A single center experience with bone marrow transplantation for high risk neuroblastoma.
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Biomedical subjects
Publications and source records attributed to M Brunat-Mentigny.
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A group of ten children and adolescents with malignant bone tumours (eight osteosarcomas, two Ewing's tumours) were treated with chemotherapy and resection with allograft reconstruction. Intercalary grafts were used in three cases and terminal osteoarticular grafts at the knee in seven. The mean follow up was 22 months. Functional results were satisfactory, but there were some complications related to the graft. Although these are early results, we believe that the method is justified and is preferable to the use of an endoprosthesis, particularly in children.
During the last 5 years massive chemotherapy and autologous bone marrow transplantation have been increasingly explored in the treatment of pediatric solid tumors, mainly for neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma, Wilms' tumor, germ cell tumors, osteosarcoma, and retinoblastoma. Although the disease course could be changed successfully in most instances, the long-term survival has not yet been improved much over the best available conventional treatments. Despite this, in responding relapsed patients this approach seems promising and may represent the only chance of cure. New and better induction regimens are needed.
We studied 10 massive - 70 degrees C frozen dried allografts (7 terminal intermediate) in children between the ages of 9 and 16 with malignant tumors (8 primary osteogenic sarcomas and 2 Ewing sarcomas). A good response to chemotherapy was observed. The average follow-up is 2 years (7-36 months). Results showed 4 mechanical complications (2 plate failures, 2 graft fractures) and no deaths. The surgical procedure and postoperative management are discussed and compared to prosthetic reconstruction.
Seventy-two patients with a localized osteosarcoma were treated between September 1979 and December 1987 by neoadjuvant chemotherapy, local surgery and post-operative chemotherapy. Chemotherapy regimens varied throughout the years but always comprised high dose methotrexate with leucovorin rescue and adriamycin pre-operatively for children under the age of 15, and ifosfamid and cis platinum in adults. Post-operative chemotherapy for bad responders (greater than 10% of residual malignant cells), was at first an association of adriamycin and cis platinum, and later of holoxan and cis platinum. Surgery changed from amputation to local conservative surgery (graft or prosthesis) which is now the most frequent surgery--61% of the patients are alive and disease-free at 5 years. Good responders to pre-operative chemotherapy have a much better prognosis (81% at 5 years) than bad responders (45%). There is no significant difference according to age or pre-operative chemotherapy regimen.
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Phase II studies using ifosfamide both alone and combined with vindesine and cisplatin have shown the effectiveness of this drug in patients with Ewing's sarcoma (ES) who had relapsed during VAC (vincristine, actinomycin, cyclosphosphamide)/VAd (vincristine, Adriamycin) therapy. In November 1984, these results led the SFOP to adopt a protocol consisting of (1) initial chemotherapy with three cycles of IVA (ifosfamide, 3 g/m2 on days 1 and 2; actinomycin D, 750 mg/m2 on days 1-3; vincristine, 1.5 mg/m2 on day 1) alternating every 3 weeks with IVAd (vincristine on day 22; ifosfamide on days 21-23; Adriamycin, 60 mg/m2 on day 22); (2) radical surgery if possible; (3) local radiotherapy (RT); and (4) maintenance chemotherapy with alternating IVA and VAd (vincristine, Adriamycin) for up to 9 months. In May 1987, 87 patients with previously untreated ES entered the study; 61 had localized ES. To date, 54 patients with localized disease and 22 with metastatic disease have finished initial chemotherapy; 40 patients with localized disease have been evaluated. In all, 28 patients (70%) were in complete remission (17 patients) or had a tumor regression of greater than 50% 11 patients) and were considered to be good responders; 12 patients were considered to be poor responders. After local radiotherapy in all but 7 patients and surgical resection in 29, 52 of 54 were considered to be in clinical remission. A total of 13 patients with metastatic disease were good responders at the completion of the initial chemotherapy. These results confirm the efficacy of primary chemotherapy using ifosfamide for the treatment of ES.
A 22 year old woman presented with a desmoid tumour located in the subspinal fossa of the right scapula. A recurrence was observed 3 years after local excision. This recurrence was accompanied by pulmonary metastases. A new excision of the tumour and a pulmonary biopsy confirmed the similarity of that tumour with the original one. Six years after the initial operation the pulmonary lesions extended in spite of chemotherapy. The pulmonary metastases of the desmoid fibromata are exceptional and only three cases have been described in literature, with fatal outcome.
The most frequent solid tumors in the pediatric age group are central nervous system tumors. Despite dramatic improvements in neurosurgery, radiotherapy and chemotherapy, the overall prognosis remains poor, and is often associated with late deleterious effects, including neuropsychologic disorders, endocrine deficiencies and physical abnormalities. In part I, we describe the common presenting symptoms and signs in children with brain tumors. We expose the significant advances in histology, immunohistochemistry, cytogenetic, radiology and therapeutic approaches during the past ten years.
In part I of this article, we reviewed the general aspects of childhood brain tumors. In part II, we present the most common neoplasms and their treatment. The quality of the surgical resection appears to be of first importance in the prognosis. Progress in radiotherapy and chemotherapy have contributed to the improvement of long-term results. However, they are responsible of late deleterious effects. Further progress in therapy must be assessed with in view a critical evaluation of the quality of life.
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Two children with active metastatic neuroblastoma after high dose chemotherapy and bone marrow transplantation (BMT) received a high dose continuous infusion of interleukin-2 (IL2) 120 days after an autologous BMT for patient 1 and 90 days after an allogeneic non T cell-depleted BMT for patient 2. Usual side effects of IL2 therapy were observed without life-threatening complications or any major hematological toxicity. The reactivation of graft-versus-host disease during IL2 infusion in patient 2 was the major BM-related complication but it improved with IL2 interruption and corticosteroids. IL2 induced a complete remission (9+ months) in patient 1 with the disappearance of bone metastases and local tumor but patient 2 progressed after cessation of therapy. Patient 1 presented with a large excess of circulating NK cells in the period after autologous BMT and IL2 induced a preferential outgrowth of this lymphocyte subset.
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Thirty broncho-alveolar lavage (BAL) were performed in order to investigate 30 infectious episodes in immunocompromised children. Twenty patients were previously treated by high-dose chemotherapy and autologous bone marrow transplantation and 6 other patients by conventional methods. A specific etiologic diagnosis was obtained in 16 of 30 episodes (56%), 22 microorganisms were identified by BAL. The most frequently involved microorganism was Candida albicans and the other agents were as follows: 3 cytomegalovirus, 2 Pneumococcus, 2 Pneumocystis carinii, 1 Aspergillosis, 1 syncytial respiratory virus, 1 myxovirus, 1 Pseudomonas aeruginosa, 1 Mycoplasma pneumoniae, 1 Haemophilus influenzae and 1 Escherichia coli. In 5 cases, more than 2 agents were involved. This study emphasizes the diagnostic interest of BAL for infectious diseases of the immunocompromised child. BAL appears to be a non invasive, rapid and reproducible method, and a useful therapeutic approach in the treatment of infectious episodes occurring in grafted children where several microorganisms could be involved at the same time.
Pretreatment characteristics of 281 children with nonmetastatic rhabdomyosarcoma, included in the registry of the International Society of Pediatric Oncology (SIOP) between January 1975 and December 1983, were examined to study the children's prognosis. The multivariate statistical method (Cox regression model) was used for each of two endpoints: survival time and disease-free time. The three most important predictors for survival time were primary site (p less than .001), clinical stage (p = .009), and sex (p = .020). The best results involved paratesticular and orbital primary sites, regardless of the clinical stage; males fared slightly better than females. These same three factors were also significant predictors for disease-free time.
A 5-day continuous infusion of vincristine (VCR; total dose 4 mg/m2) has been given as part of a high-dose chemoradiotherapy regimen with bone marrow transplantation. Evidence of neurotoxicity, such as weakness, paraesthesia and intestinal hypomotility, was evaluated prospectively in nine patients. Five patients had advanced neuroblastoma and four, relapsed sarcomas, and all had responded to initial conventional-dose therapy. VCR was combined with high-dose melphalan (180 mg/m2) and fractionated total-body irradiation. Plasma concentrations of VCR were measured by radioimmunoassay during and up to 24 h after the infusion. Serum and urine electrolytes and liver function tests were measured during VCR treatment and at regular intervals thereafter. VCR concentration at 1 h ranged from 1.8 to 10.9 (median 6.6) ng/ml, and a steady state was achieved by 13-30 h (median 16 h). Levels above 1 ng/ml were maintained throughout the 5-day period with a mean steady-state concentration of 1.7 ng/ml (range 1.3-2.15). After cessation of the infusion, serum concentrations fell to below 0.25 ng/ml within 24 h. Abdominal pain occurred in one patient, but neither constipation nor ileus was seen. In two patients severe muscle pain occurred in the lower limbs towards the end of the infusion. Significant electrolyte problems did not occur and, in particular, there was no evidence of inappropriate ADH secretion. Transient increases in liver enzymes were common but bilirubin was not elevated during the period of monitoring. This regimen allows a two-fold escalation in the dose of VCR to be administered, producing sustained high serum drug levels without major toxicity.
Twenty-one patients with advanced Wilms' tumor entered a phase II study with high-dose ifosfamide (3 g/m2 over two days every 15 days). Mesna and hyperhydration were associated with minimal bladder toxicity. After two courses, five partial responses and six complete responses were observed. Ten patients did not respond. The median duration of response was 2 months (range, 1 to 7). Therapy was delayed because of leukopenia for 1 or 2 weeks in only three cases. Fever and infection were not observed. Seven patients presented with hematuria, three of whom were among the 17 patients coadministered mesna, which did not interfere with subsequent therapy.
The authors treated 188 patients with osteosarcoma by chemotherapy followed by surgery and additional chemotherapy (Rosen's T regimen). In 14% of cases, infectious, neurologic or cardiac complications were observed, which resulted in death in 2% of the patients. Forty-six per cent responded well to the primary chemotherapy, 76% of which are alive and disease-free, as opposed to merely 42% of the bad responders.