[Alveolar hemorrhage associated with sarcoidosis]. / Sarcoïdose médiastinopulmonaire associée à une hémorragie intra-alvéolaire.

INTRODUCTION: Sarcoidosis is a systemic granulomatous disease of unknown origin. We report an unusual case associated with alveolar haemorrhage. CASE REPORT: An 18-year-old caucasian man was admitted for recent dyspnea. He reported regular tobacco- and occasional cannabis smoking. Lung CT scan revealed mediastinal lymphadenopathy and lung nodules in both fields. Bronchoalveolar lavage recovered bloody alveolar fluid containing many siderophages. Because of rapid deterioration leading to acute respiratory failure, intravenous corticosteroid treatment was started. Improvement was obtained in few days and a diagnosis of sarcoidosis was established based on lymph node biopsy performed under mediastinoscopy. CONCLUSION: This unusual case and those reported in the literature give us the opportunity to describe the characteristics of alveolar haemorrhage associated with sarcoidosis.

[Pulmonary artery stump thrombosis following pneumonectomy]. / Thrombose in situ du moignon artériel pulmonaire après pneumonectomie.

INTRODUCTION: Pulmonary artery stump thrombosis has been reported after pneumonectomy. The prevalence of risk factors for and outcome associated with this condition remain to be clearly evaluated. CASE REPORT: We describe three cases of pulmonary artery stump thrombosis occurring after pneumonectomy. No pulmonary embolism was observed despite the absence of anticoagulation therapy. The prevalence of arterial stump thrombosis after pneumonectomy has been estimated as 12%. It is often detected by CT scanning performed systematically as part of the routine follow up of lung cancer. Thrombus was identified as a filling defect with concave or convex margins, located at the bottom of the stump. DISCUSSION: Only one case of pulmonary embolism associated with pulmonary artery stump thrombosis has been described. The absence of complications associated with thrombus in this site suggests that anticoagulant therapy is not likely to be of benefit.

Dose escalation with pharmacokinetics monitoring in methotrexate chemotherapy of osteosarcoma.

This paper evaluates the influence of pharmacokinetics monitoring of HDMTX in the treatment of localized operable previously untreated high grade osteosarcoma. 44 patients (group 1) received a T10 protocol with dose adapted only to age. 27 other patients (group 2) had a pharmacokinetics monitored dose adaptation of MTX. The pharmacokinetics monitoring leads to higher dosage, higher area under the concentration/time curve and permits higher toxicity to be avoided. The higher dose intensity of MTX gave higher histologic response rate (66% compared to 45%) and higher 5 year disease free survival (92% compare to 76%). HDMTX treatment of osteosarcoma should be dose adapted to indivi-dual pharmacokinetics.

Pharmacokinetic modelling of ifosfamide administered by continuous infusion on 5 days at the dose of 6 g/m2.

BACKGROUND: We aimed to create a model for Ifosfamide (IFX) pharmacokinetics for drug monitoring in order to improve protocol dose intensity. MATERIAL AND METHODS: We studied ifosfamide pharmacokinetics in 12 patients aged 8-19 years. Sixteen courses were modelled (6 g/m2, on 5 days). The auto-induction of ifosfamide was taken into account in the model. Ifosfamide measurement was performed on serum samples by gas chromatography with thermo-ionic detection. Two pharmacokinetic models were compared. The following parameters were estimated: volume of distribution (Vd), clearance at the beginning of the induction (CLi), clearance extrapolated to infinity (CLf), clearance at the end of infusion (CL120), a rate constant (Kc) indicating the clearance variation with time and the lag time (Lag) indicating the time elapsed between the start of infusion and the start of induction. The Wilcoxon test was used to investigate possible differences between models. We tested the hypothesis that Boddy's model is an acceptable simplification of Levy's model. RESULTS: Four of six parameters were significantly different between the two models (p = 0.05). The best curve fitting was obtained using the Levy's model which provided the following estimates, Cli = 2.46 +/- 0.94 L.h-1.m-2, CLf = 5.22 +/- 1.02 L.h-1.m-2, Kc = 0.024 +/- 0.014 h-1, Vd = 18.84 +/- 5.04 L and Lag = 4.86 +/- 6.61 h. The most important difference is found for the distribution volume. CONCLUSION: Levy's model is more accurate and takes into account the integration of clearance.

[Argument for the multidisciplinary treatment of Ewing sarcoma with surgery]. / Plaidoyer pour un traitement multidisciplinaire de l'Ewing incluant la chirurgie.

The authors summarize the literature on the local treatment of Ewing's sarcoma. They remind us that including surgery in local treatment increases disease free survival rate by 20-25% while it reduces functional sequelae and radioinduced sarcoma risk. They underline the major interest of histologic examination of in bloc resected tumor to guide postoperative chemotherapy. They advocate that local treatment of Ewing's sarcoma should always be surgical and conservative with the help when necessary of massive homograft and lengthening prosthesis.

Present trends in treatment of Ewing's sarcoma.

The prognosis of Ewing's sarcoma, the first malignant tumor in children under 10, has improved dramatically in the last 10 yrs. The authors review the signs and symptoms that permit diagnosis and analyse the improvement in treatment, based on multidrug's combination, neoadjuvant chemotherapy and surgical treatment of the primary. They point out the necessity of closed multidisciplinary co-operation to treat these patients. Under these conditions, disease free survival now reaches more than 90% at 3 years 1/2.

[Experiences and perspectives on adjuvant chemotherapy in osteogenic osteosarcoma]. / Acquis et perspectives de la chimiothérapie adjuvante des ostéosarcomes ostéogéniques.

This article analyses the relevance of the published results of adjuvant chemotherapy in osteogenic osteosarcomas. It discusses the causation and prospects for treatment particularly the details of the chemotherapy, with reference to mono- or poly-chemotherapy, the influence of the dose and of the interval of administration, and also the value of pre- and post-operative chemotherapy. It is apparent that intensive pre-operative chemotherapy limited to 4 weeks is a reasonable mean of distinguishing the good responders. The problem of the choice of therapy for bad responders is also discussed.

Results of multidisciplinary limb salvage in 240 consecutive bone sarcomas.

From 1979 to 1989, 240 bone sarcomas of limbs were treated by a multidisciplinary limb salvage protocol. The tumors included 112 osteosarcomas, 71 chondrosarcomas, 3 fibrosarcomas, 10 malignant histiocytofibromas, 40 Ewing's sarcomas and 4 other rarer sarcomas. Patients mean age was 28.6 yr (range 4-91 yr). The average tumor size was 13.5 cm (3-43 cm). There were 2 grade IA, 21 IB, 1 IIA, 188 IIB, and 28 III B according to Enneking's classification. Extratumoral en bloc resection was performed in all cases (large in 113, marginal in 121, intrafocal in 6) by the same surgeon. In poor responders to preoperative chemotherapy with Ewing's sarcomas or osteosarcomas, 35 Grays postoperative radiotherapy was administered. Ewing's sarcomas and osteosarcomas received short preoperative and long postoperative chemotherapy. At last follow-up (median 60 months, range 6-120 months), 150 patients were disease-free; 4 were under treatment and had visible disease; 86 had died. Actuarial disease-free survival rate for patients seen with localized previously untreated disease was 83% at 2 yr and 77% at 3 yr. Fifteen local recurrences were observed (6%). Statistical analysis confirmed the poor prognosis factors of visible metastasis, proximal location and large tumor size, and pointed out the major prognostic value of therapeutic factors: the effectiveness of chemotherapy in Ewing's sarcoma and osteosarcomas, and the adequacy of surgery in all cases. Limb salvage can be performed by a well experienced multidisciplinary team in 96% of limb sarcomas without major risk of local recurrence. However, amputation is safer if the surgeon lacks experience.

[Objective response of desmoid fibroma to chemotherapy]. / Réponse objective du fibrome desmoïde a la chimiothérapie.

Six patients with inoperable desmoid tumors have been treated by preoperative chemotherapy. In all six cases objective response occurred and allowed conservative surgery. Objective responses included tumor softening (6/6), releasing of articular motion previously limited (3/3), and tumor size' decreasing (2/6). Few histologic modifications were seen. Such data advocates for preoperative chemotherapy in desmoid tumor when large and threatening the limb or the life of the patient.

Osteogenic osteosarcoma: a model of curable disease by multidisciplinary approach of treatment.

The authors review the mean steps for the treatment of osteogenic osteosarcoma from the 1970's: 1), demonstration of the effectiveness of HDMTX and possibility of weekly administration, dose-response effect, interest of other drugs (BCD, ADR, CDDP, IFX); 2), use of the primary as chemosensibility witness; 3), extent of conservative surgery. In order to optimize the good results obtained by Rosen (more than 80% DFS at 5y) the authors studied the HDMTX pharmacokinetics, the value of the seric peak at the end of infusion as an effective test and individualized the HDMTX treatment in each patient following his own pharmacokinetics. This individual approach allows us to obtain more than 90% actuarial event-free survival at 4 years in patients treated by conservative surgery.

CNS-side effects induced by Ifosfamide-Mesna in children with osteosarcomas.

The authors have had the opportunity to see two cases of CNS side effects of Ifosfamide-Mesna association in children. Data in the medical literature about this subject remains poor. Only a few observations are available. In the referred cases, CNS side effects (lethargy, apathy and mutism) appeared a few hours after the second day of treatment and were spontaneously reversible in a few days. After reviewing possible mechanisms of this toxicity the authors pointed out the necessity to keep this type of side effects of Ifosfamide-Mesna association in mind, and to avoid it in susceptible patients.

Importance of age and methotrexate dosage: prognosis in children and young adults with high-grade osteosarcomas.

The disease-free survival (DFS) in 87 patients with high-grade non-metastatic osteosarcoma of the limbs treated in 3 consecutive pilot studies was compared. From 1978-1982 (Group 1), 41 patients were treated after surgery by adjuvant chemotherapy alternating 2 non-cross resistant cyclic combinations each month for 1 year and early prophylactic lung irradiation. From 1982-1984 (Group 2), preoperative chemotherapy 2-drug combination: adriamycin-cisplatinum (ADR-CDDP) was tested in 20 patients. Surgery was followed by 3 treatment periods of the same combination. From 1984-1987 (Group 3), 26 patients were treated according to modified T-10 protocol with high-dose methotrexate (HDMTX) adapted to age and individual pharmacokinetics. In Group 1, the overall 5 yr DFS was 63% (average follow-up 60.6 months). The worst prognostic factor was low age: 5 yr, DFS under 15 yr was 30%; greater than 15.5 yr, DFS was 85%. The second negative prognostic factor was failure to give sufficient MTX in patients greater than 15 yr. In Group 2, the actuarial 3 yr DFS was only 35% and a low age was still a negative prognostic factor. In Group 3, the 2 yr DFS was 90%, confirming Rosen's results. With HDMTX adapted to age and individual pharmacokinetics, age was no longer a negative prognostic factor. We concluded that HDMTX has a positive effect in the treatment of osteosarcomas in young people; furthermore, in very high doses, as determined by individual pharmacokinetics. In adults, postoperative chemotherapy eventually including moderate doses of MTX, can be effective and may be better tolerated.

Possible monocytic origin of chondrosarcoma: in vitro transdifferentiation of HLA-DR blood monocyte-like cells from a patient with chondrosarcoma, into neo-fibroblasts and chondrocyte-like cells.

Nodules and multilayered areas composed of fibroblasts and chondrocyte-like cells embedded in an abundant extracellular matrix appeared spontaneously in in vitro culture of mononucleated blood cells taken from a patient with chondrosarcoma. Using specific antibodies it was demonstrated that the neo-fibroblasts which developed in the culture resulted from a direct transdifferentiation of monocytes expressing HLA-DR specificity. The experiment was carried out twice, once before surgery and then two years later. In both cases the spontaneous transdifferentiation of HLA-DR monocytes into neo-fibroblasts was observed. Previously it was shown that normal monocytes were also able to give rise in vitro to neo-fibroblasts. However, the latter are normally rapidly destroyed by cell-cell contact with T-cells. Normal T-cells adhere to normal neo-fibroblasts by which they are finally engulfed. As a result, the neo-fibroblasts lose their fibroblastic shape, no longer adhere to their support and die. Therefore the abnormal proliferation and persistence of neo-fibroblasts in pathological situations such as the present case may result either from an intrinsic defect in monocytes, T-cells or both. The question is whether or not this transdifferentiation process observed in vitro accounts for the development of chondrosarcoma in vivo. The present results suggest that in vivo chondrosarcoma may start in a necrotic zone (resulting for instance from trauma) and attract HLA-DR monocytes, where they accumulate and transdifferentiate into neo-fibroblasts and chondrocyte-like cells. The uncontrolled transdifferentiation of these HLA-DR monocytes resulting from a dysregulation of the immune system is probably linked to the malignant process which may have a retroviral origin. The question is raised regarding the embryologic origin of this special sub-population of blood monocytes in which pluripotential capabilities are retained; its origin may differ from that of the other circulating monocytes.

[Digital angiography of bone sarcoma in the child]. / Intérêt de l'angiographie digitalisée dans les sarcomes osseux de l'enfant.

The authors analyze the results of 50 computed angiographies made for osteosarcoma and Ewing's sarcoma. Better tolerated than conventional angiography computed angiography is also more sensitive in preoperative evaluation of effectiveness of neoadjuvant chemotherapy. Automatic subtraction, direct measuring of tumor size and vascularization density give to angiographic changes after chemotherapy the most predictive value. After conservative surgery or radiotherapy digital angiography provides most reliable local follow up.

Massive allografts sterilised by irradiation. Clinical results.

From 1984 to 1988 we implanted 127 massive allografts irradiated with a dose of 25,000 grays. These were reviewed at a minimum follow-up of three years to determine the effect of irradiation on infection, the complications and the functional result. No bacteriological infection was seen in the 44 patients who had allografts for revision of joint arthroplasty or for a tumour with no adjuvant therapy. For the 83 patients who also had chemotherapy or radiotherapy or both for a bone tumour, the rate of infection was 13%. The major mechanical complications were nonunion in seven grafts (5.5%) and fracture in eight (6%). These rates do not differ greatly from those reported for non-irradiated grafts. Our results suggest that irradiation, which remains the most convenient and acceptable method of sterilisation, does not jeopardize the clinical results.

The importance of systematic histological examination after loosening of an implant.

A 65-year-old man presented with a painful hip five years after a cemented replacement. Histological examination of a biopsy taken from tissue surrounding the femoral implant showed infiltration of a squamous-cell carcinoma. Further investigation revealed a primary growth in the left lung. This rare example of a metastasis in relation to a joint replacement illustrates the necessity for histological examination of the tissue adjacent to a loose prosthesis.

Methotrexate diffusion from acrylic cement. Local chemotherapy for bone tumours.

We investigated the possible use of acrylic cement containing chemotherapeutic drugs in the treatment of malignant lesions in bone. The diffusion of methotrexate (MTX) from methylpolymethacrylate implants was studied in vitro: polymerisation of the cement did not destroy the drug; liberation began immediately and about 10% was released by 18 hours. Some release continued for as long as six months. In vivo experiments on rats with induced osteosarcoma showed that MTX in cement had both local and general effects which were dependent on the dosage. A series of 17 large dogs with spontaneous osteosarcoma were then treated by local resection and cement containing MTX. General chemotherapeutic effects were detectable from 2 hours to 5 days, survival was increased and local recurrence was reduced, but there were four cases of delayed wound healing. Preliminary studies in human patients confirm the possibility that this method of local chemotherapy could be a useful addition to the treatment of malignant tumours of bone.

Prognostic factors in patients with localized Ewing's sarcoma: the effect on survival of actual received drug dose intensity and of histologic response to induction therapy.

To bring to the fore the most important prognostic factors in Ewing's sarcoma (ES) with current protocols, we studied the classical prognostic factors, dose intensity (DI) of actual received drugs, age and histological response to induction therapy and their correlation in 39 patients with localized ES treated from 11/85 to 06/95 to identify eventual predictors of event-free survival (EFS). Inclusion criteria were age 35 yr or less, definitive local treatment by our team and chemotherapy including at least 4 drugs: vincristine (VCR), dactinomycin (DACT), doxorubicin (DOXO) cyclophosphamide (CPX). The endpoint was the absence of relapse. Parameters related to the status of patients were tested using the Chi square test or Fisher's exact test. The non parametric Kruskal-Wallis test was used for quantitative data. When necessary stratified analysis was done using the Mantel Cox test. With a median follow-up of 7 yr, overall survival (OS) and EFS were both 67% at 7 yr. According to univariate analysis, the significant predictors of survival were the DI of VCR and DACT, the histological response to preoperative chemotherapy (CT), the patient's age (< 18 yr DFS: 84%; > 18 yr DFS: 38%). The risk of metastases was almost tenfold higher in patients with low received DI of VCR (DFS 40% versus 95%) and of DACT (DFS 48% versus 94%). The prognostic value of primary tumor characteristics (tumoral volume or location) was erased by the comprehensive treatment. Following multivariate analysis, the actual received DI of VCR (p < 0.02) and DACT (p < 0.03) and the histological response to preoperative CT (p < 0.05) were retained as the only significant independent predictors of EFS. Taking into account the actual received DI of VCR and DACT, the prognostic value of age disappears. In conclusion, this study points out the main role of the drug DI in ES (particularly VCR and DACT) and of histological response to preoperative CT.

[Peri-operative chemotherapy during resection of pulmonary metastases of sarcoma]. / Chimiothérapie périopératoire lors des résections de métastases pulmonaires de sarcomes.

The objective of this prospective study was to evaluate the mortality and morbidity of sarcoma pulmonary metastasis resection with continuous chemotherapy. Ifosfamide was administered at the daily dose of 1200 mg/m2/24 h. Twenty-six resections of pulmonary sarcoma were performed from December 1990 to April 1992. The primary lesion was already resected in all patients. Peri-operatory chemotherapy was started 30 minutes before surgery and continued for 6 days. Chemotherapy was associated with an uroprotector, antiemetic drugs and adequate hydration. Patients had a mean age of 30.6 years. The delay between initial and thoracic surgery was 81 months. The following was performed: tumorectomy (32), wedge (18), lobectomy (7), diaphragm resection (1), left pneumectomy (1). All patients had the 6-days chemotherapy course. None of the patients died. Respiratory failure following superinfection, but not necessitating assisted ventilation, was observed in one case. The following adverse events were noted: nausea (34.6%), uncomplicated cystitis (15.4%), leucopenia (7.6%), fever (3.8%). Mean duration of hospitalization was 11.8 days. Chemotherapy adverse effects did not result in significant morbidity. Bronchial fistula was not observed. Following the results of this pilot study, we feel that perioperatory chemotherapy can be added to sarcoma pulmonary metastasis resection surgery without increasing patient morbidity and mortality.

[Pre and postoperative chemotherapy of osteosarcoma with an adriamycin-cisplatin combination. Risks of a neoadjuvant chemotherapy which is not sufficiently effective]. / Chimiothérapie de l'ostéosarcome par l'association adriamycine-cisplatinum pré et postopératoire. Risques de la chimiothérapie néoadjuvante lorsqu'elle n'est pas suffisamment efficace.

The authors evaluated a new protocol of neoadjuvant chemotherapy for osteosarcoma, easier to manage and different from T10. The good results obtained with the postoperative ADR-CDDP association led us to undertake a pilot study between 1982 and 1984, using ADR-CDDP as preoperative chemotherapy. The records of sixteen patients were available for follow-up. The average age of the patients was 19.9 years. Patients received two or three preoperative courses, and a total of six identical courses. Tolerance was good. Pain usually disappeared but this was often misleading because associated with radiological and/or clinical tumor progression, low histological necrosis or poor outcome. The continuous disease-free survival actuarial rate was less than 57 and 40% at 18 months and two years respectively. The actuarial survival rate was 87% at one year and 65% at two years respectively. Disappointing results of this preoperative protocol, compared to results with the SO4 78 or T10 protocols for example, led to publish these data early in order to underline their potential dangers. As a result, we stopped our study. The charter of pilot studies justifies this publication. As well, these data point out the necessity of very close follow-up of neoadjuvant chemotherapy by sophisticated medical imaging. Neoadjuvant chemotherapy, if ineffective, must be stopped early, and should lead to surgery, followed by adequate postoperative chemotherapy.