[Infliximab-induced skin reaction with visceral manifestations and high levels of anti-DNA antibodies]. / Toxidermie avec manifestations systémiques et sérologie lupique induites par l'infliximab.

BACKGROUND: Infliximab is a monoclonal anti-Tumor Necrosis Factor alpha-antibody (anti-TNFalpha) that has demonstrated its efficacy in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis. CASE REPORT: We report the case of a 59 year-old woman with a 20-year history of rheumatoid arthritis consulting for an atypical erythematosus rash 18 months after her first infusion of infliximab. The rash was associated with inflammatory syndrome, incipient renal failure and high levels of antinuclear antibodies with the presence of anti-dsDNA antibodies. Lack of specificity in both skin manifestations and histology ruled out a diagnosis of drug-induced lupus. Discontinuation of treatment with infliximab resulted in improvement of all clinical signs together with a significant decrease of antinuclear antibody titers within six months. DISCUSSION: Induction of antinuclear antibodies and/or anti-dsDNA antibodies is often seen in patients treated with TNFalpha inhibitors. Cases of true systemic lupus erythematosus or anti-TNFalpha-related eruption in a context of autoimmunity, as seen in our patient, have been reported only rarely. All cases were reversible upon discontinuation of treatment.

[Neoadjuvant chemotherapy FEC-HD in locally advanced breast cancer]. / Chimiothérapie néoadjuvant FEC-HD dans le cancer du sein localement évolué.

The tolerance and the clinical and histological efficacy of a neoadjuvant chemotherapy FEC-HD including hematopoietic growth factors have been studied in 40 patients with stade II or III breast cancer between February 1991 and February 1997. Four courses were given, every 21 days, with 5-fluorouracil (750 mg/m2/day D1 to D4 by continuous infusion), epirubicin (35 mg/m2/day D2 to D4) and cyclophosphamide (400 mg/m2/day D2 to D4) with G-CSF (5 mug/kg/day D6 to D15). The surgery was performed 3 or 4 weeks after the end of the chemotherapy. All patients had radiotherapy. The neoadjuvant chemotherapy induced 37.5% CR, 45% PR, and 15% SD. In 40% of the patients, the surgery was conservative. An histological CR was obtained in 15% with no axillary involvement one time out of two. There was intraductal carcinoma without invasive carcinoma in 7.5%. There was no differences between the response of inflammatory and non inflammatory tumors. One hundred and fifty-eight courses have been delivered. A grade 3 or 4 leuconeutropenia, anemia and thrombopenia have been observed in respectively 34.6%, 6.3% and 8.8% of the courses. A grade 3 or 4 mucositis has been noticed in 2.5% of the courses. A febrile granulocytopenia has occurred in 3.8% of the courses. The median survival without metastatic progression was 48 months and the median overall survival was not achieved. In stade II and III breast cancer, neoadjuvant chemotherapy with FEC-HD obtains an important histological response with an acceptable toxicity. The role of the dose-intensity increase on survival remains to be determined.

[Identification of drug misuse. Study of spontaneous notifications of adverse drug events in a regional safety reporting centre]. / Identification du mésusage des médicaments. Etude de la notification spontanée des effets indésirables dans un centre régional de pharmacovigilance.

INTRODUCTION: The misuse of drugs, common practice for some, is a source of iatrogenic diseases and considerable supplementary costs in hospital budgets. The aim of this study was to quantify the number of adverse events (AE) related to the misuse of drugs. METHODS: This was a study conducted on 200 new validated AE case reports. In each report, we searched for the drug(s) responsible and checked whether the prescription respected the SPC (summary of product characteristics) and current guidelines or not. RESULTS: Among the 200 reports, 49 (24.5%) cases of AE were related to the misuse of a drug in 46 patients, with a mean age of 65.8 years [24 to 97]. Among these cases, 33 (67.3%) were at the origin of hospitalisation or prolongation of the latter. In 17 cases (34.7%), there was no therapeutic alternative to the drug used in the framework of misuse. DISCUSSION: The notion of good or bad use of a drug progresses with the life of the drug. We therefore selected as criterion of misuse the non-respect of the SCP but also other guidelines. Regarding the cases that could have been avoided, these concerned an AE related to poor surveillance and assessment of the benefit/risk ratio of treatments prescribed to elderly patients and also the commonplace use of non-steroidal anti-inflammatories, at the origin of digestive haemorrhages. CONCLUSION: The prevention of misuse implies all the actors of the health system. A reassessment of the prescription of certain therapeutic classes of drugs would avoid a great number of iatrogenic accidents and would lead to considerable economy in the field of health.

[Biological perspectives]. / Perspectives biologiques.

The tumour biology of non-small cell bronchial cancer integrates recent developments and a dynamic schema of the phenomena of tumour progression and diffusion of the metastatic disease. There is no leap of known biological disruption between Stage II and Stage III. The latter is defined by anatomical criteria and is a transition in the continuum of the natural history of these cancers. The moto for the tumour progression is the genotypic instability and phenotypic diversification. Metastatic microscopic disease constitutes the first cause of failure in the treatment of Stage III non-small cell bronchial cancer. Among prognostic factors for survival emphasis is placed on the alterations of p53 expression, different types of aneuploidy, anomalies of the expression of cellular adhesion molecules and finally, tumour diversification towards a metastatic phenotype.

Nitric oxide synthase in human breast cancer is associated with tumor grade, proliferation rate, and expression of progesterone receptors.

Nitric oxide (NO) is generated by a family of isoenzymes named nitric oxide synthases (NOS) which includes a cytokine-inducible form, NOSII. NO is a free radical known to inhibit cell proliferation, to induce apoptosis, and to be a mediator of macrophage cytostatic and cytotoxic effects. We investigated NOS in 40 human breast carcinomas and 8 benign breast lesions. NOSII was localized in tumor cells by immunohistochemistry. NOS activity, measured with the citrulline assay, was detected in 27 of 40 tumors. Neither immunohistologic labeling nor NOS activity was detected in benign samples. NOS labeling and activity were significantly related (p < 0.02). For the first time, a significant negative relationship between NOS activity and tumor cell proliferation (p < 0.002) was found. We also showed that tumors with high NOS activity expressed progesterone receptors (p < 0.04). These results are consistent with the observation of high NOS activity in tumors with low grade (p < 0.05). These in vivo observations were related to in vitro data: cytokines (IL-1beta, IFN-gamma, and TNF-alpha) induced NOSII expression in human MCF-7 breast cancer cells, and NO inhibited their proliferation. Thus, we show herein that tumors with high NOS activity have low proliferation rate and low grade, which correlates with the in vitro observation of the inhibition of proliferation of human breast cancer cells by NO. These results may have future therapeutic implications.

Hypodiploidy, Ki-67 growth fraction and prognosis of surgically resected lung cancers.

One hundred and thirty-seven lung cancer patients (123 non-small-cell lung cancers (NSCLC), 10 small-cell lung cancers (SCLC) and four carcinoid tumours) who underwent surgery in an attempt at complete resection were prospectively entered in a study whose aim was to determine the prognostic significance of a hypodiploidy or a multiploidy pattern of tumour cell DNA content and a high immunohistochemical reactivity of Ki-67, a nuclear antigen related to the cell cycle. Indirect immunoperoxidase reactivity of Ki-67 on frozen tumour tissue sections was evaluated both visually, using a classical semiquantitative scale, and by means of a computer-assisted image processor. Cell DNA content analysis was done using static computer-assisted cytometry on tumour cytological prints stained by the pararosaline Feulgen-Schiff technique. The ploidy was characterised for each tumour by DNA index (DI), percentage of hypodiploid cells and type of DNA content histogram (near diploid, hyperdiploid, hypodiploid and multiploid). Ki-67 immunostaining was negative in 64 tumours (48%) and positive in 69 (52%). DNA histogram classification disclosed 57 (42%) near diploid tumours. Among the 80 (58%) aneuploid tumours, 16 were hypodiploid, 44 hyperdiploid and 20 multiploid. The prevalence of both a positive Ki-67 immunostaining and an aneuploid DNA histogram differed according to histology as SCLC demonstrated a higher frequency of both features when compared with NSCLC and carcinoid tumours. On the other hand, Ki-67 immunostaining and ploidy did not significantly differ according to degree of differentiation, nodal status and Mountain's stage grouping. The percentage of cells in the hypodiploid modal DNA was significantly higher for tumours which demonstrated a high Ki-67 immunostaining, suggesting a link between growth fraction and DNA content abnormalities. In univariate analysis, survival did not differ significantly according to either the Ki-67 immunohistochemical reactivity or the DNA index. Patients with a hypodiploid tumour had a shorter survival than patients with other DNA histogram patterns but, owing to the low frequency of hypodiploidy, this difference did not reach statistical significance. In Cox's proportional hazard model, an SCLC histology, an advanced tumour status, a positive nodal status and a hypodiploid tumour (hazard ratio: 2.070; 95% confidence interval 1.041-4.116) were significant determinants of survival. We conclude that hypodiploidy in lung cancer is a distinct DNA content abnormality as it contributes significantly to prognosis. Neither visually assessed nor computer-generated Ki-67 immunostaining measurements significantly determine prognosis.