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P Chastagner

Publications and source records attributed to P Chastagner.

At least 37 records · Page 2Linked to original sources
PubMed2001

Phase I trial and pharmacological study of a 3-hour paclitaxel infusion in children with refractory solid tumours: a SFOP study.

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420 mg/m(2)). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity.

Adolescent↗
PubMed2001

Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: a multicenter trial of the French Society of Pediatric Oncology.

PURPOSE: To evaluate a strategy that avoids radiotherapy in first-line treatment in children under 5 years of age with brain or posterior fossa ependymoma, by exclusively administering 16 months of adjuvant multiagent chemotherapy after surgery. PATIENTS AND METHODS: Between June 1990 and October 1998, 73 children with ependymoma (82% with high-grade tumors) were enrolled onto this multicenter trial. Children received adjuvant conventional chemotherapy after surgery consisting of seven cycles of three courses alternating two drugs at each course (procarbazine and carboplatin, etoposide and cisplatin, vincristine and cyclophosphamide) over a year and a half. Systematic irradiation was not envisaged at the end of chemotherapy. In the event of relapse or progression, salvage treatment consisted of a second surgical procedure followed by local irradiation with or without second-line chemotherapy. RESULTS: Conventional chemotherapy was well tolerated and could be administered in outpatient clinics. No radiologically documented response to chemotherapy more than 50% was observed. With a median follow-up of 4.7 years (range, 5 months to 8 years), the 4-year progression-free survival rate in this series was 22% (95% confidence interval [CI], 13% to 43%) and the overall survival rate was 59% (95% CI, 47% to 71%). Overall, 40% (95% CI, 29% to 51%) of the patients were alive having never received radiotherapy 2 years after the initiation of chemotherapy and 23% (95% CI, 14% to 35%) were still alive at 4 years without recourse to this modality. In the multivariate analysis, the two factors associated with a favorable outcome were a supratentorial tumor location (P =.0004) and complete surgery (P =.0009). Overall survival at 4 years was 74% (95% CI, 59% to 86%) for the patients in whom resection was radiologically complete and 35% (95% CI, 18% to 56%) for the patients with incomplete resection. CONCLUSION: A significant proportion of children with ependymoma can avoid radiotherapy with prolonged adjuvant chemotherapy. Deferring irradiation at the time of relapse did not compromise overall survival of the entire patient population.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Localised and unresectable neuroblastoma in infants: excellent outcome with primary chemotherapy. Neuroblastoma Study Group, Société Française d'Oncologie Pédiatrique.

PROCEDURE: Infants with neuroblastoma (NB) were assessed according to INSS recommendations, including MIBG scan and extensive bone marrow staging to eliminate metastatic spread. Patients with unresectable tumour received chemotherapy, including two courses of carboplatin-etoposide (CE) and two of vincristinecyclophosphamide-doxorubicin (CAdO). Post-operative treatment was to be given only in infants with MYCN amplification. Between 1990 and 1994, 52 consecutive children were registered. RESULTS: Among the 44 patients who received CE as a first course, the response rate was (66%) and the primary could be removed in all children but one, who was in remission. The toxicity was mainly haematological and was always manageable. The 5 year overall survival (OS) and event-free survival (EFS) were 94 and 90 +/- 8%, respectively, with a median follow-up of 48 months. The outcome of infants with no MYCN amplification was excellent; OS and EFS were, respectively, 97 and 94%. CONCLUSIONS: Chemotherapy allows surgical excision and excellent outcome in infants with localised and unresectable NB. Less intensive Chemotherapy should be investigated in such patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Pharmacokinetic longitudinal studies of antibiotics administered via a permanent intraosseous device in micropigs.

BACKGROUND: In critically ill children, intraosseous (IO) administration of a medicine provides an alternate vascular access route when IV access is not readily available. We investigated the short and long-term efficacy and safety of a totally intraosseously implantable device. PROCEDURE: This study was undertaken in micropigs (i) to compare serum levels achieved by equal bolus dosages of two antibiotics (amikacin and vancomycin) administered through an intratibial needle, an intraosseous implantable device and central IV routes to determine whether standard parenteral dosing guidelines for antibiotics may be applied without modification for IO injection, and (ii) to show the efficiency of the implantable device over a prolonged period, as a permanent access to intraosseous space. RESULTS: The area under the plasma concentration time curves were similar for IV, intratibial and through the intraosseous implantable device, for intermittent administrations of amikacin and vancomycin, over a period of 6 months. However, vancomycin did not reach therapeutic levels via both IO routes. We did not find any alteration of amikacin and vancomycin pharmacokinetics over a period of 6 months using the implantable device. No complication occurred. CONCLUSIONS: Long-term administration of antibiotics through a totally implantable intraosseous device is feasible and safe in micropigs. Although the procedure seems promising, additional studies of the continuous infusion of chemotherapeutic agents, blood products and antimicrobial solutions are needed prior to use in humans.

Amikacin↗
PubMed2001

What have we learnt from previous phase II trials to help in the management of childhood brain tumours?

Contrary to major advances in cure rates observed for almost all childhood cancers, progress in reducing brain tumour survival rates remains very limited. Although new drug development in oncology is founded on principles outlined in the organised methodology of phase I, II, and III trials, based on rigorous study design using standardised criteria, this approach has been applied very slowly in the field of neuro-oncology. There are multiple explanations for the paucity of well-conducted prospective clinical trials, such as the rarity and the heterogeneity of these tumours, and the reluctance of some investigators to enroll their patients in constraining trials. Data from the past two decades shows that several methodological problems preclude the drawing of any definite conclusions for the majority of drugs assessed. Among them, the necessity of a central neuropathological and neuroradiological review has been highlighted in, at least, two multicentric studies. Changes in histological diagnosis and grade have been reported in a proportion as high as 20%, and changes in response rate in 14% of the cases. This review of phase II trials for brain tumours reveals a wide array of sometimes arbitrary response definitions, that is if response is defined at all, and most series have enrolled small numbers of patients. We report on the different problems encountered in childhood brain tumours in these phase II trials, and their impact on phase III trials.

Antineoplastic Agents↗
PubMed2001

IL-2-induced tumor necrosis factor (TNF)-beta expression: further analysis in the IL-2 knockout model, and comparison with TNF-alpha, lymphotoxin-beta, TNFR1 and TNFR2 modulation.

IL-2 induces the stimulation of inflammatory and immune reactions, and the apoptosis of antigen-activated cells. However, the molecular basis of these pleiotropic functions is largely unknown. We have previously reported that IL-2 induces genes involved in cytoskeleton organization, oncogene regulation and transcriptional control. In an IL-2-dependent cell line, we have also shown that IL-2 induces tumor necrosis factor (TNF)-beta mRNA through the Jak-STAT pathway. Here, we first demonstrate in vitro that IL-2 induces mature and partially spliced TNF-beta mRNA in the splenocytes and lymph node cells of both IL-2(-/-) and IL-2(+/-) mice. Under the same experimental conditions, IL-2 is seen to induce TNF-alpha mRNA. mRNA expression is followed by semiquantitative RT-PCR and this analysis is then extended in vivo by studying different lymphoid organs from IL-2(-/-)animals. Strikingly, the expression of TNF-beta mRNA is noted to be extremely low in the spleens and lymph nodes of IL-2(-/-) mice. Similarly, TNF-alpha, lymphotoxin (LT)-beta, TNFR1 and TNFR2 mRNA levels are also low in the spleens of IL-2(-/-) animals, whereas IFN-gamma and IL-4 mRNA levels remain unaffected in these animals. The experimental values are significantly different (P < or = 0.05) from those of control IL-2(+/-) animals. Western blot analysis of TNF-alpha expression confirmed and extended the results at the protein level. For the first time, we demonstrate that IL-2 directly or indirectly regulates genes of the TNF-TNFR family in secondary lymphoid organs. Furthermore, IL-2(-/-) animals in which thymopoiesis is unaffected show normal expression of these genes. Altogether, our data further define the pleiotropic effects of IL-2 at the molecular level.

Animals↗
PubMed2000

Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas.

BACKGROUND: The role of high dose chemotherapy (HDC) in patients with pediatric brain tumors currently is ill-defined. The purpose of this pilot study was to assess the feasibility and the benefit of HDC after radiotherapy in a group of children with newly diagnosed diffuse pontine gliomas. METHODS: Patients eligible for study were ages 3-18 years with diffuse intrinsic tumors arising in the pons, who were not treated previously with radiotherapy or chemotherapy. Histologic confirmation was not mandatory, provided clinical findings and magnetic resonance imaging were typical. Patients were given focal radiotherapy followed 2-3 months later by HDC. Busulfan (150 mg/m(2) on Days 8, 7, 6, and 5) and thiotepa (300 mg/m(2) on Days 4, 3, and 2) were administered prior to autologous bone marrow transplantation. Survival was the endpoint, and the statistical procedure was based on sequential subgroup analysis. RESULTS: Thirty-six patients were entered on to the study, 12 of whom underwent stereotactic biopsy or open surgery at the time of diagnosis. One patient eventually was excluded due to inappropriate eligibility criteria. All 35 eligible patients received irradiation. Early progression (9 patients) and parental refusal (2 patients) precluded the use of HDC in 11 patients. Three patients died of HDC-related complications. All 21 patients who survived HDC eventually died of disease progression. The median survival time was 10 months for the study group. The median survival time in the subgroup of patients who received HDC was 10 months (range, 3-26 months). Statistical analysis did not suggest any evidence of survival benefit. CONCLUSIONS: For patients with diffuse pontine gliomas, survival using this aggressive treatment modality does not appear to be any better than that reported for conventional radiotherapy.

Adolescent↗
PubMed2000

Mandibulo-acral dysplasia.

We report on a 7 year-old-girl with mandibulo-acral dysplasia. When she was 3 years of age it mimicked scleroderma because of skin atrophy and later on a Hutchinson-Gilford progeria syndrome (HGP). Acro-mandibular dysplasia was diagnosed because of facial hypoplasia and mandibular hypoplasia. The bilateral proximal mid-humeral notch seen in this case is unusual.

Abnormalities, Multiple↗
PubMed2000

[Opsoclonus-myoclonus syndrome associated with non-metastatic neuroblastoma. Long-term survival. Study of the French Society of Pediatric Oncologists].

UNLABELLED: Opsoclonus-myoclonus is a rare syndrome characterized by multidirectional chaotic eye movements, myoclonus and ataxia. In children, it could be a paraneoplastic syndrome in association with neuroblastoma, usually with a high survival rate, but having a high frequency of neurologic and psychologic sequelae. OBJECTIVES: The aim of this study was to describe oncologic outcome (prospectively) and neurologic outcome (retrospectively) in children with non-metastatic neuroblastoma, and to determine its best treatment. PATIENTS AND METHODS: Data were collected on 21 children diagnosed with localized neuroblastoma and opsoclonus-myoclonus between 1990-1999 from the French Society of Pediatric Oncology institutions. RESULTS: Median age at diagnosis was 18 months. Location of the tumor was abdominal in 14 cases, thoracic in three cases, pelvic in three cases, and cervical in the last case. There was a majority of small tumors with a maximal diameter < 5 cm in 13 cases. Only four tumors were initially considered as unresectable tumors and received first-line chemotherapy. Complete macroscopic resection was performed in 20 cases (four after primary chemotherapy). Nine children received chemotherapy. Twenty children remained in first complete remission, and one relapsed and died (the unique NMYC amplified case). Treatment for opsoclonus-myoclonus varied widely. Only one child received no medical treatment for opsoclonus-myoclonus, because of complete resolution of neurologic symptoms after exclusive surgery. The following agents were used: corticosteroids in 18 cases, intravenously immune globulin in five cases, and antiepileptic drugs in seven cases. Ten patients experienced relapses of opsoclonus-myoclonus symptoms, mainly related to the decrease of steroid therapy (5/10). Ten of 16 assessable children had persistent neurologic deficits including speech delay or cognitive deficits (8/16), ataxia (6/16), motor delay (2/16), and behavioral problems (2/16). There is no correlation between neurologic outcome, and either age at diagnosis or duration of neurologic symptoms, or type of treatment of the tumor, particularly chemotherapy. CONCLUSION: Persistent neurologic deficits are characteristic for children with neuroblastoma and opsoclonus-myoclonus. Neurologic outcome seems unrelated to the treatment of neuroblastoma, which should exclusively be conducted according to oncological criteria. The treatment of opsoclonus-myoclonus should be standardized, mainly based on high-dose hydrocortisone, with a very low decreasing dosage, associated to intravenously immune globulin in severe cases. A biological immunologic work-up of the disease and cautious neurologic and psychologic standardized follow-up should be performed.

Adolescent↗
PubMed2000

Adverse outcome of infants with metastatic neuroblastoma, MYCN amplification and/or bone lesions: results of the French society of pediatric oncology.

To assess the relevance of MYCN amplification and bone lesions in stage 4 neuroblastoma (NB) in infants aged <1 year, 51 infants with stage 4 NB were enrolled. Three groups of patients were defined according to the type of metastases and the resectability of the primary tumour. Group I comprised 21 infants with radiologically detectable bone lesions, Group II 22 patients with an unresectable primary tumour and Group III eight patients with only metaiodobenzylguanidine (MIBG) skeletal uptake. MYCN oncogene content was assayed in 47/51 tumours and found to be amplified in 17 (37%). The 5-year event-free survival (EFS) rate of these 51 infants was 64.1% (+/- 7.1%). In a univariate analysis, bone lesions, MYCN amplification, urinary vanillylmandelic/homovanillic acid ratio and serum ferritin levels adversely influenced outcome. In the multivariate analysis, radiologically detectable bone lesions were the most powerful unfavourable prognostic indicator: the EFS rate was 27.2% for these infants compared to 90% for infants without bone lesions (P<0.0001). Our data emphasize the poor prognosis of infants affected by stage 4 NB with bone lesions, especially when associated with MYCN amplification. Given the poor results in this group whatever the treatment, new therapeutic approaches need to be investigated in the future.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

In vivo potentiation of radiation response by topotecan in human rhabdomyosarcoma xenografted into nude mice.

The lack of new highly efficacious drugs for cancer treatment promotes the search for innovative therapeutic modalities. The authors reported the results leading to the definition of parameters needed to demonstrate a possible radiopotentiation by topotecan (TPT) on two representative human rhabdomyosarcomas (RMSs) xenografted into nude mice. Experimental studies of radiopotentiation with different doses of topotecan showed that concomitant association of topotecan and RT for 5 consecutive days provided a synergistic therapeutic effect. Response rates were statistically higher with the radiochemotherapeutic combination (P < 0.001). Efficacy enhancement factors of this combination compared with the sum of the antitumoral activity of these treatments separately administrated were 1.54 and 1.60, respectively, on both rhabdomyosarcomas. Moreover, the efficiency of the combination of radiotherapy at the dose of 20 Gy with topotecan (12.5 mg/kg) was not statistically different from that of radiotherapy at the dose of 40 Gy. According to microscopy results, the analyses performed at different periods after topotecan treatment alone, radiotherapy alone, and their combination seemed to show that tumoral repopulation by malignant cells is as fast as the dose of radiotherapy and/or topotecan is low. Furthermore, lesions observed with the dose of 40 Gy were similar to those obtained with the association of topotecan at the dose of 12.5 mg/kg and radiotherapy at the dose of 20 Gy. In conclusion, all clinical and pathological results are consistent with a radiopotentiation effect of topotecan on the two xenografted human rhabdomyosarcomas and are currently leading to the design of clinical studies.

Adolescent↗
PubMed1999

IL-2-dependent expression of genes involved in cytoskeleton organization, oncogene regulation, and transcriptional control.

IL-2 induces growth, differentiation, and/or apoptosis of lymphoid cells. To study further the molecular basis of IL-2 function, we used a cDNA subtraction approach involving a cell line grown in IL-2 or IL-4. From the corresponding library, 66 nonredundant sequences were characterized; 16 of them encode identified proteins. The kinetics of in vitro expression of 8 selected sequences, the functions of which could be associated with IL-2-induced T cell activation/differentiation, was investigated using an IL-2-dependent T cell line. IL-2 increased the expression of cytoskeleton proteins (alpha-tubulin), oncogene-regulating proteins (CCCTC-binding factor, Jun inhibitor factor-1), and transcription factors (E2F-4, cyclic AMP-responsive element-binding protein, zhx-1). IL-2 also regulated the expression of genes coding for multifunctional proteins, e.g., beta-catenin and nucleolin. These results were verified using Con A-induced T cell blasts stimulated or not by IL-2. The in vivo expression of four of these genes was also analyzed in spleen and lymph node cells of IL-2-deficient and MRL/lpr mice, which both have high numbers of activated cells, but the latter have intact IL-2 expression. The expression of beta-catenin, CCCTC-binding factor, Jun inhibitor factor-1, and nucleolin was significantly higher in MRL/lpr animals. A similar analysis of thymocytes from IL-2-/- and IL-2+/- mice demonstrated the same expression patterns of the 4 sequences in these strains. The expression of the IL-2-induced genes described herein is similar to the regulatory pattern of IL-2R alpha. Taken together, our data provide additional evidence for the pleiotropic action of IL-2 in the periphery and IL-2 independence of molecular processes involved in thymocyte differentiation.

Animals↗
PubMed1999

Combined treatment modality for intracranial germinomas: results of a multicentre SFOP experience. Société Française d'Oncologie Pédiatrique.

Conventional therapy for intracranial germinomas is craniospinal irradiation. In 1990, the Société Française d'Oncologie Pédiatrique initiated a study combining chemotherapy (alternating courses of etoposide-carboplatin and etoposide-ifosfamide for a recommended total of four courses) with 40 Gy local irradiation for patients with localized germinomas. Metastatic patients were allocated to receive low-dose craniospinal radiotherapy. Fifty-seven patients were enrolled between 1990 and 1996. Forty-seven had biopsy-proven germinoma. Biopsy was not performed in ten patients (four had diagnostic tumour markers and in six the neurosurgeon felt biopsy was contraindicated). Fifty-one patients had localized disease, and six leptomeningeal dissemination. Seven patients had bifocal tumour. All but one patient received at least four courses of chemotherapy. Toxicity was mainly haematological. Patients with diabetus insipidus (n = 25) commonly developed electrolyte disturbances during chemotherapy. No patient developed tumour progression during chemotherapy. Fifty patients received local radiotherapy with a median dose of 40 Gy to the initial tumour volume. Six metastatic patients, and one patient with localized disease who stopped chemotherapy due to severe toxicity, received craniospinal radiotherapy. The median follow-up for the group was 42 months. Four patients relapsed 9, 10, 38 and 57 months after diagnosis. Three achieved second complete remission following salvage treatment with chemotherapy alone or chemo-radiotherapy. The estimated 3-year survival probability is 98% (CI: 86.6-99.7%) and the estimated 3-year event-free survival is 96.4% (CI: 86.2-99.1%). This study shows that excellent survival rates can be achieved by combining chemotherapy and local radiotherapy in patients with non-metastatic intracranial germinomas.

Adolescent↗
PubMed1999

Chemotherapy for unresectable and recurrent intramedullary glial tumours in children. Brain Tumours Subcommittee of the French Society of Paediatric Oncology (SFOP).

Adjuvant treatment for intramedullary tumours is based on radiotherapy. The place of chemotherapy in this setting has yet to be determined. Between May 1992 and January 1998, eight children with unresectable or recurrent intramedullary glioma were treated with the BB SFOP protocol (a 16-month chemotherapy regimen with carboplatin, procarbazine, vincristine, cyclophosphamide, etoposide and cisplatin). Six children had progressive disease following incomplete surgery and two had a post-operative relapse. Three patients had leptomeningeal dissemination at the outset of chemotherapy. Seven of the eight children responded clinically and radiologically, while one remained stable. At the end of the BB SFOP protocol four children were in radiological complete remission. After a median follow-up of 3 years from the beginning of chemotherapy, all the children but one (who died from another cause) are alive. Five patients remain progression-free, without radiotherapy, 59, 55, 40, 35 and 16 months after the beginning of chemotherapy. The efficacy of this chemotherapy in patients with intramedullary glial tumours calls for further trials in this setting, especially in young children and patients with metastases.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

[Dysembryoplastic neuroepithelial tumors. Analysis of 16 cases].

OBJECTIVES: We report on 16 cases of dysembryoplastic Neuroepithelial tumor (DNT) treated in the Nancy University Hospital from 1987 to 1997. PATIENTS AND METHODS: There were 9 males and 7 females. Mean age at onset of symptoms was 9.5 years (range: 3 months to 29 years) and the mean age at surgery was 16 years. Nine patients experienced partial complex seizures, 5 patients generalized seizures, 1 patient partial seizures with secondary generalization and one patient ataxia. The diagnosis of DNT was made under consideration of clinical, radiological and neuropathological features. All patients underwent surgery. RESULTS: Removal of the tumor was complete for 10 patients, subtotal or partial for 6 patients. Histological examination revealed that 7 cases were specific forms of DNT due to the presence of the specific glioneuronal element. For the 9 remained cases, the diagnosis of DNT could only be made with the consideration of clinical and radiological features. Mean post-surgical follow-up was 3.5 years (range: 1-8 years). Eight patients were seizures-free, 7 had a significative reduction in seizures frequency with minimal anti-convulsivant treatment. The patient with ataxia remained unchanged. For the patients with partial resection of the tumor, follow-up MRI and CT scan showed no significant growth of the remnant and the remaining patients have had no recurrence to date. CONCLUSION: The recognition of this surgically curable entity is mandatory. Knowledge of the good prognosis associated with the DNT is essential to avoid deleterious side effects of overtreatment by radiotherapy and/or chemotherapy.

Adolescent↗
PubMed1998

Unresectable localized neuroblastoma: improved survival after primary chemotherapy including carboplatin-etoposide. Neuroblastoma Study Group of the Société Française d'Oncologie Pédiatrique (SFOP).

Neuroblastomas (NBs) were assessed according to INSS recommendations including MIBG scan and extensive bone marrow staging to eliminate metastatic spread. Patients with unresectable tumour received primary chemotherapy including two courses of carboplatin-etoposide (CE) and two of vincristine-cyclophosphamide-doxorubicin (CAdO). Post-operative treatment was to be given only in children over 1 year of age at diagnosis who had residual disease or lymph node (LN) involvement. Between 1990 and 1994, 130 consecutive children were registered. In comparison with resectable primaries, these tumours were more commonly abdominal, larger and associated with N-myc amplification (NMA). Complete, very good and partial response (CR, VGPR, PR) to CE were, respectively, 1%, 7% and 44%, overall response rate (RR) to two courses of CE and two courses of CAdO was 71%, and the tumour could be removed in all but four of the children. The toxicity was manageable. The 5-year overall survival (OS) and event-free survival (EFS) were, respectively, 88% and 78% with a median follow-up of 38 months. In multivariate analysis, only NMA and LN involvement adversely influenced the outcome, particularly NMA. Children with unresectable NBs and no NMA fared as well as children with resectable ones as OS were, respectively, 95% and 99% and EFS 89% and 91%. Our data show encouraging results in localized but unresectable NBs as 90% of children may be considered as definitely cured, especially those without NMA.

Adolescent↗