Expression of Cellular and Extracellular TERRA, TERC and TERT in Hepatocellular Carcinoma

Non-coding RNAs are transcribed from telomeres and the telomeric repeat-containing RNAs (TERRA) are implicated in telomere homeostasis and in cancer. In this study, we aimed to assess in hepatocellular carcinoma (HCC) the cellular and extracellular expression of TERRA, the telomerase RNA subunit (TERC) and the telomerase catalytic subunit (TERT). We determined by qPCR the expression level of TERRA 1_2_10_13q, TERRA 15q, TERRA XpYp, TERC and of TERT mRNA in HCC tissues and in the plasma of HCC patients. Further, we profiled the same transcripts in the HCC cell lines, HA22T/VGH and SKHep1C3, and in the extracellular vesicles (EVs) derived from their secretomes. We found that the expression of TERRA and TERT mRNA was significantly deregulated in HCC, being TERRA downregulated and TERT mRNA upregulated in HCC tissues vs. the peritumoral (PT) ones, and the receiver operating characteristic (ROC) curve analyses revealed a significant ability in discriminating HCC from PT tissue. Further, the determinations of circulating TERRA and TERC showed higher amounts of these transcripts in the plasma of HCC patients vs. controls and ROC analyses gave significant results. The expression characterization of the cultured HCC cells showed their ability to produce and secrete TERRA and TERC into the EVs; the ability to produce TERT mRNA that was not detectable in the EVs; and the ability to respond to sorafenib treatment increasing TERRA expression. Our results highlight that: (i) both cellular and extracellular expressions of TERRA and TERC are dysregulated in HCC as well as the cellular expression of TERT mRNA and (ii) the combined detection of TERRA and TERC in plasma may represent a promising approach for non-invasive diagnostic molecular indicators of HCC

Laparoscopic treatment of ventral hernias: the Italian national guidelines

Primary and incisional ventral hernias are significant public health issues for their prevalence, variability of professional practices, and high costs associated with the treatment In 2019, the Board of Directors of the Italian Society for Endoscopic Surgery (SICE) promoted the development of new guidelines on the laparoscopic treatment of ventral hernias, according to the new national regulation. In 2022, the guideline was accepted by the government agency, and it was published, in Italian, on the SNLG website. Here, we report the adopted methodology and the guideline's recommendations, as established in its diffusion policy. This guideline is produced according to the methodology indicated by the SNGL and applying the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Fifteen recommendations were produced as a result of 4 PICO questions. The level of recommendation was conditional for 12 of them and conditional to moderate for one. This guideline's strengths include relying on an extensive systematic review of the literature and applying a rigorous GRADE method. It also has several limitations. The literature on the topic is continuously and rapidly evolving; our results are based on findings that need constant re-appraisal. It is focused only on minimally invasive techniques and cannot consider broader issues (e.g., diagnostics, indication for surgery, pre-habilitation)

Different ways to manage Indocyanine green fluorescence to different purposes in liver surgery. A systematic review.

Fluorescent properties of indocyanine green (ICG) for hepatic tumor identification and features have been recently studied. The aim is to review the published data on the use of ICG enhanced fluorescence surgery during liver resection. A systematic search of literature was performed using MEDLINE, EMBASE, Cochrane and Web of Science libraries. For all eligible studies, the following data were extracted: study design, number of cases, management of indocyanine green (dose, time and method of administration), type of surgery, outcome variables, false positive and accuracy value, if reported. For statistical analysis, it was considered significant P<0.05, when published. 19 articles were fully analyzed and data were extracted. A total of 718 cases were globally analyzed as study group. No side effects of ICG were reported in any articles. 12 prospective observational, 1 randomized and 2 case-control studies were found. Three case reports and one experimental on animal model were also included. Detection of superficial lesions, segmental staining, biliary anatomy investigation (biliary leakage detection, biliary tree anatomy) were the main clinical application of fluorescence liver guided surgery. The overall quality of the data currently available is limited but the role of fluorescence guided liver surgery seems promising

Recurrence in node-negative advanced gastric cancer: Novel findings from an in-depth pathological analysis of prognostic factors from a multicentric series

AIM: To analyze the clinicopathological characteristics of patients with both node-negative gastric carcinoma and diagnosis of recurrence during follow-up. METHODS: We enrolled 41 patients treated with curative gastrectomy for pT2-4aN0 gastric carcinoma between 1992 and 2010, who developed recurrence (Group 1). We retrospectively selected this group from the prospectively collected database of 4 centers belonging to the Italian Research Group for Gastric Cancer, and compared them with 437 pT2-4aN0 patients without recurrence (Group 2). We analyzed lymphatic embolization, microvascular infiltration, perineural infiltration, and immunohistochemical determination of p53, Ki67, and HER2 in Group 1 and in a subgroup of Group 2 (Group 2bis) of 41 cases matched with Group 1 according to demographic and pathological characteristics. RESULTS: T4a stage and diffuse histotype were associated with recurrence in the group of pN0 patients. In-depth pathological analysis of two homogenous groups of pN0 patients, with and without recurrence during longterm follow-up (groups 1 and 2bis), revealed two striking patterns: lymphatic embolization and perineural infiltration (two parameters that pathologists can easily report), and p53 and Ki67, represent significant factors for recurrence. CONCLUSION: The reported pathological features should be considered predictive factors for recurrence and could be useful to stratify node-negative gastric cancer patients for adjuvant treatment and tailored follow-up

Effects of pre-operative isolation on postoperative pulmonary complications after elective surgery: an international prospective cohort study

We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05-1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4-7 days or >= 8 days of 1.25 (1.04-1.48), p = 0.015 and 1.31 (1.11-1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care

Perforated and bleeding peptic ulcer : WSES guidelines

Background Peptic ulcer disease is common with a lifetime prevalence in the general population of 5-10% and an incidence of 0.1-0.3% per year. Despite a sharp reduction in incidence and rates of hospital admission and mortality over the past 30 years, complications are still encountered in 10-20% of these patients. Peptic ulcer disease remains a significant healthcare problem, which can consume considerable financial resources. Management may involve various subspecialties including surgeons, gastroenterologists, and radiologists. Successful management of patients with complicated peptic ulcer (CPU) involves prompt recognition, resuscitation when required, appropriate antibiotic therapy, and timely surgical/radiological treatment. Methods The present guidelines have been developed according to the GRADE methodology. To create these guidelines, a panel of experts was designed and charged by the board of the WSES to perform a systematic review of the available literature and to provide evidence-based statements with immediate practical application. All the statements were presented and discussed during the 5th WSES Congress, and for each statement, a consensus among the WSES panel of experts was reached. Conclusions The population considered in these guidelines is adult patients with suspected complicated peptic ulcer disease. These guidelines present evidence-based international consensus statements on the management of complicated peptic ulcer from a collaboration of a panel of experts and are intended to improve the knowledge and the awareness of physicians around the world on this specific topic. We divided our work into the two main topics, bleeding and perforated peptic ulcer, and structured it into six main topics that cover the entire management process of patients with complicated peptic ulcer, from diagnosis at ED arrival to post-discharge antimicrobial therapy, to provide an up-to-date, easy-to-use tool that can help physicians and surgeons during the decision-making process.Peer reviewe

Optimized EGFR blockade strategies in <i>EGFR</i> addicted gastroesophageal adenocarcinomas

Purpose: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents.Experimental Design: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX).Results: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition.Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors