The aim of this article is to emphasize the impact of the immune response in digestive cancers, especially from colorectal (CRC) origin. In this setting, an adaptive lymphocytic infiltrate underlines the prognostic impact of the immune response, because it is associated to a favorable outcome. The next challenge will be to validate, in a prospective therapeutic trial, the integration of the immune response as decisional parameter for adjuvant therapy. The immune response is also a predictive parameter in microsatellite instable metastatic CRC, characterized by an adaptive lymphocytic infiltrate, leading to a very high response rate to immune therapies. However, prognostic and predictive biomarkers still need to be optimized in order to better select patients. These data are also valuable for digestive non-colorectal cancers, which are briefly analyzed. The methodology for the assessment of these prognostic and predictive biomarkers, which represents an important issue in precision medicine, is also discussed.

Pre-mRNA splicing is an obligatory step required to assemble the vast majority of mRNAs in eukaryotes. In humans, each gene gives rise to at least two transcripts, with an average 6-8 spliced transcripts per gene. Pre-mRNA splicing is not unequivocal. Variations may occur, such that splicing can become alternative, thereby participating in increasing protein variability and restricting the gap that exists between the relatively low number of genes - between 20,000 and 25,000 in humans - and the much higher number of distinct proteins - at least 100,000. In addition, although alternative pre-mRNA splicing often fulfils cell-specific needs, many aberrant splicing events can happen and lead to either hereditary or acquired diseases such as neurodegenerative diseases or cancers. In those cases, alternative splicing events may serve as disease-associated markers, or even as targets for corrective approaches. In this review, we will summarize the main aspects of regulated alternative splicing. We will present the spliceosome, a large ribonucleoprotein complex that orchestrates the splicing reactions and that was recently identified as a preferential target for mutations in several pathologies. We shall discuss some spliceosome-associated defects linked to either cis (i.e on the DNA) or trans (e.g. in proteins) alterations of splicing machinery, like those that have been reported in genetic or acquired diseases.

Carcinomas are rare tumors of the adolescent-young adult (AYA) with a different spectrum from those of adults. The most common sites outside of the thyroid is the nasopharynx, salivary gland, colon-rectum and ovaries. If nasopharyngeal carcinoma or salivary gland tumors are good prognosis, others are more reserved prognosis, such as digestive carcinomas, gynecological or midline. The revelation modes are non-specific and depend on the location: mass, tumor syndrome, pain, impaired general condition. The unusual of pediatric carcinomas led to propose a systematic oncogenetic exploration. The medical history of the family, the symptoms and the type of the carcinoma should guide the analysis. In the absence of guidance, analysis of TP53 gene and, for carcinomas of the expanded spectrum of the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, the search for mutation of MMR genes (mismatch repair) seems essential. Because of the rarity of these diseases and the absence of homogeneous recommendations, members of the rare tumors committee of the SFCE recommended for the management of these AJA, an histological review by a pathologist familiar with carcinomas of the adult, a double discussion between pediatric and adult oncologists, analysis of adult standards with adaptation to pediatric data, especially in terms of risk of side effects. An advice to a national opinion (by a member of FRACTURE group) or European (group EXPERT) is sometimes necessary in the most complex situations.

The concept of big data indicates a change of scale in the use of data and data aggregation into large databases through improved computer technology. One of the current challenges in the creation of big data in the context of radiation therapy is the transformation of routine care items into dark data, i.e. data not yet collected, and the fusion of databases collecting different types of information (dose-volume histograms and toxicity data for example). Processes and infrastructures devoted to big data collection should not impact negatively on the doctor-patient relationship, the general process of care or the quality of the data collected. The use of big data requires a collective effort of physicians, physicists, software manufacturers and health authorities to create, organize and exploit big data in radiotherapy and, beyond, oncology. Big data involve a new culture to build an appropriate infrastructure legally and ethically. Processes and issues are discussed in this article.

Since the first draft of the human genome sequence published in 2001, the cost of sequencing has dramatically decreased. The development of new technologies such as next generation sequencing led to a comprehensive characterization of a large number of tumors of various types as well as to significant advances in precision medicine. Despite the valuable information this technological revolution has allowed to produce, the vast amount of data generated resulted in the emergence of new challenges for the biomedical community, such as data storage, processing and mining. Here, we describe the contribution and challenges of Big Data in oncology.

Overcoming the drug resistance remains a crucial issue in cancer treatment. For refractory patients, the use of MET receptor tyrosine kinase inhibitors seems to be hopeful. Indeed, important mechanisms underlying drug resistance argue for association of MET inhibitors with targeted therapies, both on first-line to prevent a primary resistance and on the second line to overcoming acquired resistance. Indeed, met gene amplification is the second most common alteration involved in acquired resistance to anti-epidermal growth factor receptor (EGFR) therapies in non-small cells lung cancer (NSCLC). Hypoxia, for its part, can activate MET transcription and amplifies HGF signaling resulting in MET activation, which could be involved in vascular endothelial growth factor (VEGF) inhibitors escape. In HER2 positive breast cancers, MET amplification may also induce tumor cells a hatch escape, resulting in secondary resistance. Finally, some patients with BRAF mutated melanoma exhibit primary resistance to BRAF inhibition by stromal HGF (ligand of MET) secretion resulting in MET receptor activation. Experimental data highlight the role of MET in primary and secondary resistance and encourage combined treatments including MET inhibitors. In this context, several promising clinical trials are in progress in numerous cancers (NSCLC, melanoma, breast cancer, glioblastoma…) using combination of anti-MET and other specific therapies targeting EGFR, BRAF, VEGF or HER2. This review summarizes the potential benefits that MET inhibition should provide to patients with cancer refractory to targeted therapies.

The recent discovery of the earliest hominin cancer, a 1.7-million-year-old osteosarcoma from South Africa has raised the question of the origin of cancer and its determinants. We aimed to determine whether malignant and benign tumors exist in the past societies.

Desmoid tumors (DT) are rare and nonmetastasizing fibroblastic neoplasms, characterized by local invasiveness. They occur sporadically or arise in the context of familial adenomatous polyposis (FAP; 5-10% of cases). Most cases develop sporadically in young adults, but some cases also occur in children. We report the case of an adolescent girl with FAP and DT, and we discuss the therapeutic strategies. An adolescent girl with FAP underwent surgery at the age of 14 years with total proctocolectomy. She had a neo-mutation in the APC gene at codon 1068, which is not usually associated with DT. Three years later, she had painful defecations. Imaging showed two abdominal DT. After a multidisciplinary team meeting, the patient was refused for surgery, and medical treatment with antihormonal agents and nonsteroidal anti-inflammatory drugs was started. Imaging 18 months later showed DT stabilization, but the patient had difficulties to control chronic pains, which required morphine treatment, hypnotic sessions, and transcutaneous electric nerve stimulation. This case highlights the importance of DT screening in patients with FAP, mainly after surgery, regardless of their age and genetic mutation. Progress remains to be made in determining DT risk factors and in developing treatment. DT are still difficult to cure because of their potential for local invasion and local recurrence, and need to be managed by a multidisciplinary team.

Muir-Torre syndrome (MTS), a cutaneous variant of Lynch syndrome, consists of hereditary predisposition to cutaneous tumours and gastrointestinal and gynaecological neoplasms, with autosomal dominant transmission. It is associated with mutations in genes coding for proteins in the DNA mismatch repair system.

Ependymomas represent 10% of pediatric brain tumors. In the recent WHO 2016 classification, pathology is enriched by localization and molecular biology. Whatever the age, total removal by one or several looks when required remains a major prognostic factor. In children, focal radiation remains a standard, while the role of chemotherapy is matter of randomized studies. In infants, front line chemotherapy is the standard. Inclusion in the SIOP ependymoma II protocol is encouraged. In case of relapse, further surgery and radiation are advised, while inclusion in innovative trials including re-irradiation, and phase I-II should be encouraged. A better understanding of underlying mechanisms of ependymoma cell will provide in the close future, the key to use targeted therapies at time of relapse, and very soon as first line therapy for some subgroups of patients.

Comment the new WHO histological classification of tumors of the urinary system and male genital organs 2016 and expose the state of art about urothelial carcinogenesis and molecular modifications of bladder cancer, with the consequences on the treatments.

The acquisition of a resistance EGFR mutation in exon 20 (T790M) occurs in half of the cases of secondary resistance to EGFR tyrosine kinase inhibitors (TKI), given in first-line treatment in advanced EGFR-mutated non-small cell lung cancers (NSCLC). Osimertinib (AZD9291, Tagrisso®) is a third-generation, irreversible EGFR TKI, active in case of T790M mutation. A large phase I trial showed the efficacy of osimertinib after failure of first-generation EGFR TKI (erlotinib, gefitinib), with response rate at 51% and up to 61% in case of T790M mutation. Progression-free survival was 9.6 months in case of T790M. Toxicity profile was acceptable, with mainly digestive (diarrhea) and skin (rash) side effects. Preliminary data from a phase II trial confirmed these efficacy and safety data. Screening of T790M mutation at the time of progression with TKI can be performed in circulating tumor DNA in plasma, with good diagnostic performances.