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Lung cancer (LC) is the deadliest malignancy worldwide. In an operable stage I–III patient setting, the detection of minimal residual disease (MRD) after curative treatment could identify patients at higher risk of relapse. In this context, the study of circulating tumor DNA (ctDNA) is emerging as a useful tool to identify patients who could benefit from an adjuvant treatment, and patients who could avoid adverse events related to a more aggressive clinical management. On the other hand, ctDNA profiling presents technical, biological and standardization challenges before entering clinical practice as a decisional tool. In this paper, we review the latest advances regarding the role of ctDNA in identifying MRD and in predicting patients’ prognosis, with a particular focus on clinical trials investigating the potential of ctDNA, the technical challenges to address and the biological parameters that influence the MRD detection.

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.

A 57-year-old woman with epigastric pain was diagnosed with a 6-cm abdominal cystic lesion of unclear origin on cross-sectional imaging. Endoscopic ultrasound (EUS) demonstrated a unilocular cyst located between the pancreas, gastric wall, and left adrenal gland, with a regular wall filled with dense fluid with multiple hyperechoic floating spots. A 19-G needle was used to puncture the cyst, but no fluid could be aspirated. Therefore, EUS-guided through-the-needle biopsy (EUS-TTNB) was performed. Histological analysis of the retrieved fragments revealed a fibrous wall lined by “respiratory-type” epithelium with ciliated columnar cells, consistent with the diagnosis of a bronchogenic cyst. Laparoscopic excision was performed, and the diagnosis was confirmed based on the findings of the surgical specimen. Abdominal bronchogenic cysts are extremely uncommon, and a definitive diagnosis is commonly obtained after the examination of surgical specimens due to the lack of pathognomonic findings on cross-sectional imaging and poor cellularity on EUS-guided fine-needle aspiration cytology. EUS-TTNB is useful for establishing a preoperative histological diagnosis, thus supporting the decision-making process.

Non-small-cell lung cancer (NSCLC) is the primary cause of cancer-related death. Gene rearrangements involving the anaplastic lymphoma kinase (ALK) tyrosine kinase identify a clinical and molecular subset of NSCLC patients, who benefit from the monotherapy with ALK tyrosine kinase inhibitors. Nonetheless, responsiveness to TKIs and prognosis of these patients are influenced by several factors, including resistance mechanisms and mutations affecting genes involved in key molecular pathways of cancer cells. In a cohort of 98 NSCLC patients with ALK gene rearrangements, we investigated the role of Tumor Protein (TP53) gene mutations in predicting patients prognosis. TP53 mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).Results: In patients with available clinical and TP53 mutation information, we found that 13 patients (20.3%) were affected by TP53 mutations. Considered together, even though showing a trend, TP53 mutations were not associated with PFS and OS. Considering the different TP53 mutations by functionality in terms of disruptive and non-disruptive mutations, we observed that TP53 non-disruptive mutations were able to predict worse OS in the overall case series. Moreover, a worse PFS was seen in the subgroup of patients with TP53 non-disruptive mutation, in first-, second-, and third line of treatment. Our results show that mutations affecting TP53 gene, especially non-disruptive mutations, are able to affect prognosis of ALK-rearranged NSCLC patients.

Abstract 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.

The relationship between chronic intestinal disease, including inflammatory bowel disease (IBD) and celiac disease (CelD), and pancreatic disorders has been little investigated. Although an increased risk of acute pancreatitis (AP), exocrine pancreatic insufficiency with or without chronic pancreatitis, and chronic asymptomatic pancreatic hyperenzymemia have been described in these patients, the pathogenetic link remains unclear. It may potentially involve drugs, altered microcirculation, gut permeability/motility with disruption of enteric-mediated hormone secretion, bacterial translocation, and activation of the gut-associated lymphoid tissue related to chronic inflammation. In addition, the risk of pancreatic cancer seems to be increased in both IBD and CelD patients with unknown pathogenesis. Finally, other systemic conditions (e.g., IgG4-related disease, sarcoidosis, vasculitides) might affect pancreatic gland and the intestinal tract with various clinical manifestations. This review includes the current understandings of this enigmatic association, reporting a clinical and pathophysiological overview about this topic.

Background: Same-session endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) is an attractive policy for patients with distal malignant biliary obstruction (DMBO) requiring fine-needle biopsy (FNB) and biliary drainage. However, scanty and conflicting data exists regarding safety and efficacy when comparing these two procedures performed in same versus separate sessions. Methods: Single-center, retrospective, propensity score-matched study including patients with DMBO who underwent EUS-FNB followed by ERCP during the same or separate sessions. The primary outcome was the safety of the procedure [number of patients experiencing adverse events (AEs), overall AEs, its severity, post-ERCP pancreatitis (PEP)]. Secondary outcomes were successful ERCP, use of advanced cannulation techniques, EUS-FNB adequacy, length of hospital stay, overall procedure time, and time to recurrent biliary obstruction. Results: After propensity matching, 87 patients were allocated to each group. AEs developed in 23 (26.4%) vs. 17 (19.5%) patients in the same and separate sessions group, respectively (p = 0.280). The overall number, the severity of AEs, and the rate of PEP were similar in the two groups. Secondary outcome parameters were also comparable in the 2 groups. Conclusions: Same-session EUS-FNB followed by ERCP with biliary drainage is safe and does not impair technical outcomes of tissue adequacy and biliary cannulation. [ABSTRACT FROM AUTHOR]

Pancreatic cystic lesions (PCLs) pose a diagnostic challenge due to their increasing incidence and the limitations of cross-sectional imaging and endoscopic-ultrasound-guided fine-needle aspiration (EUS-FNA). EUS-guided through the needle biopsy (EUS-TTNB) has emerged as a promising tool for improving the accuracy of cyst type determination and neoplastic risk stratification. EUS-TTNB demonstrates superior diagnostic performance over EUS-FNA, providing critical preoperative information that can significantly influence patient management and reduce unnecessary surgeries. However, the procedure has risks, with an overall adverse event rate of approximately 9%. Preventive measures and further prospective studies are essential to optimize its safety and efficacy. This review highlights the potential of EUS-TTNB to enhance the diagnostic and management approaches for patients with PCLs. It examines the current state of EUS-TTNB, including available devices, indications, procedural techniques, specimen handling, diagnostic yield, clinical impact, and associated adverse events. [ABSTRACT FROM AUTHOR]

Abstract We consider de Sitter vacua realised in concrete type IIB Calabi-Yau compactifications with an anti D3-brane at the tip of a warped throat of Klebanov-Strassler type. The Kähler moduli are stabilised together with the complex structure modulus of the warped throat. The volume is exponentially large as in the large volume scenario (LVS). We analyse the conditions on the parameters of the EFT such that they are in the region of validity of our approximations, there are no runaway problems and the vacua satisfy all consistency constraints, such as tadpole cancellation. We illustrate our results with an explicit Calabi-Yau orientifold with two Kähler moduli and one antibrane on top of an O3-plane in a warped throat, that has the goldstino as its only massless state. The moduli are stabilised with g s ∼ 0.2 and volume V $$ \mathcal{V} $$ ∼ 104 in string units, justifying the approximation used to derive the corresponding EFT. Although the model lacks chiral matter, it is presented as a proof of concept, chosen to be the simplest realisation of antibrane uplift.

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

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.

BackgroundThe quality of gastrointestinal (GI) endoscopy has been recently identified as a major priority being associated with many outcomes and patient's experience.ObjectiveTo assess adherence of endoscopists to the European Society of Gastrointestinal Endoscopy (ESGE) quality performance measures for upper and lower GI endoscopy in Italy.MethodsAll endoscopist members of the Italian Society of Digestive Endoscopy (SIED) were invited from October 2018 to December 2018 to participate to a self-administered questionnaire-based survey. The questionnaire included questions on demographics and professional characteristics, and the recent ESGE quality performance measures for upper and lower GI endoscopy.ResultsA total of 392 endoscopists participated in the study. Only a minority (18.2%) of participants recorded the duration of esophagogastroduodenoscopy (EGD) and 51% provided accurate photo documentation in the minimum standard of 90% of cases. Almost all endoscopists correctly used Prague and Los Angeles classifications (87.8% and 98.2%, respectively), as well as Seattle and Management of precancerous conditions and lesions in the stomach (MAPS) biopsy protocols (86.5% and 91.4%, respectively). However, only 52.8% of participants monitored complications after therapeutic EGD, and 40.8% recorded patients with a diagnosis of Barrett's esophagus (BE). With regard to colonoscopy, almost all endoscopists (93.9%) used the Boston Bowel Preparation Scale for measuring bowel preparation quality and reported a cecal intubation rate ≥90%. However, about a quarter (26.2%) of participants reported an adenoma detection rate of

Background/ObjectivesThe present study aimed to validate the Italian version of the Hyperphagia Questionnaire (HQ), a 11-items questionnaire developed to assess hyperphagia in individuals with Prader-Willi syndrome (PWS). This is a complex neurodevelopmental disorder characterized by endocrine dysfunction, hypotonia, intellectual disability, psychiatric disorders and obesity.MethodsParents of 219 individuals with PWS (age range 3–54 years; Mage = 17.90; 108 Males), recruited in 12 hospitals in Italy responded to HQ during routine visits. In function of the level of analyses the sample was divided into two subgroups ( years) or into four age-subgroups (2.5–4.5; 4.5–8; 8–18; >18 years) corresponding to different clinical stages.ResultsConfirmatory factor analysis (CFA) confirmed the three hyperphagic subdimensions of the original structure (behavior, drive, and severity), but one item was dropped out, reducing the final version to 10 items. Using multi-group CFA, HQ showed satisfactory indexes of measurement invariance by age. Good indexes of internal consistency (Cronbach's alpha and McDonald's Omega coefficients) were found for each subdimension. The three hyperphagia subdimensions positively converged with other food-related measures: emotional overeating, food enjoyment, food responsiveness, and satiety responsiveness. A significant increase of all hyperphagic subdimensions was found across age groups. Higher hyperphagic levels were found in participants with higher body mass index. Hyperphagic drive differently increased in function of the interaction between age and underlying genetic mechanisms.ConclusionThe Italian version of the HQ is a psychometrically valid and reliable instrument for assessing hyperphagia in individuals with PWS. This tool may prove useful to evaluate the efficacy of pharmacologic and rehabilitative treatments.

In the frame of metabolic syndrome, type 2 diabetes emerges along a continuum of the risk from the clustering of all its components, namely visceral obesity, high blood pressure and lipids, and impaired glucose homeostasis. Insulin resistance is the hallmark common to all the components and, in theory, is a reversible condition. Nevertheless, the load that this condition can exert on the β-cell function at the pubertal transition is such as to determine its rapid and irreversible deterioration leading to plain diabetes. The aim of this review is to highlight, in the context of metabolic syndrome, age-specific risk factors that lead to type 2 diabetes onset in youth; resume age specific screening and diagnostic criteria; and anticipate potential for treatment. Visceral obesity and altered lipid metabolism are robust grounds for the development of the disease. Genetic differences in susceptibility to hampered β-cell function in the setting of obesity and insulin resistance largely explain why some adolescents with obesity do develop diabetes at a young age and some others do not. Lifestyle intervention with a healthy diet and physical activity remains the pillar of the type 2 diabetes treatment in youth. As to the pharmacological management, metformin and insulin have failed to rescue β-cell function and to ensure long-lasting glycemic control in youth. A new era might start with the approval for use in pediatric age of drugs largely prescribed in adults, such as dipeptidyl peptidase-4 and sodium-dependent glucose transport inhibitors, and of new weight-lowering drugs in the pipeline such as single and multiple agonists of the glucagon-like peptide 1 receptor. The latter drugs can have tremendous impact on the natural history of the disease. By treating diabetes, they will reduce the burden of all the metabolic abnormalities belonging to the syndrome while causing a tremendous weight loss hitherto never seen before.

Introduction: The development of dedicated endoscopes and the technical evolution of endoscopic ultrasound (EUS) have allowed a direct approach to pancreatic neoplastic lesions both for diagnosis and treatment. Among the more promising targets are pancreatic neuroendocrine tumors (Pan-NETs). Aim: to describe the evolution of endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) with particular attention to the treatment of PanNETs, focusing on safety and clinical efficacy of the technique. Methods: MEDLINE, Scopus, and Cochrane Library databases were searched for studies reporting about EUS-RFA for the treatment of PanNETs. Studies with outcomes of interest were selected and results were reported to describe clinical success, complications, fol-low-ups, and electrodes used. Clinical success was defined as the disappearance of clinical symp-toms for functional (F-) PanNETs and as complete ablation per nonfunctional (NF)-PanNETs. The pooled data were analyzed by a random-effects model. Results: Nineteen studies were selected, including 183 patients (82 males, 44.8%) with 196 lesions (101 F-PanNETs and 95 NF-PanNETs). Pooled estimates for the overall AE rates for the clinical efficacy were 17.8% (95% CI 9.1–26.4%) and 95.1% (95% CI 91.2–98.9%) for F-PanNETs and 24.6% (95% CI 7.4–41.8%) and 93.4% (95% CI 88.4–98.4%) for NF-PanNETs. Conclusions: EUS-RFA appears to be a mini-invasive technique with a good safety and efficacy profile for the treatment of F- and NF-PanNETs. EUS-RFA could be of-fered as possible alternative to surgery for the treatment of low-grade NF- or F-PanNETs, especially for those patients that are not eligible or are at high-risk for surgery.