Peripheral T-cell lymphomas (PTCL) belong to the group of non-Hodgkin lymphoma and particularly that of mature T/NK cells lymphoproliferative neoplasms. The 2008 WHO classification describes different PTCL entities with varying prevalence. With the exception of the histological subtype "ALK positive anaplastic large cell lymphoma", PTCL are characterized by a poor prognosis. The mechanisms underlying the pathogenesis of these lymphomas are not yet fully understood, but development of genomic high-throughput analysis techniques now allows to extensively identify the molecular abnormalities present in tumor cells. This review aims to summarize the current knowledge and recent advances about the molecular events occurring at the origin or during the natural history of main entities of PTCL. It will be published in two parts : the first is focused on the three more frequent entities, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified, and anaplastic large cell lymphoma. The second (which will appear in the november issue) will describe other subtypes less frequent and of poor prognosis : extranodal NK/T-cell lymphoma, nasal type, adult T-cell leukemia/lymphoma, and enteropathy-associated T-cell lymphoma. T or NK cell lymphoproliferative disorders with leukemic presentation, primary cutaneous T-cell lymphoma and very rare subtypes of PTCL whose prevalence is less than 5% (hepatosplenic T-cell lymphoma and subcutaneous panniculitis-like T cell lymphoma) will not be discussed herein.

Should all women with BRCA1 or BRCA2 genes mutations be considered at risk of prematurely impaired fertility, and thus should a fertility preservation systematically be proposed? Women carrying mutations of BRCA1 or BRCA2 are at high risk for breast and tubo-ovarian cancer. The treatment of a breast cancer at a young age, unrare in this population, is associated with a risk of infertility, due to the ovarian toxicity of chemotherapy, to the recommended duration of hormonotherapy when indicated, and to the time advised before starting a pregnancy. Furthermore, some data in the literature suggest a higher risk of premature ovarian failure among women with BRCA1/2 mutation: advance of the age at menopause and poorer response to ovarian stimulation have been observed. Several pathophysiological hypotheses support this finding, as the involvement of the BRCA genes in maintaining telomere length, the DNA repair anomalies promoting oocyte apoptosis, differences in FMR1 genotype. Current fertility preservation techniques have limitations, some of them being specific to BRCA1/2 women: absence of oncological risk due to stimulation in BRCA1/2 women not clearly demonstrated, oocyte vitrification techniques limited rentability, graft of ovarian cortex not suitable in these women at high risk. Thus, data on the increased risk of premature ovarian failure remaining weak, such a systematic proposal seems questionable.

Tubal lesions detected in specimen of risk reducing salpingo oophorectomy (RRSO) for mutation BRCA1/2 seems to play a role in ovarian carcinogenesis. The main objective of this study is to evaluate the prevalence of occult neoplasia, of Serous Tubal Intraepithelial Carcinoma (STIC), and signature P53 in a cohort of patients who underwent a risk reducing salpingo oophorectomy.

Poly(ADP-ribosyl)ation is a post-translational modification catalyzed by poly(ADP-ribose) polymerases. PARP-1 is a molecular sensor of DNA breaks, playing a key role in the spatial and temporal organization of their repair, contributing to the maintenance of genome integrity and cell survival. The fact that PARP inhibition impairs efficacy of break repair has been exploited as anticancer strategies to potentiate the cytotoxicity of anticancer drugs and radiotherapy. Numerous clinical trials based on this innovative approach are in progress. PARP inhibition has also proved to be exquisitely efficient to kill tumour cells deficient in double strand break repair by homologous recombination, such as cells mutated for the breast cancer early onset genes BRCA1 or BRCA2, by synthetic lethality. Several phase III clinical trials are in progress for the treatment of breast and ovarian cancers with BRCA mutations and the PARP inhibitor olaparib has just been approved for advanced ovarian cancers with germline BRCA mutation. This review recapitulates the history from the discovery of poly(ADP-ribosyl)ation reaction to the promising therapeutic applications of its inhibition in innovating anticancer strategies. Benefits, hopes and obstacles are discussed.

Angiomatoid fibrous histiocytoma (AFH) is a soft-tissue tumour of uncertain differentiation most often arising in the extremities of children and young adults. AFH is a little-known neoplasm and its rarity may result in it being misdiagnosed as either a reactive lesion or a benign or higher-grade tumour. We report 6 cases of AFH in children and we review the clinicopathological and molecular features of this neoplasm published in the literature.

Pheochromocytoma and functional paraganglioma (PH/PGL) are classical causes of secondary hypertension. The clinical practice guidelines for PH/PGL have been changed by the recent identification of a dozen of susceptibility genes. PH/PGL is the neuroendocrine tumor most affected by genetics. Total metanephrin should be measured in every young patient suffering of a resistant hypertension. The diagnosis is based on conventional imaging assciated with nuclear imaging. Genetic testing should be offered to every patient diagnosed for PH/PGL because the identification of a germline mutation, which is found in over 30% of the cases, will change his work-up and follow-up as well as offer the opportunity of a familial genetic testing in relatives. A specialized management is indicated, especially for patients with hereditary or metastatic PH/PGL, and should be performed in an expert center with a multidisciplinary team.

In colorectal cancer (CRC), genetic alterations are involved in disease progression from adenoma to carcinoma and metastatic disease. Three different carcinogenesis mechanisms exist: chromosomal instability phenotype (CIN), microsatellite instability phenotype (MSI) and the hypermetylator phenotype (CIMP for CpG Island methylation phenotype). These molecular alterations lead to signal transduction dysfunction, and signaling pathways alterations are involved in cancer mechanisms, such as EGFR pathway, WNT/APC pathway, TGFB pathway and p53 pathway. Recently, molecular signatures have been established, allowing distinction of 4 different types of CCR. Finally, circulating biomarkers are investigated for molecular characterization.

The authors review the principles of systemic therapy in breast cancer. They analyze the degree of treatment individualization in our current approach. New technologies allow the detection of genomic alterations in cancer cells. Unfortunately, we do not know yet how to best use this knowledge for routine patient care. Most genomic alterations are rare events complicating further drug development. Temporal and spatial heterogeneity in tumors also has to be taken into account. An intense international collaboration is ongoing to try and demonstrate that precision medicine will really improve treatment outcome.

Recent advances in medical genomics open new perspectives for personalized medicine through the identification of genetic variants that influence drug response and/or the risk of side effects. Today, the clinical applications of pharmacogenetics remain scarce as a consequence of the cost and turn-around-time of genetic tests. However, a few tests are recommended, for instance before the prescription of some anti-cancer agents or the anti-retroviral agent abacavir. In the future, we will probably move either towards rapid targeted tests or towards a large screening, before any diagnosis, of all the genetic factors influencing the therapeutic response. In that case, physicians will have to consult the patient genomic data before drug prescription in order to personalize the choice of the therapeutic agent or its dosage. However, such a genomic approach brings economical and ethical questions and will require further progress in our capacity to interpret and store the personal genomic data without compromising their confidentiality.

Alveolar soft part sarcoma, ASPS, is a rare malignant tumor, with preferential primary localization in limbs, usually occurring in adolescents and young adults. This sarcoma, well defined histologically and at molecular level, has an indolent course, but a high potential metastatic pulmonary and cerebral evolution, sometimes late. ASPS is characterized by an almost specific translocation t(X, 17)(p11;25) which creates a fusion protein, APSL-TFE3, acting as an aberrant transcription factor. An in-bloc resection of the primary tumor is the treatment of choice in cases of localized disease. Conventional chemotherapy is generally ineffective. The role of radiotherapy is discussed in case of micro- or macroscopical incomplete residue. It seems to reduce local recurrence, but did not influence overall survival. The 5 years survival rate in children, adolescents and young adults is close to 80% in case of localized disease but poorer in presence of metastases. Recently, systemic anti-tumoral treatments have been focused on the use of targeted therapies. Anti-angiogenic drugs and tyrosine kinase inhibitors are the most promising approaches, but require further study. Prognostic risk factors in the literature are age (>10Y), tumor size (>5cm) and presence of metastases. This article reviews the clinical manifestations, diagnosis modalities, radiographic characteristics and therapeutic strategy of this disease in the pediatric population.

Activating EGFR mutations discovery and efficacy of 1st generation tyrosine kinase inhibitors (TKI), such as erlotinib or gefitinib, inaugurated the beginning of personalized medicine in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, all patients showed a tumor progression of 10 to 16 months after the onset of TKI therapy related to molecular resistance mechanisms as T790M mutation. Till now, patients suffering from EGFR-mutated NSCLC with acquired resistance have conventional treatment options. Two new 3rd generations' TKI, AZD9291 and rociletinib, are currently being studied in phases 1-3 studies. Preliminary results show relevant therapeutic properties in patients with T790M mutated-EGFR NSCLC. This review aims to highlight these new molecules, their effectiveness and their clinical toxicities in the treatment of advanced stages of NSCLC expressing the T790M mutation.

Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen disease, is one of the most frequent human genetic diseases, with a prevalence of one case in 3000 births, an autosomal dominant mode of inheritance, and a high rate of new mutations. NF1 has markedly variable clinical expression, with manifestations ranging from mild lesions to several complications and functional impairment. The complications are age-specific. Psychiatric disorders are more frequent in NF1 than in the general population, especially in children. They include dysthymia, depressive mood, anxiety, and personality disorders. Bipolar mood disorders or schizophrenia are rather rare. The majority of studies have focused on physical health and neurocognitive function in NF1, whereas psychiatric disorders associated with this disease remain unclear and poorly documented. This report is based on a clinical case and discusses the relationship between neurofibromatosis type 1 and psychiatric disorders, particularly anxiety disorders.

With the emergence of molecular targeted therapies in the management of non-small cell lung cancer, the role of conventional chemotherapy can be questioned. This article presents the key arguments against the use of cytotoxics in presence of a targetable alteration.