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Biomedical subjects

P Chastagner

Publications and source records attributed to P Chastagner.

72 records · Page 4Linked to original sources

Monomorphic organization of human diversity (DH) heavy chain variable genes.

While recent evidence indicates that human immunoglobulin heavy chain variable (VH) genes exhibit a high degree of heterogeneity, little is known concerning the polymorphism of the diversity (DH) gene complex. This locus comprises two clusters, major and minor, which are physically linked with the VH locus. In assessing the variability of the human major and minor DH clusters, we found no evidence for a substantial restriction site polymorphism. We also noted that, in contrast to what was found in the Japanese population, the DH1 gene is not deleted in an appreciable proportion of the European population. We propose that, because DH genes impart the critical functions associated with the third complementarity-determining region, the genomic organization of the human DH locus has been evolutionarily conserved through selection pressure mechanisms.

Antibody Diversity↗

Etoposide and carboplatin in neuroblastoma: a French Society of Pediatric Oncology phase II study.

PURPOSE: A phase II study of etoposide (VP 16) and carboplatin (CBDCA) was performed in patients with metastatic neuroblastoma (NB). The aim of the study was to find an alternative treatment for induction with different toxicities than the VP 16/cisplatin (CDDP) combination. PATIENTS AND METHODS: Forty-seven patients who were from 6 months to 16 years of age, with either relapsed (29) or primary resistant (18) NB, were included in a cooperative multicenter phase II study of the French Society of Pediatric Oncology (SFOP). The schedule consisted of 5 consecutive days of VP 16 100 mg/m2/d and CBDCA 160 mg/m2/d. RESULTS: The response rate for the 39 assessable patients was 43%; there were four complete remissions and 13 partial remissions. Neither the status of the patients nor the total dose of CDDP that was received previously influenced response. Hematologic toxicity was marked and caused considerable delay between courses (median interval, 39 days). In these heavily pretreated patients, 16% had a more than 50% decrease in creatinine clearance and a 22% World Health Organization (WHO) grade 2 ototoxicity. CONCLUSION: This VP 16/CBDCA combination deserves further evaluation for efficacy and toxicity in newly diagnosed patients, and the combination of both drugs should be considered for high-dose therapy with bone marrow transplantation.

Adolescent↗

Brain tissue heterotopia in the nasopharynx. Contribution of MRI to assessment of extension.

The authors report two cases of brain tissue heterotopia in the nasopharynx, without other malformations and, in one of the cases, with a persistent craniopharyngeal canal opening onto the heterotopia. This exceptional malformation is very similar to brain heterotopia in the nose, or "nasal glioma", which is more frequent and less diversified at histology. The malformation is revealed by obstruction of the pharynx with respiratory distress immediately after birth or during the first weeks of life. Total surgical excision provides cure without sequelae. The diagnosis is based on histology. MRI is essential to the diagnostic and pretherapeutic evaluation, notably to avoid missing an ectopic hypophysis, but it is insufficient to diagnose a sphenoidal meningoencephalocele.

Brain↗

Cloning of a gene encoding a lupus-associated human autoantibody VK region using the polymerase chain reaction and degenerate primers.

The variable light-chain-encoding gene of a human autoantibody secreted by a B-cell hybridoma derived from a patient with systemic lupus erythematosus was amplified using the polymerase chain reaction and degenerate primers. After cloning, the nucleotide sequence of the EcoRI-HindIII region was determined. It is highly homologous to a previously described gene expressed by a human lymphoid cell line.

Autoantibodies↗

In vitro combination of high dose busulfan with radiotherapy on medulloblastoma cells: additive effect without potentiation.

The aim of this in-vitro study was to evaluate the combination of busulfan with radiotherapy on TE-671 human medulloblastoma cells since unexpected clinical toxicity of busulfan was reported during the treatment of brain tumors, suggesting a possible radiopotentiation. The cytotoxicity of busulfan was determined by using colony forming assays, and doses inducing growth inhibitions of 10, 20 and 50% were selected to be tested in association: 6, 12 and 32 mumol/l for busulfan and 0.5, 1 and 3 Gy for irradiation. All possible combinations were considered within this frame and the results showed that the combination of busulfan with radiotherapy exerted an additive effect without potentiation.

Busulfan↗

[Histological and immunohistochemical diagnosis of bone marrow metastases of neuroblastomas].

A retrospective, morphological and immunochemical study was performed on 60 bone marrow biopsies (BOM) and 12 tumor specimens surgically excised, from 9 patients with neuroblastoma (NB). Immunochemistry concerned "neuron-specific enolase" (NSE), chromogranin A (CGA) and synaptophysin (SP). The results of immunochemical stains and the study of reticulin network on the argentic stain were compared to the results of morphological evaluation on the routine stain. NSE, CGA and SP staining of tumor cells (part or all of them) was obtained from all surgical specimens. 17/75 BOM (20%) were discarded because of poor material. NB cells were observed in 24 BOM from 3 patients. Tumor cells formed large strands (1 patient) or nests (2 patients) associated with segregated cells. Diagnosis of metastatic BM involvement was negative or doubtful for 6 BOM (3 obtained at the same time, 2 patients), in which NB cells were clearly demonstrated by immunochemical staining of NSE and/or CGA. Reticulin and/or collagen myelofibrosis was present in 32/35 BOM from the 3 patients metastatic in bone marrow (BM+) even if NB cells could not be demonstrated in these samples.

Biopsy↗

[Role of chemotherapy in the treatment of brain tumors].

Chemotherapy is a treatment of choice for children with brain tumors, since 20% are unresectable (hypothalamic and brainstem), or incompletely removed, and since radiation therapy often induces cognitive and endocrine sequellae. However, tumor cell heterogeneity and blood-brain barrier which play a role in restricting delivery of chemotherapy represent limiting factors to its efficiency. Neuroradiological procedures such as CT scan and magnetic resonance imaging may bring objective criteria in order to evaluate the efficacity of chemotherapy. Chemotherapy is tested in phase II trials to identify the most efficient drugs for each histological tumor type. This provides a rationale to elaborate phase III trials where polychemotherapy is combined to surgery and radiotherapy. Attempts to enhance drug penetration, such a high-dose chemotherapy and blood-brain barrier disruption, are under study. Primary and acquired drug resistance are being studied as well as the means of overcoming them.

Antineoplastic Agents↗

[Chemotherapy of brain tumors in children].

The present recovery rate of brain tumors (20% of solid tumors in children) is 50%. Besides the progress made in neurosurgery and radiotherapy, those of chemotherapy have indisputably had an impact on the improvement of the rate of recovery. Protocols in use differ according to the histologic type of the tumor (astrocytoma, glioma, medulloblastoma). Indications for therapeutic trials for phase II and III tumors will require a longer period of follow-up as well as strict analysis of the result.

Adolescent↗

[Systemic chemotherapy with conventional doses for brain tumors in children: phase II trials].

The analysis of Phase II trials with regard to brain tumors in children, aiming to test the activity of 1 drug or a combination of drugs is not easy, due to the following reasons: poor selection of patients (clinical and pathological heterogeneity), not always rational choice of the drugs and mostly, variability of the criteria and the methods used to assess the tumor response. When using a single drug, the current most efficient agents seem to be: cisplatinum, carboplatin, cyclophosphamide and etoposide, while nitroso-ureas have not been strictly studied. When using polychemotherapy, the best results have been obtained with the "8 drugs in 1 d" regimen. The most chemo-sensitive tumors are: medulloblastomas, primitive neurectodermal tumors, pinealoblastomas; high grade ependymomas and astrocytomas have been studied less in children than in adults. Present and future strict organisation of Phase II trials in brain tumors is compulsory in order to select the active agents, and to establish the best modalities of administration. The need to assess chemotherapy not only in refractory or relapsing patients, but also at diagnosis in high-risk patients is emphasized (after incomplete surgery and before radiotherapy).

Antineoplastic Agents↗

Role of parenteral antibiotherapy in gastrointestinal tract flora suppression. A study in children treated with high-dose chemotherapy and autologous bone marrow transplantation.

In order to determine the effect of parenteral antibiotherapy on the fecal flora in patients with profound and prolonged granulocytopenia, we initiated a prospective study of 62 cases of autologous bone marrow transplantation following high-dose chemotherapy. All patients were children from 2 to 18 years old, isolated in a protective environment, receiving a diet low in viable microbial content but no oral non-absorbable prophylactic antibiotics to decontaminate the gastrointestinal tract. Bacteriological analysis of fecal flora was conducted at least once a week before and during parenteral antibiotherapy, administered at the first greater than 38 degrees C febrile episode in these granulocytopenic patients (granulocyte count less than 0.5 X 10(9)/l). The 58 evaluable patients fell into three groups with regard to the systemic antibiotherapy: group A (n = 16): moxalactam + mezlocillin; group B (n = 15): moxalactam + tobramycin; and group C (n = 27): cefotaxime plus gentamicin. Fecal flora suppression was observed in 51/58 cases (88%) (group A: 15/16, group B: 13/15, group C: 23/27). It always occurred within 5 days of initiating parenteral antibiotherapy and persisted in 88% of the 51 patients over the whole period of systemic antibiotherapy. During the latter, fecal recolonization was observed in seven cases (12%), always by Enterobacteriaceae sensitive to the prescribed systemic antibiotherapy, never responsible for septicemia. Since parenteral antibiotherapy alone was able to suppress the gastrointestinal tract flora, the effects of this treatment should be considered in all trials of digestive tract decontamination.

Adolescent↗

p55 IL-2 receptor mRNA precursors in murine T lymphocyte nuclei.

An unusual family of cDNA clones homologous to human p55 IL-2R sequences was isolated from the murine HT-2 Th cell line. These clones were mapped, partially sequenced, and compared with previously published human and mouse IL-2R sequences. They appear to consist of various combinations of exons and introns, suggesting that they are derived from p55 IL-2R mRNA precursors. The configuration of exons in the splicing intermediates indicates that the murine and human gene organizations are similar and that the 3' end of intron 3 is well conserved between the two species. RNA mapping experiments using nuclear, cytoplasmic, and total RNA and probes derived from various parts of the p55 IL-2R gene support and extend the sequence data. They indicate that detectable amounts of immature p55 IL-2R mRNA are found specifically in the cell nucleus of the HT-2 cell line. Similar data were obtained for the Th cell clone 52.3 and the cytotoxic T cell line CTLL. All these results indicate that the T cell nucleus contains significant amounts of immature p55 IL-2R mRNA.

Animals↗

[Allergy to mercurothiolate in an infant during heparinization of an intracaval catheter].

A 4-month old infant developed an immediate and proven systemic allergic reaction to mercurothiolate. The acute accident occurred while an intracaval catheter was being treated with a dry-frozen heparin which excipient contains mercurothiolate. This conservative agent is present in numerous pharmaceutical preparations for topical and systemic use.

Catheters, Indwelling↗

[Efficacy of the "8 drugs in a day" protocol in brain tumors in children].

In the present study, the "8 drugs in 1 day" regimen was tested in 54 children: 27 relapses (brain and/or spinal and/or meningeal sites), 10 refractory progressive diseases, 13 macroscopic residual tumors after partial excision and/or radiotherapy; in 4 cases, this regimen was prescribed as first line treatment. The response rate (complete and partial remission) was 46%. Results were very encouraging in medalloblastomas with a response rate of 76.5% whereas in brain stem gliomas it was only 23% and 33% in other astrocytomas. Immediate toxicity, mainly hematological, was very moderate. These results justify to propose this regimen as adjuvant chemotherapy, mostly in medulloblastomas and to plan other similar trials, using the most active drugs which seem presently to be alkylating and platinum-derived agents.

Adolescent↗

B cell activating factor(s) (BCAF) containing supernatant can induce all classes of immunoglobulin and IgG switches in resting B cells.

We have previously shown (L. Leclercq et al., Proc. Nat. Acad. Sci. 1984, 81:6491) that the supernatants of activated T helper cells can stimulate resting B cells to proliferate and to express early activation markers. The corresponding activity has been called B Cell Activating Factor or BCAF. Here we show that BCAF-containing supernatants can induce resting B cells to produce immunoglobulins of all isotypes as measured by enzyme linked immunoabsorbent assay. The isotype pattern obtained is similar to the one obtained when TH cells are cocultured with unprimed resting B cells. Furthermore, BCAF-containing supernatants induce IgG switches as measured by the secretion of IgG3, IgG1, IgG2a and IgG2b immunoglobulin by cell sorted surface IgG- resting B cells. These investigations confirm that BCAF-containing supernatants can act on resting B cells.

Animals↗

Induction of mouse p55 interleukin-2 receptor gene expression by IL-2 and IL-4 and characterization of its transcription initiation sites.

Two murine T cell lines (C30.1 and Line 1) were used to study the expression of the p55 interleukin-2 receptor gene. C30.1 is an IL-2-dependent T cell line that can be stimulated for a short period of time by IL-4. Line 1 cells are propagated in IL-4 but they also proliferate in response to IL-2. In both cell lines stimulation by IL-2 leads to a strong induction of p55 IL-2 receptor mRNA while stimulation by IL-4 leads only to a very moderate increase in expression of this mRNA. The induction of p55 IL-2 receptor mRNA by IL-4 is comparable to that of beta-actin mRNA. These data confirm that IL-2 upregulates p55 IL-2 receptor gene expression while IL-4, which also activates T cells, does not lead to specific induction of this gene. We have also determined the transcription initiation sites utilized by the p55 IL-2 receptor gene in C30.1 and Line 1 cells. Seven sites were identified, one of which predominates. Resting cells, or cells stimulated with IL-2 or IL-4, display the same pattern of transcription site utilization.

Animals↗