Azacitidine has been approved in January 2009 in Europe in the treatment of higher-risk myelodysplastic syndromes (MDS). This represents the first time a drug is specifically labelled in MDS in Europe, and is a cornerstone in the development of hypomethylating agents 5-azacytidine (azacitidine) and 5-deoxyazacytidine (decitabine). Clinical trials of hypomethylating agents in MDS still raise a number of questions regarding the precise mode of action of these drugs, as well as the optimal sequencing of treatment in MDS. The positive results of these trials also open the field of epigenetic therapeutic strategies combining hypomethylating agents with other classes of drugs targeting epigenetic processes.

With the improvement of the anticancerous treatments, the preservation of the feminine fertility before gonadotoxic treatment tends at present to stand out as a legal obligation, with a duty of information to patients. When emergency IVF can be performed, the cryopreservation of embryos is the best mastered method which offers most chances to patients to obtain a pregnancy after cancer remission thanks to the transfer of frozen embryos. This article proposes an overview about the indications, the feasibility and the ethical and practical limitations of IVF emergency for embryo freezing before gonadotoxic anticancerous treatment.

Thymidylate synthase (TS) is an enzyme, which catalyzes the methylation of deoxyuridylate to deoxythymidylate using 5.10-methylenetetrahydrofolate as a cofactor. For this reason, TS has been widely investigated and is one of the best-known drug targets in the anticancer area. Antimetabolites have been developed to target TS and among them, pemetrexed is now considered as part of the standard treatment for lung cancer and mesothelioma. Intratumoral expression of TS mRNA has been shown to be associated with prognosis and with the response to 5-FU therapy in patients with breast, colorectal, head and neck cancer types. Recent findings suggest that TS might be a biomarker for NSCLC treated with pemetrexed, as lower response rates in squamous cell carcinoma and small cell carcinoma may be due to a higher expression of TS. Specific validation for this use as a biomarker is awaited. All these recent findings suggest that TS could be a useful predictive marker of the treatment efficacy of antifolate drugs and indicate that both Real-Time PCR and immuno-histochemistry might be used to assess TS expression levels. This may help in defining the best therapeutic strategy.

The IKKε kinase, an atypical member of the IKK family of kinases, was recently identified as an oncogene overexpressed in over 30% of breast cancers. Besides its role in the regulation of the NF-κB transcription factor, which is well recognized for its implication in the development of breast cancers, IKKε was shown to phosphorylate numerous targets. Analysis of the phosphorylation of some of these substrates in the context of breast cancer highlighted new oncogenic signaling pathways that constitute potential targets for new therapies. Interestingly, IKKε is involved in the development of resistance to Tamoxifène. Thus, IKKε is a promising therapeutic target for newly developed breast cancer treatment.

Fifty-two thousand new breast cancers occur each year in France, 7% in patients less than 40 years. The standard regimens of adjuvant chemotherapy for breast cancer now include anthracyclines and taxanes. These therapeutics advances have significantly improved the prognosis of these young women who may later wish to become mother and have biological offspring. The impact of chemotherapy on reproductive function should be accurately assessed and the ovarian reserve has to be taken into account. The estimated risk of chemo-induced amenorrhea and infertility has to be balanced with the expected results and risks of methods of fertility preservation. The place of different options for fertility preservation depends on patient age, presence or not of a partner and the time available before the initiation of treatment. For these breast cancer patients who will receive chemotherapy, new techniques of in vitro oocyte maturation seem promising. Even if some ethical and technical issues are unresolved, fertility preservation must now be part of the management of these young patients receiving adjuvant chemotherapy for breast cancer. This new approach must be multidisciplinary and complex.

Currently in oncology a novel agent entering development has only 5% chance of making it to commercial use. One of the ways to mitigate this problem would be to conduct exploratory or 'phase 0' clinical trials, conducted before phase 1 dose-escalation safety and tolerance studies. These phase 0 studies are a first administration of the novel agent to humans, at limited doses, on a small number of patients and over a short period. The objectives are to validate preclinical development and to acquire pharmacokinetic and pharmacodynamic data in order to better justify the scientific rational. In this article, we focus on phase 0 trials and their usefulness for the development of new drugs in oncology. We performed a literature review of questions related to phase 0 trials in articles published during 2006 to 2009. Thirty articles on phase 0 clinical trials have been published. The affected fields are oncology and pharmacology. Phase 0 clinical trials are discussed in the literature in terms of theoretical issues and from academic, pharmaceutical industry and patient point of views. If phase 0 clinical trials are a future prospect for drug development against cancer, the clinical applications of these trials need to be specified.

Pancreatic carcinoma is the fifth leading cause of cancer-related mortality. The 5-year overall survival is less than 5 %. This very poor prognosis can be explained both by late diagnosis and by treatment resistance, including resistance to radiation therapy. A better understanding of the pancreatic tumorigenesis and knowledge of the most frequent mutations in pancreatic adenocarcinoma (KRAS, p16, TP53, Smad4) open new perspectives for the development of more effective treatments. This review presents the major genetic and molecular alterations in pancreatic cancer that could be targeted to improve radiosensitization.

A 53-year-old man is treated by L-asparaginase for an acute lymphoblastic leukaemia. He received anti thrombin infusions. A systematic electrocardiogram showed an asymptomatic subepicardium ischemia without troponin elevation. Echocardiography and heart magnetic resonance imaging showed an apical thrombus facing a zone of myocardial necrosis. A thrombus regression was observed under anticoagulation. Atypical and asymptomatic coronary thrombosis may occur following L-asparaginase treatment. Regular electrocardiogram monitoring is proposed along this treatment. Arterial thrombosis associated with anti tumor chemotherapies are reviewed.

The Canadian oncology community was devastated by the news in August 2006 that a patient had died from an overdose of fluorouracil. Where we once thought our checks and balances ensured patient safety, we now knew they were not enough. Practice immediately began to change around the country. However, the incident report highlighted that there was much we still didn't know about safety issues in intravenous ambulatory chemotherapy safety in Canada. In response, an interdisciplinary, pan-Canadian team launched an 18-month exploratory study, resulting in a report identifying several safety issues and associated recommendations. This paper summarizes the key insights we have gathered for Canadian oncology nurses in being part of this study: that we need courage to come forward and disclose safety concerns; we should collaborate to come up with safety improvements that work for everyone; and we should strive to simplify our work at the sharp end by reducing complexity upstream and throughout the system.

New molecular classification is one of the cornerstones of current and future progress in research and patient care for breast carcinoma. For the larger hormone-receptor positive and Her-2 negative subgroup, which concerns 75% of the patients, endocrine therapy and chemotherapy may be considered. Looking toward new-targeted therapies, this paper reviews the current use of these two treatment modalities in adjuvant, neoadjuvant and metastatic settings of this disease.

The molecular classification of Perou and Sørlie breast tumors has to streamline, systematize and make effective use of targeted therapies against specific molecular subtypes, including breast HER2 positive. Trastuzumab and lapatinib are currently the two therapies targeting HER2, which have demonstrated their effectiveness in clinical practice. This literature review aims to make the data points on pertinent and useful data for physicians in daily.

Cancer and venous thromboembolism are frequently associated.

Leptomeningeal metastases are very commonly associated with breast cancer. The prognosis is very poor in the short term with an overall median survival less than 6 months. Based on pragmatic and historical considerations intrathecal chemotherapy (IT) are considered to be the adequate treatment. However overall results are disappointing. Despite specific and symptomatic treatment, improvement in survival and quality of life remains very modest, highlighting the importance for ongoing research for developing new molecules or on improving the use a better use of those available today. The incidence of leptomeningeal metastases is particularly marked in cases of overexpression of HER2. The main hypothesis is there may be a better control of extra-cerebral localisations with trastuzumab therefore intra-cerebral recurrences may be encountered preferentially as they are not reached by this high molecular weight monoclonal antibody (148  kD). Analyses performed in the cerebrospinal fluid following intravenous trastuzumab showed extremely low levels of the antibody and support the hypothesis that leptomeningeal metastasis of HER2-overexpressing breast carcinoma remain potentially sensitive to HER2-type receptor inhibition by a target agent under the condition of by-passing the meningeal blood brain barrier. Intra-ventricular or IT administered with trastuzumab would reach high loco-regional therapeutic concentrations in the cerebro-meningeal without risk for normal non-expressing HER2 leptomeningeal tissue. This strategy has been successfully tested on several animal models. A limited number of administrations in humans have been described in the literature, with weekly doses up to 100  mg. No specific toxicity has been described and some data suggest a potential benefit in survival despite the real difficulties for adequate interpretations. Furthermore, a multicentric phase I-II clinical trial, of which the Curie institute is the sponsor and investigating the intra-thecal administration and the efficacy of the trastuzumab will begin very soon. More studies are needed to measure the exact impact of small molecule inhibitors of tyrosine kinase on the leptomeningeal localizations.

Brain metastases are prevalent in solid tumours and lymphomas. They are associated with poor survival. The brain is regarded as a sanctuary site for metastatic tumour cells where they exist partially protected from drugs by the blood brain barrier. Amongst the different molecular sub-types of breast cancer, HER2 positive tumours and triple negative tumours exhibit the highest incidence of brain metastasis. Specific strategies are needed to fight brain metastatic disease. Preclinical models for brain metastasis have been developed, yielding mechanistic molecular knowledge and new therapeutic approaches.

Allogeneic hematopoietic stem cell transplantation is the most widely used form of immunotherapy. The allogeneic immune effectors infused with the graft can recognize and eradicate the patients' tumoral cells. The curative potential of allogeneic hematopoietic stem cell transplantation is classically based on two mechanisms: the conditioning myelo-ablative or immunosuppressive inducing either the cytoreduction of tumoral cells or tolerance and the immune control mediated by allogeneic immune effectors (graft-versus-leukemia or tumor effect, GVL or GVT). Allogeneic hematopoietic stem cell transplantation is currently under important mutations because of better understanding of the GVT mechanisms and the development of new treatment techniques with: (a) allo-hematopoietic stem cell transplantation of peripheral blood stem cells after mobilization with G-CSF and allotransplant of cord blood cells; (b) increase number of allogeneic hematopoietic stem cell transplantation from unrelated and haplo-identical donors; (c) immunomodulation according to the chimerism and residual disease documentation with donor lymphocyte infusion (DLI); (d) development of reduced intensity conditioning regimens aiming to reduce the toxicity while favoring the immune component of the anti-tumoral effect; (e) development of sequential chemotherapy followed by allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning in case of refractory diseases. In addition the present experience shows clearly that the allogeneic hematopoietic stem cell transplantation strategy should be developed and refined because of the potential benefit that can be expected in some patients' sub-groups and then allogeneic hematopoietic stem cell transplantation, real immunotherapy should be included in the global therapeutic strategy in onco-hematology.

To study the biological mechanisms of the repair of the radiation-induced DNA damage leads to two major medical applications: (1) the identification of the radiosensitive patients by using appropriate predictive assays in order to avoid toxicity due to radiation therapy and sometimes to chemotherapy; (2) the decrease of the radioresistance of tumour cells to obtain a better local control. To transpose fundamental biological knowledge from experimental in vitro clinic is delicate and sometimes too hasty, though necessary. In mechanistic terms, clinical features are once again a very rich and under-exploited approach to identify the molecular mechanisms of the DNA repair function. An exhaustive survey of the clinical cases of radiosensitivity with biological samples and with long course surveillance is an inverse approach, probably promising but still difficult to apply. Unlike classical reviews, this article attempts to identify the major genetic syndromes associated with radiosensitivity and cancer predisposition in order to deduce the different stages of major mechanisms of DNA double-strand breaks repair. Emphasis is placed on the importance of studying this repair at the functional level. Surprisingly, among the genetic syndromes associated to radiosensitivity there are some anomalies, not linked to DNA repair itself but to the intracellular trafficking. The repair function but therefore also the signalling are then logically therapeutic targets applicable in radiotherapy but with a very accurate ballistic sparing of the healthy tissues.