Massimo Rugge

MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets

Small non‐coding microRNAs (miRNAs) contribute to cancer development and progression, and are differentially expressed in normal tissues and cancers. However, the specific role of miRNAs in the metastatic process is still unknown. To seek a specific miRNA expression signature characterizing the metastatic phenotype of solid tumours, we performed a miRNA microarray analysis on 43 paired primary tumours (ten colon, ten bladder, 13 breast, and ten lung cancers) and one of their related metastatic lymph nodes. We identified a metastatic cancer miRNA signature comprising 15 overexpressed and 17 underexpressed miRNAs. Our results were confirmed by qRT‐PCR analysis. Among the miRNAs identified, some have a well‐characterized association with cancer progression, eg miR‐10b, miR‐21, miR‐30a, miR‐30e, miR‐125b, miR‐141, miR‐200b, miR‐200c, and miR‐205. To further support our data, we performed an immunohistochemical analysis for three well‐defined miRNA gene targets (PDCD4, DHFR, and HOXD10 genes) on a small series of paired colon, breast, and bladder cancers, and one of their metastatic lymph nodes. We found that the immunohistochemical expression of these targets significantly follows the corresponding miRNA deregulation. Our results suggest that specific miRNAs may be directly involved in cancer metastasis and that they may represent a novel diagnostic tool in the characterization of metastatic cancer gene targets. Copyright

Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report

Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.

Gastric dysplasia: the Padova international classification.

A worldwide-accepted histologic, classification of the gastric carcinomatous and precancerous lesions is a prerequisite for a consistent recording of epidemiologic data and for both developing and evaluating primary and secondary preventive efforts. Different nomenclatures have been proposed for gastric precancerous lesions in eastern countries and in Japan. This article presents a classification of gastric precancerous lesions resulting from an international consensus conference involving pathologists of different countries. Five main diagnostic categories are identified. To allow comparisons with the nomenclature proposed by the Japanese Research Society for Gastric Cancer, each category was also assigned a numeric identification: 1 = normal, 2 = indefinite for dysplasia, 3 = noninvasive neoplasia, 4 = suspicious for invasive cancer, and 5 = cancer. The interobserver reproducibility of the histologic classification was tested in a series of 46 cases. By collapsing benign alterations (categories 1+2) versus noninvasive neoplasia (category 3) versus suspicious for invasive cancer and fully appearing carcinomatous lesions (categories 4+5), the general agreement value was 77.7%, whereas kappa coefficient was 0.63. By examining gastric precancerous lesions from diverse populations, the authors agreed that the gastric precancerous process is universal and the differences in nomenclatures are merely semantics. The international Padova classification of the gastric precancerous lesions is submitted to the attention of the international scientific community, which is invited to test and to improve on it.

Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma.

Objective:To determine the long-term results of liver transplantation for well- or moderately differentiated hepatocellular carcinoma (HCC). Summary Background Data:HCC patient selection for liver transplantation remains controversial, and deciding exclusively on the strength of criteria such as number and size of nodules appears prognostically inaccurate. Methods:Since 1991, preoperative tumor grading has been used at our center to establish whether a patient with HCC is fit for transplantation. Poorly differentiated HCC cases were excluded, while size and number of nodules were not considered as absolute selection criteria. Thirty-three patients with moderately or well-differentiated HCC were prospectively studied after liver transplantation. A group of 15 patients with incidental HCC transplanted during the same period were also evaluated and compared with the 33 patients with preoperatively diagnosed HCC. Results:On histologic examination, 38% of the entire group of 48 patients did not meet the “Milan criteria” and 42% were pTNM stages III and IV. The median follow-up was 44 months. The 5-year actuarial survival rate was 75% and recurrence-free survival was 92%. HCC recurred in only 3 patients (6%). The only histomorphologic variable differing significantly between incidental and nonincidental HCC was nodule size. The timing of diagnosis (incidental vs. nonincidental HCC), the Milan criteria, and the TNM stage revealed no statistically significant impact on overall and recurrence-free survival rates. Conclusions:The routine pre-orthotopic liver transplantation tumor grading may represent a valid tool in the selection of unresectable HCC patients for transplantation.

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Germ-Layer Specification and Control of Cell Growth by Ectodermin, a Smad4 Ubiquitin Ligase

TGF-beta signaling is essential for development and proliferative homeostasis. During embryogenesis, maternal determinants act in concert with TGF-beta signals to form mesoderm and endoderm. In contrast, ectoderm specification requires the TGF-beta response to be attenuated, although the mechanisms by which this is achieved remain unknown. In a functional screen for ectoderm determinants, we have identified Ectodermin (Ecto). In Xenopus embryos, Ecto is essential for the specification of the ectoderm and acts by restricting the mesoderm-inducing activity of TGF-beta signals to the mesoderm and favoring neural induction. Ecto is a RING-type ubiquitin ligase for Smad4, a TGF-beta signal transducer. Depletion of Ecto in human cells enforces TGF-beta-induced cytostasis and, moreover, plays a causal role in limiting the antimitogenic effects of Smad4 in tumor cells. We propose that Ectodermin is a key switch in the control of TGF-beta gene responses during early embryonic development and cell proliferation.

Oxidative DNA damage accumulation in gastric carcinogenesis

Background—Gastric carcinogenesis is a multifactorial, multistep process, in which chronic inflammation plays a major role. Aims—In order to ascertain whether free radical mediated oxidative DNA damage is involved in such a process, concentrations of 8-hydroxydeoxyguanosine (8OHdG), a mutagenic/carcinogenic adduct, and thiobarbituric acid reactive substances (TBARS), as an indirect measure of free radical mediated damage, were determined in biopsy specimens from patients undergoing endoscopy. Patients—Eighty eight patients were divided into histological subgroups as follows: 27 with chronic non-atrophic gastritis, 41 with atrophic gastritis, six with gastric cancer, and 14 unaffected controls. Methods—Intestinal metaplasia,Helicobacter pylori infection, and disease activity were semiquantitatively scored. 8OHdG concentrations were assessed by HPLC with electrochemical detection, and TBARS concentrations were fluorimetrically assayed. Results—8OHdG concentrations (mean number of adducts/105 dG residues) were significantly higher in chronic atrophic gastritis (p=0.0009). Significantly higher concentrations were also detected in the presence of severe disease activity (p=0.02), intestinal metaplasia (p=0.035), and H pylori infection (p=0.001). TBARS concentrations were also higher in atrophic gastritis, though not significantly so. In a multiple logistic regression analysis, 8OHdG concentrations correlated best with the presence and severity of H pylori infection (r=0.53, p=0.002). Conclusions—Chronic gastritis is characterised by the accumulation of oxidative DNA damage with mutagenic and carcinogenic potential. H pylori infection is the major determinant for DNA adduct formation.

Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading

Background and aims : Considerable difficulties persist amongst pathologists in agreeing on the presence and severity of gastric atrophy. An international group of pathologists pursued the following aims: (i) to generate an acceptable definition and a simple reproducible classification of gastric atrophy; and (ii) to develop guidelines for the recognition of atrophy useful for increasing agreement among observers.

Gastritis staging in clinical practice: the OLGA staging system

Background: The available classifications of gastritis are inconsistently used, possibly because none provides immediate prognostic/therapeutic information to clinicians. As histology reporting of hepatitis in terms of stage is clinically useful and widely accepted, an international group (Operative Link on Gastritis Assessment (OLGA)) proposed an equivalent staging system for reporting gastric histology. Gastritis staging integrates the atrophy score (obtained by biopsy) and the atrophy topography (achieved through directed biopsy mapping). Aim: To test in a prospective cross-sectional study whether OLGA staging consistently stratified patients according to their cancer risk and provided clear prognostic/therapeutic information. Methods: OLGA staging for gastric cancer risk (0–IV) and gastritis grading (overall score of the inflammatory infiltrate, grade 1–4) were applied in 439 prospectively enrolled, consecutive, dyspeptic outpatients who underwent endoscopy with standardised biopsy sampling. Incidental neoplastic lesions and coexisting peptic ulcers were recorded. Results were presented as stage (including antral (A) and corpus (C) atrophy scores) and H pylori status (eg, A = 3; C = 2: stage IV; Hp+ve). Results: Benign conditions (including duodenal ulcers; p<0.001) consistently clustered in stages 0–II, whereas all neoplastic (invasive and non-invasive) lesions clustered in stages III–IV (p<0.001). Conclusions: Gastritis staging, combined with H pylori status, provided clinically relevant information on the overall status of the gastric mucosa with implications for prognosis, therapy and management.

Gastric epithelial dysplasia in the natural history of gastric cancer: A multicenter prospective follow-up study

BACKGROUND/AIMS Because the precancerous significance of gastric epithelial dysplasia (GED) is still under debate, this study attempts to ascertain whether a prospective follow-up of GED can contribute to clarifying its clinical and pathological relationships with gastric cancer (GC). METHODS One hundred twelve patients with mild (G1), moderate (G2), and severe (G3) GED or diagnosed as indefinite for dysplasia were prospectively followed up with a standardized endoscopic and bioptic protocol. RESULTS Evaluation of GED outcome refers only to 93 patients with a follow-up period longer than 12 months. Regression of dysplasia was documented in 36%, 27%, and 0% of G1, G2, and G3 GED cases, respectively. Progression to more severe dysplasia or evolution into GC was detected in 21%, 33%, and 57% of G1, G2, and G3 GED cases, respectively. Evolution into GC was documented for all grades of dysplasia and correlated significantly with high-grade atrophic gastritis. A high prevalence of early GC (86.9%) was also observed. CONCLUSIONS GED is a pre-invasive lesion, and carcinomatous evolution increases proportionally with its histological grade. Bioptical follow-up is mandatory for all histological grades of GED and significantly increases the likelihood of GC being detected in its early stages.