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Background and Aims Electrocautery-tip lumen-apposing metal stents (EC-LAMSs) have extended the indications of therapeutic EUS. We aimed to retrospectively evaluate safety and technical and clinical success of a newly developed EC-LAMS, the Hot-Spaxus (Taewoong Medical Co, Gimpo, Korea), for various EUS-guided procedures. Methods We included and retrospectively analyzed consecutive patients at 8 tertiary care referral centers who had undergone EUS interventional procedures using the Hot-Spaxus between October 2018 and February 2021. Results Of 58 included patients (male-to-female, 36:22; mean age, 63.5 ± 14.9 years), 29 had undergone pancreatic fluid collection drainage (50%), 22 (37.9%) biliary drainage for malignant distal obstruction, 3 (5.1%) gallbladder drainage for acute cholecystitis, 3 gastroenteroanastomoses, and 1 (1.7%) pelvic collection drainage. Technical success was achieved in 54 of 58 patients (93.1%) and clinical success in all 58. Adverse events occurred in 6 patients (11.1%): 2 early (3.7%), 1 late (1.8%), and 3 long term (5.6%). The outcomes were similar to those observed in a control group of patients treated with the Hot-Axios (Boston Scientific, Marlborough, Mass, USA), the other available EC-LAMS. Conclusions Our study showed that the novel EC-LAMS has high technical and clinical success rates for various interventional EUS indications. Future multicenter prospective studies will better clarify the role of this new EC-LAMS for different indications.

Objectives Endoscopic ultrasound through-the-needle biopsy (EUS-TTNB) is a useful tool for differential diagnosis among pancreatic cystic lesions (PCLs). Cystic fluid cytology (CFC) is recommended by guidelines, but its diagnostic accuracy is about 50%. The aim of this meta-analysis is to assess the clinical impact of EUS-TTNB in terms of technical success (TS), histological accuracy (HA) and diagnostic yield (DY). Methods Original studies in English language on EUS-TTNB were searched in MEDLINE and EMBASE until October 2019. Diagnostic accuracy of EUS-TTNB for identification of mucinous PCLs was calculated using individual diagnostic data of patients who underwent CFC and surgery. Results Nine studies, including 454 patients who underwent EUS-TTNB, met the inclusion criteria for the meta-analysis. TS and HA of EUS-TTNB were, respectively, 98.5% (95% Confidence Interval [CI] 97.3%-99.6%) and 86.7% (95%CI 80.1-93.4). DY was 69.5% (95%CI 59.2-79.7) for EUS-TTNB and 28.7% (95%CI 15.7-41.6) for CFC. Heterogeneity persisted significantly high in most of subgroup analyses. In the multivariate meta-regression, cyst size was independently associated with higher DY. Sensitivity and specificity for mucinous PCLs were 88.6 and 94.7% for EUS-TTNB, and 40 and 100% for CFC. Adverse events rate was 8.6% (95%CI 4.0-13.1). Conclusions This meta-analysis shows that EUS-TTNB is a feasible technique that allows a high rate of adequate specimens to be obtained for histology; in about two-thirds of patients a specific histotype diagnosis could be assessed. The number of adverse events is slightly higher respect to standard EUS-FNA, but complications are very rarely severe.

Background Coronavirus disease 2019 (COVID-19) significantly affected endoscopy practice, as gastrointestinal endoscopy is considered a risky procedure for transmission of infection to patients and personnel of endoscopy units (PEU). Aim To assess the impact of COVID-19 on endoscopy during the first European lockdown (March-May 2020). Methods Patients undergoing endoscopy in nine endoscopy units across six European countries during the period of the first European lockdown for COVID-19 (March-May 2020) were included. Prior to the endoscopy procedure, participants were stratified as low- or high- risk for potential COVID-19 infection according to the European Society of Gastrointestinal Endoscopy (ESGE) and the European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) joint statement, and contacted 7-14 d later to assess COVID-19 infection status. PEU were questioned regarding COVID-19 symptoms and/or infection via questionnaire, while information regarding hospitalizations, intensive care unit-admissions and COVID-19-related deaths were collected. The number of weekly endoscopies at each center during the lockdown period was also recorded. Results A total of 1267 endoscopies were performed in 1222 individuals across nine European endoscopy departments in six countries. Eighty-seven (7%) were excluded because of initial positive testing. Of the 1135 pre-endoscopy low risk or polymerase chain reaction negative for COVID-19, 254 (22.4%) were tested post endoscopy and 8 were eventually found positive, resulting in an infection rate of 0.7% [(95%CI: 0.2-0.12]. The majority (6 of the 8 patients, 75%) had undergone esophagogastroduodenoscopy. Of the 163 PEU, 5 [3%; (95%CI: 0.4-5.7)] tested positive during the study period. A decrease of 68.7% (95%CI: 64.8-72.7) in the number of weekly endoscopies was recorded in all centers after March 2020. All centers implemented appropriate personal protective measures (PPM) from the initial phases of the lockdown. Conclusion COVID-19 transmission in endoscopy units is highly unlikely in a lockdown setting, provided endoscopies are restricted to emergency cases and PPM are implemented.

Extracellular vesicles (EVs) and their cargo represent an intriguing source of cancer biomarkers for developing robust and sensitive molecular tests by liquid biopsy. Prostate cancer (PCa) is still one of the most frequent and deadly tumor in men and analysis of EVs from biological fluids of PCa patients has proven the feasibility and the unprecedented potential of such an approach. Here, we exploited an antibody-based proteomic technology, i.e. the Reverse-Phase Protein microArrays (RPPA), to measure key antigens and activated signaling in EVs isolated from sera of PCa patients. Notably, we found tumor-specific protein profiles associated with clinical settings as well as candidate markers for EV-based tumor diagnosis. Among others, PD-L1, ERG, Integrin-β5, Survivin, TGF-β, phosphorylated-TSC2 as well as partners of the MAP-kinase and mTOR pathways emerged as differentially expressed endpoints in tumor-derived EVs. In addition, the retrospective analysis of EVs from a 15-year follow-up cohort generated a protein signature with prognostic significance. Our results confirm that serum-derived EV cargo may be exploited to improve the current diagnostic procedures while providing potential prognostic and predictive information. The approach proposed here has been already applied to tumor entities other than PCa, thus proving its value in translational medicine and paving the way to innovative, clinically meaningful tools.

Background and aims The present study was aimed to assess the risk of SARS-CoV-2 infection and associated factors among HCWs in endoscopy centers in Italy. Methods All members of the Italian Society of Digestive Endoscopy (SIED) were invited to participate to a questionnaire-based survey during the first months of the COVID-19 outbreak in Italy. Results 314/1306 (24%) SIED members accounting for 201/502 (40%) endoscopic centers completed the survey. Personal Protection Equipment (PPE) were available in most centers, but filtering face-piece masks (FFP2 or FFP3) and negative pressure room were not in 10.9 and 75.1%. Training courses on PPE use were provided in 57.2% of centers only; there was at least one positive HCW in 17.4% of centers globally, 107/3308 (3.2%) HCWs were diagnosed with COVID-19 with similar rates of physicians (2.9%), nurses (3.5%) and other health operators (3.5%). Involvement in a COVID-19 care team (OR: 4.96) and the lack of training courses for PPE, (OR: 2.65) were associated with increased risk. Conclusions The risk of COVID-19 among endoscopy HCWs was not negligible and was associated with work in a COVID-19 care team and lack of education on proper PPE use. These data deserve attention during the subsequent waves.

Endoscopic ultrasound (EUS) is a minimally invasive modality used to assess digestive diseases. EUS is combined with fine needle aspiration (FNA) or fine-needle biopsy (FNB) to obtain fluid and tis...

Studies comparing EUS-guided fine-needle aspiration (EUS-FNA) with EUS-guided fine-needle biopsy (EUS-FNB) for the evaluation of pancreatic neuroendocrine tumors (pNETs) are lacking. We aimed at comparing EUS-FNA with EUS-FNB in terms of Ki-67 proliferative index (PI) estimation capability, cellularity of the samples, and reliability of Ki-67 PI/tumor grading compared with surgical specimens.Patients diagnosed with pNETs on EUS and/or surgical specimens were retrospectively identified. Specimens were re-evaluated to assess Ki-67 PI feasibility, sample cellularity by manual counting, and determination of Ki-67 PI value. Outcomes in the EUS-FNA and EUS-FNB groups were compared. Kendall rank test was used for Ki-67 PI correlation between EUS and surgical specimens. Subgroup analysis including small (≤20 mm), non-functioning pNETs was performed.Three-hundred samples from 292 lesions were evaluated: 69 EUS-FNA cytology and 231 EUS-FNB histology. Ki-67 PI feasibility was similar for EUS-FNA and EUS-FNB (91.3% vs. 95.7%, p = 0.15), while EUS-FNB performed significantly better in the subgroup of 179 small pNETs (88.2% vs. 96.1%, p = 0.04). Rate of poor cellulated (500 cells) specimens was equal between EUS-FNA and EUS-FNB. A significant correlation for Ki-67 PI values between EUS and 92 correspondent surgical specimens was found in both groups, but it was stronger with EUS-FNB (tau = 0.626, p 0.0001 vs. tau = 0.452, p = 0.031). Correct grading estimation was comparable between the two groups (p = 0.482).Our study showed stronger correlation for Ki-67 values between EUS-FNB and surgical specimens, and that EUS-FNB outperformed EUS-FNA in the evaluation of small pNETs. EUS-FNB should become standard of care for grading assessment of suspected pNETs.

Introduction: The combined use of 68gallium (68Ga)-DOTA-peptides and 18fluorine-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scans in the workup of pancreatic neuroendocrine tumors (PanNETs) is controversial. This study aimed at assessing both tracers’ capability to identify tumors and to assess its association with pathological predictors of recurrence. Methods: Prospectively collected, preoperative, dual-tracer PET/CT scan data of G1-G2, nonmetastatic, PanNETs that underwent surgery between January 2013 and October 2019 were retrospectively analyzed. Results: The final cohort consisted of 124 cases. There was an approximately equal distribution of males and females (50.8%/49.2%) and G1 and G2 tumors (49.2%/50.8%). The disease was detected in 122 (98.4%) and 64 (51.6%) cases by 68Ga-DOTATOC and by 18F-FDG PET/CT scans, respectively, with a combined sensitivity of 99.2%. 18F-FDG-positive examinations found G2 tumors more often than G1 (59.4 vs. 40.6%; p = 0.036), and 18F-FDG-positive PanNETs were larger than negative ones (median tumor size 32 mm, interquartile range [IQR] 21 vs. 26 mm, IQR 20; p = 0.019). The median Ki67 for 18F-FDG-positive and -negative examinations was 3 (IQR 4) and 2 (IQR 4), respectively (p = 0.029). At least 1 pathological predictor of recurrence was present in 74.6% of 18F-FDG-positive cases (vs. 56.7%; p = 0.039), whereas this was not found when dichotomizing the PanNETs by their dimensions (≤/>20 mm). None of the 2 tracers predicted nodal metastasis. The receiver operating characteristic curve analysis showed that 18F-FDG uptake higher than 4.2 had a sensitivity of 49.2% and specificity of 73.3% for differentiating G1 from G2 (AUC = 0.624, p = 0.009). Conclusion: The complementary adoption of 68Ga-DOTATOC and 18F-FDG tracers may be valuable in the diagnostic workup of PanNETs despite not being a game-changer for the management of PanNETs ≤20 mm.

Hepatic calcifications have been increasingly identified over the past decade due to the widespread use of high-resolution Computed Tomography (CT) imaging. Calcifications can be seen in a vast spectrum of common and uncommon diseases, from benign to malignant, including cystic lesions, solid neoplastic masses, and inflammatory focal lesions. The purpose of this paper is to present an updated review of CT imaging findings of a wide range of calcified hepatic focal lesions, which can help radiologists to narrow the differential diagnosis.

OBJECTIVES Type 1 autoimmune pancreatitis (AIP) is a manifestation of immunoglobulin G4-related diseases (IgG4-RD). To evaluate the activity of the disease, the IgG4-RD responder index (RI) has been created. This study evaluated the IgG4-RD RI as prognostic factor of 1-year disease relapse. METHODS Patients diagnosed with type 1 AIP between January 2012 and December 2016, with available magnetic resonance imaging and IgG4 dosage, were enrolled. Immunoglobulin G4-RD RI was calculated at baseline (time 0), and at 3 to 6 and 12 to 18 months after the end of steroid therapy (time 1 and time 2, respectively). RESULTS Thirty-three patients were included in the study. Immunoglobulin G4-RD RI was 8.9 (standard deviation [SD], 3.8) at time 0, 2.4 (SD, 3.1) at time 1 (P < 0.0001 vs time 0), and 4.2 (SD, 3.9) at time 2 (P = 0.02 vs time 1). Fourteen patients who relapsed within 1 year showed a higher mean value of IgG4-RD RI at time 0 (10.9; SD, 4.3) versus 19 who did not (7.4; SD, 2.6; P = 0.012). This difference was observed also at time 2 (6.8 vs 2.1; P = 0.002). CONCLUSIONS Immunoglobulin G4-RD RI correlates with type 1 AIP disease activity, and it predicts disease relapse within 1 year.

Background Nivolumab has shown a survival benefit compared with docetaxel as second-line treatment for patients with previously treated advanced squamous non-small cell lung cancer (NSCLC) in a randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program. Patients and Methods Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information. Results The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2–9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy (n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression (n = 65). In the overall population, the rate of any-grade and grade 3–4 adverse events was 29% and 6%, respectively. Treatment-related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment-related deaths. Conclusion To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real-world setting are consistent with those obtained in clinical trials. Implications for Practice Nivolumab is approved in the U.S. and Europe for the treatment of advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real-world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials.

Purpose Angiopoietin-like 8 (ANGPTL8) is a liver- and adipose tissue-produced protein that predicts non-alcoholic fatty liver disease (NAFLD) and altered metabolic homeostasis in the general population as well as in persons with common and genetic obesity, including the Prader–Willi syndrome (PWS). However, its metabolic correlate in paediatric patients with respect to PWS is unknown. Methods This cross-sectional study investigated circulating ANGPTL8 and adipocytokines levels in 28 PWS and 28 age-, sex- and BMI-matched children and adolescents (age, 7.0–17.8y) in relation to NAFLD and metabolic homeostasis assessed by OGTT, paediatric metabolic index (PMI) and fatty liver index (FLI), liver ultrasonography (US), as well as dual-energy X-ray absorptiometry (DEXA) for analysis of fat (FM) and fat-free mass (FFM). Results At the set level of significance, PWS children showed lower values of FFM (p p p Conclusion ANGPTL8 levels are similar in PWS and controls and, overall, they are directly associated with the presence and severity of NAFLD in patients with PWS.

Primary hepatic malignancies in non-cirrhotic liver include a wide spectrum of tumors, which are classified based on their cells of origin. Hepatocellular carcinoma is the most common primary malignant tumor, followed by intrahepatic cholangiocarcinoma. Beside these tumors, other primary malignancies in the non-cirrhotic liver are quite rare. Accurate diagnosis is often difficult with imaging alone and biopsy with further histopathological analysis is often necessary. However, many of these tumors exhibit suggestive or characteristic imaging features due to their different cellular components, allowing radiologists to suggest the correct diagnosis. Thus, the aim of this article is to provide an overview of imaging presentation of primary malignant liver tumors that develop in the non-cirrhotic liver, including potential differential diagnoses. Such knowledge is essential as it may contribute to accurate radiological diagnosis and improved patient outcome.

BACKGROUND: Autoimmune pancreatitis (AIP) is a rare, and relatively new, form of chronic pancreatitis. The management of AIP can vary considerably among different centres in daily clinical practice. OBJECTIVES: The aim of this study is to present a picture of epidemiological, clinical characteristics, outcomes, and the real-life practice in terms of management in several academic and non-academic centres in Italy. METHODS: Data on the clinical presentation, diagnostic work-up, treatments, frequency of relapses, and long-term outcomes were retrospectively collected in a cohort of AIP patients diagnosed at 14 centres in Italy. RESULTS: One hundred and six patients were classified as type 1 AIP, 48 as type 2 AIP, and 19 as not otherwise specified. Epidemiological, clinical, radiological, and serological characteristics, and relapses were similar to those previously reported for different types of AIP. Endoscopic cytohistology was available in 46.2% of cases, and diagnostic for AIP in only 35.2%. Steroid trial to aid diagnosis was administered in 43.3% cases, and effective in 93.3%. Steroid therapy was used in 70.5% of cases, and effective in 92.6% of patients. Maintenance therapy with low dose of steroid (MST) was prescribed in 25.4% of cases at a mean dose of 5 (±1.4) mg/die, and median time of MST was 60 days. Immunosuppressive drugs were rarely used (10.9%), and rituximab in 1.7%. Faecal elastase-1 was evaluated in only 31.2% of patients, and was pathological in 59.2%. CONCLUSIONS: In this cohort of AIP patients, diagnosis and classification for subtype was frequently possible, confirming the different characteristics of AIP1 and AIP2 previously reported. Nevertheless, we observed a low use of histology and steroid trial for a diagnosis of AIP. Steroid treatment was the most used therapy in our cohort. Immunosuppressants and rituximab were rarely used. The evaluation of exocrine pancreatic insufficiency is underemployed considering its high prevalence.

Objectives Treatment options for malignant pleural mesothelioma (MPM) are limited but some studies on immune checkpoint inhibitors (ICIs) in MPM have reported antitumor activity. Very little is known about immune-related predictive factors. Materials and methods Here we report the case of a 45-year-old woman presenting with dyspnea and evidence of pleural effusion. She was diagnosed with malignant epithelioid pleural mesothelioma with brain metastasis and peritoneal carcinosis, refractory to initial standard chemotherapy treatment. Because of high PDL1 expression (100 %), she was treated with the anti-PD1 agent, pembrolizumab. Results Chemotherapy with cisplatin and pemetrexed was started, imaging studies showing stable disease after 3 treatment cycles. The patient underwent pleural decortication but rapidly progressed and thus started chemotherapy with carboplatin and gemcitabine. After 2 cycles she experienced seizures caused by a brain metastasis. This secondary lesion was surgically removed and confirmed as a metastasis from mesothelioma. Samples from both the primary tumor and the metastasis were molecularly characterized, the pleural sample proving ALK-positive and the brain sample, ALK-negative. PD-L1 was positive in 10 % of tumor cells in the pleural biopsy and 100 % in the brain lesion. Next generation sequencing analysis was negative for both samples. It was decided to start alectinib. Disease progression (peritoneal carcinosis and liver metastases) was documented after one month followed by complete bowel obstruction and recurrence in the site of the brain surgery. Alectinib was stopped and supportive care begun with parenteral nutrition via nasogastric tube. Pembrolizumab was started and after 15 days the patient’s condition had significantly improved, enabling recanalization and restoration of enteral nutrition. Imaging displayed complete response of the brain metastasis, peritoneal carcinosis, bone lesions and mediastinal nodal metastases. A partial response was documented in the pleural and pulmonary nodules, with stable liver metastases. The patient is still undergoing immunotherapy and has no cancer-related symptoms. Conclusions Our findings indicate that the use of immunotherapy in MPM warrants further investigation. Furthermore, the impressive clinical response obtained by our patient suggests that immune checkpoint inhibitors could help in the management of the disease after the failure of other treatments.

The proximity of the endoscopic ultrasound (EUS) transducer to the pancreas and the possibility to place needles or other accessories into a target located adjacent to the wall of the GI tract have encouraged researchers to develop various EUS-guided local treatments directed towards pancreatic neuroendocrine neoplasms (PanNENs). The use of pre-operative EUS-guided tattooing or fiducial marker placement to facilitate intraoperative tumor localization has proven effective in reducing operative time of laparoscopic surgeries. To reduce the mortality and morbidity rates of surgical resection, which is presently the mainstay treatment of PanNENs. EUS-guided loco-regional treatments, such as injection of alcohol and radiofrequency ablation have been proposed and results are hitherto promising. The present paper summarizes currently available data in the field of EUS-guided interventions to pancreatic neuroendocrine tumors, as well as possible future applications.

Background Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison’s disease (AD). Methods Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. Results The prevalence of APS-1 was 2.6 cases/million (range 0.5–17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. Conclusions In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Programmed death ligand 1 (PD-L1) is an immune checkpoint with a role in cancer-related immune evasion. It is a target for cancer immunotherapy and its expression is detected for the use of some immune checkpoint inhibitors in advanced non-small cell lung cancer patients (NSCLC). Vimentin is a key component of the epithelial-to-mesenchymal transition phenotype. Its expression has negative prognostic effects in NSCLC. In this study, we retrospectively evaluated PD-L1 and vimentin expression in tumor cells, immune infiltrate and PD-L1 positive immune infiltrate via immunohistochemistry in tissue samples from resected non-metastatic NSCLC patients. We explored the interplay between PD-L1 and vimentin expression through Spearman’s correlation test. We performed univariate analysis through the Cox models for demographic and clinico-pathological variables, and also for dichotomized biomarkers, i.e., PD-L1 and vimentin in tumor cells, both with 1 and 50% cutoffs. We used Kaplan-Meier method to estimate the overall survival, comparing both vimentin and PD-L1 positive patients with all the others. We found a weak positive correlation between PD-L1 and vimentin expressions in tumor cells (r = 0.25; p = 0.001). We also observed a statistically not significant trend towards a shorter overall survival in patients with both PD-L1 and vimentin expression >1% (HR = 1.36; 95% CI: 0.96–1.93, p = 0.087). In conclusion, these findings suggest that interplay between PD-L1 and vimentin may exist in non-metastatic NSCLC patients and the positivity of both markers in tumor tissue is associated with a trend towards a worse prognosis.

Background and study aims Little is known about outcomes of biliopancreatic endosonography (EUS) in patients with surgically altered upper gastrointestinal (gastrointestinal) anatomy. We aimed to assess the rate of procedural success and EUS-related adverse events (AEs), according to post-surgical anatomies. Patients and methods Retrospective study including patients with post-surgical altered upper gastrointestinal anatomy who underwent EUS for evaluation of the biliopancreatic region between January 2008 and June 2018 at eight European centers. Results Of 242 patients (162 males, mean age 66.4 ± 12.5), 86 had (35.5 %) Billroth II, 77 (31.8 %) pancreaticoduodenectomy, 23 (9.5 %) Billroth I, 19 (7.9 %) distal esophagectomy, 15 (6.2 %) total gastrectomy, 14 (5.8 %) sleeve gastrectomy, and eight (3.3 %) Roux-en-Y. Sleeve gastrectomy, Billroth I, and pancreaticoduodenectomy were associated with high rates of success (100 %, 95.7 %, and 92.2 %, respectively). Visualization of the head of the pancreas was significantly impacted by total gastrectomy, Billroth II, and Roux-en-Y (success rates 6.7 %, 53.7 %, and 57.1 %, respectively). Examination of the pancreatic body and tail was impaired in esophagectomy and total gastrectomy (82.4 % and 71.4 %, respectively). Technical success and diagnostic accuracy of EUS-guided tissue acquisition (EUS-TA) was 78.2 % and 71.3 % (95 % CI, 60.6–80.5), respectively. Four (1.6 %) AEs were observed: one mucosal tearing in a Billroth II patient, one cardiac arrest in a distal esophagectomy patient, one bleed after EUS-TA in a Billroth I patient, and one acute pancreatitis after EUS-TA in a sleeve gastrectomy patient. Conclusions The yield of bilio-pancreatic EUS is dependent on lesion location and surgery type. Before considering EUS in these patients, one must carefully consider whether the lesion may be approachable by EUS.

ObjectivesTo evaluate an algorithm developed for identifying non-small cell lung cancer (NSCLC) candidates among patients with lung cancer with a diagnosis International Classification of Diseases: ninth revision (ICD-9) 162.x code in administrative databases. Algorithm could then be applied for identifying the NSCLC population in order to assess the appropriateness and quality of care of the NSCLC care pathway.DesignAlgorithm discrimination capacity to select both NSCLC or non-NSCLC was carried out on a sample for which electronic health record (EHR) diagnosis was available. A bivariate frequency distribution and other measures were used to evaluate algorithm’s performances. Associations between possible factors potentially affecting algorithm accuracy were investigated.SettingAdministrative databases used in a specific geographical area of Emilia-Romagna region, Italy.ParticipantsAlgorithm was carried out on patients aged >18 years, with a lung cancer diagnosis from January to December 2017 and resident in Emilia-Romagna region who have been hospitalised at IRST or in one of the hospitals placed in the Forlì-Cesena area and for which EHR diagnosis data were available.Outcome measuresOverall accuracy, positive (PPV) and negative (NPV) predictive values, sensitivity and specificity, positive and negative likelihood ratios and diagnostic OR were calculated.ResultsA total of 430 patients were identified as lung cancer cases based on ICD-9 diagnosis. Focusing on the total incident cases (n=314), the algorithm had an overall accuracy of 82.8% with a sensitivity of 88.8%. The analysis confirmed a high level of PPV (90.2%), but lower specificity (53.7%) and NPV (50%). Higher length of stay seemed to be associated with a correct classification. Hospitalisation regimen and a supply of antiblastic therapy seemed to increase the level of PPV.ConclusionThe algorithm demonstrated a strong validity for identifying NSCLC among patients with lung cancer in hospital administrative databases and can be used to investigate the quality of cancer care for this population.Trial registration numberNCT04676321.

Prader-Willi syndrome (PWS) is a complex genetic syndrome characterized by hyperphagia, intellectual disability, hypotonia and hypothalamic dysfunction. Adults with PWS often have hormone deficiencies, hypogonadism being the most common. Untreated male hypogonadism can aggravate PWS-related health issues including muscle weakness, obesity, osteoporosis, and fatigue. Therefore, timely diagnosis and treatment of male hypogonadism is important. In this article, we share our experience with hypogonadism and its treatment in adult males with PWS and present a review of the literature. In order to report the prevalence and type of hypogonadism, treatment regimen and behavioral issues, we retrospectively collected data on medical interviews, physical examinations, biochemical measurements and testosterone replacement therapy (TRT) in 57 Dutch men with PWS. Fifty-six (98%) of the patients had either primary, central or combined hypogonadism. Untreated hypogonadism was associated with higher body mass index and lower hemoglobin concentrations. TRT was complicated by behavioral challenges in one third of the patients. Undertreatment was common and normal serum testosterone levels were achieved in only 30% of the patients. Based on the Dutch cohort data, review of the literature and an international expert panel discussion, we provide a practical algorithm for TRT in adult males with PWS in order to prevent undertreatment and related adverse health outcomes.

Autoimmune pancreatitis (AIP) is an increasingly recognized disease classified into two different subtypes based on histology. According to the International Diagnostic Criteria (ICDC), the diagnosis is achieved using a combination of different criteria. In patients presenting with a typical imaging appearance, the diagnosis may be straightforward, and steroid treatment is recommended, even without histological confirmation. In patients with atypical imaging or mass-forming appearance, the differential diagnosis with pancreatic cancer is challenging and crucial for treatment strategy. Endoscopic ultrasound (EUS)-guided tissue acquisition has been proposed to achieve a histological diagnosis. Fine-needle aspiration (FNA) was first proposed to aspirate cells from pancreatic lesions. Despite excellent results in terms of sensitivity for pancreatic cancer, the data are disappointing regarding the diagnosis of AIP. The recent development of new needles allowing fine-needle biopsy (FNB) has been associated with improved diagnostic accuracy based on preserving the tissue architecture, which is necessary to detect the typical histological features of AIP. However, the published literature on the role of EUS-guided FNA and FNB is limited and mainly focused on type 1 AIP. The present study aimed to review the available literature on the role of EUS-guided FNA and FNB in the diagnosis of AIP.

There is a paucity of evidence on the comparison between endoscopic ultrasound (EUS) fine-needle biopsy (FNB) and fine-needle aspiration (FNA) for lymph node (LNs) sampling. The aim of this study was to compare these two approaches in a multicenter series of patients with abdominal tumors. Out of 502 patients undergoing EUS sampling, two groups following propensity score matching were compared: 105 undergoing EUS-FNB and 105 undergoing EUS-FNA. The primary outcome was diagnostic accuracy. Secondary outcomes were diagnostic sensitivity, specificity, sample adequacy, optimal histological core procurement, number of passes, and adverse events. Median age was 64.6 years, and most patients were male in both groups. Final diagnosis was LN metastasis (mainly from colorectal cancer) in 70.4% of patients in the EUS-FNB group and 66.6% in the EUS-FNA group (p = 0.22). Diagnostic accuracy was significantly higher in the EUS-FNB group as compared to the EUS-FNA group (87.62% versus 75.24%, p = 0.02). EUS-FNB outperformed EUS-FNA also in terms of diagnostic sensitivity (84.71% vs. 70.11%, p = 0.01), whereas specificity was 100% in both groups (p = 0.6). Sample adequacy analysis showed a non-significant trend in favor of EUS-FNB (96.1% versus 89.5%, p = 0.06) whereas the histological core procurement rate was significantly higher with EUS-FNB (94.2% versus 51.4%, p &lt, 0.001). No procedure-related adverse events were observed. These findings show that EUS-FNB is superior to EUS-FNA in tissue sampling of abdominal LNs.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder typically characterized by body composition abnormalities, hyperphagia, behavioural challenges, cognitive dysfunction, and hypogonadism. Psychotic illness is common, particularly in patients with maternal uniparental disomy (mUPD), and antipsychotic medications can result in hyperprolactinemia. Information about hyperprolactinemia and its potential clinical consequences in PWS is sparse. Here, we present data from an international, observational study of 45 adults with PWS and hyperprolactinemia. Estimated prevalence of hyperprolactinemia in a subset of centres with available data was 22%, with 66% of those related to medication and 55% due to antipsychotics. Thirty-three patients were men, 12 women. Median age was 29 years, median BMI 29.8 kg/m2, 13 had mUPD. Median prolactin was 680 mIU/L (range 329–5702). Prolactin levels were higher in women and patients with mUPD, with only 3 patients having severe hyperprolactinemia. Thyroid function tests were normal, 24 were treated with growth hormone, 29 with sex steroids, and 20 with antipsychotic medications. One patient had kidney insufficiency, and one a microprolactinoma. In conclusion, severe hyperprolactinemia was rare, and the most common aetiology of hyperprolactinemia was treatment with antipsychotic medications. Although significant clinical consequences could not be determined, potential negative long-term effects of moderate or severe hyperprolactinemia cannot be excluded. Our results suggest including measurements of prolactin in the follow-up of adults with PWS, especially in those on treatment with antipsychotics.

Background: Lung cancer is a complex disease with many subtypes. However, histochemical characteristics, and genetic mutation determinations are contributing to better define therapeutic targets and new drugs. Although this guarantees patients the possibility of obtaining tailored treatment, it makes it more difficult for clinicians patient management more difficult for clinicians who have to define the most suitable therapeutic strategy and to deal with new treatment-related adverse events (TRAEs). It has been seen that the administration of a tyrosine kinase inhibitor (TKI) sequential to an immune checkpoint inhibitor (ICI) can lead to a higher rate of severe and life-threatening TRAEs. We report the case of a patient with advanced non-small cell lung cancer (NSCLC) who experienced severe hepatotoxicity and Stevens-Johnson syndrome (SJS) induced by osimertinib sequential to pembrolizumab.Case presentation: A 54-year-old woman with advanced NSCLC received one cycle of chemotherapy plus pembrolizumab after diagnosis. Ten days later she began osimertinib 80 mg daily because epidermal growth factor receptor (EGFR) analysis had revealed an exon 19 deletion. On day 23 of osimertinib the patient experienced an episode of grade (G) 3 hepatotoxicity resolved by discontinuing osimertinib and corticosteroid therapy. The patient restarted osimertinib 80 mg daily after the remission of symptoms but was hospitalized 14 days later following a second episode of severe G3 hepatotoxicity and the onset of SJS, successfully treated with high-dose corticosteroids. Despite the short exposure to osimertinib, the patient obtained a good pathological response.Conclusion: It is important to alert clinicians to carefully evaluate the sequential therapeutic strategy in patients with NSCLC who are candidates for TKI- or ICI-based treatment. Our experience suggests that the use of tyrosine kinase inhibitors (TKIs) as front-line treatment is a more reasonable and safe option for EGFR-mutated lung adenocarcinoma, with ICIs considered as a possible further treatment in sequential approaches.

Background & Aims Several endoscopic methods have been proposed for the treatment of large biliary stones. We assessed the comparative efficacy of these treatments through a network meta-analysis. Methods Nineteen randomized controlled trials (2752 patients) comparing different treatments for management of large bile stones (>10 mm) (endoscopic sphincterotomy, balloon sphincteroplasty, sphincterotomy followed by endoscopic papillary large balloon dilation [S+EPLBD], mechanical lithotripsy, single-operator cholangioscopy [SOC]) with each other were identified. Study outcomes were the success rate of stone removal and the incidence of adverse events. We performed pairwise and network meta-analysis for all treatments, and used Grading of Recommendations, Assessment, Development, and Evaluation criteria to appraise the quality of evidence. Results All treatments except mechanical lithotripsy significantly outperformed sphincterotomy in terms of stone removal rate (risk ratio [RR], 1.03–1.29). SOC was superior to other adjunctive interventions (vs balloon sphincteroplasty [RR, 1.24; 95% CIs, 1.07–1.45], vs S+EPLBD [RR, 1.23; range, 1.06–1.42] and vs mechanical lithotripsy [RR, 1.34; range, 1.14–1.58]). Cholangioscopy ranked the highest in increasing the success rate of stone removal (surface under the cumulative ranking [SUCRA] score, 0.99) followed by S+EPLBD (SUCRA score, 0.68). SOC and S+EPLBD outperformed the other modalities when only studies reporting on stones greater than 15 mm were taken into consideration (SUCRA scores, 0.97 and 0.71, respectively). None of the assessed interventions was significantly different in terms of adverse event rate compared with endoscopic sphincterotomy or with other treatments. Post-ERCP pancreatitis and bleeding were the most frequent adverse events. Conclusions Among patients with large bile stones, cholangioscopy represents the most effective method, in particular in patients with larger (>15 mm) stones, whereas S+EPLBD could represent a less expensive and more widely available alternative.

In Prader–Willi syndrome (PWS), conditions that are associated with hyponatremia are common, such as excessive fluid intake (EFI), desmopressin use and syndrome of inappropriate antidiuretic hormone (SIADH) caused by psychotropic medication. However, the prevalence of hyponatremia in PWS has rarely been reported. Our aim was to describe the prevalence and severity of hyponatremia in PWS. In October 2020, we performed a retrospective study based on the medical records of a large cohort of children and adults with PWS from seven countries. Among 1326 patients (68% adults), 34 (2.6%) had at least one episode of mild or moderate hyponatremia (125 ≤ Na &lt, 135 mmol/L). The causes of non-severe hyponatremia were often multi-factorial, including psychotropic medication in 32%, EFI in 24% and hyperglycemia in 12%. No obvious cause was found in 29%. Seven (0.5%) adults experienced severe hyponatremia (Na &lt, 125 mmol/L). Among these, five recovered completely, but two died. The causes of severe hyponatremia were desmopressin treatment for nocturnal enuresis (n = 2), EFI (n = 2), adrenal insufficiency (n = 1), diuretic treatment (n = 1) and unknown (n = 1). In conclusion, severe hyponatremia was very rare but potentially fatal in PWS. Desmopressin treatment for nocturnal enuresis should be avoided. Enquiring about EFI and monitoring serum sodium should be included in the routine follow-ups of patients with PWS.

Introduction Alectinib is a highly selective and potent ALK inhibitor, approved for the treatment of patients with metastatic ALK+ NSCLC based on results from the Phase II global NP28673 (NCT01801111) and North American NP28761 (NCT01871805) studies. Methods This exploratory analysis of two Phase II studies of alectinib (NP28673/NP28761) investigated time to systemic response (TTR) and time to central nervous system (CNS) response (TTCR) in patients with previously treated advanced anaplastic lymphoma kinase fusion gene-positive (ALK+) non-small-cell lung cancer. Patients (n=225) received 600 mg oral alectinib twice daily and had scans every 6/8 weeks (NP28673/NP28761). Results For NP28673 and NP28761, respectively: median follow-up was 21.3 months/17.0 months; most responders (72.6%/82.9%) responded by the first disease assessment; median TTR was 8 weeks (95% confidence interval [CI]: 8.00-8.14)/6 weeks (95% CI: 5.86-6.14); median TTCR in responders with measurable baseline CNS disease was 8 weeks (95% CI: 7.86-10.29)/6 weeks (95% CI: 5.71-not evaluable). Similar results were observed regardless of measurable/non-measurable disease. Discussion These data suggest that alectinib achieves a rapid response in patients, both systemically and in the CNS.

Summary Background Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival. Methods We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab. Findings Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11–17) for all patients (n=664), 19% (15–24) for those with at least 1% PD-L1 expression, and 11% (7–16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11–18) in patients treated with nivolumab, compared with 5% (3–7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0·18 (95% 0·12–0·27) for nivolumab and 0·43 (0·29–0·65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52 (0·37–0·71) for nivolumab and 0·80 (0·61–1·04) for docetaxel. Long-term data did not show any new safety signals. Interpretation Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage. Funding Bristol-Myers Squibb.

Interventional endoscopic ultrasound (EUS) is a rapidly expanding field with a wide variety of indications, including different drainage procedures and delivery of locoregional treatment mainly for pancreatic solid tumors. Transgastric or transduodenal gallbladder drainage in high-risk patients with acute cholecystitis or biliary decompression in patients with unresectable distal biliary malignant obstruction who failed endoscopic retrograde colangiography is one of the newest areas of EUS-guided intervention. The large-caliber lumen apposing metal stents placed during these procedures allow direct endoscopic gallbladder access and the possibility of performing gallstone treatment or resection of mucosal polyps. The current review presents the indications of endoscopic gallbladder interventions and discusses the results of available studies, foreseeing future potential applications.

KRAS mutation has been associated with enhanced dependency on the folate metabolism in preclinical studies. However, whether KRAS mutation correlates to increased sensitivity to pemetrexed in patients with advanced NSCLC is unknown. Patients with advanced non-squamous NSCLC who had a documented EGFR and ALK WT genotype with simultaneous KRAS mutation assessment were evaluated for clinical outcome to pemetrexed- and non-pemetrexed-based first-line platinum doublet according to KRAS mutation status. Of 356 patients identified, 138 harbored a KRAS mutation. Among KRAS-mutant NSCLCs, those treated with platinum/pemetrexed (81/138) had significantly lower ORR (30.9% versus 47.4%, P = 0.05), DCR (51.8% versus 71.9%, P = 0.02) and shorter median progression-free survival [mPFS 4.1 versus 7.1 months, HR 1.48 (95% CI 1.03–2.12), P = 0.03] and median overall survival [mOS 9.7 versus 26.9 months, HR 1.93 (95% CI 1.27–2.94), P = 0.002] compared to those who received a non-pemetrexed-based platinum doublet (57/138). No difference in ORR, DCR, mPFS and mOS was observed between KRAS WT patients who received a pemetrexed-based (124/218) versus non-pemetrexed base platinum doublets (94/218). After adjusting for performance status, age and the presence of brain metastasis at baseline, treatment with pemetrexed-based platinum doublet was associated with an increased risk of death [HR 2.27 (95% CI 1.12–4.63), P = 0.02] among KRAS-mutant patients in multivariate analysis. Patients with KRAS-mutant lung adenocarcinoma have a poorer outcome on pemetrexed-based first-line chemotherapy. Whether KRAS-mutant NSCLCs should be excluded from pemetrexed-containing regimens should be assessed prospectively.

The treatment landscape of metastatic non-small cell lung cancer (NSCLC) has dramatically evolved in recent years, since the recognition of several clinical–biological entities requiring personalized treatment approaches, leading to significant improvements in patients’ survival outcomes. In particular, targeted therapies acting against EGFR, ALK, and ROS1, and immunotherapeutic agents modulating the PD-1/PD-L1 axis, represent new milestones in the treatment of advanced disease, supporting a chemotherapy backbone within a multidisciplinary model. The Italian Association of Medical Oncology (AIOM) has developed evidence-based guidelines for the management of lung tumors. Given the epidemiologic relevance, this report is dedicated to the treatment of advanced/metastatic NSCLC. These guidelines serve as a practical tool for oncologists, physicians, and other healthcare professionals to easily embrace the updated key points of NSCLC treatment strategies. Considering the upcoming introduction of potential new standards of care in several disease settings, these guidelines represent a benchmark from which to move forward.

Non-small-cell lung cancer (NSCLC) patients with mutated or rearranged oncogene drivers can be treated with upfront selective inhibitors achieving higher response rates and longer survival than chemotherapy. The RET gene can undergo chromosomal rearrangements in 1%-2% of all NSCLC patients, involving various upstream fusion partners such as KIF5B, CCDC6, NCOA4, and TRIM33. Many multikinase inhibitors are active against rearranged RET. Cabozantinib, vandetanib, sunitinib, lenvatinib, and nintedanib achieved tumor responses in about 30% of these patients in retrospective studies. Prospective phase II trials investigated the activity and toxicity of cabozantinib, vandetanib, sorafenib, and lenvatinib, and did not reach significantly higher response rates. VEGFR and EGFR inhibition represented the main ways of developing off-target toxicity. An intrinsic resistance emerged according to the type of RET fusion partners, as KIF5B-RET fusion is the most resistant. Also acquired mutations in rearranged RET oncogene developed as resistance to these multikinase inhibitors. Interestingly, RET fusions have been found as a resistance mechanism to EGFR-TKIs in EGFR-mutant NSCLC patients. The combination of EGFR and RET inhibition can overcome this resistance. The limitations in terms of activity and tolerability of the various multikinase inhibitors prompted the investigation of new highly selective RET inhibitors, such as RXDX-105, BLU-667, and LOXO-292. Some data emerged about intracranial antitumor activity of BLU-667 and LOXO-292. If these novel drugs will achieve high activity in RET rearranged NSCLC, also these oncogene-addicted tumors can undergo a significant survival improvement.

BACKGROUND: Innovative approaches to improve diagnostic yield of endoscopic ultrasound-guided tissue acquisition (EUS-TA) have focused on needle design with development of fine-needle biopsy (FNB) needles with microcore-acquisition technology. Recently, a 20-gauge (20G) antegrade-cutting-side-bevelled biopsy needle (ProCore®) was developed for EUS-TA, but data about its diagnostic performance and histological capability are scant. OBJECTIVES: We assessed the diagnostic performance and histologic retrieval rate of a new 20G antegrade-cutting-side-bevelled biopsy needle compared with a 22G reverse-side-bevelled needle for EUS sampling of solid pancreatic lesions. PATIENTS AND METHODS: A retrospective analysis of 238 consecutively collected patients who underwent EUS-TA using a 20G or a 22G ProCore® needle, without rapid on-site evaluation (ROSE), was conducted at two centres. Sensitivity, specificity, positive predictive value and negative predictive value were calculated. Histologic tissue retrieval was evaluated applying a scoring system for each case. RESULTS: Sensitivity and specificity were estimated as 98.4–100% in the 20G-, and 94.9–100% in the 22G-needle groups, respectively (p > 0.99). The 20G procured more histologic-grade tissues (92.6% vs 49.5%, p

Background It is unclear whether patients with intraductal papillary mucinous neoplasia harbor a higher risk of developing extrapancreatic malignancies. Aims We performed a pooled estimate of the incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasia, with a particular focus on the comparison to the general population. Methods Computerized bibliographic search of main databases was performed through February 2021. The primary endpoint was the pooled incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasms. Additional outcome was the comparison between intraductal papillary mucinous neoplasia patients and the general population, expressed in terms of standardized incidence ratio along with 95% confidence intervals. Results Eighteen studies with 8709 patients were included. The pooled rate of metachronous extrapancreatic malignancies was 10 (6–13)/1000 persons-year. No difference was observed according to intraductal papillary mucinous neoplasia histology and sex, whereas a significantly superior incidence of extrapancreatic malignancies was observed in patients with main-duct (36.7%, 25.4%–48%) as compared to branch-duct intraductal papillary mucinous neoplasia (26.2%, 17.6%–34.8%; p = 0.03). Pooled standardized incidence ratio comparing expected rates in the general population was 1.01 (0.79–1.29); no difference was observed concerning rates of metachronous gastric cancer (standardized incidence ratio 1.60, 0.72–3.54) and colorectal cancer (1.29, 0.92–1.18), whereas biliary cancer was observed more frequently in intraductal papillary mucinous neoplasia patients (2.29, 1.07–4.93). Conclusion Patients with intraductal papillary mucinous neoplasia harbor an overall rate of extrapancreatic malignancies as high as 27.3%. The rate of metachronous extrapancreatic malignancies is not superior to the general population.

We report a case of successful percutaneous transhepatic, embolization of an iatrogenic extra-hepatic pseudoaneurysm (PsA) of the right hepatic artery (RHA) under combined fluoroscopic and ultrasonographic guidance. A 73-year-old man underwent percutaneous transhepatic biliary drainage placement in another hospital, complicated by haemobilia and development of a RHA PsA. Endovascular embolization was attempted, resulting in coil embolization of the proper hepatic artery, and persistence of the PsA. At this point, the patient was referred to our hospital. Computed tomography and direct angiography confirmed the iatrogenic extra-hepatic PsA of the RHA, refilled by small collaterals from the accessory left hepatic artery (LHA) and coil occlusion of the proper hepatic artery. Attempted selective catheterization of these vessels was unsuccessful due to the tortuosity and very small caliber of the intra-hepatic collaterals, the latter precluding endovascular treatment of the PsA. Percutaneous trans-hepatic combined fluoroscopic and ultrasound-guided embolization of the PsA was performed with Lipiodol® and cyanoacrylate-based glue (Glubran®2). Real time fluoroscopic images and computed tomography confirmed complete occlusion of the pseudoaneurysm. Surgical repair, although feasible, was considered at high risk. In our patient, we decided to perform a percutaneous trans-hepatic combined fluoroscopic and ultrasound-guided embolization of the PsA using a mix of Lipiodol® and Glubran®2 because of the fast polymerization time of the glue allowing the complete occlusion of the PsA in few seconds, thus eliminating the risk of coil migration, reducing the risk of PsA rupture and avoid a difficult surgical repair.

Immune checkpoint inhibition induced a great step forward in the treatment of non-small cell lung cancer patients. In cancer immune microenvironment many checkpoints were studied and their involvement could represent a mechanism of resistance to cancer immunotherapy. For this reason, the inhibition of multiple immune checkpoints is under development. However, myeloid-derived suppressor cells (MDSC) and exhausted immune cells could limit the efficacy of cancer immunotherapy. We analyzed the variation of circulating immune suppressive-like cell subsets and exhausted immune cells in three non-small cell lung cancer patients treated with the combination of anti-CTLA-4 plus anti-PD-1 plus anti-LAG-3 at T0 (baseline), T1 (after 2 months) and T2 (after 4 months). We also describe the clinical and radiological course of the disease during this treatment in all three patients. We observed both clinical differences and changes in the composition of immune suppressive-like cell subsets and exhausted immune cells between the patients receiving the same schedule of treatment with immune checkpoint inhibitors. The study on a wider patient population and experimental model design could help to clarify the kinetics of these cell subpopulations with the perspective to find new targets for treatment or new biomarkers for resistance to cancer immunotherapy.

Objective Acinar cell carcinoma (ACC) of the pancreas are known to be rare and difficult to be recognize because they mimic other unrelated tumors (neuroendocrine, solid pseudopapillary) with different clinical behavior. Especially in the setting of inoperable patients, fine needle aspiration cytology (FNAC), core needle biopsy (FNAB) and immunocyto/histochemistry (ICC/IHC) play a crucial role in the differential diagnosis. The biological material available for ICC tests obtained by minimal invasive procedures is usually limited. Aim of the current study was to evaluate diagnostic panel based on a limited number of ICC markers for typing preoperatively ACC of the pancreas. Methods Of 1820 needle sampling procedures performed and related to pancreatic lesions, 21 cases were extracted with a confirmed diagnosis of ACC on histology. Of them,12 were pure ACC and 9 mixed acinar-neuroendocrine carcinoma (MANEC). Smears of ACC, MANEC and a control group composed of 34neuroendocrine, 7solid pseudopapillary, 50ductal and 4 adenosquamous carcinoma were assessed with an ICC panel made up of BCL10, trypsin, synaptophysin, chromograninA, β-catenin. Results On cytology, BCL10 sensitivity and specificity for ACC was 100%. Trypsin correctly recognized 90% of the cases. Synaptophysin was helpful to correctly identify all the cases with a mixed neuroendocrine component. No significant cross-reaction was observed between BCL10 and trypsin in any of the control group case. Conclusions BCL10 is a determinant marker for the diagnosis of acinar cell carcinoma and mixed acinar neuroendocrine cell carcinoma of the pancreas in a pre-operative citologic/histologic setting.

BackgroundCurrent therapy for non-small-cell lung cancer (NSCLC) frequently includes immune checkpoint inhibitors, such as pembrolizumab, and programmed death ligand 1 (PD-L1) positivity is mandatory for its use in this setting. Vimentin plays a role in carcinogenesis through the activation of the epithelial-to-mesenchymal transition (EMT) process. Its prognostic impact in NSCLC has been investigated in numerous studies but little data are available on its relation with PD-L1 expression.Patients and MethodsWe retrospectively retrieved data on patients with advanced NSCLC consecutively enrolled in a clinical trial at our institute. PD-L1 and vimentin expression were determined by immunohistochemistry. Correlations between variables were assessed using the Spearman correlation coefficient. The Kaplan-Meier method was used to estimate overall survival (OS) and the Log-rank test was used to compare survival curves. The association between demographic, clinical and biomarker information and survival was investigated with the Cox model.ResultsFifty-three patients were included in the study. A weak positive correlation was observed between the PD-L1 and vimentin (ρ=0.41, P=0.003). Patients with PD-L1 values P=0.080). No difference in overall survival (OS) was observed on the basis of vimentin expression (HR=1.25; 95% CI: 0.59–2.66; P=0.554). Patients harboring both vimentin and PD-L1 negative expression (P=0.093). No significant associations were observed between gender, age at diagnosis, stage at diagnosis, histology, KRAS or EGFR status, radical surgery or immunotherapy and OS.ConclusionsThe weak positive association between PD-L1 and vimentin suggests a potential interplay between these biomarkers. Further research is warranted to evaluate EMT and immune escape as two components of the same process.

Introduction: Among the oncogene-addicted non-small cell lung cancer patients, those bearing ALK rearrangement can be currently treated with next-generation ALK inhibitors. Brigatinib was first use...

Pancreatic neuroendocrine neoplasms (PanNENs) are relatively rare, but their incidence has increased significantly in the last decades. Precise diagnosis and prognostic stratification are crucial for proper patient management. Endoscopic ultrasound (EUS) is the modality of choice for diagnosis of solid pancreatic tumors, showing a higher tumor detection rate than other imaging modalities, especially for small size lesions. EUS also serves as a guide for preoperative sampling and other interventions. EUS-tissue acquisition is a safe and highly accurate technique for cyto/histological diagnosis of PanNENs with a well-demonstrated correlation between Ki-67 proliferation index values and tumor grading on EUS and surgical specimens according to the WHO 2017 classification. Furthermore, the possibility of a preoperative EUS-guided fine needle tattooing or fiducial markers placement may help the surgeon to locate small and deep tumors, thus avoiding formal pancreatic resections in favor of parenchymal-sparing surgery. Finally, locoregional ablative treatments using either ethanol injection or radiofrequency ablation have been proposed in recent studies with promising results in order to control symptoms or reduce tumor burden in selected patients unfit for surgery with functioning or non-functioning PanNENs. This article review highlights the current role of EUS in PanNENs management, focusing on the present and future applications of EUS-guided interventions.

Background and study aims Feasibility of EUS-guided choledochoduodenostomy (EUS-CDS) using available lumen-apposing stents (LAMS) is limited by the size of the common bile duct (CBD) (≤ 12 mm, cut-off for experts; 15 mm, cut-off for non-experts). We aimed to assess the prevalence and predictive factors associated with CBD size ≥ 12 and 15 mm in naïve patients with malignant distal biliary obstruction (MDBO). Patients and methods This was a prospective cohort study involving 22 centers with assessment of CBD diameter and subjective feasibility of the EUS-CDS performance in naïve jaundiced patients undergoing EUS evaluation for MDBO. Results A total of 491 patients (mean age 69 ± 12 years) with mean serum bilirubin of 12.7 ± 6.6 mg/dL entered the final analysis. Dilation of the CBD ≥ 12 and 15 mm was detected in 78.8 % and 51.9 % of cases, respectively. Subjective feasibility of EUS-CDS was expressed by endosonographers in 91.2 % for a CBD ≥ 12 mm and in 96.5 % for a CBD ≥ 15 mm. On multivariate analysis, age (P Conclusions Our study showed that at presentation in a large cohort of patients with MDBO, EUS-CDS can be potentially performed in three quarters to half of cases by expert and less experienced endosonographers, respectively. Dedicated stents or devices with different designs able to overcome the limitations of existing electrocautery-enhanced LAMS for EUS-CDS are needed.

PURPOSE Immunotherapy has revolutionized the treatment of advanced non–small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials. METHODS Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated. RESULTS After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3–5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs. CONCLUSION At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.

Aims COVID-19 has significantly affected endoscopic practice, as GI-endoscopy is considered a risky procedure fortransmission of infection towards personnel of endoscopy units (PEU) and patients. ESGE recommended reduction of non-emergency endoscopies, personal protection measures (PPM) and post-endoscopy calls to patients, to check their COVID-19 status. This study aimed to assess the impact of COVID-19 on endoscopy during the first European lockdown (March-May 2020). Methods Demographic data, patients' COVID-19 status before and after endoscopy, clinical data for those developingCOVID-19, implementation of PPM, number and type of overall endoscopies, as well as information for possible COVID-19infection of patients and PEU were retrospectively recorded. Results 1267 endoscopies (EGDs:46 %, colonoscopies/rectosigmoidoscopies:35 %, ERCPs:14 %, EUS:4 %) were performedin 1222 patients (mean age:63.4 y.o., males:59 %, inpatients:44 %) in 9 centers (6 countries). Pre-endoscopic testing forCOVID-19 was available for 326 (26.7 %) patients;87(7 %) tested positive. 7-14 days after endoscopy, 1204 patients werecontacted by telephone. Among 1135 pre-endoscopically COVID-19 negative patients 254 were tested post-endoscopy and8 were found positive (0.6 % of the total), with 6, 1 and 1 cases turning positive after EGD, colonoscopy and EUS,respectively. Of these, 4 were considered “obviously” irrelevant to endoscopy, but for the other 4 (3 post-EGD and 1 post-colonoscopy) the route of transmission remained obscure. Appropriate PPM were implemented and adhered to in allcenters;moreover, a significant reduction in the number of endoscopies was noted in all centers after March 2020. Finally,data regarding 163 PEU was recorded;5 (3 %) tested positive during the study period. In 4 of them (2 % of the total), theinfection was considered to be associated to their work environment. Conclusions COVID-19 transmission in endoscopic units is highly unlikely in a lockdown setting, provided endoscopies arereduced to emergency cases and appropriate PPM are implemented and followed.

Objectives: It is still unclear whether endoscopic ultrasound (EUS) contrast-enhanced fine-needle aspiration (CH-EUS-FNA) determines superior results in comparison to standard EUS-FNA in tissue acquisition of pancreatic masses. Aim of this meta-analysis was to compare the diagnostic outcomes of these two techniques. Methods: We searched the PubMed/Medline and Embase database through October 2020 and identified 6 studies, of which 2 randomized controlled trials (recruiting 701 patients). We performed pairwise meta-analysis through a random effects model and expressed data as odds ratio (OR) and 95% confidence interval (CI). Results: Pooled diagnostic sensitivity was 84.6% (95% CI 80.7%-88.6%) with CH-EUS-FNA and 75.3% (67%-83.5%) with EUS-FNA, with evidence of a significant superiority of the former (OR 1.74, 95% CI 1.26–2.40; p

On contrast-enhanced imaging studies, nonhypovascular (i. e., isovascular and hypervascular) patterns can be observed in solid pancreatic lesions (SPLs) of different nature, prognosis, and management. We aimed to identify endoscopic ultrasound (EUS) features of nonhypovascular SPLs associated with malignancy/aggressiveness. The secondary aims were EUS tissue acquisition (EUS-TA) outcome and safety in this setting of patients. This prospective observational study included patients with nonhypovascular SPLs detected on cross-sectional imaging and referred for EUS-TA. Lesion features (size, site, margins, echotexture, vascular pattern, and upstream dilation of the main pancreatic duct) were recorded. Malignancy/aggressiveness was determined by evidence of carcinoma at biopsy/surgical pathology, signs of aggressiveness (perineural invasion, lymphovascular invasion, and/or microscopic tumor extension/infiltration or evidence of metastatic lymph nodes) in the surgical specimen, radiologic detection of lymph nodes or distant metastases, and/or tumor growth 5 mm/6 months. Uni- and multivariate analyses were performed to assess the primary aim. A total of 154 patients with 161 SPLs were enrolled. 40 (24.8 %) lesions were defined as malignant/aggressive. Irregular margins and size 20 mm were independent factors associated with malignancy/aggressiveness (p 0.001, OR = 5.2 and p = 0.003, OR = 2.1, respectively). However, size20 mm was not significant in the subgroup of other-than-neuroendocrine tumor (NET) lesions. The EUS-TA accuracy was 92 %, and the rate of adverse events was 4 %. Irregular margins on EUS are associated with malignancy/aggressiveness of nonhypovascular SPLs. Size20 mm should be considered a malignancy-related feature only in NET patients. EUS-TA is safe and highly accurate for differential diagnosis in this group of patients.ZIEL: In kontrastverstärkten Bildgebungsstudien werden in soliden Pankreasläsionen (SPLs) nicht hypovaskuläre (d. h. isovaskuläre und hypervaskuläre) Muster unterschiedlichsten Ursprungs, Prognose und Behandlung beobachtet. Unser Ziel war die Bestimmung der Merkmale des endoskopischen Ultraschalls (EUS) bei nicht hypovaskulären SPLs, die mit Malignität/Aggressivität assoziiert sind. Die sekundären Ziele waren das Outcome der EUS-Gewebeaufnahme (EUS-TA) und die Patientensicherheit. Diese prospektive Beobachtungsstudie umfasste Patienten mit nicht hypovaskulären SPLs, die in einem Schnittbildverfahren entdeckt wurden und zur EUS-TA einbestellt wurden. Läsionsmerkmale (Größe, Lage, Ränder, Echotextur, Gefäßmuster und stromaufwärts gerichtete Dilatation des Hauptpankreasgangs) wurden erfasst. Die Malignität/Aggressivität wurde durch Nachweis eines Karzinoms in der Biopsie/Pathologie, durch Zeichen von Aggressivität (perineurale Invasion, lymphovaskuläre Invasion und/oder mikroskopische Tumorausdehnung/-infiltration oder Nachweis metastasierter Lymphknoten) in der chirurgischen Probe, durch den radiologischer Nachweis von Lymphknoten oder entfernten Metastasen und/oder durch Tumorwachstum 5 mm in 6 Monaten definiert. Zur Beurteilung des Primärziels wurden uni- und multivariate Analysen durchgeführt. Insgesamt wurden 154 Patienten mit 161 SPLs aufgenommen. 40 (24,8 %) Läsionen wurden als maligne/aggressiv definiert. Unabhängige, mit Malignität/Aggressivität assoziierte Faktoren waren unregelmäßige Ränder (p 0,001; OR = 5,2) und eine Größe 20 mm (p = 0,003; OR = 2,1). Allerdings war der Faktor Größe 20 mm in der Untergruppe der nicht neuroendokrinen Tumor (NET) -Läsionen nicht signifikant. Die Genauigkeit der EUS-TA betrug 92 % und die Rate der unerwünschten Ereignisse 4 %. Unregelmäßige Ränder in EUS sind mit Malignität/Aggressivität von nicht hypovaskulären SPLs assoziiert. Eine Größe 20 mm sollte nur bei NET-Patienten als Marker für Malignität angesehen werden. Die EUS-TA ist sicher und von hoher Genauigkeit für die Differenzialdiagnose in dieser Patientengruppe.

We aimed to assess factors impacting the endoscopic minor papilla sphincterotomy (EMPS) success rate, clinical efficacy, and safety in a large cohort of patients with symptomatic pancreas divisum (PD).Retrospective study including patients with PD referred to the Pancreas Institute of Verona from May 2009 to May 2020 to undergo EMPS. The whole population was analyzed to assess EMPS technical success, defined as the rate of deep cannulation of the dorsal duct. Patients treated for recurrent pancreatitis (RP) with a minimum follow-up of 1 year were included to evaluate the clinical efficacy, defined as resolution or significant reduction of acute pancreatitis (AP) episodes. Safety was defined as the rate of procedure-related adverse events (AEs) according to an international lexicon. The effects of the main determinants on study outcomes were evaluated.Overall, 106 patients were evaluated. Technical success was obtained in 87 (82.1%). The presence of pancreatic calcifications was associated with failure (p 0.0001). Clinical efficacy was evaluated in 59 patients. Resolution/reduction of AP episodes after EMPS was observed in 93% of patients over a median follow-up of 49 months (IQR 37-92). Smoking habit was associated with AP recurrence (p = 0.026). The overall AE rate was 14.9%, with post-ERCP pancreatitis as the most common complication (12.6%).In our study, performed at a tertiary center, EMPS showed satisfactory technical success and an acceptable safety profile. If confirmed by prospective multicenter studies, EMPS could become the standard of care for the treatment of RP in PD.