Analysis of the burden and economic impact of digestive diseases and investigation of research gaps and priorities in the field of digestive health in the European Region—White Book 2: Executive summary

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Insight toward the microRNA profiling of laryngeal cancers: Biological role and clinical impact

Head and neck squamous cell carcinoma (HNSCC), a heterogeneous disease arising from various anatomical locations including the larynx, is a leading cause of death worldwide. Despite advances in multimodality treatment, the overall survival rate of the disease is still largely dismal. Early and accurate diagnosis of HNSCC is urgently demanded in order to prevent cancer progression and to improve the quality of the patient’s life. Recently, microRNAs (miRNAs), a family of small non-coding RNAs, have been widely reported as new robust tools for prediction, diagnosis, prognosis, and therapeutic approaches of human diseases. Abnormally expressed miRNAs are strongly associated with cancer development, resistance to chemo-/radiotherapy, and metastatic potential through targeting a large variety of genes. In this review, we summarize on the recent reports that emphasize the pivotal biological roles of miRNAs in regulating carcinogenesis of HNSCC, particularly laryngeal cancer. In more detail, we report the characterized miRNAs with an evident either oncogenic or tumor suppressive role in the cancers. In addition, we also focus on the correlation between miRNA deregulation and clinical relevance in cancer patients. On the basis of intriguing findings, the study of miRNAs will provide a new great opportunity to access better clinical management of the malignancies

miRNA signature predittivo di metastasi linfonodali da carcinoma della laringe

The discovery that miRNAs are frequently deregulated in tumours offers the opportunity to identify them as prognostic and diagnostic markers. The aim of this multicentric study is to identify a miRNA expression profile specific for laryngeal cancer. The secondary endpoint was to identify specific deregulated miRNAs with potential as prognostic biomarkers for tumour spread and nodal involvement, and specifically to search for a miRNA pattern pathognomonic for N+ laryngeal cancer and for N-tissues. We identified 20 miRNAs specific for laryngeal cancer and a tissue-specific miRNA signature that is predictive of lymph node metastases in laryngeal carcinoma characterized by 11 miRNAs, seven of which are overexpressed (upregulated) and four downregulated. These results allow the identification of a group of potential specific tumour biomarkers for laryngeal carcinoma that can be used to improve its diagnosis, particularly in early stages, as well as its prognosis

Overview on Molecular Biomarkers for Laryngeal Cancer: Looking for New Answers to an Old Problem

Laryngeal squamous cell cancer (LSCC) accounts for almost 25–30% of all head and neck squamous cell cancers and is clustered according to the affected districts, as this determines distinct tendency to recur and metastasize. A major role for numerous genetic alterations in driving the onset and progression of this neoplasm is emerging. However, major efforts are still required for the identification of molecular markers useful for both early diagnosis and prognostic definition of LSCC that is still characterized by significant morbidity and mortality. Non-coding RNAs appear the most promising as they circulate in all the biological fluids allowing liquid biopsy determination, as well as due to their quick and characteristic modulation useful for non-invasive detection and monitoring of cancer. Other critical aspects are related to recent progress in circulating tumor cells and DNA detection, in metastatic status and chemo-refractoriness prediction, and in the functional interaction of LSCC with chronic inflammation and innate immunity. We review all these aspects taking into account the progress of the technologies in the field of next generation sequencing

Future research demands of the United European Gastroenterology (UEG) and its member societies

AIMS: The purpose of this study was to initiate and stimulate collaborative research efforts to support United European Gastroenterology Federation (UEG) member societies facilitating digestive health research in European on the one hand and, on the other hand, to increase EU-funded digestive health research by providing evidence and advice to funding bodies on priority areas. The UEG Research Committee initiated a survey of the current and future research interests of each individual UEG ordinary member society (specialist societies). METHODS: A questionnaire was sent by mail to 17 UEG ordinary member societies asking them to specify research demands related to the most urgent medical need including basic science research, translational research, clinical research, patient management research and research on disease prevention, in an open fashion but with limited word count. RESULTS: The responses from 13 societies were analysed in a semi-quantitative and in a qualitative way, and were clustered into five domains with two aspects each that were consented and shared between three and seven of the responding 13 societies. These clusters resemble topics such as ‘Hot topics’ (e.g. life-style, nutrition, microbial-host interaction), Biomarkers (genetic profiling, gut-brain interaction), Advanced technology (artificial intelligence, personalised medicine), Global research tools (bio-banking, EU trials), and Medical training (education, prevention). CONCLUSION: The generated topic list allows both collaboration between individual specialist societies as well as initiating and fostering future research calls at the EU level and beyond when approaching stakeholders

Definition of miRNA Signatures of Nodal Metastasis in LCa: miR-449a Targets Notch Genes and Suppresses Cell Migration and Invasion

The need to identify molecular markers for early detection of laryngeal cancer prompted Kawasaki et al. to define a miRNA signature of tumor transformation and spreading. They showed the diagnostic and predictive potential of miR-133b and miR-449a, respectively, and demonstrated miR-449a-mediated suppression of the metastatic factors Notch1 and Notch2

Poorly differentiated neuroendocrine larynx carcinoma: Clinical features and mirnas signature—a new goal for early diagnosis and therapy?

Laryngeal neuroendocrine carcinomas (LNECs) are rare and highly heterogeneous malignancies presenting a wide range of pathological and clinical manifestations. Herein, we retrospectively characterize ten patients diagnosticated with LNEC, five of which were defined as well‐moderately differentiated neuroendocrine carcinomas, and five that were defined as poorly differentiated neuroendocrine carcinomas, according to the latest WHO classification. Clinical features were analyzed and compared between the two subgroups together with a microRNA study which evidenced a peculiar signature likely related to poorly differentiated larynx neuroendocrine carcinomas. These findings may offer new useful insights for clinicians to improve diagnosis efficiency, therapy response, and patients’ outcome for this aggressive neoplasm

Combined low densities of FoxP3+ and CD3+ tumor-infiltrating lymphocytes identify stage II colorectal cancer at high risk of progression

The densities of CD3+ and CD8+ tumor-infiltrating lymphocytes (TILs), combined with TNM (tumor-node-metastasis) staging, have prognostic value for nonmetastatic colorectal cancer (CRC) patients. We compared the prognostic value of CD3+ and FoxP3+ TILs at the invasive front, TNM classifiers, and microsatellite (MS) status in a trial set of patients with stage II-III CRC (n = 413), by recursive partitioning with a classification and regression tree (CART). Significant prognostic factors and interactions were re-assessed by logistic regression and Cox proportional-hazards modeling in the trial and a validation set (n = 215) of patients with stage II CRC. In the trial set, CART indicated that TIL numbers were of value only in predicting recurrence risk for stage II cancers, where low densities of FoxP3+ TILs ranked first and low densities of CD3+ TILs further stratifiying risk. Multivariate analysis showed that TILs interacted with tumor stage (FoxP3+, P = 0.06; CD3+, P = 0.02) and MS instability (FoxP3+; P = 0.02). In stage II MS-stable cancers, concomitant low densities of both FoxP3+ and CD3+ TILs identified patients with the highest progression risk in the trial (HR 7.24; 95%CI, 3.41-15.4; P < 0.001) and the validation (HR 15.16; 95% IC, 3.43-66.9; P < 0.001) sets. FoxP3+ and CD3+ TIL load in CRC was more informative than other prognostic factors before the cancer progressed to lymph nodes. This prognostic information about TILs, including FoxP3+ cells, suggests that randomized controlled trials might be refined to include interactions between TNM status, molecular classifiers, and post-surgical treatments

Association between hMLH1 hypermethylation and JC virus (JCV) infection in human colorectal cancer (CRC)

Incorporation of viral DNA may interfere with the normal sequence of human DNA bases on the genetic level or cause secondary epigenetic changes such as gene promoter methylation or histone acetylation. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the USA. Chromosomal instability (CIN) was established as the key mechanism in cancer development. Later, it was found that CRC results not only from the progressive accumulation of genetic alterations but also from epigenetic changes. JC virus (JCV) is a candidate etiologic factor in sporadic CRC. It may act by stabilizing β-catenin, facilitating its entrance to the cell nucleus, initialing proliferation and cancer development. Diploid CRC cell lines transfected with JCV-containing plasmids developed CIN. This result provides direct experimental evidence for the ability of JCV T-Ag to induce CIN in the genome of colonic epithelial cells. The association of CRC hMLH1 methylation and tumor positivity for JCV was recently documented. JC virus T-Ag DNA sequences were found in 77% of CRCs and are associated with promoter methylation of multiple genes. hMLH1 was methylated in 25 out of 80 CRC patients positive for T-Ag (31%) in comparison with only one out of 11 T-Ag negative cases (9%). Thus, JCV can mediate both CIN and aberrant methylation in CRC. Like other viruses, chronic infection with JCV may induce CRC by different mechanisms which should be further investigated. Thus, gene promoter methylation induced by JCV may be an important process in CRC and the polyp-carcinoma sequence