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Adding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC.Eligible patients were randomized 1:1 to erlotinib plus bevacizumab or erlotinib alone. Investigator-assessed PFS and blinded independent centrally reviewed PFS were coprimary end points. With 80% power in detecting a 0.60 hazard ratio and two-sided α error of 0.05, 126 events of 160 patients were needed. The trial was registered as NCT02633189 and EudraCT 2015-002235-17.From April 11, 2016, to February 27, 2019, a total of 160 patients were randomized to erlotinib plus bevacizumab (80) or erlotinib alone (80). At a median follow-up of 36.3 months, median investigator-assessed PFS was 15.4 months (95% confidence interval [CI]: 12.2-18.6) with erlotinib plus bevacizumab and 9.6 months (95% CI: 8.2-10.6) with erlotinib alone (hazard ratio = 0.66, 95% CI: 0.47-0.92). Blinded independent centrally reviewed PFS analysis confirmed this result. A statistically significant interaction with treatment effect was found for smoking habit (p = 0.0323), with PFS prolongation being clinically significant only among current or previous smokers. Hypertension (grade ≥3: 24% versus 5%), skin rash (grade ≥ 3: 31% versus 14%), thromboembolic events (any grade: 11% versus 4%), and proteinuria (any grade: 23% versus 6%) were more frequent with the combination.The addition of bevacizumab to first-line erlotinib prolonged PFS in Italian patients with EGFR-mutated NSCLC; toxicity was increased with the combination but without unexpected safety issues.

Transjugular intrahepatic portosystemic shunt (TIPS) is an effective therapy for portal hypertension complications and can successfully treat variceal bleeding and refractory ascites. Although TIPS is relatively safe, procedural- or shunt-related morbidity can reach 20%, and procedural complications have a fatality rate of 2%. Delayed recognition and treatment of TIPS complications can lead to life-threatening clinical scenarios. Complications can vary from stent migration or malpositioning to nontarget organ injury, TIPS dysfunction, encephalopathy, or liver failure. This review aims to outline the role of diagnostic radiology in assessing post-TIPS complications.[GRAPHICS].

A direct comparison between endoscopic ultrasound (EUS) fine-needle biopsy (FNB) and current endoscopic biopsy techniques in patients with subepithelial lesions (SELs) is still lacking. Aim of this multicenter study was to compare the diagnostic performance and safety profile between EUS-FNB and bite-on-bite jumbo biopsy.Out of 416 patients undergoing endoscopic sampling of SELs between 2017 and 2021, after propensity score matching two groups were compared: 120 undergoing EUS-FNB and 120 sampled with bite-on-bite jumbo biopsy. Primary outcome was sample adequacy. Secondary outcomes were diagnostic accuracy, sensitivity, specificity, and adverse events.Median age was 61 years and most patients were male in both groups. Final diagnosis was GIST in 65 patients (54.1%) in the EUS-FNB group and 62 patients in the bite-on-bite biopsy group (51.6%; p = 0.37). Sample adequacy was significantly higher in the EUS-FNB group as compared to the bite-on-bite biopsy group (94.1% versus 77.5%, p0.001). EUS-FNB outperformed bite-on-bite biopsy also in terms of diagnostic accuracy (89.3% versus 67.1%, p0.001) and sensitivity (89% vs 64.5%; p0.001), whereas specificity was 100% in both groups (p = 0.89). These findings were confirmed in subgroup analysis according to SEL location, final diagnosis, and wall layers of the sampled SEL. Adverse event rate was 6.6% in the EUS-FNB group and 30% in the bite-on-bite biopsy group (p0.001).EUS-FNB outperforms bite-on-bite biopsy both in terms of diagnostic yield and safety profile.

Background and study aims Endoscopic ultrasound-guided through-the-needle biopsy (TTNB) of pancreatic cystic lesions (PCLs) is associated with a non-negligible risk for adverse events (AEs). We aimed to identify the hierarchic interaction among independent predictors for TTNB-related AEs and to generate a prognostic model using recursive partitioning analysis (RPA). Patients and methods Multicenter retrospective analysis of 506 patients with PCLs who underwent TTNB. RPA of predictors for AEs was performed and the model was validated by means of bootstrap resampling. Results Mean cysts size was 36.7 mm. Most common diagnoses were intraductal papillary mucinous neoplasm (IPMN, 45 %), serous cystadenoma (18.8 %), and mucinous cystadenoma (12.8 %). Fifty-eight (11.5 %) AEs were observed. At multivariate analysis, age (odds ratio [OR] 1.32, 1.09–2.14; p = 0.05), number of TTNB passes (OR from 2.17, 1.32–4.34 to OR 3.16, 2.03–6.34 with the increase of the number of passes), complete aspiration of the cyst (OR 0.56, 0.31–0.95; p = 0.02), and diagnosis of IPMN (OR 4.16, 2.27–7.69; p Conclusion TTNB should be selectively used in the evaluation of patients with IPMN. The present model could be applied during patient selection as to optimize the benefit/risk of TTNB.

To develop and validate a risk score for predicting clinical success after duodenal stenting using self-expanding metallic stents (SEMS) for malignant gastric outlet obstruction (GOO).Consecutive patients who underwent duodenal stenting for malignant GOO were evaluated. Potential predictors of clinical success were determined by uni/multivariate logistic regression analysis.Multiplication of the regression coefficients of the logistic regression model by a factor of two and rounding to obtain easy-to-use point numbers enabling the calculation of the score. Using 10-fold cross-validation, the model was internally validated.One hundred twelve patients were included. Clinical success was achieved in 93 (83.0%) patients. On multivariate logistic regression, selected age ≤65 years (p = 0.05, 1.5 points), stenosis type I (p = 0.04, 3 points), and pancreatic cancer (p = 0.01, 3.5 points) were significant predictors of clinical success. On the Receiver Operating Characteristic (ROC) analysis, a score of 5 had higher specificity and sensitivity.Our score could be useful at identifying, among poor surgical candidates, patients more likely to benefit from SEMS.

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.

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.

Background and aims: Therapy and prognosis of pancreatic neuroendocrine tumors (PanNETs) are strictly related to the Ki-67 index, which defines tumor grading. The criterion standard for the assessment of grading of PanNETs is EUS-guided FNA (EUS-FBAFNA) or EUS-guided fine-needle biopsy sampling (EUS-FNB). Because data on diagnostic accuracy of EUS-FNA and EUS-FNB are heterogeneous, we aimed to analyze the variability in concordance between EUS grading and surgical grading. Methods: The MEDLINE, SCOPUS, and EMBASE databases were searched until November 2021 to identify studies reporting the concordance rate between EUS grading and surgical grading. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled events were calculated using a random-effects model and expressed in terms of pooled prevalence rates. A multivariate meta-regression was performed to find possible sources of heterogeneity. Where available, individual data were analyzed. Results: Twenty-six studies with 864 patients undergone EUS-FNA or EUS-FNB and surgical resection for PanNETs were included. The pooled estimate rate for the overall concordance of EUS grading and surgical grading was 80.3% (95% confidence interval, 75.6-85.1). Undergrading (EUS grading< surgical grading) was significantly more frequent with respect to overgrading (14.7% vs 3.5%, P< .001). Individual data analysis showed that among nonconcordant patients, the median Ki-67 difference was 3% (interquartile range, 2-6.15). The type of World Health Organization classification adopted and the median lesion diameter were significantly associated with heterogeneity at meta-regression. Conclusions: EUS is an accurate technique in defining grading in patients with PanNETs, but a margin of error still exists, which should be the focus of future studies to minimize the risk of over- and/or undertreatment.

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.

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.

Intraparenchymal lung masses inaccessible through bronchoscopy or endobronchial ultrasound guidance pose a diagnostic challenge. Furthermore, some fragile or hypoxic patients may be poor candidates for transbronchial approaches. Endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) offers a potential diagnostic approach to lung cancers adjacent to the esophagus. We aimed to evaluate the feasibility, accuracy, and safety of trans-esophageal EUS-FNA/FNB for tissue sampling of pulmonary nodules.We retrospectively analyzed data from patients with pulmonary lesions who underwent EUS-FNA/FNB between March 2015 and August 2021 at eight Italian endoscopic referral centers.A total of 47 patients (36 male; mean age 64.47 ± 9.05 years) were included (22 EUS-FNAs and 25 EUS-FNBs). Overall diagnostic accuracy rate was 88.9% (76.3-96.2%). The sensitivity and diagnostic accuracy were superior for EUS FNB sampling versus EUS-FNA (100% vs. 78.73%); P = 0.05, and (100% vs. 78.57%); P = 0.05, respectively. Additionally, sample adequacy was superior for EUS-FNB sampling versus EUS-FNA (100% vs. 78.5%); P = 0.05. Multivariate logistic regression analysis for diagnostic accuracy showed nodule size at the cutoff of 15 mm (OR 2.29, 1.04-5.5, P = 0.05) and use of FNB needle (OR 4.33, 1.05-6.31, P = 0.05) as significant predictors of higher diagnostic accuracy. There were no procedure-related adverse events.This study highlights the efficacy and safety of EUS-FNA/FNB as a minimally invasive procedure for diagnosing and staging peri-esophageal parenchymal lung lesions. The diagnostic yield of EUS-FNB was superior to EUS-FNA.

BackgroundImmunotherapy has become the standard of care for non-small cell lung cancer (NSCLC) patients. Some patients experience primary resistance to immunotherapy. Currently, we lack a marker of resistance to immunotherapy. Myeloid-derived suppressive-like cells (MDSCs) can reduce tumor response rate and survival outcomes.MethodsThis is an exploratory prospective observational study on metastatic NSCLC patients starting immunotherapy. Baseline peripheral blood samples were collected. Monocytic (M)-MDSCs were analyzed by flow cytometry. The main clinical outcomes were tumor response, progression-free survival (PFS), and overall survival (OS). The association between MDSC levels and tumor response was assessed. The association of PFS with OS was investigated using the Kaplan–Meier method and the Cox proportional hazards model.ResultsTwenty-two patients were included. The median M-MDSC value was higher in patients with progressive disease than patients with stable disease or partial response, p = 0.045. The median MDSC value in the overall population was 1.9. We found worse PFS (HR = 2.51; p = 0.046) and OS (HR = 2.68; p = 0.042) in patients with M-MDSC values higher than the median.ConclusionsIn this exploratory analysis, high M-MDSC levels are strongly associated with primary resistance to immunotherapy. If validated in larger studies, MDSC levels in blood samples could help to select NSCLC patients for higher benefit from immunotherapy.

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.

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.

To generate a prognostic model based on a nomogram for adverse event (AE) prediction after lumen-apposing metal stents (LAMS) placement in patients with pancreatic fluid collections (PFC).Data from a large multicenter series of PFCs treated with LAMS placement were retrieved. AE (overall and excluding mild events) prediction was calculated through a logistic regression model and a nomogram was created and internally validated after bootstrapping. Results were expressed in terms of odds ratio (OR) and 95% confidence interval (CI). Discrimination was assessed by c-statistics and calibrated by comparing deciles of predicted and observed ORs.Overall, 516 patients were included (males 68%, mean age 61.6 ± 15.2 years). PFCs were predominantly walled-off necrosis (52.1%). Independent predictors of AE occurrence were injury of main pancreatic duct (OR in the case of leak 2.51, 95% CI 1.06-5.97, P = 0.03; OR in the case of complete disruption 2.61, 1.53-4.45, P = 0.01), abnormal vessels (OR in the case of perigastric varices 2.90, 1.31-6.42, P = 0.008; OR in the case of pseudoaneurysm 2.99, 1.75-11.93, P = 0.002), using a multigate technique (OR 3.00, 1.28-5.24; P = 0.05), and need of percutaneous drainage (OR 2.81, 1.03-7.65, P = 0.04). By nomogram, a score beyond 200 points corresponded to a 50% probability of AE occurrence. The model was confirmed even when excluding mild AEs and it showed optimal discrimination (c-index 76.8%, 95% CI 74-79), confirmed after internal validation.Patients with preprocedural evidence of pancreatic duct leak/disruption, vessel alteration, requiring percutaneous drainage or a multigate technique are at higher risk for AE.

The prevalence of inflammatory bowel disease (IBD) has been described in 5% to 40% of autoimmune pancreatitis (AIP) patients. The aim of our study was to evaluate the prevalence, endoscopic features, and outcome of IBD in association with AIP. A retrospective analysis including all consecutive patients with AIP and a histological diagnosis of IBD from 2010 to 2020 was performed. Demographical data, AIP, and IBD features, as well as clinical course, were recorded. Among 267 AIP patients, 45 were diagnosed with ulcerative colitis (UC) (27 men, mean age 31.6), all with a diagnosis of type 2 AIP. The most frequent presentation of AIP was acute pancreatitis (55.5%). Both diffuse (51.1%) and focal (48.9%) pancreatic involvement were observed. The AIP relapse rate was 11.1% over a mean follow-up of 55 months. In 69% of patients, the interval time between the diagnosis of AIP and UC was

Irisin is a myokine involved in the browning of white adipose tissue and regulation of energy expenditure, glucose homeostasis and insulin sensitivity. Debated evidence exists on the metabolic role played by irisin in children with overweight or obesity, while few information exist in children with Prader Willi Syndrome (PWS), a condition genetically prone to obesity. Here we assessed serum irisin in relation to the metabolic profile and body composition in children and adolescents with and without PWS. In 25 PWS subjects [age 6.6-17.8y; body mass index standard deviation score (BMI SDS) 2.5 ± 0.3] and 25 age, and BMI-matched controls (age 6.8-18.0y; BMI SDS, 2.8 ± 0.1) we assessed irisin levels and metabolic profile inclusive of oral glucose tolerance test (OGTT), and body composition by dual-energy X-ray absorptiometry (DXA). In PWS, we recorded lower levels of fat-free mass (FFM) (p 0 (p120 (p120. These results suggest a link between irisin levels and insulin sensitivity in two divergent models of obesity.

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.

There is increasing interest in expanding the use of lumen-apposing metal stents (LAMSs) in patients with pancreatic fluid collections (PFCs). The aim of this study was to determine whether there is a hospital volume threshold for which patient outcomes could be optimized.Data from a large multicenter series of patients with PFCs treated with LAMSs were retrieved. Rate of adverse events (AEs) was the primary outcome. Multivariable models with restricted cubic splines were used to identify a hospital volume threshold by plotting hospital volume against the log odds ratio (OR) of AE rate. Propensity score matching was applied to obtain 2 well-balanced groups according to hospital volume, and univariate/multivariate logistic regression analysis was performed to identify significant predictors of AEs.Overall, 516 patients were included. Increasing hospital volume was associated with a reduced AE rate (P = .03), and the likelihood of experiencing an AE declined as hospital volume increased up to 15 cases. After propensity score matching, 175 patients in the high-volume (15 cases) and 132 in the low-volume hospital group were compared. Overall, 41 AEs were observed (13.3%), of which 14 (8%) and 27 (20.4%) occurred at high-volume and low-volume centers, respectively (P = .001). Severe and fatal events were observed more frequently in low-volume centers (6% vs 1.7% and 2.2% vs 0%, respectively; P = .05). In multivariate analysis, main pancreatic duct injury (OR, 2.62; 95% confidence interval [CI], 1.26-4.67; P = .02), presence of abnormal vessels (OR, 2.93; 95% CI, 1.41-5.02; P = .006), and institutional experience (OR, 2.95; 95% CI, 1.48-5.90; P = .002) were significant predictors of AEs.With 15 procedures representing the minimum number of cases associated with the lowest risk for postprocedural AEs, hospital volume is associated with improved outcomes. (Clinical trial registration number: NCT03903523.).

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.

KRAS mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) KRAS on druggable targets can uncover new vulnerabilities for the treatment of KRAS mutant lung adenocarcinomas. Using commercially available KRAS mutant lung adenocarcinoma cell lines, we explored the influence of WT KRAS on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the KRAS WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the KRAS WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT KRAS impacts on signaling events and druggable targets in KRAS mutant lung adenocarcinomas.

Juvenile polyposis (JP) is a rare familial syndrome characterized by the development of numerous hamartomatous polyps of the gastrointestinal tract and by an increased risk of developing gastrointestinal cancers. It follows a pattern of autosomal dominant inheritance and is associated with germline variants of SMAD4 or BMPR1A genes. Differential diagnosis may be difficult based on histology alone, due to morphological similarities to other familial syndromes. Here we report a case of familial JP diagnosed in a 50-years woman with a familial history positive for gastrointestinal cancers and other tumor types. The patient presented with severe iron deficiency anemia and showed numerous polyps in the stomach and jejunum according to endoscopy and imaging. She underwent an intra-gastric laparoscopic removal of the major gastric polyp, followed by jejunal exploration and resection of a segment with multiple neoformations. Histological examination revealed the presence of hamartomatous polyposis. Gastric and intestinal samples were analyzed with next-generation sequencing. Molecular analysis showed that the patient harbored a germline splicing site variant of SMAD4, c.1139 + 3A > G, which was complemented by different somatic variants of the same gene in the different polyps. Immunohistochemistry for SMAD4 confirmed loss of protein expression in the polyps, with regular expression in normal cells. cDNA sequencing further confirmed the findings. We thus definitively diagnosed the woman as having JP thanks to an integrated approach based on histology, immunohistochemistry and molecular analysis. The identified variants, all previously reported as variants of unknown significance, were classified as pathogenic as they complemented each other leading to SMAD4 loss.

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.

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.

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...

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.

The interest for pancreatic neoplasm ablation under endoscopic ultrasound (EUS) guidance has increased during the last decade because of technology advancement and availability of dedicated devices for thermal ablation. The most commonly used technique is radiofrequency ablation (RFA). Currently, three needle-electrodes and one "through-the-needle" probe are available. Published studies mainly demonstrated the feasibility and safety of the procedure. However, the role of EUS-RFA for the treatment of pancreatic ductal adenocarcinoma is not yet well defined. Randomized studies are needed to assess any advantage in terms of survival and quality of life when RFA is included in a multimodal treatment strategy compared with chemo(radio)therapy alone. In the setting of pancreatic neuroendocrine tumors (pNETs), published studies are consistent in demonstrating the efficacy of EUS-RFA in relieving symptoms related to hormone secretion by functioning pNETs. Moreover, EUS-RFA could find a role even in selected patients with small non-functioning pNETs when treatment is indicated but surgical resection would like to be avoided. Finally, EUS-RFA can be applied also for the treatment of pancreatic cystic neoplasm. However, patients should be carefully selected taking into account the low incidence of progression of cystic neoplasms towards malignancy and factors related to the patient, such as age, symptoms, comorbidity, and life expectancy.

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.

INTRODUCTION : There is increasing evidence to support the efficacy of endoscopic ultrasound (EUS)-guided through-the-needle biopsy (TTNB) technique as a means of sampling pancreatic cystic lesions (PCLs). Results provide evidence demonstrating the benefits of this procedure over standard EUS fine-needle aspiration (FNA), thus supporting a push for its widespread implementation in clinical practice. Though this technique has demonstrated advantages, achieving these advantages in clinical practice is contingent upon careful considerations to ensure safety and efficacy. AREAS COVERED : The purpose of this review is to assess the level of evidence supporting the use of through-the-needle biopsy, revise its main technical and procedural characteristics, and to develop suggested guidelines outlining the safe assimilation of this device in clinical practice. EXPERT OPINION : EUS-TTNB enables more definitive and accurate diagnosis of PCLs by providing higher quality histological samples. However, EUS-TTNB is not appropriate for all PCLs. Selection of suitable patients as well as morphology and risk factors of the cystic lesion is a crucial component of achieving the described benefits of this procedure while minimizing risks of adverse effects. Subjects with weak or absent indications for this procedure are susceptible to a range of complications and may even result in fatality.

The mutational status of the epidermal growth factor receptor (EGFR) guides the stratification of non‐small cell lung cancer (NSCLC) patients for treatment with tyrosine kinase inhibitors (TKIs). A liquid biopsy test on cell‐free DNA is recommended as a clinical decision‐supporting tool, although it has limited sensitivity. Here, we comparatively investigated the extracellular vesicle (EV)‐RNA as an independent source for multidimensional and longitudinal EGFR profiling in a cohort of 27 NSCLC patients. We introduced and validated a new rapid, highly specific EV‐RNA test with wild‐type (WT) and mutant‐sensitive probes (E746‐A750del, L858R, and T790M). We included a cohort of 20 NSCLC patients with EGFR WT tumor tissues and systematically performed molecular EV‐RNA and circulating tumor DNA analyses with clinical data statistics and biophysical profiles of EVs. At the single‐patient level, we detected variegated tumor heterogeneity dynamics supported by combinations of driver EGFR mutations. EV‐RNA‐based mutation analysis showed an unprecedented sensitivity of over 90%. The resistance‐associated mutation T790M frequently pre‐existed at baseline with a gained EV‐transcript copy number at progression, while the general mutational burden was mostly decreasing during the intermediate follow‐up. The biophysical profile of EVs and the quantitative assessment of T790M revealed an association with tumor size determined by the sum of the longest diameters in target lesions. Vesicular RNA provides a validated tool suitable for use in clinical practice to investigate the dynamics of common driver EGFR mutations in NSCLC patients receiving TKIs., We applied a rapid and quantitative pipeline for detecting driver EGFR mutations in a retrospective cohort of NSCLC patients using circulating tumor DNA and extracellular vesicles' RNA (EV‐RNA) as independent longitudinal sources. The EV‐RNA provided sensitive and consistent dynamics of tumor heterogeneity with the potential to advance liquid biopsy tests in patients receiving tyrosine kinase inhibitors.

Evidence is limited on the comparative diagnostic performance of newer end-cutting fine-needle biopsy (FNB) needles for tissue sampling of pancreatic masses. We performed a systematic review with network meta-analysis to compare the diagnostic accuracy of available FNB needles for sampling of solid pancreatic lesions.A systematic literature review (Medline and Cochrane Database) was conducted for studies evaluating the accuracy of newer FNB needles in adults undergoing EUS-guided sampling of solid pancreatic masses. The primary outcome was diagnostic accuracy. Secondary outcomes were sample adequacy, diagnostic sensitivity, specificity, and adverse event rate. We performed pairwise and network meta-analyses and appraised the quality of evidence using Grading of Recommendations Assessment, Development and Evaluation methodology.Overall, 16 RCTs (1934 patients) were identified. On network meta-analysis, Franseen needles (Acquire; Boston Scientific, Marlborough, Mass, USA) significantly outperformed reverse-bevel needles (risk ratio [RR], 1.21 [95% confidence interval {CI}, 1.05-1.40] for accuracy and 1.31 [95% CI, 1.05-1.22] for adequacy) and FNA needles (RR, 1.21 [95% CI, 1.01-1.25] for accuracy and 1.07 [95% CI, 1.02-1.13] for adequacy). Likewise, the Fork-tip needle (SharkCore; Medtronic, Dublin, Ireland) was significantly superior to the reverse-bevel needle (RR, 1.17 [95% CI, 1.03-1.33] for accuracy and 1.09 [95% CI, 1.02-1.16] for adequacy) and to the FNA needle (RR, 1.09 [95% CI, 1.01-1.19] for accuracy and 1.03 [95% CI, 1.01-1.07] for adequacy). Other comparisons did not achieve statistical significance. As a consequence, Franseen (surface under the cumulative ranking score, .89 for accuracy and .94 for adequacy) and Fork-tip needles (surface under the cumulative ranking score, .76 for accuracy and .73 for adequacy) ranked as the 2 highest-performing FNB needles. When considering different needle sizes, 25-gauge Franseen and 25-gauge Fork-tip needles were not superior to 22-gauge reverse-bevel needles (RR, 1.18 [95% CI, .96-1.46] and 1.04 [95% CI, .62-1.52]). None of the tested needles was significantly superior to the other FNB devices or to FNA needles when rapid onsite cytologic evaluation was available.Franseen and Fork-tip needles, particularly 22-gauge size, showed the highest performance for tissue sampling of pancreatic masses, with low confidence in estimates.