Quinagolide is a non-ergot dopaminergic agonist recently available on the French market. The endocrine and tumoral efficacy as well as the safety and tolerability of quinagolide in the treatment of macroprolactinomas are reviewed. In this situation, plasma prolactin levels are normalized in about 60% of patients and in about one third of those who are resistant to bromocriptine. A significant decrease in pituitary tumor size is demonstrated by radiographic studies in 58 to 69% of patients. About one third of patients show more than 50% tumor shrinkage. The tolerability of quinagolide is satisfactory in most cases and clearly better than that of bromocriptine. Thus, quinagolide is a useful tool in the treatment of macroprolactinomas.

Tamoxifen is the most currently used antiestrogen in the endocrine treatment of breast cancer. However, despite a small proportion of estrogen receptor positive tumors presenting de novo resistance to treatment, numerous tumors develop acquired resistance after a first phase of response. Many mechanisms have been proposed, but none could be identified as a real explanation of these phenomena of resistance. The hypotheses suggested are related to the series of events implied in the transduction of the signal following the ligand binding to estrogen receptor and concerning several levels: (1) loss or mutation of the estrogen receptor; (2) modification in estrogen receptor associated parameters; (3) alteration in the estrogen response element; (4) high levels of antiestrogen binding sites; (5) alteration of metabolism or availability of tamoxifen. The tamoxifen resistance certainly concerns several of these mechanism. Therefore, it is necessary to go on studying these mechanisms and to elucidate the connections existing between all of them.

Tamoxifen is widely used nowadays in the management of breast cancer, having established its efficacy in this indication, especially for postmenopausal patients with ER-positive breast tumours. However, tamoxifen has recently been recognized as carcinogenic for the human endometrium, probably with an effect of duration of treatment. Moreover, this drug may be associated with the occurrence of endometrial cancers of unusual histological types and/or of a more aggressive nature. We describe a case series of 11 patients who developed such cancers after having previously received tamoxifen for breast cancer. Several assumptions on the mechanisms underlying the attributed carcinogenic properties of tamoxifen, for the endometrium and potentially for other organs, are discussed on the basis of current knowledge.

Pulmonary aspergillosis is a common complication in neutropenic patients. The most important fungus is Aspergillus fumigatus. We report a case of invasive pulmonary aspergillosis due to Aspergillus nidulans secondary to fludarabine therapy. There are few cases of pulmonary aspergillosis due to Aspergillus nidulans (one chronic necrotizing pulmonary aspergillosis, one aspergilloma). Fludarabine induces a marked decreased of CD4 lymphocyte count responsible for opportunistic infections. It is the first case of aspergillosis after fludarabine therapy and the occurrence of such infection must be considered after purine analog therapy.

Enantioselective synthesis of new anthracyclinones is reported by chiral pool synthesis, using readily available lactose or glucose as starting materials. Glycosidation of such aglycones with various carbohydrates, including or not an amino function, led to anthracyclines endowed with significant antitumor activity but having some cross-resistance with daunorubicin and doxorubicin. Lowered cross-resistance was observed when the anthracycline beared an alkyl side-chain at C-9 and a morpholinyl residue at C-4'.

This is a retrospective study on the use of cytarabine at low doses in acute myeloid leukemias in 41 patients. Four groups of AML are included: group A: 19 cases of de novo AML in elderly patients; group B: ten cases of AML in relapse; group C: five cases of AML refractory to previous treatment and group D: seven cases of secondary AML. Cytarabine was given subcutaneously at the dose of 10 mg/m2 of body surface, for 21 days per month for the first course; then 15 days per month for the following courses. The response rates were 42, 20, 0, and 43% respectively for the A, B, C, and D groups. A complete remission was attained in only 15% (six patients). Extra haematological tolerance was excellent. Infection complications were noted in 66%, whereas a severe neutropenia was observed in 34% of patients. Hemorrhagic complications were more rare (20% of patients). The mean duration of complete remission was 10 months. The median survival was 10.5 months (2 to 31 months) for the responder patients, and 2.4 months (1 to 7 months) for the non-responders. Cytarabine at low doses seems to be a good indication for first intention treatment of AML in elderly patients. It does not give a bone marrow aplasia, the infection and hemorrhagic episodes are less numerous than with conventional dose chemotherapy, the life quality is improved, and treatment at home is often possible.

Chemotherapy-induced nausea and vomiting, two of the most distressing side-effects of cancer chemotherapy, have been the subject of a number of fundamental and clinical investigations. These have led to the development of a novel class of antiemetic agents, the 5-HT3 receptor antagonists. The pathophysiology of the emetic reflex and the clinical management of emesis are very complicated. Two experimental preclinical animal models are available (ferret and dog) and are particularly used to assess monochemotherapy as a single dose. Results are fairly good for acute nausea and vomiting. However, no optional animal model is available for the assessment of delayed and anticipated emesis. The clinical settings are so complex and variable that they preclude the development of an adequate model in all cases. It is also impossible to carry out clinical studies to assess each issue. Management of nausea and vomiting depends on the analysis by the physician of individual and drug-related parameters and on his own expertise. Scores can be assigned to each parameter and a decision tree can be elaborated to help the decision and improve the management of patients. The first goal is to obtain an optimal control of emesis from the very first cycle of chemotherapy in order to ensure good control during subsequent cycles.

High-dose anthracyclines, doxorubicin 75 mg/m2 and epirubicin 150-180 mg/m2, are the most active drugs in the treatment of advanced soft tissue sarcoma. These dosages are associated with significant hematological toxicity for both drugs and a high risk of cardiotoxicity for doxorubicin. The aim of this pilot study was to investigate the activity of zorubicin in advanced soft tissue sarcoma, with a dosage supposed to be equihematotoxic to epirubicin 180 mg/m2. Twenty of 21 patients who had been included in the study were evaluable for response, 15 males and five females, median age 41 (range 20-67) years. All patients received zorubicin 600 mg/m2 per cycle divided in 3 days, the intercycle interval being 4 weeks. The cardiac function was monitored by determinations of left ventricular ejection fraction before each cycle. Therapeutic response was the following: 2/20 patients (10%) complete response, 6/20 (30%) partial response, 6/20 (30%) stable disease and 6/20 (30%) progressive disease, the overall response rate being 8/20 (40%). Complete responses were observed in a patient with undifferentiated sarcoma of the mediastinum and in a patient with unresectable angiosarcoma of subcutaneous tissues. The major toxicity was hematological, with granulocytopenia grade 4 occurring in 42/66 cycles, and the nadir on day 10 of the treatment cycle. Nine of 66 cycles were complicated by febrile neutropenia and stomatitis of any grade was recorded in only 1/66 cycles. No cumulative cardiotoxicity was observed up to a total cumulative zorubicin dose of 3,000 mg/m2.

Drug induced pneumonias accompanying acute respiratory failure are defined by a delay in presentation of less two months and severe hypoxaemia (PaO2 < 60 mmHg in ambient air). They are poorly indexed, often poorly understood by the clinician and pose difficult problems both of diagnosis and treatment. This general review touches successively on hypoxaemic drug induced pneumonia observed in oncology and haematology then those observed outside this very specific context. In each of the two groups five questions are posed: 1) Which patients? 2) Which clinical patterns? 3) What initial diagnostic discussion? 4) Which successful elements support the drug induced hypothesis? 5) What outcome? The replies obtained were compared to case reports from the literature (188 references) or from recent general reviews concerned more specifically with the hypoxaemic forms.

The androgen sensitivity test used in male pseudohermaphroditism for clinical assessment of the androgen sensitivity and prediction of penile development is an important element in choice of gender. However, there is a wide range of testosterone dosage and no standardized test.

Nowadays more and more children survive after an intensive anti-tumoral therapy. The price to pay consists of numerous and relatively frequent long-term sequelae (secondary tumors, neuropsychological deficits, endocrine or cardiac damage). After chemotherapy, we sometimes observe renal side-effects, either tubular (metabolic acidosis, hypokalemia, hypomagnesemia, proteinuria, Fanconi syndrome, rickets) or glomerular (acute or chronic decreased GFR). These renal toxic side-effects are encountered especially after cisplatinum and ifosfamide, less frequently after carboplatin and cyclophosphamide. The pediatrician has to be aware of these toxic nephrologic side-effects, to look out for them and monitor carefully the renal function of all paediatric patients receiving these potentially nephrotoxic chemotherapies.

Bone marrow transplantation (BMT) is a potentially curative therapy in selected patients with hematologic disorders (acute leukemia, chronic myelogenous leukemia, lymphoma) or solid tumors (testicular or breast cancer). Pulmonary complications occur in 40 to 60% of patients receiving BMT, and are related to various mechanisms: chemotherapy-induced neutropenia, pulmonary toxicity of radiotherapy or chemotherapy, graft-versus-host disease. Bacterial or fungal pneumonia occurring during the initial period of neutropenia, and interstitial pneumonia (related to cytomegalovirus or of unknown origin) are the major respiratory complications of the first 100 days. Bacterial sinusitis and pulmonary infections, and obstructive airways disease related to bronchiolitis are the main late-onset respiratory disorders. No single risk factor can predict the development of these complications, which result from a sequence of events including infections, pulmonary injuries related to chemotherapy or radiotherapy, and inappropriate immunological reaction after transplantation. Antimicrobial prevention has been shown to reduce the mortality of these complications, but they still result in both important morbidity and mortality. They are the most frequent non relapse cause of death among long term surviving patients. Better understanding of their pathogenesis, and early recognition and treatment of respiratory complications of BMT should improve the efficacy of this therapy.

Polymorphonuclear neutrophils (PNN) chemiluminescence results from the luminescence emission in oxidative reactions during phagocytosis. This activity is easily detectable and measurable using a luminometer. PNN luminescence allows precociously the evaluation of the end of the aplasia. We have analysed PNN luminescence emission stimulated by latex beads in 69 patients with hemopathies after 72 aplasias following autologous bone marrow transplantation (9 pts), allogeneic bone marrow transplantation (26 pts) and acute myeloblastic leukemia (AML) induction chemotherapies (37 pts). Luminescence emission was measured in whole blood using a luminometer before, during and after aplasia and was compared to PNN manual count. Chemiluminescence measurement is a simple and reproductable method. Its allows more earlier than the PNN blood count the detection of PNN recovery: chemiluminescence nadir is reached on average on the fourth day of aplasia and correspond to the value procured by sample tubes without PNN. The onset of the chemiluminescence increasing is definite by the doubling of the nadir value. It is reached on average on the fourteenth day of aplasia. It precedes 3.5 days and 10.5 days a total PNN count > or = 0.1 x 10 9/1 and > or = 0.5 x 10 9/1 respectively, in the 72 aplasias. In autologous and allogeneic bone marrow transplantation, chemiluminescence increasing precedes at least PNN > or = 0.1 x 10 9/1 of 4.6 days whereas in AML induction chemotherapies, the advantage is only 1.5 day (p = 0.0078). The chemiluminescence could be considered as an additional tool in daily management of sustained aplasia.

The antiestrogen tamoxifen (TAM) has been successfully used to treat breast cancer expressing estrogen and progesterone receptors (ER+ and PR+). However, the development of antiestrogen resistance is frequently observed in patients following long-term treatment. To better understand the mechanism of action of TAM and its main metabolites: N-desmethyltamoxifen (N-des-TAM) and 4-hydroxytamoxifen (4-OH-TAM), their growth inhibitory effect was studied in 5 breast cancer cell lines characterized by different estrogen receptor levels: MDA-MB 231 (ER-), MCF-7 R (ER-), T47D (ER+), ZR-75/1 (ER+) and MCF-7 (ER+) trying to reproduce a cellular heterogeneity encountered in human breast tumors. In this study, the effects of TAM, N-des-TAM and 40-H-TAM on the cell growth were tested at concentrations ranging from 10(-8) to 10(-6)M with or without estradiol (10(-8)M). Only 4-OH-TAM showed a clear antiestrogen dose-dependent effect. Moreover, the finding of an antiproliferative activity at the highest dose (10(-6)M) for TAM, 4-OH-TAM and N-des-TAM in the ER- and PR- cell line MDA-MB 231 supports the hypothesis that TAM could be effective on ER+ as well as ER- tumors by an ER-independent mechanism. Despite ER+ and PR+ status after 2, 4 and 6 days of treatment, the T47D cell line displayed an increased growth rate with N-des-TAM at 10(-6)M. It should be noted that such concentration is within the range of the plasma level of N-des-TAM (10(-6)M) in patients receiving TAM per os (40 mg/day). These results and the well-known cell heterogeneity of human breast tumors may significantly account for some failure of antiestrogen treatment.

In vitro models have been intensively developed for several years for selecting new anticancer agents. The National Cancer Institute has even chosen as a primary screen of new molecules a panel of 60 human tumor cell lines. However, it may seem hazardous to rely too much on in vitro models for the discovery and selection of new anticancer drugs: (1 because no metabolism of the compounds occurs in cell culture; (2 because an in vitro cell line cannot be representative of an in situ tumor cell population; (3 because antiproliferative activity is only part of antitumor activity; (4 because the toxicologic properties of the molecules are not taken into account by in vitro systems; (5 because cell cultures do not allow any selectivity study between tumor cells and normal cells. With examples drawn from three different therapeutic classes, anthracyclines, taxoids and camptothecin derivatives, we show that in vitro tests are insufficiently predictive of antitumor potential. The excess of confidence allowed to these models may lead to premature decisions which are not after that justified by clinical trials.

16 cases of acute methotrexate (MTX) poisoning were reported to the Paris Poison Control Centre and 62 others were published between 1974 and 1995. Until 1992, MTX was mainly prescribed for neoplastic diseases. Clinical features involve acute renal failure, pancytopenia, and cutaneous or mucous injury. These cases emphasise major risk factors responsible for misuse and overdosage. Since 1992, MTX has been increasingly used in rheumatological or pulmonary diseases (rheumatoid arthritis, steroid-dependent asthma). Most of the overdosages were due to a medical misuse (in the dosage regimen or a misunderstanding of the prescription by nurse, pharmacist or patient). All patients had a bone marrow suppression. The treatment is based especially on early administration of folinic acid rescue.