATION: We retrospectively collected mesenchymal tumors of the lower GI tract in our institution (Fondazione IRCSS Ca' Granda - Ospedale Maggiore Policlinico di Milano) during the last 10 years. We reviewed the histological slides, and, when necessary, we performed immunohistochemical analyses to better characterize the tumors. A total of 99 cases were identified: 45 GISTs, 42 lipomas, 4 leiomyomas, 3 Kaposi sarcomas, 1 schwannoma, 1 ganglioneuroma, 1 hemangioma, 1 inflammatory fibroid polyp, and 1 challenging case of spindle cell melanoma. We focused on the most rare entities excluding therefore all GISTs and lipomas from re-evaluation. CONCLUSION: Mesenchymal tumors of the lower GI tract represent a highly heterogeneous group of lesions encompassing GISTs, lipomas, smooth muscle tumors (leiomyoma and leiomyosarcoma), GI schwannomas, inflammatory fibroid polyps, solitary fibrous tumors, and other unusual spindle cell tumors. Immunohistochemistry and, in selected cases, molecular biology remain a useful tool which, in addition to a meticulous study of the morphology, helps the pathologist in the tangled jungle of differential diagnosis.

A prospective study on quality in endoscopic retrograde cholangiopancreatography (ERCP): trend in Italy from the REQUEST study.

Background and study aims Endoscopic retrograde cholangiopancreatography (ERCP) is a complex procedure with a relatively high rate of adverse events. Data on training of operators and fulfillment of quality indicators in Italy are scarce. The goal of this study was to assess the overall quality of ERCP in Italy compared to international standards. Patients and methods This was a prospective, observational study from different Italian centers performing ERCP. Operators answered a questionnaire, then recorded data on ERCPs over a 1-to 3-month period. Results Nineteen Italian centers participated in the study. The most common concern of operators about training was the lack of structured programs. Seven/19 centers routinely used conscious sedation for ERCP. Forty-one experienced operators and 21 trainees performed 766 ERCPs: a successful deep biliary cannulation in native-papilla patients was achieved in 95.1 % of cases; the post-ERCP pancreatitis (PEP) rate was 5.4 % in native-papilla patients; cholangitis rate was 1.0 %; bleeding and perforation occurred in 2.7 % and 0.4 % of the patients, respectively. Conclusions This study revealed that, overall, ERCP is performed in the participating Italian centers meeting good quality standards, but structured training and sedation practice are still subpar. The bleeding and perforation rate slightly exceeded the American Society of Gastrointestinal Endoscopy indicator targets but they are comparable to the reported rates from other international surveys.

Percutaneous Transhepatic Electrohydraulic Lithotripsy for the Treatment of Difficult Bile Stones.

OBJECTIVES: To evaluate the efficacy and safety of percutaneous transhepatic lithotripsy (PTL) using an electro-hydraulic (EH) system for difficult bile stones. METHODS: We retrospectively evaluated two patients with recurrent cholangitis, jaundice and fever for the presence of difficult bile stones, inaccessible by an endoscopic approach, treated with PTL. Both procedures were conducted using the same protocol, with two different accesses. The treatments were performed using a 10 Fr flexible choledoscopy SpyGlass DSTM for visualization and an EH system for lithotripsy. RESULTS: Technical success, clinical success and complications were evaluated. The two procedures were successfully concluded in both patients without any residual stones in the biliary tree. For both patients, a short follow-up period of six months was available, during which they remained asymptomatic. Neither major nor minor complications were registered. CONCLUSION: PTL was determined to be an effective and safe technique. This procedure allows a direct visualization of the stone, reducing fluoroscopy time and permitting a less invasive and less traumatic method for the percutaneous management of difficult bile stones. Advances in knowledge: The direct visualization, the high quality of the digital view, the adequate length of the device and the less traumatic approach of EH systems represent advantages compared with other available technologies.

Cost analysis of a long-term randomized controlled study in biliary duct-to-duct anastomotic stricture after liver transplantation.

Multiple plastic stent (MPS) for biliary anastomotic stricture (AS) after liver transplantation requires multiple procedures with consequent costs. To compare the success, adverse events and treatment-related costs of fully covered self-expandable metal stents (FCSEMS) versus MPS. Thirty liver transplant (LT) patients with clinically relevant naïve AS were prospectively randomized to FCSEMS or MPS, with stent numbers increased at 3-month intervals. Treatment costs per patient were calculated for endoscopic retrograde cholangiopancreatography (including all devices and stents) and overall hospital stay. Radiological success was achieved in 73% of FCSEMS (median indwelling period of 6 mos) and 93% of MPS patients (P = NS) (median period of 11 mos). AS recurrence occurred in 36% of FCSEMS and 7% of MPS patients (P = NS), and AS re-treatment was needed in 53% and 13% (P < 0.01), respectively, during follow-up of 60 (34-80) months. Stents migrated after 29% and 2.6% of FCSEMS and MPS procedures, respectively (P < 0.01). Including re-treatments, long-term clinical success was achieved in 28/30 (93%) patients. Overall treatment-related costs were similar between groups. In the subgroup of LT patients in clinical remission after first-line treatment, treatment costs were 41% lower per FCSEMS patient compared with MPS patients. FCSEMS did not perform better than MPS. FCSEMS migration increased the rate of re-treatment and costs.

Dilation assisted stone extraction for complex biliary lithiasis: Technical aspects and practical principles.

Common bile duct stones are frequently diagnosed worldwide and are one of the main indications for endoscopic retrograde cholangio-pancreatography. Endoscopic sphincterotomy (EST) has been used for the removal of bile duct stones for the past 40 years, providing a wide opening to allow extraction. Up to 15% of patients present with complicated choledocholithiasis. In this context, additional therapeutic approaches have been proposed such as endoscopic mechanical lithotripsy, intraductal or extracorporeal lithotripsy, or endoscopic papillary large balloon dilation (EPLBD). EPLBD combined with EST was introduced in 2003 to facilitate the passage of large or multiple bile duct stones using a balloon greater than 12 mm in diameter. EPLBD without EST was introduced as a simplified technique in 2009. Dilation-assisted stone extraction (DASE) is the combination of two techniques: EPLBD and sub-maximal EST. Several studies have reported this technique as safe and effective in patients with large bile duct stones, without any increased risk of adverse events such as pancreatitis, bleeding, or perforation. Nevertheless, it is difficult to analyze the outcomes of DASE because there are no standard techniques and definitions between studies. The purpose of this paper is to provide technical guidance and specific information about the main issues regarding DASE, based on current literature and daily clinical experience in biliary referral centers.

An Unprecedented Challenge: The North Italian Gastroenterologist Response to COVID-19.

BACKGROUND: COVID-19 pandemic has profoundly changed the activities and daily clinical scenarios, subverting organizational requirements of our Gastroenterology Units. AIM: to evaluate the clinical needs and outcomes of the gastroenterological ward metamorphosis during the COVID-19 outbreaks in a high incidence scenario. METHODS: we compared the pertinence of gastroenterological hospitalization, modality of access, mortality rate, days of hospitalization, diagnostic and interventional procedures, age, Charlson comorbidity index, and frequency of SARS-CoV-2 infections in patients and healthcare personnel across the first and the second COVID-19 outbreaks in a COVID-free gastroenterological ward in the metropolitan area of Milan, that was hit first and hardest during the first COVID-19 outbreak since March 2020. RESULTS: pertinence of gastroenterological hospitalization decreased both during the first and, to a lesser degree, the second SARS-CoV2 waves as compared to the pre-COVID era (43.6, 85.4, and 96.2%, respectively), as occurred to the admissions from domicile, while age, comorbidities, length of stay and mortality increased. Endoscopic and interventional radiology procedures declined only during the first wave. Hospitalized patients resulted positive to a SARS-CoV-2 nasopharyngeal swab in 10.2% of cases during the first COVID-19 outbreak after a median of 7 days since admission (range 1-15 days) and only 1 out of 318 patients during the second wave (6 days after admission). During the first wave, 19.5% of healthcare workers tested positive for SARS-CoV-2. CONCLUSIONS: a sudden metamorphosis of the gastroenterological ward was observed during the first COVID-19 outbreak with a marked reduction in the gastroenterological pertinence at the admission, together with an increase in patients' age and multidisciplinary complexity, hospital stays, and mortality, and a substantial risk of developing a SARS-CoV-2 test positivity. This lesson paved the way for the efficiency of hospital safety protocols and admission management, which contributed to the improved outcomes recorded during the second COVID-19 wave.

Infection Control Practices and Outcomes of Endoscopy Units in the Lombardy Region of Italy: A Survey From the Italian Society of Digestive Endoscopy During COVID-19 Spread.

GOALS: The present survey from the Italian Society of Digestive Endoscopy (SIED-Società Italiana di Endoscopia Digestiva) was aimed at reporting infection control practice and outcomes at Digestive Endoscopy Units in a high-incidence area. BACKGROUND: Lombardy was the Italian region with the highest coronavirus disease-2019 (COVID-19) prevalence, at the end of March 2020 accounting for 20% of all worldwide deaths. Joint Gastro-Intestinal societies released recommendations for Endoscopy Units to reduce the risk of the contagion. However, there are few data from high-prevalence areas on adherence to these recommendations and on their efficacy. METHODS: A survey was designed by the Lombardy section of SIED to analyze (a) changes in activity and organization, (b) adherence to recommendations, (c) rate of health care professionals' (HCP) infection during the COVID-19 outbreak. RESULTS: In total, 35/61 invited centers (57.4%) participated; most modified activities were according to recommendations and had filtering face piece 2/filtering face piece 3 and water-repellent gowns available, but few had negative-pressure rooms or provided telephonic follow-up; 15% of HCPs called in sick and 6% had confirmed COVID-19. There was a trend (P=0.07) toward different confirmed COVID-19 rates among endoscopists (7.9%), nurses (6.6%), intermediate-care technicians (3.4%), and administrative personnel (2.2%). There was no correlation between the rate of sick HCPs and COVID-19 incidence in the provinces and personal protective equipment availability and use, whereas an inverse correlation with hospital volume was found. CONCLUSIONS: Adherence to recommendations was rather good, though a minority were able to follow all recommendations. Confirmed COVID-19 seemed higher among endoscopists and nurses, suggesting that activities in the endoscopy rooms are at considerable viral spread risk.

Post-operative biliary strictures.

Post-operative biliary stricture is a cumbersome condition, secondary to biliary or vascular damage. Its risk factors include biliary or vascular anatomical variants, local inflammation, and poor surgical expertise. Intra-operative diagnosis is difficult, and in most cases, patients present with obstructive symptoms within a few weeks. Magnetic resonance cholangiography is a pivotal test to confirm the clinical picture, to study the level of the damage, and to guide treatment. Nowadays, endoscopic stenting is the first-line treatment in most centers. Multi-stenting treatment achieves long-term clinical success for more than 90% of patients, however multiple procedures are needed. In order to optimize healthcare provider costs, shorter duration endotherapies with covered metal stents are under evaluation. Radiological and surgical approaches are considered in the event of endoscopy failure.

Reopening Endoscopy after the COVID-19 Outbreak: Indications from a High Incidence Scenario.

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