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PURPOSE: We analyzed the clinical features and outcome of patients with radiation-associated osteosarcoma treated during the era of contemporary chemotherapy. PATIENTS AND METHODS: The characteristics and outcome of 23 patients (17 males and six females) treated during childhood or adolescence for a solid tumor who later developed osteosarcomas within the radiation field between 1981 and 1996 were reviewed. RESULTS: The median dose of radiation delivered to the first cancer was 47 Gy. Nineteen patients also received chemotherapy. The median time between radiotherapy and the diagnosis of secondary osteosarcoma was 8 years. Histologic slide review showed conventional central osteosarcoma with various differentiation patterns in 21 cases, together with one case of high-grade surface osteosarcoma and one of periosteal osteosarcoma. The sites of involvement were the craniofacial bones in six cases, the first cervical vertebra in one, the girdle bones in seven, and the extremities of long bones in nine. Three patients had metastatic disease at the diagnosis of osteosarcoma. Palliative therapy was administered to seven patients. The aim of treatment was curative for 16 patients, two of whom underwent amputation without further therapy. Intensive chemotherapy regimens were administered to 14 patients before and/or after surgery. Fifteen patients achieved complete surgical remission. Twelve patients were alive and disease-free at a median follow-up duration of 7.5 years. Overall and event-free survivals at 8 years were 50% and 41%, respectively. CONCLUSION: Patients with radiation-related osteosarcoma and resectable lesions can be cured with surgery and intensive preoperative and postoperative chemotherapy.

Thirty-three leukaemic patients in CR were treated by high-dose therapy followed by ABMT: 18 of them had acute non-lymphoblastic leukaemia (ANLL) in first remission (CR1) with a mean age of 23.7 years (3-44). All but one of them were conditioned with a polychemotherapy regimen including 6-thioguanine, Ara-C, CCNU, and cyclophosphamide. The marrow cells were purged by chemical means in 16 cases. Five transplant-related deaths were observed: three cardiac failures, one interstitial pneumonitis and one aspergillus pneumonia. At the time of analysis (October 1984), four patients had relapsed and eight were still in unmaintained CR1 (44+, 46+, 30+, and five between 2.5+ and 8+ months post transplant). Fifteen patients had acute lymphoblastic leukaemia: four were autografted in CR1 and 11 children were grafted in CR2; the conditioning regimen was fractionated total body irradiation followed by cyclophosphamide for all but one patient who was conditioned with BACT (Burkitt leukaemia); the marrow was purged by a chemical agent in 11 patients and by monoclonal antibodies and C' in four: four out of 15 patients relapsed (two grafted in CR1 and two grafted in CR2); 10 patients are still in unmaintained CR: two adults grafted in CR1 (26+; 12+ months) and eight children with a mean follow-up of 13.4 months post graft (2 + -45+ months). The clinical study leads to the following conclusions: in adult patients the marrow should be harvested during CR1 and at the time of minimal residual disease. The quality of previous chemotherapy and conditioning regimen prior to ABMT play a prominent role in the in vivo eradication of the leukaemic cells. The real impact of marrow purging is still unknown and a larger series of homogeneous patients, conditioned with the same protocols and the same transplant timing, is required before any conclusions can be drawn.

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.

Three patients with malignant histiocytosis treated with combination chemotherapy are reported. Induction treatment included bleomycin, adriamycin, cyclophosphamide, vincristine and prednisone (BACOP). Complete response was obtained in one patient who is alive and well 32 months after diagnosis. A partial response was obtained in the second patient, who is alive and well 35 months after diagnosis. The third patient died with drug-induced agranulocytosis and sepsis.

Sixty children with Hodgkin's disease were clinically staged and treated by MOPP primary chemotherapy followed by 40 Gy nodal radiation limited to involved fields. Overall 5-year survival is 93% while relapse-free survival is 86%. Four patients relapsed. These results confirm that laparotomy no longer has a place in routine staging when chemotherapy is given to all patients and that radiotherapy of localized disease (IA and IIA) can be limited to involved fields. On the basis of these results and data of other published series, the French Society of Clinical Oncology and Hopital Saint Louis initiated a new joint national study to minimize the late effects of combined modality therapy without jeopardizing the good survival. Outlines and preliminary results of this study are presented.

We report the results of a French multicentric pilot study of remission induction therapy in metastatic neuroblastoma. Thirty-five successive unselected patients entered the study over 1 year and were treated by alternating sequences of cisplatin/VM-26 (PE) and vincristine/cyclophosphamide/doxorubicin (CADO). Three courses of each sequence were delivered. Disease reevaluation was extensive, with special focus on bone marrow status. Using strict criteria, 24 patients (68%) achieved a good partial response (GPR), which comprised normalization of bone marrow, and ten (28%) achieved a partial response (PR), and one progressed. The overall response rate was 96%. Thirty-two patients underwent surgery, and complete macroscopic removal of the primary was achieved in 21 (65%). After completion of induction and surgery, six patients (17%) were in complete remission (CRm), without evidence of any residual disease; nine (26%) were in very good partial remission (VGPRm; same as CRm except persistence of nonpathologically evaluable improved bone scan), and 19 (51%) were in partial remission (PRm). Toxicity was acceptable, and no treatment-related deaths occurred. These results show no substantial improvement compared with those previously reported with similar but nonalternating regimens. We advocate a two-category concept (response, remission) to describe initial therapy results in metastatic neuroblastoma and emphasize the need to assess bone marrow by an extensive evaluation.

We saw bone marrow necrosis in a case of acute myelomonocytic leukemia. The diagnosis was made during the patient's life, and the bone marrow microcirculation was studied immediately postmortem. Histology and injection of the bone marrow arteries showed an acute microcirculation failure. The pathogenesis and possible relationship with soluble immune complexes was studied. ( Arch Intern Med 138:1567-1569, 1978)

Open heart surgery was performed in a 5 year-old boy with severe hemophilia A and large ventricular septal defect with pulmonary stenosis. High doses of Factor VIIIC superconcentrates delivered as small transfusion volumes allowed the use of extracorporeal circulation with heparin. Transfusions began 5 hours before surgery and were stopped 21 days later. No adverse reaction was observed. Thus major surgery is possible in severe hemophiliacs provided strict rules for replacement therapy are followed.

Ten children were autografted for ALL in second complete remission (CR). The conditioning regimen consisted of cyclophosphamide (60 mg/kg/day X 2) and total body irradiation (10 to 13.2 grays). It was well tolerated, no deaths occurred during the first 3 months post-graft. Nine children remained in second CR, without any maintenance therapy, from 2 to 40 months after ABMT and the median survival time was 11 months. One child died 112 days post-graft, following a cerebral hemorrhage (thrombocytopenia less than 10 X 10(9) platelets/liter). One girl, affected by B ALL, was autografted while in first CR after intensive chemotherapy (modified BACT) 5 months after diagnosis. She relapsed 8 months later. Seven bone marrows have been purged ex vivo by chemotherapy (ASTA-Z) and 3 by anti-CALLA monoclonal antibodies and complement.

One hundred and six patients with stage Ic to IV ovarian carcinoma were treated by a protocol consisting of optimal debulking surgery followed by 9 cycles of CHAP chemotherapy. Clinical response was confirmed by a second-look procedure. Sixty-nine patients (65%) responded with 54 histological complete remissions (50.8%). Nineteen patients did not receive any complementary treatment due to a negative reaction, or prolonged neutropenia. Seven patients received maintenance chemotherapy, 10 an abdominal radiotherapy, 22 intraperitoneal chemotherapy and 11 autologous bone marrow transplantation. The 5-year survival rate was 32.5% and disease-free survival rate was 39.7%. Prognostic-factor analysis showed that age, initial staging, residual disease and cytological grading were significant. The authors propose a classification based on the risk of relapse, and different therapeutic indications for improving response rate and patient survival.

In 1981, 13 French and Belgian institutions started a clinical study using the German BFM protocol for the treatment of children with acute lymphoblastic leukemia (ALL). The objectives of the study were (a) to evaluate the feasibility and toxicity of this aggressive regimen, (b) to reevaluate the weight of the prognostic factors (number of circulating blasts, hepatomegaly, and splenomegaly) used for the classification of patients into different risk categories, and (c) to identify other possible prognostic features.

The authors report a microbiological study of the flora of high risk adults with blood diseases isolated in hermetically sealed plastic isolater. This type of isolation is very effective in the prevention of infections due to hospital germs as such contamination occurred only twice in 292 days isolation and was found in only 0.8% on samples. The efficacy of methods of body decontamination and the incidence of infective complications in our series is also reported.

Haemorragic cystitis is a well known complication of cyclophosphamide therapy. In the reported case, a 7 years old boy treated for lymphosarcoma, as an excretory urogram demonstrated important focal irregularity of the bladder wall. Cystoscopy revealed areas of important bullous oedema with generalized hyperemia. A biopsy disclosed normal urothelium raised by oedematous and congestive chorion and excluded a malignant tumor. Various kinds of endoscopic and surgical procedures are reported to control persisting hematuria after withdrawal of the cyclophosphamide treatment.

Left ventricular function in 21 patients treated by polychemotherapy including adriamycin (ADM) has been studied by repeated echocardiographic examination. The mean rate of circumferential, the ejection fraction, and the shortening fraction are the most significant data obtained by this investigation. They permit the detection of early damage of left ventricular performance which increases progressively, confirming the dose-dependent nature of the cardiomyopathy. Supervision of patients under ADM is necessary to recognize those who rapidly develop cardiomyopathy. In these cases, treatment interruption may be beneficial. In contrast, patients with little left ventricular damage can be treated by a total dosage of ADM superior to that actually recommended.

Class II antigen expression on leukemic cells has been mainly studied using monoclonal antibodies (Mabs). On the other hand, class II polymorphism has been mainly studied using alloantisera. The present study shows that the reactivity of leukemic cells from different lineages with class II Mabs was not always the same as that obtained with alloantisera and that the reactivity varied depending on the leukemic cell-type studied.

A total of twenty-six patients with idiopathic thrombocytopenic purpura ITP refractory to corticosteroids were alternately allocated to undergo splenectomy alone (N = 12) or to receive a 5 day course of high dose immunoglobulin G i.v. immediately followed by splenectomy (N = 14). Although there were less initial failures after splenectomy in patients receiving IgG, the proportion of sustained complete remission at 1 and 2 years was identical in both groups. It is concluded that high dose IgG infusions do not improve the results of splenectomy in refractory ITP.

Primary undifferentiated sarcomas (also called embryonal sarcomas or malignant mesenchymomas) are an exceptional form of cancer of the liver, occurring preferentially in children or adolescents. They can exhibit poor differentiation, embryonal rhabdomyosarcoma being the most frequent. To date, therapeutic success has been reported only rarely. The authors describe the case of a 16 year old boy with primary hepatic sarcoma showing a rhabdomyoblastic differentiation, who is in complete remission two years after total surgical resection and polychemotherapy.

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.

Immune impairment or dysfunction is associated with cancers, and is frequently aggravated by conventional therapies. As a consequence, the development of agents active on the immune system in ways that restore or regulate host defenses, has become a major objective. An overall appreciation of the published data led us to conceptualize the following requirements for suitable immunopharmacologic agents. Absence of carcinogenicity, of tumor promoting influence and of antigenicity or sensitizing effects, is an essential prerequisite since these agents will be administered for long periods of time to patients already at risk. They should have defined influences on populations or subpopulations of immunocompetent cells, as their essential activities. Their toxic levels and pharmacologic effects should be known to delineate the range of doses and predict most side effects. Such requirements will reasonably eliminate most of the inconsistencies which have somewhat dampened confidence in therapies intended to modify the immune system.

Infection is the most important cause of mortality in leucopenic patients. A broad spectrum antibiotic therapy is imperative in febrile and neutropenic patients. In a multicentric study we have used ceftazidime (100 mg/kg/d) and netilmicin (6 mg/kg/d) in 88 children (fever greater than or equal to 38.5 degrees C, neutropenia less than 500/mm3) treated for acute leukemias (59), non Hodgkin lymphomas (13) or solid tumors (16). Median age was 7 years (2 months-16 years). In patients who continued to remain febrile, vancomycin (40 mg/kg/d) was added after 48 hours. The effective treatment was continued until a neutrophil count greater than 1,000/mm3. The first combination (ceftazidime + netilmicin) was effective in 64 children (73%) and the second combination (ceftazidime + netilmicin + vancomycin) in 11 patients. Bacteria were isolated in 39 children: Escherichia coli: 9, Staphylococcus epidermidis: 9, Staphylococcus aureus: 8, Streptococcus: 6, Pseudomonas aeruginosa: 3, Streptococcus pneumoniae: 1, Haemophilus: 1, Klebsiella pneumoniae: 1, Proteus: 1, Serratia: 1, Flavobacterium: 1. In these 39 patients, 30 became apyretic with ceftazidime and netilmicin and 6 after vancomycin. All blood culture were negative after the first combination. The median duration of antibiotic therapy was 14 days (5-9 days: 28, 10-20 days: 43, greater than 20 days: 17). There were no death, no superinfection. Tolerance was good without kidney or liver or biological perturbation. We conclude that the combination ceftazidime and netilmicin is effective in neutropenic children.

The anti-leukaemic effect of low-dose cytosine arabinoside was assessed in 36 patients; 15 patients presented with an acute myeloblastic leukaemia and were treated in first induction because of age or preexisting disease and clinical and biological stabilization was obtained in 7 cases, with a mean duration of 8.7 months. In 4 relapsed patients 2 complete remissions were obtained, 1 of which after several courses of cytosine arabinoside. In all cases an important haematopoietic and extra-haematopoietic toxicity was noticed. In 15 patients treated for a myelodysplastic syndrome terminating in acute myeloblastic leukaemia stabilization was obtained in 8 cases, but final conclusions were difficult. The cytotoxic effect of cytosine arabinoside even at low dosage remains important. The optimal modalities in the administration, and the actual advantages of this treatment compared with conventional chemotherapy have still to be defined.