Challenges and perspectives for immunotherapy in oesophageal cancer: A look to the future (Review).

Oesophageal cancer is one of the most aggressive malignancies with limited treatment options, thus resulting in a high morbidity and mortality. With 5­year survival rates of only 5­10%, oesophageal cancer holds a dismal prognosis for patients. In order to improve overall survival, the early diagnosis and tools for patient stratification for personalized treatment are urgent needs. A minority of oesophageal cancers belong to the spectrum of Lynch syndrome­associated cancers and are characterized by microsatellite instability (MSI). Microsatellite instability is a consequence of defective mismatch repair protein functions and it has been well characterized in other gastrointestinal tumours, such as colorectal and gastric cancer. In the latter, high levels of MSI are associated with a better prognosis and with an increased benefit to immune­based therapies. Therefore, similar therapeutic approaches could offer an opportunity of treatment for oesophageal cancer patients with MSI. Apart from immune checkpoint inhibitors, other immunotherapies such as adoptive T­cell transfer, peptide vaccine and oncolytic viruses are under investigation in oesophageal cancer patients. In the present review, the rationale and current knowledge about immunotherapies in oesophageal cancer are summarised.

MicroRNAs (miRNAs) and Long Non-Coding RNAs (lncRNAs) as New Tools for Cancer Therapy: First Steps from Bench to Bedside.

Non-coding RNAs represent a significant proportion of the human genome. After having been considered as 'junk' for a long time, non-coding RNAs are now well established as playing important roles in maintaining cellular homeostasis and functions. Some non-coding RNAs show cell- and tissue-specific expression patterns and are specifically deregulated under pathological conditions (e.g. cancer). Therefore, non-coding RNAs have been extensively studied as potential biomarkers in the context of different diseases with a focus on microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) for several years. Since their discovery, miRNAs have attracted more attention than lncRNAs in research studies; however, both families of non-coding RNAs have been established to play an important role in gene expression control, either as transcriptional or post-transcriptional regulators. Both miRNAs and lncRNAs can regulate key genes involved in the development of cancer, thus influencing tumour growth, invasion, and metastasis by increasing the activation of oncogenic pathways and limiting the expression of tumour suppressors. Furthermore, miRNAs and lncRNAs are also emerging as important mediators in drug-sensitivity and drug-resistance mechanisms. In the light of these premises, a number of pre-clinical and early clinical studies are exploring the potential of non-coding RNAs as new therapeutics. The aim of this review is to summarise the latest knowledge of the use of miRNAs and lncRNAs as therapeutic tools for cancer treatment.

Immune-Based Therapies and the Role of Microsatellite Instability in Pancreatic Cancer.

Pancreatic cancer is one of the most aggressive malignancies with limited treatment options thus resulting in high morbidity and mortality. Among all cancers, with a five-year survival rates of only 2-9%, pancreatic cancer holds the worst prognostic outcome for patients. To improve the overall survival, an earlier diagnosis and stratification of cancer patients for personalized treatment options are urgent needs. A minority of pancreatic cancers belong to the spectrum of Lynch syndrome-associated cancers and are characterized by microsatellite instability (MSI). MSI is a consequence of defective mismatch repair protein functions and it has been well characterized in other gastrointestinal tumors such as colorectal and gastric cancer. In the latter, high levels of MSI are linked to a better prognosis and to an increased benefit to immune-based therapies. Therefore, the same therapies could offer an opportunity of treatment for pancreatic cancer patients with MSI. In this review, we summarize the current knowledge about immune-based therapies and MSI in pancreatic cancer.

DNA methylation in patients with colorectal cancer--correlation with some clinical and morphological features and with local tumour invasion.

AIM: To study quantitatively the promoter methylation of hMLH1, p16INK, TIMP3 and TPEF genes in patients with colorectal cancer and synchronous polyps, and correlate it with some clinicomorphological features. METHODS: DNA was extracted from all studied tumours and the corresponding normal mucosa. Microsatellite instability was analysed using two mononucleotide (BAT 25 and BAT 26) and three dinucleotide markers (D2S123, D5S356, D17S250) and automated DNA sequencing. Quantitative analysis of methylation was performed using DNA bisulfite modification, PCR with biotinylated primers, visualisation by 2% agarose gel electrophoresis and pyrosequencing. RESULTS: High methylation levels of hMLH1 and p16INK were found in elderly patients (mean age 73.8 +/- 9.5 years and 65.7 +/- 16.6 years, p < 0.03, t-test). Proximal tumours were more often associated with microsatellite instability (p < 0.05, Fisher's test) and higher level of methylation of hMLH1, p16INK and TIMP3 (p < 0.02, Kruskal-Wallis test), while tumours with poor differentiation tended to have higher methylation of the p16INK gene (p < 0.02, Kruskal-Wallis test). Local tumour invasion was correlated with the level of methylation of hMLH1, TIMP3 and the CpG island methylator phenotype (CIMP) status. Tumours with liver metastases showed a lower level of TIMP3 methylation than tumours with no systemic invasion (p < 0.05, Kruskal-Wallis test). We found concordance of methylation in 56% of the cases with colonic cancer and synchronous adenomas; the remaining 44% were discordant. CONCLUSIONS: Tumours with microsatellite instability, high level methylation and CIMP have distinctive clinical and morphological features. The level of hMLH1 and TIMP3 methylation and CIMP status can be correlated with the local tumour invasion. Different mechanisms, even for one and the same patient, can be responsible for the development of more than one third of the synchronous polyps and carcinomas.