Tiziana Morbin

Background/Objectives: Esophageal and esophagogastric junction adenocarcinoma (EADC-EGJA), which mainly develops from Barrett’s esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), has a poor prognosis and several unmet clinical needs, among which is the detection of minimal residual disease (MRD) after endoscopic/surgical resection. Long interspersed nuclear element-1 (LINE-1), a surrogate marker of global methylation, is considered an emerging biomarker for MRD monitoring. The aim of this study was to determine, by LINE-1 methylation analysis, at which carcinogenesis step global methylation is affected and whether this biomarker could be followed in longitudinal to monitor the disease behavior post-surgery. Methods: Cell-free DNA of 90 patients with non-dysplastic Barrett’s esophagus (NDBE), HGD/early EADC-EGJA, or locally advanced/advanced EADC-EGJA were analyzed for LINE-1 methylation, by Methylation-Sensitive Restriction Enzyme droplet digital PCR (MSRE-ddPCR). Twenty-six patients were longitudinally studied by repetitive blood sampling. Results: Global hypomethylation increased during carcinogenesis, with significant difference between locally advanced/advanced EADC-EGJA and NDBE patients (p = 0.028). Longitudinal cases confirmed the rareness of hypomethylation in NDBE cases. The majority of HGD/early EADC-EGJA and locally advanced/advanced EADC-EGJA patients showed methylation changes after resection according to clinical status. Conclusions: This study suggests that global hypomethylation occurs just prior to cancer invasiveness and that it is a promising biomarker to monitor MRD.

Background: Incidence of pancreatic cancer (PC) is increasing worldwide and is set to become the second leading cause of cancer-related death in 2040 with a poor 5-year overall survival (OS). The aim of this study was to analyze the impact of microscopic diagnosis of PC (MiDPC) on diagnostic–therapeutic management and outcome. Methods: The Veneto region (north-eastern Italy) has been covered by a cancer registry (CR) since 1987. Clinical and oncological data about all cases of PC in the Veneto region from 1987 were extracted from the Veneto CR database. Results: In 2018, 1340 incident cases of PC in the Veneto population were registered (4.1% of all malignant tumors), with an increasing trend in females and stable incidence in males. Five-year OS in patients with PC was 8%. The percentage of MiDPC increased from 44% in 2010 to 60% in 2018 (p = 0.001). MiDPC was higher among patients aged < 75 years old (84.4%) compared to those aged ≥75 years old (38.9%), p = 0.001. Between 2010 and 2018, a significant increase in biopsy on the primary neoplasm (24.9% vs. 13%, p < 0.001) was reported. Patients with MiDPC had higher 5-year survival than patients with no MiDPC (12.9% vs. 1.2%, p < 0.001). Conclusions: The implementation of MiDPC was essential to improve diagnostic–therapeutic pathways and consequently the survival of PC patients.

Obesity and associated insulin resistance (Ins-R) have been identified as important risk factors for esophageal adenocarcinoma development. Elevated calories and protein consumption are also associated with Ins-R and glucose intolerance. We investigated the effect of a 24-month moderate calorie and protein restriction program on overweight or obese patients affected by Barrett’s esophagus (BE), as no similar dietary approach has been attempted to date in this disease context. Anthropometric parameters, levels of serum analytes related to obesity and Ins-R, and the esophageal insulin/IGF-1 signaling pathway were analyzed. This study is registered with ClinicalTrials.gov, number NCT03813381. Insulin, C-peptide, IGF-1, IGF-binding protein 3 (IGFBP3), adipokines, and esophageal expression of the main proteins involved in insulin/IGF-1 signal transduction were quantified using Luminex-XMAP^® technology in 46 patients who followed the restriction program (IA) and in 54 controls (CA). Body mass index and waist circumference significantly decreased in 76.1% of IA and 35.2% of CA. IGF-1 levels were reduced in 71.7% of IA and 51.8% of CA. The simultaneous reduction of glycaemia, IGF-1, the IGF-1/IGFBP3 ratio, and the improvement in weight loss-dependent insulin sensitivity, were associated with the downregulation of the insulin/IGF-1 signal on BE tissue. The proposed intervention program was an effective approach to counteract obesity-associated cancer risk factors. The improvement in metabolic condition resulted in a downregulation of the ERK-mediated mitogenic signal in 43.5% of patients, probably affecting the molecular mechanism driving adenocarcinoma development in BE lesions.