Antimutagens and anticarcinogens are natural or synthetic substances able to inhibit or to reduce spontaneous or induced DNA alteration. These inhibitors act at different levels from the penetration of the xenobiotic to the expression of the mutation and cancer. They act in extracellular and intracellular levels; they react directly with mutagens or on the processes of their activation. Antimutagens and anticarcinogens also act on DNA-repair process.

In cancer chemotherapy, it is important to design treatment strategies that ensure a desired rate of tumor cell kill without unacceptable toxicity. To optimize treatment, we used a mathematical model describing the pharmacokinetics of anticancer drugs, antitumor efficacy, and drug toxicity. This model was associated with constraints on the allowed plasma concentrations, drug exposure, and leukopenia. Given a schedule of drug administrations, the mathematical model optimized the drug doses that could minimize the tumor burden while limiting toxicity on the white blood cells. Simulation suggests that the optimal drug administration is an initial high dose chemotherapy up to saturation of constraints associated with normal cell toxicity followed by a maintenance continuous infusion at a moderate rate. Data related to etoposide investigations were next used in a feasibility study. Simulations made with the usual clinical protocols and optimized protocols revealed that model-based optimal drug doses lead to greater cytoreduction. Also, examples showed how to use this new approach for the dose ranging problem and they evaluated the sensitivity of the optimized protocols with respect to the clinical constraints.

The main objective of this prospective multicenter randomised phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation versus fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma brain metastases.

The analysis of biological processes has been revolutionized by the emergence of the DNA array technology. As cellular biological events are controlled by gene expression, their modulations are markers of the cellular activity. These modulations can be indicative of either a physiological process or a pathological one. Monitoring of the expression levels of thousands of genes simultaneously, the expression profiling method is based upon comparative studies where the identification of the differentially expressed genes in two samples is aimed. The two samples under study may be compared temporally or following drug treatment, they may also originate from different sources, e.g. normal versus pathological samples. In that case, gene expression profiling is conducted for diagnostics purposes or therapy monitoring, and offers an opportunity to identify new drug targets. Using different examples, we describe the potentialities of this approach in oncology.

To assess the MR imaging (MRI) findings in symptomatic tamoxifen treated-women with abnormal transvaginal sonography.

Thromboembolic complications are well known side effects of treatment with tamoxifen in patients with breast cancer. The authors review the pathophysiology and the risk factors that increase the probability to develop these complications. The most appropriate treatment is discussed.

Gastrointestinal stromal tumors (GIST) are rare tumors occuring at all levels of the gastrointestinal tract, whose estimated incidence may be close to 2 new cases per 100 000 persons per year. GIST derive from the interstital cells of Cajal (ICC) responsible for the motility of the GI tract, or from a common precursor of ICC and of the smooth muscle cells of the digestive tract. GIST cells express the c-kit protoconcogene under an activated form, either mutated or constitutively activated, as well as the CD34 Ag. Mutations of the KIT gene is an early event in the process of transformation in these tumors. Until recently, GIST were not recognized as a distinct entity among soft tissue sarcoma. It is now clear that conventional chemotherapy is generally inactive in this tumor, surgery being the only efficient therapeutic modality even in patients with advanced disease. Rapidly accruing phase I, II and III trials in the USA and Europe (EORTC) have demonstrated since 2000 that imatinib mesylate (STI571) is an active agent in GIST with an initial response rate of 70 % and 10 % only of primary refractory tumors, yelding an improved overall survival as compared to historical series. Resistance are now being observed however. GIST has become the first model of a solid tumor treated efficiently by a treatment targetting the initial genetic alteration of the disease. Numerous question regarding the integration of this treatment with surgery and the long term outcome of these patients still remain to be answered however.

In 2002, new developments in anti-angiogenic strategies encompassed two main aspects. Firstly, essential improvements were made in the field of methodology : novel techniques permitted to measure directly on patients the biological effects induced by anti-angiogenic treatments in the course of clinical trials. Secondly, results of the first phase I trials of endostatin, one of the most awaited anti-angiogenic drugs, were published. These studies proved that endostatin was not toxic and that doses equivalent to the one effective in animals could safely be used in man, but efficacy results were not up to expectations. On the other hand, treatment targeting the VEGF pathway, and especially humanised anti-VEGF monoclonal antibody, had promising results. Further clinical trials are needed to gain clear insight into the precise role of those promising strategies for the management of solid tumours.

Lung cancer is the most frequent form of malignant tumours. The prognosis is poor with a 5-year cure rate which increased from approximately 6% in the sixties to only 15% in the nineties. Surgery remains the reference treatment but only a small minority of patients (about 25%) present with operable disease. The post-surgical 5-year survival is only 25%, providing the rationale for the current research on adjuvant treatments for control of both local and metastatic disease. In that context, the combination of radiotherapy and chemotherapy, commonly referred to as chemo-radiotherapy, has assumed considerable importance: either exclusively in inoperable patients (inoperable tumour or patients inoperable for medical reasons), or pre-operatively. This article reviews the results of the pivotal definitive chemoradiotherapy studies in non-metastatic non-small-cell lung cancer. With exclusive chemoradiation, the concomitant scheme seems to be the most favourable, results issued from randomised studies are expected to confirm that point. An increased toxicity is observed, and the advent of conformal therapy may allow another survival gain. Optimal treatments integration will be necessary.

Two randomized trials, in 1994, have demonstrated the benefit of neoadjuvant chemotherapy, in term of median survival, for stage III lung cancer. Further studies have evaluated the potential benefit of chemotherapy or chemotherapy-radiotherapy association, either for patients suitable for surgery, or for non resectables tumors. However, these treatments treatments may increase the morbidity of surgery. Such an increase has not been demonstrated, except in one study, after chemotherapy alone before surgery. When radiation therapy is associated with pre-operative chemotherapy, the risk of complications seems to be dose dependent: low for doses below 50 Gy, important for doses over 55 Gy. These datas justify pre-operative lung function measurements and modifications of the surgical technic, especially for the lymphadenectomy extension. Despite this potential increase of morbidity, the benefit of neoadjuvant treatment is real.

Prevention of adverse events of non-cardiological medicinal products is essentially based on the knowledge that they exist and quantification of the risk to which the patient is exposed, both in terms of frequency and potential severity.

Integrins are a family of heterodimeric transmembrane receptors that mediate cell-cell and cell-extracellular matrix adhesion. Integrin-mediated signaling is essential for the regulation of fundamental cellular functions, including proliferation and survival, and for tumor development. According to in vitro studies, integrin ligation by extracellular matrix proteins can modulate the cytotoxicity of anti-tumor agents, in a cell-type sensitive manner. Underlying molecular mechanisms are not well understood, but may be based on the interrelations between integrin signaling pathways and pathways that control cell cycle and apoptosis. On the other hand, alterations of integrin expression and/or function have been observed during the acquisition of chemoresistance in cells chronically exposed to cytotoxic agents. These data are in favor of a role of integrins in chemoresistance processes, and open new perspectives in the field of cancer therapy and prognosis.

Alpha interferon is currently used in the treatment of malignant melanoma mainly as adjuvant therapy at the first stage of the illness (primary tumor) and at the second stage (lymph node invasion).

Gemcitabine is used to treat solid tumours such as non small-cell lung cancer. In general, it is a well tolerated cytotoxic agent and myelosuppression is the major dose limiting side-effect. Pulmonary toxicity has been described and dyspnoea occurs in approximately 8% of patients in whom, for the majority, it is mild and reversible. But several cases of acute respiratory distress syndrome (ARDS) related to Gemcitabine treatment have been reported since 1997 and a few were fatal. We present a case of Gemcitabine toxicity in a patient treated for a lung cancer. He presented with a respiratory distress syndrome due to acute interstitial pneumonitis from which he promptly recovered with corticosteroid therapy.

To report the case of significant growth of a myoma in a premenopausal woman with a suspicion of BRCA1 and BRCA2 mutation, treated by tamoxifen for a hormonodependent breast cancer and to point out the carcinologic ovarian risks with a mutation BRCA1-BRCA2 in this context. Case. Four months after surgical treatment, chemotherapy and the beginning of tamoxifen, an explosive growth of the abdomen justified pelvic echography and laparoscopy confirming the diagnosis of uterine myoma. A polymyomectomy by laparotomy was performed.

A 74-year- man was hospitalized for subacute aphasia and right hemiparesis. He had had chronic lymphoid leukemia for 11 years and had been treated 5 months earlier with 3 courses of fludarabine. Magnetic resonance imaging showed lesions of the temporo-occipital white matter compatible with progressive multifocal leukoencephalitis (PML). The presence of JC virus was demonstrated first by in situ hybridation after a brain biopsy and second with polymerase chain reaction on CSF. The diagnosis of PML was confirmed. The causality of fludarabine treatment is discussed.

The efficacy of gemcitabine containing regimens has been explored in a large number of studies presented at ASCO 2002. The activity of gemcitabine-platinum based combinations was confirmed in lung cancer and bladder cancer. In pancreatic cancer, single agent gemcitabine remains the reference treatment, but newer combinations with oxaliplatin or docetaxel show promising activity in phase II trials and are currently being evaluated in phase III. Gemcitabine has demonstrated promising activity in phase II studies in metastatic breast cancer and gynaecologic tumors; phase III trials are ongoing. Concomitant chemo-radiation using gemcitabine as a radiosensitizer have been shown to be highly effective in pancreatic and in bladder cancer and deserve further investigation. The growing interest in gemcitabine-based combinations in various tumor types together with the results presented at ASCO 2002 confirm the broad range of activity of this drug. This is a review of papers presented at ASCO 2002.

Gemcitabine is a molecule presenting with major radiosensitizing or radio-potentiator capacities. This property has been extensively studied in vitro, with clinical therapeutic implications. Chemotherapy and radiation are very often used together, most of the time concurrently. This review analyses the results obtained with combined gemcitabine and radiation, for non small cell lung cancer, pancreatic adenocarcinoma, head and neck and uterine cervix carcinomas. Several therapeutic schemes are presented, for each tumor location. A description of the toxicities observed is presented, including the recall phenomenon description. Promising results justify the numerous current trials, as well as enthusiasm initiated by this therapeutic association.