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Biomedical subjects

K Winkler

Publications and source records attributed to K Winkler.

At least 37 records · Page 2Linked to original sources
PubMed2000

HDL steady state levels are not affected, but HDL apoA-I turnover is enhanced by Lifibrol in patients with hypercholesterolemia and mixed hyperlipidemia.

Lifibrol (4-(4'-tert-butylphenyl)-1-(4'carboxyphenoxy)-2-butanol) is a new hypocholesterolemic drug effectively reducing total cholesterol, LDL cholesterol, and apolipoprotein (apo) B in experimental animals and in humans. In contrast to fibrates and HMG-CoA reductase inhibitors the cholesterol and triglyceride lowering effect of Lifibrol is not accompanied by increases in HDL cholesterol and apoA-I levels. We examined the impact of Lifibrol on the metabolism of HDL apoA-I in patients with hyperlipoproteinemia, using endogenous labeling with stable isotopes. Kinetic studies were performed in five male hypercholesterolemic individuals (type IIa), before and on treatment with 450 mg of Lifibrol daily for 4 weeks and in five male individuals suffering from mixed hyperlipidemia (type IIb), before and on therapy, for 12 weeks. Lifibrol reduced total cholesterol by 14% (P=0.02) and LDL cholesterol by 16% (P=0. 014) in all patients, and decreased triglycerides by 34% in type IIb patients. During Lifibrol therapy, HDL cholesterol and ApoA-I concentrations did not change. Tracer kinetics revealed that the fractional catabolic rate (FCR) of HDL apoA-I increased by 22% (P=0. 013). This increase in the apoA-I FCR was accompanied by a 23% increase in HDL apoA-I production rate (P=0.006). We conclude that Lifibrol, although not changing HDL steady state concentrations, enhances the turnover of apoA-I containing HDL particles.

Adult↗
PubMed2000

Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a neurodegenerative disease affecting the anterior horn cells of the spinal cord and cortical motor neurons. Previous findings have suggested a specific impairment of mitochondrial function in skeletal muscle of at least a limited number of patients. Applying flavoprotein/NAD(P)H autofluorescence imaging of mitochondrial function in saponin-permeabilized muscle fibres, we detected a heterogeneous distribution of the respiratory chain defect among individual fibres in muscle biopsies of patients (11 out of 17) with sporadic amyotrophic lateral sclerosis (SALS). These findings correlate with the presence of cytochrome c oxidase (COX)-negative muscle fibres detected histologically. We established the molecular basis for the decreased activities of NADH:CoQ oxidoreductase and COX in SALS muscle. In the skeletal muscle of the investigated patients, diminished levels (13 out of 17) or multiple deletions (one out of 17) of mitochondrial DNA (mtDNA) were observed. These alterations of mtDNA seem to be related to decreased levels of membrane-associated mitochondrial Mn-superoxide dismutase. Our results support the viewpoint that an oxygen radical-induced impairment of mtDNA is of pathophysiological significance in the aetiology of at least a subgroup of patients with SALS.

Adult↗
PubMed2000

Increased production of HDL ApoA-I in homozygous familial defective ApoB-100.

Familial defective apolipoprotein (apo) B-100 (FDB) is a frequent cause of hypercholesterolemia. Hypercholesterolemia in homozygous FDB is less severe than in homozygotes for familial hypercholesterolemia. Recently, we showed decreased low density lipoprotein (LDL) apoB-100 fractional catabolism and decreased production of LDL due to an enhanced removal of apoE-containing precursors in a patient with homozygous FDB. The effects of defective apoB-100 on high density lipoprotein (HDL) metabolism are unknown. We studied HDL apoA-I metabolism in this FDB patient and in 6 control subjects by using (2)H(3)-L-leucine as a tracer. ApoA-I levels were normal in all study subjects. However, the fractional catabolic rate and the production rate of apoA-I were increased, by 79% and 70%, respectively, in FDB; the fractional catabolic rate of apoA-I in FDB was 0.34 day(-1) compared with 0.19+/-0.03 day(-1) in normal controls. The production rate of apoA-I in FDB was 18.4 mg. kg(-1). d(-1) compared with 10.8+/-2.3 mg. kg(-1). d(-1) in controls. Thus, we have shown for the first time that defective apoB-100 may influence HDL kinetics. The increase in total HDL turnover might enhance reverse cholesterol transport and could contribute to the seemingly benign clinical course of FDB compared with that of familial hypercholesterolemia.

Adult↗
PubMed2000

Low density lipoprotein (LDL) subfractions during pregnancy: accumulation of buoyant LDL with advancing gestation.

Pregnancy is accompanied by changes in the maternal lipoprotein metabolism that may serve to satisfy the nutritional demands of the fetus. In this study lipoprotein metabolism was investigated in 23 women during normal pregnancy in the first, second, and third trimesters and in 15 healthy nonpregnant women with regular menstrual cycles. Lipid and apolipoprotein concentrations were measured in total plasma, very low density, intermediate density, low density (LDL), and high density lipoproteins, and in each of six LDL subfractions. During early pregnancy, triglycerides, and dense LDL were higher than in the nonpregnant state. With advancing gestation, triglycerides increased and the distribution of apolipoprotein B-100-containing lipoproteins became increasingly dominated by the accumulation of very low density and intermediate density lipoproteins and buoyant, triglyceride-rich LDL. This is the first study that investigates LDL subfractions in pregnancy using a method that strictly separates LDL subfractions by virtue of density. The accumulation of buoyant, triglyceride-rich lipoproteins may be related to the down-regulation of maternal lipase activities by placental hormones. As a consequence, the metabolic changes of late pregnancy may result in an increased flux of lipoprotein-derived lipids to the placenta, which, with advancing gestation, increasingly expresses receptors with a high affinity for triglyceride-rich lipoproteins.

Adult↗
PubMed2000

Identification of a new missense mutation (Gly95Glu) in a highly conserved codon within the high-mobility group box of the sex-determining region Y gene: report on a 46,XY female with gonadal dysgenesis and yolk-sac tumor.

Leydig cells and Sertoli cells of the testes produce hormones that cause male differentiation, if receptors are present. The Y chromosomal SRY gene (sex determining Region Y gene) acts as TDF and is required for regular male sex determination. SRY represents a transcription factor belonging to the superfamily of genes sharing the HMG-box motif(high-mobility group-box), which acts as DNA binding region. Here, we describe a nonmosaic XY sex-reversed female with pure gonadal dysgenesis (46,XY karyotype, completely female external genitalia, normal Müllerian ducts, absence of Wolffian ducts, streak gonads) who harbored a yolk-sac tumor and was referred for the assessment of primary amenorrhea. Using genomic PCR analysis, a 423-bp PCR product, encompassing the HMG-box of the SRY gene, was amplified from the proposita, her father, and her three brothers, whereas no band was visible in the patient's mother and her three sisters. The PCR products were sequenced for mutations subsequently. A new de novo missense mutation within the HMG-box of the SRY gene was discovered in the proposita. A G is replaced by an A in codon 95 at position +284, resulting in the replacement of the nonpolar aminoacid glycine by the polar amino acid glutamate. The glycine at codon 95 is highly conserved between the family of HMG-box proteins and between species. This point mutation has not been described earlier and brings the total number of SRY mutations described so far to 36, each mutation being unique. This mutation was not detected in the patient's father and her male siblings. The present data provide further evidence to support the functional importance of the putative DNA binding activity of the SRY HMG-box domain.

Adult↗
PubMed1999

Visualization of defective mitochondrial function in skeletal muscle fibers of patients with sporadic amyotrophic lateral sclerosis.

The mitochondrial function in skeletal muscle was investigated in skeletal muscle biopsies of 26 patients with sporadic amyotrophic lateral sclerosis (ALS) and compared with investigations of 28 age-matched control muscle samples and biopsies of 6 patients with spinal muscular atrophy (SMA) and two patients with Tay-Sachs disease. In comparison to the control, SMA and Tay-Sachs biopsies, we observed in the ALS samples a significant about two-fold lower activity of complex I of mitochondrial respiratory chain. To visualise the distribution of the mitochondrial defect in skeletal muscle fibers we applied confocal laser-scanning microscopy and video fluorescence microscopy of NAD(P)H and fluorescent flavoproteins. The redox change of mitochondrial NAD(P)H and flavoproteins on addition of mitochondrial substrates, ADP, or cyanide were determined by measurement of fluorescence intensities with dual-photon UV-excitation and single-photon blue excitation. In skeletal muscle fibers of ALS patients with abnormalities of mitochondrial DNA (multiple deletions, n=1, or lower mtDNA levels, n=14) we observed a heterogeneous distribution of the mitochondrial defects among individual fibers and even within single fibers. In some patients (n=3) a mitochondrial defect was also detectable in cultivated skin fibroblasts. These findings support the viewpoint that the observed impairment of mitochondrial function in muscle of certain ALS patients is caused by an intrinsic mitochondrial defect which may be of pathophysiological significance in the etiology of this neurodegenerative disease.

Adult↗
PubMed1999

Maintenance of G2 arrest in the Xenopus oocyte: a role for 14-3-3-mediated inhibition of Cdc25 nuclear import.

Cdc2-cyclin B1 in the G2-arrested Xenopus oocyte is held inactive by phosphorylation of Cdc2 at two negative regulatory sites, Thr14 and Tyr15. Upon treatment with progesterone, these sites are dephosphorylated by the dual specificity phosphatase, Cdc25, leading to Cdc2-cyclin B1 activation. Whereas maintenance of the G2 arrest depends upon preventing Cdc25-induced Cdc2 dephosphorylation, the mechanisms responsible for keeping Cdc25 in check in these cells have not yet been described. Here we report that Cdc25 in the G2-arrested oocyte is bound to 14-3-3 proteins and that progesterone treatment abrogates this binding. We demonstrate that Cdc25, apparently statically localized in the cytoplasm, is actually capable of shuttling in and out of the oocyte nucleus. Binding of 14-3-3 protein markedly reduces the nuclear import rate of Cdc25, allowing nuclear export mediated by a nuclear export sequence present in the N-terminus of Cdc25 to predominate. If 14-3-3 binding to Cdc25 is prevented while nuclear export is inhibited, the coordinate nuclear accumulation of Cdc25 and Cdc2-cyclin B1 facilitates their mutual activation, thereby promoting oocyte maturation.

14-3-3 Proteins↗
PubMed1999

Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study.

BACKGROUND: The Cooperative Ewing Sarcoma Study (CESS 86), conducted by the German Society of Pediatric Oncology and Hematology (GPOH), was planned on the basis of the results of the preceding CESS 81 study. The prognostic significance of tumor volume in localized Ewing sarcoma of bone was well documented in the CESS 81 trial. As a consequence, the treatment intensity was adapted to volume in the follow-up CESS 86 trial: the four-drug combination used in CESS 81 was amended for patients with large tumor volume (> or = 100 ml), where ifosfamide was substituted for cyclophosphamide. PROCEDURE: From January 1986 to June 1991, 177 protocol patients with localized Ewing sarcoma of bone were registered in CESS 86. The prognostic implication of tumor volume and several covariates was evaluated using Kaplan-Meier life table analysis and Cox's proportional hazard model. RESULTS: The estimated 5- and 8-year event-free survival (EFS) rates were both 59%. Age, gender, tumor site, and a tumor volume of 100 ml did not distinguish groups of patients with different prognosis. However, the prognosis of patients with tumors >200 ml (8-year EFS rate: 42%) was significantly inferior compared to patients with tumors both of 100 to 200 ml (70%) and of <100 ml (63%). In contrast to CESS 81, the histological response to chemotherapy was no longer a significant prognostic factor (EFS: 64% for good and 50% for poor responders, respectively). CONCLUSIONS: Despite risk-adapted treatment intensity, tumor volume retained its prognostic significance; the cut point, however, was shifted toward larger volumes.

Adolescent↗
PubMed1999

Loss of heteroplasmy in the displacement loop of brain mitochondrial DNA in astrocytic tumors.

The aim of this study was the determination of D-loop heteroplasmy in astrocytic brain tumors. DNA fragments corresponding to the hypervariable region 2 of the mitochondrial displacement loop (D-loop) from 12 astrocytic tumors and 2 corresponding brain samples were cloned into a plasmid vector. Heteroduplex analysis revealed high sequence variability in the brain samples and a subfraction of grade 2 and grade 3 tumors. Furthermore, the results were suggestive of a very low degree of heteroplasmy in all glioblastomas. This was confirmed by direct sequencing of 223 cloned DNA samples from nine individuals. Heteroplasmy was caused in most cases by a well-known length polymorphism of a homopolymeric c-tract. Heteroplasmy of the two reference brain samples was lost in the corresponding tumors. Genes Chromosomes Cancer 26:80-83, 1999.

Adult↗
PubMed1999

Lifibrol enhances the low density lipoprotein apolipoprotein B-100 turnover in patients with hypercholesterolemia and mixed hyperlipidemia.

Lifibrol (4-(4'-tert-butylphenyl)-1-(4'carboxyphenoxy)-2-butanol), a new hypocholesterolemic drug, effectively reduces total cholesterol (CH), low density lipoprotein (LDL)-CH, and apolipoprotein (apo) B in experimental animals and in humans. The impact of Lifibrol on the metabolism of apoB-100 containing lipoproteins in patients with hyperlipoproteinemia using endogenous labeling with stable isotopes is examined. Kinetic studies were performed in four male hypercholesterolemic individuals (type IIa) before and on treatment with 450 mg of Lifibrol daily for 4 weeks, and in five male individuals suffering from mixed hyperlipidemia (type IIb) before and on therapy for 12 weeks. Kinetic parameters were estimated by multicompartmental modeling. Lifibrol therapy reduced total CH by 16% (P = 0.012) in all patients, increased triglycerides (TG) by 11% (not significant) in type IIa patients and decreased TG by 34% (P = 0.059) in type IIb patients. During Lifibrol therapy, LDL apoB-100 concentrations decreased by 19% (P = 0.011) in all patients. The decrease in LDL apoB concentrations with Lifibrol therapy was due to an overall increase (75%, P = 0.006) of the fractional catabolic rates (FCR) of LDL apoB. This increase was partially attenuated by a 33% increase in LDL apoB production rate (PR) (P = 0.041). The overall production of apoB increased only slightly. Our data suggest that the major mechanism by which Lifibrol lowers LDL-CH is an increase in receptor-mediated catabolism of LDL rather than a decrease in hepatic apoB production.

Adult↗
PubMed1999

Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling.

Linear and convergent routes for the large-scale preparation of the hematoregulatory nonapeptide (Glp-Glu-Asp)2-DAS-(Lys)2 (2, SK&F 107647) were investigated. A convergent approach ('3 + 2'-route employing Boc-and benzyl ester protecting groups) was selected for the preparation of multihundred-gram quantities of 2. Key steps were the preparation and the coupling of tripeptide hydrochloride (HCl.H)2-DAS-(Lys(Z)-OBn)2 (6, DAS-2,7-L,L-diaminosuberic acid) and tripeptide Glp-Glu(OBn)-Asp(OBn)-OH (26). Several coupling reagents were investigated in order to reduce the amount of epimerization of this fragment coupling. TDBTU [O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl-1,1,3,3-tetrameth yluronium tetrafluoroborate] was identified as the condensation reagent of choice. Using this synthetic route > 97% pure final product in an overall yield of 35% calculated on di-Boc protected 2,7-L,L-diaminosuberic acid was prepared.

Indicators and Reagents↗
PubMed1999

Genetic fingerprinting in mouthwashes of patients after allogeneic bone marrow transplantation.

Detection of chimerism by PCR analysis of short tandem repeats (STR) in blood samples of patients who received allogeneic bone marrow transplantation (BMT) has proved to be an important method for early detection of relapse. The prerequisite for this type of analysis is knowledge of donor and recipient pretransplantation genotypes. In some cases, recipient cells from time points prior to BMT are not available and the pretransplant fingerprint cannot be determined. As BM recipients only alter their genotype in blood cells, we attempted to identify patient's pretransplantation genotypes after transplantation in mouthwash samples that contain easily accessible epithelial cells. Of 17 patients who had undergone BMT between one week and 45 months prior to analysis, DNA was isolated from mouthwash cell pellets or from epithelial cells obtained from mouthwashes. PCR analysis of STR loci in the von Willebrand and the tyrosine hydroxylase genes were performed. Even though the mouthwash cell pellets contained about 75% epithelial cells (presumably of recipient origin) and only about 25% leukocytes (presumably of donor origin), three of five patients showed donor genotype and only two patients exhibited chimeric DNA patterns, when cellular DNA was obtained by boiling of mouthwash cell pellets. Following phenol/chloroform extraction, eight of 10 DNA samples exhibited a chimeric pattern, while two of 10 DNAs showed only donor genotype. Of three patients, epithelial cells were attached to magnetic beads prior to DNA isolation. Even this DNA contained donor and recipient material. From our results it appears that blood cells serve as preferential DNA source in mouthwash samples and cannot be removed by epithelial cell separation.

Adult↗
PubMed1999

Altered lipid metabolism in preeclampsia and HELLP syndrome: links to enhanced platelet reactivity and fetal growth.

Normal pregnancy is a physiological condition of balanced hypercoagulability. However, in preeclamptic pregnancies, the coagulation and fibrinolytic cascades are highly activated, accompanied by pathological blood rheology and endothelial dysfunction. This may result in disseminated intravascular coagulation (DIC). Atherosclerosis research showed that lipids may interfere with coagulation and cause endothelial dysfunction. Therefore, we analyzed the lipoprotein distribution and platelet counts in uncomplicated preeclamptic and HELLP syndrome pregnancies. In addition, a correlation between the fetal circulation determined by Doppler velocimetry and the maternal lipid metabolism was investigated. Fasting serum was collected from 24 women in the third trimester of uncomplicated pregnancies, 9 women with severe preeclampsia, and 6 women with HELLP syndrome. Cholesterol (CH), triglycerides (TGs), and apolipoproteins were analyzed in serum and in very-low-density (VLDL), intermediate-density (IDL), low-density (LDL), and high-density (HDL) lipoproteins separated by ultra-centrifugation. Compared with normal pregnancies, TGs in serum, VLDL, IDL, LDL, and HDL were significantly increased in preeclampsia; no difference in CH concentrations was observed. During HELLP syndrome, IDL-TGs were increased compared with normal pregnancies. There was no clear correlation between fetal hemodynamics and maternal lipid metabolism, but there was a significant negative correlation between maternal platelet counts and serum TG levels. Because TG-rich particles may play an important role in thrombin generation and may induce platelet aggregation, the observed changes in lipoprotein metabolism in preeclampsia and HELLP syndrome may contribute to the coagulopathy seen in these conditions.

Adult↗
PubMed1999

Clonality analysis using X-chromosome inactivation at the human androgen receptor gene (Humara). Evaluation of large cohorts of patients with chronic myeloproliferative diseases, secondary neutrophilia, and reactive thrombocytosis.

Chronic myeloproliferative diseases (MPDs) are not associated with consistent cytogenetic or molecular abnormalities. Demonstration of clonal cell growth by analysis of X-chromosome inactivation (XCI) patterns in females provides a promising tool for diagnosis. However, this technique can be complicated by excessive lyonization of normal cells mimicking clonal cell growth: We analyzed XCI patterns at the human androgen receptor (HUMARA) locus in 146 healthy females, 65 women with secondary neutrophilia, 31 women with reactive thrombocytosis, and 86 women with chronic MPDs. A skewed XCI pattern with greater than 75% amplification of 1 allele (allele ratio > 3:1) was found in 22 (9.1%) of 242 control subjects. The incidence of skewing was statistically significantly lower in women younger than 30 years (2/73) compared with women older than 60 years (10/53). Of 86 patients with a chronic MPD, 71 (82%) exhibited an allele ratio greater than 3:1, whereas only 10 (12%) of 86 age-matched control subjects showed a skewed XCI pattern. Although statistical evaluation of the data showed a significant difference between patients with a chronic MPD and control subjects, proof of clonality in individual, especially elderly, patients is difficult.

Adolescent↗
PubMed1999

Combined polymerase chain reaction approach for clonality detection in lymphoid neoplasms.

The present study analyzes the efficiency of a combination of four immunoglobulin heavy chain (IgH) gene polymerase chain reaction (PCR) primer systems and a multiplex T-cell receptor gamma chain (TRG) gene PCR for detection of clonality in 409 samples (234 paraffin sections, 175 bone marrow aspirates) of different lymphomas. Using the four IgH PCR systems together, clonality was detected in all samples of B-cell chronic lymphocytic leukemias, hairy cell leukemias, common acute lymphoblastic leukemias, and Burkitt-like B-cell lymphomas. Clonality was detected in all bone marrow aspirates with lymphoplasmacytoid immunocytoma, mantle cell lymphoma, marginal zone B-cell lymphoma, and unclassifiable low-grade B-cell lymphomas. The combined IgH gene PCR approach allowed clonality detection in 78.2% of myelomas, 75% of Burkitt lymphomas, 74.4% of diffuse large B-cell lymphomas, 68.7% of follicular center lymphomas, 50% of posttransplant lymphomas, 28.6% of anaplastic large cell lymphomas, 29% of T-cell lymphomas, and 18.8% of Hodgkin diseases. The combination of the four IgH gene primer systems with the multiplex TRG gene PCR allowed detection of clonality in 84.2% of B-cell neoplasms, 92.1% of T-cell non-Hodgkin lymphomas, and 18.8% of Hodgkin diseases, which was much more efficient than single PCR protocols.

Clone Cells↗
PubMed1999

Combined modality treatment for osteosarcoma occurring as a second malignant disease. Cooperative German-Austrian-Swiss Osteosarcoma Study Group.

PURPOSE: The prognosis of osteosarcoma occurring as a second malignant disease (OS-SMD) is thought to be poor. We attempted to evaluate whether this holds true when OS-SMD is treated with combined modality therapy as developed for primary osteosarcoma and if factors that influence survival might be identified. PATIENTS AND METHODS: All patients with OS-SMD registered at the Cooperative German-Austrian-Swiss Osteosarcoma Study Group (COSS) study center between 1980 and June 1996 were evaluated for patient- and treatment-related factors, local and systemic outcome, and survival. Therapy was to be given according to contemporary COSS protocols for primary extremity osteosarcoma, including surgery and multiagent chemotherapy. RESULTS: Thirty patients with OS-SMD were registered (median latency period, 9 years 2 months). The first malignancies had been retinoblastoma (10 patients), sarcoma (10 patients), lymphoma (five patients), carcinoma (four patients), and medulloblastoma (one patient). Treatment for these malignancies had included radiotherapy in 24 patients, surgery in 20, and chemotherapy in 14. Twelve osteosarcomas were located axially and 18 were located in an extremity; 17 were radiation-related. Twenty-seven patients presented with localized disease; three presented with primary metastases (two skip, one lung). All 30 patients received chemotherapy, 29 with multiple drugs. Twenty-eight patients underwent operation. At 7 years, actuarial overall survival, survival free from osteosarcoma progression, and survival free from progression of any cancer were 50%, 34%, and 30%, respectively. In 24 patients with local tumor control, the corresponding values were 63%, 46%, and 38%. All seven local failures occurred in patients with axial osteosarcomas who did not undergo operation with wide surgical margins. CONCLUSION: Provided that local tumor control is achieved, OS-SMD treated with combined modality therapy may have a prognosis that approaches that of otherwise comparable primary osteosarcoma.

Adolescent↗
PubMed1999

Malignant fibrous histiocytoma of bone: a retrospective EMSOS study of 125 cases. European Musculo-Skeletal Oncology Society.

In an effort to learn more about malignant fibrous histiocytoma (MFH) of bone and its prognosis with different treatment approaches, the European Musculo-Skeletal Oncology Society (EMSOS) initiated a retrospective survey among its members. Data requested included patient and treatment variables and outcome. The information on all patients with histologically proven, primary, localized osseous extremity MFH was analyzed if surgical tumor removal was performed and disease status was documented for at least one follow-up date. 125 such patients were evaluable (74 male, 51 female; median age 34 years; tumor site femur 81, tibia 26, humerus 12, other 6). Local treatment was surgery only (110) or surgery plus radiotherapy (15). Chemotherapy was used in 97/125. On last follow-up, 85 patients remained in remission, 33 had developed metastases, 6 a local recurrence, and 1 a combined relapse. With a median follow-up of 3.9 years for patients at risk, actuarial 5-year disease-free survival was 59%. In univariate analyses, younger age and the use of chemotherapy were associated with a more favorable outcome, as was limb-salvage surgery. 23 of 66 tumors with information on response to preoperative chemotherapy responded well (> 90% necrosis). Among these 23, only one relapsed.

Adolescent↗