MicroRNAs as possible biomarkers for diagnosis and prognosis of hepatitis b- and c-related-hepatocellularcarcinoma

Aim of the present review is to summarize the current knowledge about the potential relationship between mi RNAs and hepatitis B virus(HBV)-hepatitis C virus(HCV) related liver diseases. A systematic computerbased search of published articles, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis Statement, was performed to identify relevant studies on usefulness of serum/plasma/urine mi RNAs, as noninvasive biomarkers for early detection of HBV and HCV-induced hepatocellular carcinoma(HCC) development, as well as for its prognostic evaluation. The used Medical Subject Headings terms and keywords were: "HBV", "HCV", "hepatocellular carcinoma", "micro RNAs", "mi RNAs", "diagnosis", "prognosis", "therapy", "treatment". Some serum/plasma mi RNAs, including mi R-21, mi R-122, mi-125a/b, mi R-199a/b, mi R-221, mi R-222, mi R-223, mi R-224 might serve as biomarkers for early diagnosis/prognosis of HCC, but, to date, not definitive results or well-defined panels of mi RNAs have been obtained. More well-designed studies, focusing on populations of different geographical areas and involving larger series of patients, should be carried out to improve our knowledge on the potential role of mi RNAs for HCC early detection and prognosis.

Levofloxacin/amoxicillin-based schemes vs quadruple therapy for Helicobacter pylori eradication in second-line

Worldwide prevalence of Helicobacter pylori(H.pylori) infection is approximately 50%,with the highest being in developing countries.We compared cure rates and tolerability(SE) of second-line anti-H.pylori levofloxacin/amoxicillin(LA)-based triple regimens vs standard quadruple therapy(QT).An English language literature search was performed up to October 2010.A meta-analysis was performed including randomized clinical trials comparing 7-or 10-d LA with 7-d QT.In total,10 articles and four abstracts were identified.Overall eradication rate in LA was 76.5%(95% CI:64.4%-97.6%).When only 7-d regimens were included,cure rate was 70.6%(95% CI:40.2%-99.1%),whereas for 10-d combinations,cure rate was significantly higher(88.7%;95% CI:56.1%-109.9%;P < 0.05).Main eradication rate for QT was 67.4%(95% CI:49.7%-67.9%).The 7-d LA and QT showed comparable efficacy [odds ratio(OR):1.09;95% CI:0.63-1.87],whereas the 10-d LA regimen was significantly more effective than QT(OR:5.05;95% CI:2.74-9.31;P < 0.001;I 2 = 75%).No differences were reported in QT eradication rates among Asian and European studies,whereas LA regimens were more effective in European populations(78.3% vs 67.7%;P = 0.05).Incidence of SE was lower in LA therapy than QT(OR:0.39;95% CI:0.18-0.85;P = 0.02).A higher rate of side effects was reported in Asian patients who received QT.Our findings support the use of 10-d LA as a simple second-line treatment for H.pylori eradication with an excellent eradication rate and tolerability.The optimal second-line alternative scheme might differ among countries depending on quinolone resistance.

Tumor budding as a potential histopathological biomarker in colorectal cancer:Hype or hope?

Colorectal cancer （CRC）, the third most commonly di- agnosed type of cancer in men and women worldwide is recognized as a complex multi-pathway disease, an observation sustained by the fact that histologically identical tumors may have different outcome, including various response to therapy. Therefore, particularly in early and intermediate stage （stages Ⅱ and Ⅲ, respec- tively） CRC, there is a compelling need for biomarkers helpful of selecting patients with aggressive disease that might benefit from adjuvant and targeted therapy. Histopathological examination shows that likely other solid tumors the development and progression of hu- man CRC is not only determined by genetically abnor- mal cells, but also by intricate interactions between malignant cells and the surrounding microenvironment. This has led to reconsider the features of tumor mi- croenvironment as potential predictive and prognostic biomarkers. Among the histopathological biomarkers, tumor budding （i.e., the presence of individual cells and small clusters of tumor cells at the tumor invasive front）has received much recent attention, particularly in the setting of CRC. Although its acceptance as a reportable factor has been held back by a lack of uniformity with respect to qualitative and quantitative aspects, tumor budding is now considered as an independent adverse prognostic factor in CRC that may allow for stratifica- tion of patients into risk categories more meaningful than those defined by tumor-node-metastasis staging alone, and also potentially guide treatment decisions, especially in T2-T3 NO （stage Ⅱ） CRCs.

Prognostic value of innate and adaptive immunity in colorectal cancer

Colorectal cancer(CRC) remains one of the major public health problems throughout the world.Originally depicted as a multi-step dynamical disease,CRC develops slowly over several years and progresses through cytologically distinct benign and malignant states,from single crypt lesions through adenoma,to malignant carcinoma with the potential for invasion and metastasis.Moving from histological observations since a long time,it has been recognized that inflammation and immunity actively participate in the pathogenesis,surveillance and progression of CRC.The advent of immunohistochemical techniques and of animal models has improved our understanding of the immune dynamical system in CRC.It is well known that immune cells have variable behavior controlled by complex interactions in the tumor microenvironment.Advances in immunology and molecular biology have shown that CRC is immunogenic and that host immune responses influence survival.Several lines of evidence support the concept that tumor stromal cells,are not merely a scaffold,but rather they influence growth,survival,and invasiveness of cancer cells,dynamically contributing to the tumor microenvironment,together with immune cells.Different types of immune cells infiltrate CRC,comprising cells of both the innate and adaptive immune system.A relevant issue is to unravel the discrepancy between the inhibitory effects on cancer growth exerted by the local immune response and the promoting effects on cancer proliferation,invasion,and dissemination induced by some types of inflammatory cells.Here,we sought to discuss the role played by innate and adaptive immune system in the local progression and metastasis of CRC,and the prognostic information that we can currently understand and exploit.

Metrically measuring liver biopsy:A chronic hepatitis B and C computer-aided morphologic description

AIM： To describe a quantitative analysis method for liver biopsy sections with a machine that we have named ＂Dioguardi Histological Metriser＂ which automatically measures the residual hepatocyte mass （including hepatocytes vacuolization）, inflammation, fibrosis and the loss of liver tissue tectonics.METHODS： We analysed digitised images of liver biopsy sections taken from 398 patients, The analysis with Dioguardi Histological Metriser was validated by comparison with semi-quantitative scoring system.RESULTS： The method provides： （1） the metrical extension in two-dimensions （the plane） of the residual hepatocellular set, including the area of vacuoles pertinent to abnormal lipid accumulation; （2） the geo- metric measure of the inflammation basin, which distinguishes intra-basin space and extra-basin dispersed parenchymal leukoo/tes; （3） the magnitude of collagen islets, （which were considered truncated fractals and classified into three degrees of magnitude）; and （4） the tectonic index that quantifies alterations （disorders） in the organization of liver tissue. Dioguardi Histological Metriser machine allows to work at a speed of 0.1 mm^2/s, scanning a whole section in 6-8 min.CONCLUSION： The results are the first standardized metrical evaluation of the geometric properties of the parenchyma, inflammation, fibrosis, and alterations in liver tissue tectonics of the biopsy sections. The present study confirms that biopsies are still valuable, not only for diagnosing chronic hepatitis, but also for quantifying changes in the organization and order of liver tissue structure.

Enhanced endoscopic ultrasound imaging for pancreatic lesions: The road to artificial intelligence

Early detection of pancreatic cancer has long eluded clinicians because of its insidious nature and onset.Often metastatic or locally invasive when symptomatic,most patients are deemed inoperable.In those who are symptomatic,multi-modal imaging modalities evaluate and confirm pancreatic ductal adenocarcinoma.In asymptomatic patients,detected pancreatic lesions can be either solid or cystic.The clinical implications of identifying small asymptomatic solid pancreatic lesions(SPLs)of<2 cm are tantamount to a better outcome.The accurate detection of SPLs undoubtedly promotes higher life expectancy when resected early,driving the development of existing imaging tools while promoting more comprehensive screening programs.An imaging tool that has matured in its reiterations and received many image-enhancing adjuncts is endoscopic ultrasound(EUS).It carries significant importance when risk stratifying cystic lesions and has substantial diagnostic value when combined with fine needle aspiration/biopsy(FNA/FNB).Adjuncts to EUS imaging include contrast-enhanced harmonic EUS and EUS-elastography,both having improved the specificity of FNA and FNB.This review intends to compile all existing enhancement modalities and explore ongoing research around the most promising of all adjuncts in the field of EUS imaging,artificial intelligence.

Liver fibrosis and tissue architectural change measurement using fractal-rectified metrics and Hurst's exponent

AIM： To provide the accurate alternative metrical means of monitoring the effects of new antiviral drugs on the reversal of newly formed collagen. METHODS： Digitized histological biopsy sections taken from 209 patients with chronic C virus hepatitis with different grade of fibrosis or cirrhosis, were measured by means of a new, rapid, user-friendly, fully computeraided method based on the international system meter rectified using fractal principles. RESULTS： The following were described： geometric perimeter, area and wrinkledness of fibrosis; the collation of the Knodell, Sheuer, Ishak and METAVIR scores with fractal-rectified metric measurements; the meaning of the physical composition of fibrosis in relation to the magnitude of collagen islets; the intra- and inter-biopsy sample variability of these parameters; the ＂staging＂ of biopsy sections indicating the pathway covered by fibrosis formation towards its maximum known value; the quantitative liver tissue architectural changes with the Hurst exponent. CONCLUSION： Our model provides the first metrical evaluations of the geometric properties of fibrosis and the quantitative architectural changes of the liver tissue. The representativeness of histological sections of the whole liver is also discussed in the light of the results obtained with the Hurst coefficient.

Celiac disease: From pathophysiology to treatment

Celiac disease, also known as "celiac sprue", is a chronic inflammatory disorder of the small intestine, produced by the ingestion of dietary gluten products in susceptible people. It is a multifactorial disease, including genetic and environmental factors. Environmental trigger is represented by gluten while the genetic predisposition has been identified in the major histocompatibility complex region. Celiac disease is not a rare disorder like previously thought, with a global prevalence around 1%. The reason of its under-recognition is mainly referable to the fact that about half of affected people do not have the classic gastrointestinal symptoms, but they present nonspecific manifestations of nutritional deficiency or have no symptoms at all. Here we review the most recent data concerning epidemiology, pathogenesis, clinical presentation, available diagnostic tests and therapeutic management of celiac disease.

Localized intra-abdominal fibromatosis of the small bowel mimicking a gastrointestinal stromal tumor: A case report

Intra-abdominal fibromatosis （IAF） is a benign mesenchymal lesion that can occur throughout the gastrointestinal tract. Although rare, it is the most common primary tumor of the mesentery and can develop at any age. We describe a rare case of primary IAF involving the mesentery and small bowel which clinically, macroscopically and histologically mimicked malignant gastrointestinal stromal tumor （GIST）. This report highlights the fact that benign IAF can be misdiagnosed as a malignant GIST localized in the mesentery or arising from the intestinal wall. Their diagnostic discrimination is essential because of their very different biological behaviors and the fact that the introduction of effective therapies involving tyrosine kinase inhibitor ST1571 （imatinib mesylate） has greatly changed the clinical approach to intra-abdominal stromal spindle cell tumors.

Possible association between hepatitis C virus and malignancies different from hepatocellular carcinoma:A systematic review

AIM: To summarize the current knowledge about the potential relationship between hepatitis C virus(HCV) infection and the risk of several extra-liver cancers. METHODS: We performed a systematic review of the literature, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis(PRISMA) Statement. We extracted the pertinent articles, published in MEDLINE and the Cochrane Library, using the following search terms: neoplasm/cancer/malignancy/tumor/carcinoma/adeno-carcinoma and non-Hodgkin lymphomas, kidney/renal-, cholangio-, pancreatic-, thyroid-, breast-,oral-, skin-, prostate-, lung-, colon-, stomach-, haematologic. Case series, case-series with control-group, case-control, cohort-studies as well as meta-analyses, written in English were collected. Some of the main characteristics of retrieved trials, which were designed to investigate the prevalence of HCV infection in each type of the above-mentioned human malignancies were summarised. A main table was defined and included a short description in the text for each of these tumours, whether at least five studies about a specific neoplasm, meeting inclusion criteria, were available in literature. According to these criteria, we created the following sections and the corresponding tables and we indicated the number of included or excluded articles, as well as of meta-analyses and reviews:(1) HCV and haematopoietic malignancies;(2) HCV and cholangiocarcinoma;(3) HCV and pancreatic cancer;(4) HCV and breast cancer;(5) HCV and kidney cancer;(6) HCV and skin or oral cancer; and(7) HCV and thyroid cancer. RESULTS: According to available data, a clear correlation between regions of HCV prevalence and risk of extra-liver cancers has emerged only for a very small group of types and histological subtypes of malignancies. In particular, HCV infection has been associated with:(1) a higher incidence of some B-cell Non-HodgkinLymphoma types, in countries, where an elevated prevalence of this pathogen is detectable, accounting to a percentage of about 10%;(2) an increased risk of intra-hepatic cholangiocarcinoma; and(3) a correlation between HCV prevalence and pancreatic cancer(PAC) incidence. CONCLUSION: To date no definitive conclusions may be obtained from the analysis of relationship between HCV and extra-hepatic cancers. Further studies, recruiting an adequate number of patients are requiredto confirm or deny this association.

Immunological treatment of liver tumors

Although multiple options for the treatment of liver tumors have often been described in the past, including liver resection, radiofrequency ablation with or without hepatic pump insertion, laparoscopic liver resection and the use of chemotherapy, the potential of immunotherapy and gene manipulation is still largely unexplored.Immunological therapy by gene manipulation is based on the interaction between virus-based gene delivery systems and dendritic cells. Using viruses as vectors, it is possible to transduce dendritic cells with genes encoding tumor-associated antigens, thus inducing strong humoral and cellular immunity against the antigens themselves.Both chemotherapy and radiation therapy have the disadvantage of destroying healthy cells, thus causing severe side-effects. We need more precisely targeted therapies capable of killing cancer cells while sparing healthy cells. Our goal is to establish a new treatment for solid liver tumors based on the concept of cytoreduction,and propose an innovative algorithm.

Sampling variability of computer-aided fractal-corrected measures of liver fibrosis in needle biopsy specimens

AIM： TO assess the sampling variability of computeraided, fractal-corrected measures of fibrosis in liver biopsies. METHODS： Samples were derived from six to eight different parts of livers removed from 12 patients with clinically and histologically proven cirrhosis undergoing orthotopic liver transplantation. Sirius red-stained sections with a thickness of 2 μm were digitized using a computer-aided image analysis system that automatically measures the surface of fibrosis, as well as its outline perimeter, fractal surface and outline dimensions, wrinldedness, and Hurst coefficient. RESULTS： We found a high degree of inter-sample variability in the measurements of the surface [coefficient of variation （CV） = 43% ± 13%] and wrinkledness （CV = 28% ± 9%） of fibrosis, but the inter-sample variability of Hurst＇s exponent was low （CV = 14% ± 2%）. CONCLUSION： This study suggests that Hurst＇s exponent might be used in clinical practice as the best histological estimate of fibrosis in the whole organ, and evidences the fact that biopsy sections, which are fundamental for the qualitative diagnosis of chronic hepatitis, play a key role in the quantitative estimate of architectural changes in liver tissue.

Fractal nature of human gastrointestinal system:Exploring a new era

The morphological complexity of cells and tissues,whether normal or pathological,is characterized by two primary attributes:Irregularity and self-similarity across different scales.When an object exhibits self-similarity,its shape remains unchanged as the scales of measurement vary because any part of it resembles the whole.On the other hand,the size and geometric characteristics of an irregular object vary as the resolution increases,revealing more intricate details.Despite numerous attempts,a reliable and accurate method for quantifying the morphological features of gastrointestinal organs,tissues,cells,their dynamic changes,and pathological disorders has not yet been established.However,fractal geometry,which studies shapes and patterns that exhibit self-similarity,holds promise in providing a quantitative measure of the irregularly shaped morphologies and their underlying self-similar temporal behaviors.In this context,we explore the fractal nature of the gastrointestinal system and the potential of fractal geometry as a robust descriptor of its complex forms and functions.Additionally,we examine the practical applications of fractal geometry in clinical gastroenterology and hepatology practice.