Comparative measurements of mineral elements in milk powders with laser-induced breakdown spectroscopy and inductively coupled plasma atomic emission spectroscopy.

Mineral elements contained in commercially available milk powders, including seven infant formulae and one adult milk, were analyzed with inductively coupled plasma atomic emission spectrometry (ICP-AES) and laser-induced breakdown spectroscopy (LIBS). The purpose of this work was, through a direct comparison of the analytical results, to provide an assessment of the performance of LIBS, and especially of the procedure of calibration-free LIBS (CF-LIBS), to deal with organic compounds such as milk powders. In our experiments, the matrix effect was clearly observed affecting the analytical results each time laser ablation was employed for sampling. Such effect was in addition directly observed by determining the physical parameters of the plasmas induced on the different samples. The CF-LIBS procedure was implemented to deduce the concentrations of Mg and K with Ca as the internal reference element. Quantitative analytical results with CF-LIBS were validated with ICP-AES measurements and nominal concentrations specified for commercial milks. The obtained good results with the CF-LIBS procedure demonstrate its capacity to take into account the difference in physical parameters of the plasma in the calculation of the concentrations of mineral elements, which allows a significant reduction of the matrix effect related to laser ablation. We finally discuss the way to optimize the implementation of the CF-LIBS procedure for the analysis of mineral elements in organic materials.

Hand-modelled composite prostheses after resection of peri-acetabular bone malignancies.

PURPOSE: To improve function after pelvic resection involving the acetabulum, using an anatomic composite implant built with screws and cement. MATERIAL AND METHOD: Since 1990, 66 patients with peri-acetabular bone malignancies have been treated by extensive resection followed by hand-modelled innominate prosthesis with partially constrained total hip prosthesis. The hand-modelled innominate prosthesis was made of a titanium cup, a set of long titanium screws and two or three packs of gentamycine-loaded cement. RESULTS: Many postoperative complications were observed: deep infection (14%), hip prosthesis dislocation (25%) and local recurrence (15%). Sixteen patients (25%) had to be reoperated. Nevertheless, at last follow-up, 62 patients still had composite prosthesis. The mean functional result, rated according to a modified Enneking's staging system, was 80% with unlimited walking without support, average hip flexion 100 degrees , length discrepancy less than 1 cm. DISCUSSION: These results were similar to those described in the literature for custom-made innominate prostheses and much better than those of alternative reconstructive procedures. Hand-modelled composite prostheses are cheaper, easier, more adaptable and enables better anchorage than custom-made prostheses. Such a procedure can be used even after total iliac wing resection. CONCLUSION: The advantages of such a procedure plead for its extensive use after acetabular resection. But long-term follow-up is necessary to validate indications.

[Periosteal Ewing's sarcoma]. / Sarcome d'Ewing périosté

Periosteal Ewing's sarcoma is a histologically typical Ewing's sarcoma arising in the periosteum with no involvement of the medullary canal or cancellous bone. We describe four cases in our experience and review the literature, recalling the usual computed tomography diagnostic criteria and the therapeutic consequences. Prognosis of periosteal Ewing's sarcoma is generally better than for ordinary Ewing's sarcoma. In order to avoid inoculating the canal, the operator must strictly avoid perforating the cortical during the biopsy. At surgical resection, cortical resection can be partial maintaining a continuous diaphysis; this should be examined as a possibility for young patients in order to avoid the problems encountered with massive reconstruction followed by chemotherapy.

[Diagnosis and treatment of malignant bone fibrohistiocytoma]. / Diagnostic et traitement des histiocytofibromes malins de l'os.

Malignant fibrous histiocytoma (MFH) and giant cells sarcoma arise from fibrous tissue and histiocytic cells evenly distributed in all age group, except children much less common than osteosarcoma and chondrosarcoma. They most commonly localize in the major long bones (femur, tibia, humerus) and in pelvis. Pain and sometimes swelling are the most frequent symptoms but pathologic fractures are rather common. Medical imaging shows a purely osteolytic tumor centrally or eccentrically located, ill defined with a permeative or even moth eaten patterns. Periosteal reaction is scarce or absent. Osteogenic reaction or tumor calcifications are absent. Outcome was historically better than those of osteosarcoma but hangs on the grading of tumors; low grade sarcoma have a regional evolution while high grade malignant histiocytofibroma are threatened with metastases. Therapy must be adapted to the histological grading and the extent of the illness. Low grade localized MFH are best treated by wide resection. High grade MFH are preferentially treated by a comprehensive multidisciplinary approach with preoperative chemotherapy including high dose methotrexate, wide resection and postoperative chemotherapy. With such a treatment, nearly 80% of patients seen with localized tumor of the limb can be cured and keep a functional limb.

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.

Expanding prostheses in conservative surgery for lower limb sarcoma.

Conservative resection of bone sarcoma in the lower limbs in children is very likely to be followed by a progressive problem of leg length inequality resulting from removal of the growth cartilage. To overcome this we have been using an expanding prosthesis and we report our experiences during the period 1985-1996. The prostheses are made of titanium and comprise 3 parts: an articular component, an expanding mechanism, and tibial and femoral stems. The degree of possible lengthening of the prostheses is virtually unlimited, and they can be inserted in children of 5 or more years of age. We report the use of 28 prostheses in patients aged from 5 to 18 years, of which 4 were tibial, 5 total femur, and 16 distal femur. There were 6 Ewing's sarcoma, 21 osteosarcoma, and 1 synovial sarcoma. The average follow-up was for 5 years. Five patients died from their disease, and 21 benefited from an average lengthening of 2.6 cm (range: 2 mm-120 mm). Using the Société Européenne des Tumeurs Osseouses (EMSOS) criteria, the functional results were excellent or very good in 16, fair in 7 and bad in 5. Five patients developed an infection; one required amputation and the others received a new expanding prosthesis. We conclude that an expanding prosthesis is an excellent alternative to amputation in young children. However, the risk of infection associated with repeat surgery has led us to develop a prosthesis which can be lengthened externally, without the need for reopening the wound.

Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin.

PURPOSE: In osteosarcoma of the extremity, a strong correlation between chemotherapy-induced necrosis and prognosis has been reported. The aim of this study was to investigate the possible factors that influence histologic response to primary chemotherapy. PATIENTS AND METHODS: In 272 patients with high-grade osteosarcoma of the extremity preoperatively treated with high-dose methotrexate (HDMTX), cisplatin (CDP), and doxorubicin (ADM), the histologic response to chemotherapy was evaluated and graded as complete (no viable tumor cells) or incomplete (persistence of viable tumor cells). Several factors, such as metastatic disease to the lung at diagnosis, sex, age, site and tumor volume, histologic subtype, serum alkaline phosphatase, lactate dehydrogenase (LDH), and methotrexate (MTX) pharmacokinetics were investigated to test their predictive significance on histologic response. RESULTS: Fifty-one patients with localized disease (20.6%) and none of the 25 patients with metastatic disease at presentation had a complete histologic response (P = .006). After multivariate analysis, performed on patients with localized disease only, MTX serum peak (> or = 700 micromol/L) and histologic subtype were proven to be significant predictive factors of histologic response. A complete response was seen in 28.8% of patients with 700 micromol/L or greater MTX serum levels and in 9.9% of those patients with lower levels (P = .001). The chondroblastic subtype was less responsive (6.1% of complete response), compared with the osteoblastic (16.3%), fibroblastic (33.3%), and telangiectatic (42.3%). CONCLUSION: Patients with metastatic osteosarcoma and localized chondroblastic osteosarcoma have a reduced chemosensitivity to primary chemotherapy with MTX, CDP, and ADM. MTX serum peak significantly influences tumor necrosis. A dose adaptation of MTX is recommended to obtain a serum peak of 700 micromol/L or greater when MTX is infused in 6 hours.

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.

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.

Influence of methotrexate dose intensity on outcome of patients with high grade osteogenic osteosarcoma. Analysis of the literature.

BACKGROUND: The authors surveyed the published clinical trial literature on the subject of localized high grade osteosarcoma in order to develop new hypotheses dealing with drug-dose combinations in the treatment of this disease. METHODS: A computerized literature search was conducted to identify all available published reports of the clinical trials using high dose methotrexate (MTX) in multidrug protocols treating osteosarcoma. Thirty studies, including discussion of high dose MTX (> 7.5 g/m2 per course) and precise quantification of 5-year disease free survival (DFS), fulfilled the inclusion criteria of this dose-intensity analysis. The total number of patients treated in eligible studies was 1909. Correlation among the planned total doses, the dose intensities of the drugs, and the 5-year DFS were tested by regression analysis. RESULTS: No correlation of any other drug dose or dose intensity with DFS appeared as important as the MTX finding. In multivariate analysis, the dose intensity of MTX was found to be the one most correlated with DFS. This correlation appeared to hold for adjuvant and neoadjuvant trials. CONCLUSIONS: The dose intensity of MTX seems to be a major factor in predicting the outcome of patients with localized high grade osteosarcoma.

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.

[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.

[Knee prostheses for tumors]. / Prothèses du genou pour tumeurs.

Because of the advances achieved in conservative surgery for bone cancers of the limbs, megaprostheses of the knee are increasingly used to replace the epiphysio-metaphysio-diaphyseal region resected. Initially, these prostheses were metallic ones, and as such they did not lend themselves to satisfactory reinsertion of the extensor system and exposed the patients to the risk of decementation--a risk which is particularly high in adolescents whose prognosis for life is now excellent. For this reason we have been using, since 1984, a combination of long-tail titanium prosthesis made to measure, and bank allografts. The titanium prosthesis provides immediate solidity, whereas the allograft ensures long-term stability of the material and better functional result.

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.

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.

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.