LMCE3 treatment strategy: results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis.

PURPOSE: To tailor postinduction therapy for stage 4 neuroblastoma in children who are older than 1 year at diagnosis according to status after induction. PATIENTS AND METHODS: From March 1987 to December 1992, 99 patients who were consecutively admitted were included in the Lyon-Marseille-Curie East of France (LMCE)3 strategy. After induction with the French Society of Pediatric Oncology NB87 regimen and surgery, patients who were in complete remission immediately proceeded to consolidation therapy with vincristine, melphalan, and fractionated total-body irradiation (VMT). All other patients underwent a postinduction strategy before VMT, either an additional megatherapy regimen or further chemotherapy with etoposide/carboplatin. RESULTS: The progression-free survival (PFS) is 29% at 7 years from diagnosis, which compares favorably with that of a similar cohort of 72 patients previously reported by our group (LMCE1; PFS of 20% at 5 years and 8% at 14 years, P =.004). In the multivariate analysis, only age younger than 3 years at diagnosis (P =.0085) and achievement of complete or very good partial remission after NB87 and surgery (P =.00024) remained significant. The PFS of the 87 patients who were included in the postinduction strategy was significantly better than that of the comparable 62 patients on the LMCE1 study (32% v 11% at 7 years; P =.005). CONCLUSION: The progressive improvements in the LMCE results over the last 10 years suggest that improvements in supportive care measures and increases in each component of this strategy (induction, postinduction, consolidation) may all contribute to increased survival rates.

Does nephroblastomatosis influence the natural history and relapse rate in Wilms' tumour? A single centre experience over 11 years.

The presence of multifocal or diffuse nephrogenic rests (NRs) in one or both kidneys is termed nephroblastomatosis (Nbm). Nbm may be a predisposing factor for Wilms' tumour (WT). The aim of this retrospective study was to evaluate the impact of Nbm on the outcome of WT in children. We assessed the outcome of 81 children with Wilms tumours and practical implications of Nbm in the treatment and follow-up. All the pathology slides have been reviewed in 1997. 63 had WT without Nbm (group A) and 18 had WT associated with Nbm (group B). There was no statistical difference between the two groups according to the age at diagnosis and histology. Clinical abnormalities were more frequent in group B (33 versus 8%). There was no statistical difference between the percentage of stage IV in both groups, but bilaterality (stage V) was present only in the group B. Relapse was observed in 20/81 patients (25%): 11 (17%) in group A and 9 (50%) in group B. Mean delay of relapse was longer (25 months) in group B than in group A (10 months). For the whole population, with a median follow-up of 9 years, the event-free survival (EFS) and the overall survival (OS) probabilities were respectively 74%+/-10 and 83%+/-9 at 120 months. The difference in EFS between groups A (82+/-9%) and B (38%+/-29) was significant (P=0.004). The discovery of Nbm in the non-tumoral part of the kidney with WT can be an adverse factor and in particular favours the subsequent development of a new Wilms tumour. It justifies separate follow-up guidelines.

The reversibility of the inhibition of intestinal amino-acid transport by harmaline.

The inhibitory aciton of harmaline on L-phenylalanine uptake by guinea-pig intestinal rings is fully reversible provided only low concentrations of the inhibitor are used; if the concentration is raised to a sufficient extent to enable the drug to interfere with sodium pumping or cellular metabolic reactions, as witnessed by its effect on tissue oxygen consumption, then the inhibition of L-phenylalanine uptake is only reversible if short contact times are employed.

Differential effects of harmaline and ouabain on intestinal sodium, phenylalanine and beta-methyl-glucoside transport.

Harmaline inhibits both the Na+ -K+ -ATPase activity and the uptake of L-phenylalanine in guinea-pig intestinal mucosa. The latter effect is not a direct consequence of the former, since higher concentrations are needed to inhibit the enzyme than the influx into the mucosa; Furthermore the uptake is still sensitive to harmaline when the Na+ -K+ -ATPase has been fully inhibited by ouabain. Harmaline can inhibit L-phenylalanine influx at a concentration at which it does not affect intracellular ion concentrations. Ouabain, however, inhibits the uptake of L-phenylalanine only after a 30 min preincubation period, when the intracellular sodium concentration reached the extracellular level. Harmaline also interferes with the influx of beta-methyl-D-glucoside in the mucosa of the dog colon. Addition of harmaline at the mucosal face of the tissue suppresses all net transport of sodium and chloride ions and L-phenylalanine across the mucosa. Thus the same mode of action appears to apply in both the guinea-pig ileum and the dog colon.

[Permeability of sublingual mucosa to organic molecules. Limited role of sublingual absorption in aerosol vaccinations]. / La perméabilité de la mugueuse sub-linguale aux molécules organiques. Les limites du rôle de la voie sub-linguale dans la vaccination par aérosols

131I labelled tetanus anatoxin was placed in vivo, in the sublingual area in the rat. The radioactivity appearing in blood was insignificant, even after that the disappearance rate in reference animal had been taken into account. It is concluded that immunisation with aerosols is fundamentally carried out through the respiratory tract.

Cytotoxic effect and electrophysiological activity of (S)-bgugaine, an alkylpyrrolidine alkaloid against MRC-5 fibroblasts.

(+)-S-bgugaine [1], is an alkaloid prepared by enantioselective synthesis. This alkaloid is an isomer of R-bgugaine [2], an alkaloid isolated from Arisarum vulgare, an Araceae toxic plant of Morocco. The cytotoxic effect and the electrophysiological activity of (+)-S-bgugaine [1] against MRC-5 fibroblasts of (+)-S-bgugaine 1, were studied. (+)-S-bgugaine [1] showed a cytotoxic potential at 40 microg/ml against these MRC-5 cells. The electrophysiological study on MRC-5 cells was carried out using the technique of patch-clamp and showed that the activity of compound 1 involved a reduction of outward potassic current at the concentration of 100 microM (28.1 microg/ml) and was accentuated by 200 microM (56.2 microg/ml). In this study we show that S-bgugaine [1], decreases the outward potassic current.

Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Français d'Immunothérapie.

Interleukin-2 (IL-2) or/and interferon (IFN) are routinely used for treating patients with metastatic renal cell cancer. However, results have been disappointing, with a majority of treatment failure. Over 6 years, the Groupe Français d'Immunothérapie enrolled 782 patients in successive multicenter trials using cytokine regimens. Univariate and multivariate analyses were performed on this large prospective database to identify prognostic factors for survival. The presence of biological signs of inflammation, short time interval from renal tumor to metastases (<1 year), elevated neutrophil counts, liver metastases, bone metastases, patient performance status (PS), the number of metastatic sites, alkaline phosphatases and hemoglobin levels were predictive of survival outcome. When compared with previous results, our study showed that PS, number of metastatic sites, disease-free interval, biological signs of inflammation and hemoglobin levels can be considered as validated prognostic factors. We also identified four independent factors predictive of rapid progression under cytokine treatment: presence of hepatic metastases, short interval from renal tumor to metastases (<1 year), more than one metastatic site and elevated neutrophil counts. Patients who combined at least three of these factors have >80% probability of rapid progression despite treatment. We think that these results must be taken into account when making the decision to treat with cytokine.

Initial management of advanced Burkitt lymphoma in children: is there still a place for surgery?

This retrospective study compared the overall survival, the event-free survival, and the timing of chemotherapy in patients with advanced Burkitt lymphoma with and without laparotomy. Thirty-five patients with advanced abdominal Burkitt lymphoma treated at least partially at the Centre Léon Bérard between 1981 and 1992 were included in this study. The diagnosis was obtained by laparotomy (LAP group) in 21 patients (17 stage III, 4 stage IV) and by other methods (non-LAP group) in 14 patients (5 stage III, 9 stage IV). The overall survival (71 and 93%) and the event-free survival (66 and 79%) were similar in the LAP and non-LAP groups, and the relapse rate was five (three local) in the LAP group compared with three (none local) in the non-LAP group. The local complication rate (9 of 21 versus 2 of 14) and the toxic death rate (2 of 21 versus 1 of 14) were slightly higher in the LAP group. Laparotomy also caused delays in therapy and increased the overall hospital stay. The mean interval from diagnosis to the start of the fourth course of chemotherapy was 57 days compared with 48 days and the average hospital stay was 44.4 days compared with 39 days for the LAP and non-LAP groups, respectively. Because advanced Burkitt lymphoma can be diagnosed by fine-needle aspiration, and chemotherapy cures more than 80% of the patients, there is no need for initial surgery, apart from acute emergencies. Furthermore, laparotomy delay chemotherapy and might reduce the survival rate.

High-dose chemotherapy for ovarian carcinoma: long-term results from the Solid Tumour Registry of the European Group for Blood and Marrow Transplantation (EBMT).

PURPOSE: to determine the outcome of epithelial ovarian cancer in patients registered with the European Group for Blood and Marrow Transplantation (EBMT). PATIENTS AND METHODS: A retrospective analysis was performed on 254 patients with advanced or recurrent disease, median age 46 years (14-63) from 39 centres treated between 1982 and 1996. Only 25% of patients were known to have no or microscopic disease after initial surgery; in approximately 20% the disease status was unknown, the remainder had macroscopic disease. RESULTS: One hundred five patients received high-dose chemotherapy in complete or very good partial remission, twenty-seven in second remission and the remainder in the presence of residual disease. Most received melphalan or carboplatin, or a combination (86%) supported by autologous bone marrow or peripheral blood stem cells. The survival of patients treated in remission was significantly better than in other groups (median 33 vs. 14 months; P = 0.0001). The durability of remission was longer after transplantation in first remission than in second remission (median disease-free survival 18 vs. 9 months; P = 0.005). With a median follow-up of 76 months from diagnosis the median disease-free and overall survival in stage III disease transplanted in remission is 42 and 59 months and for stage IV disease 26 and 40 months. CONCLUSIONS: High-dose chemotherapy has a potential benefit for patients in remission. The results support the conduct of randomised studies to determine whether there is a real value from this treatment.

Improving survival in recurrent medulloblastoma: earlier detection, better treatment or still an impasse?

Early detection of relapse has been advocated to improve survival in children with recurrent medulloblastoma. However, the prognostic factors and the longer term outcome of these patients remains unclear. Pattern of recurrences were analysed in three consecutive protocols of the Société Française d'Oncologie Pédiatrique (1985-91). A uniform surveillance programme including repeated lumbar puncture combined with computerized tomography (CT) or magnetic resonance imaging (MRI) scan was applied for all registered patients. Forty-six out of 116 patients had progressive or recurrent disease. The median time from diagnosis to recurrence was 10.5 months and 76% relapses occurred during the first 2 years. Seventeen patients had asymptomatic relapses that were detected by the surveillance protocol. Forty-one patients were treated at time of progression. Twenty-three responded to salvage therapy and 11 achieved a second complete remission. The median survival time after progression was 5 months (<1-41 months), and only two patients remained alive at time of follow-up. Length of survival is primarily related to some specific patterns of relapse (time from diagnosis to recurrence, circumstances of relapse, extent of relapse) and to the response to salvage therapy. No evidence of long-term benefit appeared from any form of treatment.