Childhood acute lymphoblastic leukemia is a model in oncology. The outcome was dismal 40 years ago but is now generally excellent, owing to the recent advent of new drugs. These advances were made possible by the creation of specialized units, better supportive care (transfusions, antibiotics and pain control) and intense biological and clinical research coordinated by national and international cooperative groups, allowing the use of available drugs to be optimized. The current aims are to de-escalate treatment for better-defined low-risk groups, and to develop the use of new drugs and targeted therapies for high-risk groups, based on genome-wide analysis of the patient and the leukemic cell.

Acute lymphoblastic leukemia is a malignant disorder of lymphoid progenitor cells. Advances in our understanding of lymphoblastic leukemia have mainly come from new molecular technologies and genomics. This article describes recent advances in our understanding of maturation arrest of leukemic cells, initial and subsequent gene defects and rearrangements, the role of chemokines, and lymphoid cell homing. These advances point to new ways of targeting leukemic cells.

Acute lymphoblastic leukaemia is the most frequent childhood malignancy. The first effective drugs, which provided only short-lived complete remission, started to be used in the 1950s. All the effective drugs currently in use were discovered in the 1960s, when the first multidrug chemotherapy regimens were shown to confer prolonged complete remission, raising the possibility of a cure. Simultaneously, progress in our knowledge of leukaemic cells, and the identification of prognostic factors such as leukocytosis, age, cytogenetic and molecular abnormalities, and the early therapeutic response of leukaemic cells, led to randomized multicenter national and international trials. As a result, the chance of cure increased gradually over the last three decades. In rich countries, the overall survival rate among children with acute lymphoblastic leukaemia now reaches 85 to 90%.

Neuroendocrine tumors are rare but their incidence is increasing and might be underestimated. The prognosis is highly variable and depends on the tumor type, its location, metastatic status, and the degree of differentiation. The diagnosis relies primarily on imaging methods. Various investigations must be combined for accurate staging, prognostication and decision-making. Current management combines symptomatic treatment (with antisecretory drugs for example) and surgery, which must be as comprehensive as possible, even when metastases are present. Second-line treatment options include chemotherapy, embolization, chemoembolization and radio-frequency therapies. Upcoming targeted therapies and metabolic radiotherapy should improve these patients' prognosis.

Multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) are major genetic disorders carrying a high risk of endocrine tumor development. The mutated genes were identified in 1993 (MEN2-RET) and 1997 (MEN1), enabling genetic testing and functional studies. Genetic analysis has led to new clinical and therapeutic strategies for MEN1/2 patients, and has improved our understanding of the pathways underlying the development of such tumors, which occur in an autosomal dominant manner and with high penetrance. The MEN1 gene encodes menin, a protein involved in many cell functions, such as transcription, genome stability, cell cycling and apoptosis. The MEN1 gene has 10 exons, and its exhaustive analysis in MEN1 patients helps guide their management. MEN2 is related to activating missense mutations in the RET protooncogene, which encodes a tyrosine kinase receptor (TKR). RET activation occurs upon autodimerization induced by the binding of specific ligands belonging to glial cell-derived neurotrophic factor-like family (GFL) proteins, regulated by coreceptors. The position of missense mutations--in the extracellular or intracellular TK domains--influences the aggressiveness of the most frequent malignancy, medullary thyroid carcinoma, establishing a genotype-phenotype correlation. We also briefly describe the genetic basis of three other inherited states predisposing individuals to endocrine tumors, namely Carney's syndrome, hyperparathyroidism type 2 (HRPT2) and familial isolated pituitary adenoma (FIPA), which are related to inactivating mutations in the PRKAR1-alpha, HRPT2 and AIP genes, respectively.

Multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) are autosomal dominant inherited multiglandular diseases with familial and individual age-related penetrance and variable expression. The most frequent endocrine features of MEN1 are parathyroid involvement (> 95%), duodeno-pancreatic endocrine tissue involvement (80%), pituitary adenoma (30%), and adrenal cortex tumors (25%), with no clear syndromic variants. Identification of the germline MEN1 mutation confirms the diagnosis, but there is no phenotype-genotype correlation. All patients with MEN2 have medullary thyroid carcinoma (MTC). The most distinctive MEN2 variants are MEN2A (MTC+pheochromocytoma+hyperparathyroidism), MEN2B (MTC+pheo), and isolated familial MTC (FMTC). The prognosis of MEN2 is linked to the progression of MTC, which depends mainly on the stage at diagnosis and the quality of initial surgical treatment. This emphasizes the need for early diagnosis and management. The specific RET codon mutation correlates with the MEN2 syndromic variant and with the age of onset and aggressiveness of MTC. Consequently, RET mutational status should guide major management decisions, such as whether and when to perform thyroidectomy.

Advances in chromosome dynamics have increased our understanding of the significant role of telomeres and telomerase in cancer. Telomerase is expressed in almost all cancer cells but is inactive in most normal somatic cells. Therefore, telomerase is an important target for the design of therapeutic agents that might have minimal side effects. Herein, we evaluate current approaches to telomerase/telomere-targeted therapy, discuss the benefits and disadvantages, and speculate on the future direction of telomerase inhibitors as cancer therapeutics.

The histological criteria of uterine cervix lesions are well known. However, there is a poor diagnostic reproducibility especially concerning low-grade precancerous lesions. Therefore, the aim of our study was to evaluate the utility of p16INK4A overexpression as a surrogate biomarker of precancerous lesions of the uterine cervix. A retrospective study was carried out by the International Center for Research on Cancer, Lyon, on 79 uterine cervix lesions. Specimens included 4 normal tissue samples, 24 benign lesions, 9 low-grade precancerous lesions (CIN1), 40 high-grade precancerous lesions (CIN2-3) and 2 squamous cell carcinomas. Immunohistochemistry was used to find p16INK4A expression. HPV infection was detected by HPV testing. No p16INK4A expression was detected in normal tissues and benign lesions of the uterine cervix. p16INK4A immunolabeling was weak in CIN1 cases (77.8%). Strong and diffuse p16INK4A expression was detected among all precancerous lesions (CIN2-3) and squamous cell carcinomas. p16INK4A overexpression was associated to the CIN grade (p<0.0001) and high-risk HPV infection (p<0.0001). In conclusion, p16INK4A overexpression should be regarded as a surrogate biomarker of precancerous lesions of the uterine cervix. p16INK4A overexpression is useful in reducing the variability during evaluation of suspicious biopsies of the uterine cervix.

Ras genes encode a family of membrane proteins involved in the regulation of cell growth. Mutations of Ras stimulate cell growth and thus can play a role in carcinogenesis. The search for mutations of Ras is possible by PCR on bronchial biopsies or surgical specimens. They are found in 15 to 20% of non-small cell lung cancers. In the disease's early stage, the presence of a Ras mutation can be a negative predictor of the effectiveness of adjuvant chemotherapy. In the advanced stage of the disease, it is a factor predicting a poor prognosis. Although prospective studies have found no statistically significant negative influence of the presence of a mutation of Ras on the effectiveness of tyrosine kinase inhibitors of EGFR, it is likely that these treatments will be of limited value in this population given the lack of response observed when Ras is mutated. Prospective and functional studies are needed to determine the value of the different mutations observed.

During the past decade, molecular signatures allowed a better classification of breast carcinoma and a better evaluation of their prognosis. However, we still need predictive factors of treatment and /or prognosis factors specific of each patient. Regarding hormonal therapy, expression of hormone receptors is essential, but not sufficient to accurately predict response to treatment for all patients. To date, numerous data have identified different pathways of resistance to hormonal treatment, associated with heterogeneity in response to long term treatment. The challenge remains to identify and to anticipate these changes for each patient.

Biology, genetics and environment of childhood solid tumours set them apart from adult solid tumours. The nature of the progenitor cells from which these tumours arise, and their immature tissue environment, allows childhood solid tumours to develop with fewer defects in cell regulatory processes. Constitutional molecular defects are known to play a role in childhood solid tumours, as shown by the increased incidence of embryonic cancers in children carrying malformations associated with childhood cancer. These rare diagnoses are commonly missed. In this article, we reviewed the spectrum of these tumour predisposition syndromes.

Since the prolongation of survival for patients treated by radiotherapy second primary cancers are not rare. Cumulative incidence of second primary malignancy after radiotherapy (SPMAR) 40 years after treatment can reach 20 % when patients were 40 years old at treatment time. Among SPMAR some of them can be promoted by irradiation. Relative risk (RR) analysis is the most common method used to estimate the proportion of such second cancers. Most of studies reported a RR around 1.1 in adult patients. In young patients RR is about 6, meaning that SPMAR attributable to irradiation is more elevated in this subgroup. Quantification of these events, biomolecular mechanisms, risk factors are complex and not yet fully understood. Information given to patients must be adapted and the cost/benefit ratio has to be justified regarding SPMAR risk. Irradiation technique optimisation is an important point especially in young patient and adults, in order to reduce at maximum the volume of organ at risk exposed while not compromising optimal dose given to the tumour volume, although no standard rules of irradiation are definitively established at the present time.

Breast cancer is a frequent and heterogeneous disease. The choice of systemic treatments such as chemotherapy is based on predicting factors of response that did not much evolve. Preoperative chemotherapy provides an opportunity to directly assess tumor response to therapy. Predictors based on mathematical models could optimize those treatments. To go on this way, three different concepts have been developed to predict the preoperative chemotherapy complete response. Predictors based on clinical and pathological variables are specific of a tumor. They combine into mathematical models variables that have been previously identified as predicting the preoperative chemotherapy complete response. Predictors based on gene expression profile have been developed from groups of patients who received preoperative chemotherapy. They integrate multigene information to predict the tumor behaviour in front of several cytotoxic agents. Those predictors developed for each type of drug characterize the genetic chemoresistance of a tumor. In the same time, predictors of chemosensitivity developed from cell lines of diverse human cancer appeared. The authors established a genetic profile involved into chemoresistance and extrapolated the drug sensitivity for another type of cancer which was not represented, as breast cancer. All those predictors seem interesting but evolution of patients' characteristics and treatments induces a perpetual reassessment to optimize our predictive abilities.

Polycystic ovary syndrome (PCOS) is the most common etiology of menstrual disorders and hyperandrogenism. It is characterized by an excess of ovarian follicles. The mechanisms that underlie folliculogenesis disorder in PCOS appear to arise from primitive ovarian hyperandrogenism. This can be modulated by hormonal factors, such as LH or insulin. Ovarian hyperandrogenism results from a real theca cells dysfunction, whose origin is still poorly understood. It seems that complex genetic factors may be involved, but these have not yet been clearly identified. PCOS also results from granulosa cells dysfunction. For example, intra-ovarian factors, such as anti-mullerian hormone, are possibly involved in ovulation's disorders by blocking the physiological process of follicular recruitment. In turn, the oocyte could also be one of the actors possibly involved in the follicular excess in PCOS.

Excellent local control rates can be achieved using multidisciplinary approach and combined surgical technics. Better vascular and nervous dissections, use of different flaps and isolated limb perfusion have been determinant. Resection's extent of retroperitoneal sarcoma is still debated, but compartmental surgery seems to achieve better local control. The impact of pre operative radiotherapy will be explored soon in a randomized EORTC trial. Concerning desmoids, authors address the question whether surgery and other aggressive treatments should systematically be part of first-line treatment, as growth arrest occurred in 2/3 of non-operated patients. The objective of on going biological studies is to use molecular findings to individualize the selection of management protocols. In the same way, surgical indications for gastrointestinal stromal tumors evolved: with the development of investigations, more micro-GIST are discovered, rising the question of wait and see policy for some of them. In locally advanced inoperable patients and metastatic patients, imatinib is the standard treatment. Secondary excision of residual disease has been shown to be related to a good prognosis in responding patients to imatinib, but it is still not demonstrated whether this is due to surgery itself or to a selection bias. An ongoing phase III EORTC randomises this secondary surgery after 6 to 12 months of imatinib in responding patients.

Regional tumour banks are nowadays an important tool for the management of patients with a sarcoma. Centralized databases with information on frozen or paraffin-embedded tumour samples are necessary tools for clinical and biological research projects for rare tumours and particularly sarcomas. Diagnostic procedures have evolved during the last years with a multidisciplinary management of patients by a national and structured network specialized in sarcomas, a common use of core needle biopsies, a daily use of immunohistochemistry and molecular analyses and the implementation of standardized and structured reports.

The diagnosis of localized prostate cancer is in constant modification. Recent studies on early diagnosis and prognosis analysis have demonstrated the limits of using PSA. The challenge for the upcoming years will be to adapt therapeutic strategies for each patient according to more reliable tests. These objectives apply for DNA methylation analysis. Hypermethylation of the promoter of gene implicated in the carcinogenesis of prostate cancer has been shown as an interesting filed for new tests. So far, DNA methylation tests were assessed on small cohorts of localized prostate cancer patients with promising results when applied on primary tumours and in urine, particularly for patients at high risk of progression after radical prostatectomy. Since the last phase of development for DNA methylation tests will be the industrialization and evaluation on large scale, it is important to have a synthesis on current knowledge of DNA methylation tests in the diagnosis of prostate cancer.