Biomedical subjects

H Jürgens

Publications and source records attributed to H Jürgens.

At least 37 records · Page 2Linked to original sources

PubMed2001

Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone: results of Study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster 93.

PURPOSE: To improve outcome in high-risk patients, high-dose cytarabine and mitoxantrone (HAM) was introduced into the treatment of children with acute myelogenous leukemia (AML) in study AML-BFM 93. Patients were randomized to HAM as either the second or third therapy block, for the purpose of evaluation of efficacy and toxicity. PATIENTS AND METHODS: A total of 471 children with de novo AML were entered onto the trial; 161 were at standard risk and 310 were at high risk. After the randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical in the two risk groups and also comparable to that in study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster (AML-BFM) 87. RESULTS: Overall, 387 (82%) of 471 patients achieved complete remission, and 5-year survival, event-free survival (EFS), and disease-free survival rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell reduction in the bone marrow on day 15. Estimated survival and probability of EFS were superior in study AML-BFM 93 compared with study AML-BFM 87 (P =.01, log-rank test). This improvement, however, was restricted to the 310 high-risk patients (remission rate and probability of 5-year EFS in study AML-BFM 93 v study AML-BFM 87: 78% v 68%, P =.007; and 44% v 31%, P =.01, log-rank test). Probability of 5-year EFS among standard-risk patients in study AML-BFM 93 was similar to that in study AML-BFM 87 (65% v 63%, P = not significant). Whether HAM was placed as the second or third therapy block was of minor importance. However, patients who received the less intensive daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Improved treatment results in children with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.

Adolescent↗

PubMed2001

Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89.

PURPOSE: To evaluate a multimodal approach including surgery and cisplatinum chemotherapy for treatment of children with malignant sacrococcygeal germ cell tumors (GCT) and to compare adjuvant and neoadjuvant strategies in advanced tumors. PATIENTS AND METHODS: Between 1983 and 1995, 71 patients with malignant sacrococcygeal GCT were prospectively enrolled onto the German protocols for nontesticular GCT Maligne Keimzelltumoren 83/86 and 89. Five patients who received no chemotherapy (n = 2) or nonplatinum chemotherapy (n = 2) or who did not undergo tumor resection (n = 1) were excluded from this analysis. Among the 66 patients analyzed were 14 boys and 52 girls. The median age was 17.4 months (range, 7 months to 119 months). Median follow-up was 79 months (range, 4 months to 145 months). RESULTS: Fifty-two patients presented with locally advanced stage T2 tumors, and 30 patients had distant metastases at diagnosis. Patients received a median of eight cycles (range, four to nine cycles) of cisplatinum-based chemotherapy. Thirty-five patients underwent tumor resection at diagnosis and received adjuvant cisplatinum-based chemotherapy (group A). Thirty-one patients received up-front chemotherapy followed by delayed tumor resection (group B). Group B included more metastatic tumors than group A (group B, 19 of 31 patients; group A, 11 of 35 patients, P =.01). Preoperative chemotherapy facilitated complete tumor resections (group B, 20 of 31 patients; group A, five of 35 patients, P <.001) and avoided second-look surgery. Metastases at diagnosis and completeness of the first attempt of tumor resection were significant prognostic predictors; however, metastases were not predictive for patients treated with up-front chemotherapy. At 5 years follow-up, event-free survival was 0.76 +/- 0.05 (50 of 66 patients), and overall survival was 0.81 +/- 0.05 (54 of 66 patients). Four patients died as a result of therapy-related complications, and eight patients died of their tumors. Patients with locally advanced and metastatic tumors (T2b M1) fared better with neoadjuvant treatment [overall survival: 0.83 +/- 0.09 (16 of 19 patients) versus 0.45 +/- 0.15 (five of 11 patients), P =.01]. CONCLUSION: Even locally advanced and metastatic sacrococcygeal GCT can be successfully treated with up-front cisplatinum-based chemotherapy followed by delayed but complete tumor resection.

Actuarial Analysis↗

PubMed2001

Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86.

PURPOSE: Cooperative Ewing's Sarcoma Study (CESS) 86 aimed at improving event-free survival (EFS) in patients with high-risk localized Ewing tumor of bone. PATIENTS AND METHODS: We analyzed 301 patients recruited from January 1986 to July 1991 (60% male; median age 15 years). Tumors of volume >100 mL and/or at central-axis sites qualified patients for "high risk" (HR, n = 241), and small extremity lesions for "standard risk" (SR, n = 52). Standard-risk patients received 12 courses of vincristine, cyclophosphamide, and doxorubicin alternating with actinomycin D (VACA); HR patients received ifosfamide instead of cyclophosphamide (VAIA). Tumor sites were pelvis (27%), other central axis (28%), femur (19%), or other extremity (26%). The initial tumor volume was <100 mL in 33% of cases and > or =100 mL in 67%. Local therapy was surgery (23%), surgery plus radiotherapy (49%), or radiotherapy alone (28%). Event-free survival rates were estimated by Kaplan-Meier analyses, comparisons were done by log-rank test, and risk factors were analyzed by Cox models. RESULTS: On May 1, 1999 (median time under study, 133 months), the 10-year EFS was 0.52. Event-free survival did not differ between SR-VACA (0.52) and HR-VAIA (0.51, P =.92). Tumor volume of >200 mL (EFS, 0.36 v 0.63 for smaller tumors; P =.0001) and poor histologic response (EFS, 0.38 v 0.64 for good responders; P =.0007) had negative impacts on EFS. In multivariate analyses, small tumor volumes of <200 mL, good histologic response, and VAIA chemotherapy augured for fair outcome. Six of 301 patients (2%) died under treatment, and four patients (1.3%) developed second malignancies. CONCLUSION: Fifty-two percent of CESS 86 patients survived after risk-adapted therapy. High-risk patients seem to have benefited from intensified treatment that incorporated ifosfamide.

Adolescent↗

PubMed2001

Prognostic impact of tumor perfusion in MR-imaging studies in Ewing tumors.

BACKGROUND: Intratumoral hypoxia is associated with poor prognosis in various solid tumors. Severe and long-lasting hypoxia results in necrosis. The presence of necrosis therefore might also be correlated with unfavorable outcome. This has been demonstrated for head and neck cancers, gliomas and adult soft tissue sarcomas. We have investigated whether or not the patterns of contrast enhancement and the presence of visible necrosis on pretreatment MR images has prognostic impact in Ewing tumors. PATIENTS AND METHODS: From December 1993 though March 1997, 79 patients with Ewing tumors were prospectively analyzed for the presence and amount of necrosis in their tumors. The median age was 12 years (range 4-30 years). The median follow-up at the time of this analyses was 3 years. All patients were treated according to the multicentric EICESS-92 protocol with multi-agent chemotherapy (VACA or VAIA or EVAIA) and local therapy (radiotherapy with 50-60 Gy or surgery or surgery with pre- or postoperative irradiation with 45-50 Gy). For the measurement of necrosis, gadolinium contrast-enhanced T1-weighted MR images were used. Necrosis was defined as non-perfused areas in the tumor and the necrotic volume was expressed as percentage of total volume. RESULTS: Out of 79 tumors, 10 (13%) showed no necrosis, 30 (38%) had 1-25% necrosis, 21 (27%) had 26-50% necrosis and the remaining 18 (23%) more than 50% necrosis. There was a correlation between tumor size and necrosis (p = 0.001): the median tumor volume increased with amount of necrosis (47 cm3 in non-necrotic tumors, 59 cm3 vs 280 cm3 vs 284 cm3 for tumors with 1-25% vs 26-50% vs > 50% necrosis). Tumor site (central location vs proximal extremities vs distal extremities) had no impact on necrosis (p = 0.71). 23 out of 79 patients had metastases (M1) at the time of diagnosis. The frequency of metastatic spread increased with the amount of necrosis: 1/10 (10%) patients with non-necrotic tumors had metastases vs 7/30 (23%) vs 6/21 (28%) vs 9/18 (50%) for tumors with 1-25% vs 26-50% vs > 50% necrosis. "Unfavorable" metastatic spread (bone or multiple metastases) was only noted in patients with high amount of necrosis (> 25% necrosis) whereas even large tumors did not show unfavorable metastases if they contained no or only small amounts of necrosis. All patients with non-necrotic tumors survived event-free during the observation period. Patients with necrotic tumors had a 3-year event-free survival of 55% (p = 0.06 vs tumors without necrosis). CONCLUSIONS: The presence of non-perfused (presumably necrotic) areas on pretreatment contrast-enhanced MR-images is associated with an increased risk of metastases, especially an unfavorable pattern of metastatic spread at diagnosis. This observation may be explained by a more aggressive biological behavior of hypoxic tumor cells. The small group of patients with non-necrotic tumors (13%) had an excellent prognosis suggesting that the absence of necrosis might be helpful in identifying a very favorable prognostic subgroup in Ewing tumors.

Adolescent↗

PubMed2001

[Clinical value of positron emission tomography (PET) in the diagnosis of bone and soft tissue tumors. 3rd Interdisciplinary Consensus Conference "PET in Oncology": results of the Bone and Soft Tissue Study Group].

PURPOSE: In the framework of the 3rd Consensus Conference "PET in Oncology" the bone and soft-tissue tumors study group evaluated the present position of PET for these tumor entities on the basis of international publications. METHODS: After a systematic review of the literature, publications were evaluated according to previously defined quality criteria. For various indications the clinical usefulness of PET was assessed using a classification system. RESULTS: Most studies had been performed with a small number of patients (n < 35). Therefore, only 8 of 46 publications were judged relevant. On the basis of these literature data, use of FDG-PET for grading was classified 1b (literature results predominantly show clinical usefulness). As before (1995/97), all other indications were categorized with 3 (assessment not yet possible, literature data inadequate). OUTLOOK: According to the opinion of experts, the detection of osseous metastases of Ewing's sarcoma, therapy monitoring and the diagnosis of recurrences are potentially useful clinical indications for FDG-PET. Therefore, prospective studies with large patient groups are essential to further evaluate the benefit of FDG-PET in these indications.

Age Factors↗

PubMed2001

Autologous peripheral blood stem cell transplantation and anti-B-cell directed immunotherapy for refractory auto-immune haemolytic anaemia.

UNLABELLED: We report the clinical course of a 6.5-year-old boy with refractory auto-immune haemolytic anaemia. Due to failure of conventional immunosuppressive therapy, an autologous peripheral blood stem cell transplantation was performed. The conditioning regimen consisted of cyclophosphamide and anti-thymocyte globulin. The patient was reinfused with 2.6 x 10(6) CD34 positive selected, B- and T-cell-depleted peripheral blood stem cells per kg body weight. He showed a partial response with a reduced demand for red blood cell transfusions. However, due to persistence of the haemolytic process he was started on rituximab therapy on day +40 post-transplant. Following two doses of rituximab, the patient improved rapidly and developed a sustained complete response. After 10 months, haemolysis recurred and responded again to rituximab therapy without the necessity for red blood cell transfusions. 15 months after initial antibody treatment, however, the patient developed a second relapse which was now refractory to rituximab therapy although CD20+ B-lymphocytes were cleared from the peripheral blood. CONCLUSION: Our case report suggests that rituximab and autologous peripheral blood stem cell transplantation are important though not curative elements in the treatment of patients with severe auto-immune haemolytic anaemia who are refractory to conventional immunosuppressive therapy.

Anemia, Hemolytic, Autoimmune↗

PubMed2001

Pediatric high-grade astrocytomas show chromosomal imbalances distinct from adult cases.

We studied 23 pediatric high-grade astrocytomas by comparative genomic hybridization. Chromosomal imbalances were found in 10 of 10 anaplastic astrocytomas and 11 of 13 glioblastomas and consisted of +1q (43%), +3q (26%), +1p, +2q, +5q (22%), -22q (34%), -6q, -10q (30%), -9q, -11q, -13q, -16q, and -17p (22%). Anaplastic astrocytomas frequently showed +5q (40%), +1q (30%), -22q (50%), -6q, -9q (40%), and -12q (30%); glioblastomas +1q (54%), +3q (38%), +2q, +17q (23%), -6q, -8q, -10q, -13q, and -17p (31%). Minimal common regions mapped to +1q21-41, +3q27-qter, +2q31-32, +5q14-22, -22q12-qter, -10q23-25, -6q25-qter, -9q34.2, -11q14-22, -16q22-qter, and -17p. High-level gains were located on 1q (7 cases), 2q, 7q (4 cases), 3q (3 cases), 9, 17q (2 cases), 4q, 8q, 18, and 20q (1 case). A significantly shorter survival was found for anaplastic astrocytomas showing +1q (P: < 0.05), MIB-1 proliferation index >25% (P: < 0.001) and glioblastomas (P: < 0.05). Compared with adult cases, +1p, +2q, and +21q as well as -6q, -11q, and -16q were more frequent in pediatric malignant astrocytomas. Among the latter +5q, -6q, -9q, -12q, and -22q were characteristic for pediatric anaplastic astrocytomas and +1q, +3q, +16p, -8q, and -17p for pediatric glioblastomas. Our results show that chromosomal aberrations differ between pediatric anaplastic astrocytomas and glioblastomas as well as between pediatric and adult high-grade astrocytomas, supporting the notion of a different genetic pathway. Furthermore, gains of chromosomal material on 1q might be correlated with a worse prognosis in pediatric anaplastic astrocytomas.

Adolescent↗

PubMed2001

FDG-PET for detection of pulmonary metastases from malignant primary bone tumors: comparison with spiral CT.

BACKGROUND: The purpose was the comparison of positron emission tomography using F-18-fluorodeoxy-glucose (FDG-PET) and spiral thoracic CT to detect pulmonary metastases from malignant primary osseous tumors. PATIENTS AND METHODS: In 71 patients with histologically confirmed malignant primary bone tumors (32 osteosarcomas, 39 Ewing's sarcomas) 111 FDG-PET examinations were evaluated with regard to pulmonary/pleural metastases in comparison with spiral thoracic CT. Reference methods were the clinical follow-ups for 6-64 months (median 20 months) or a histopathologic analysis. RESULTS: In 16 patients (23%) reference methods revealed a pulmonary/pleural metastatic disease. FDG-PET had a sensitivity of 0.50, a specificity of 0.98, and an accuracy of 0.87 on a patient based analysis. Comparable values for spiral CT were 0.75, 1.00, and 0.94. It was shown that no patient who had a true positive FDG-PET had a false negative CT scan, nor was a pulmonary metastases detected earlier by FDG-PET than by spiral CT. CONCLUSIONS: There seems to be a superiority of spiral CT in the detection of pulmonary metastases from malignant primary bone tumors as compared with FDG-PET. Therefore, at present a negative FDG-PET cannot be recommended to exclude lung metastases. However, as specificity of FDG-PET is high, a positive FDG-PET result can be used to confirm abnormalities seen on thoracic CT scans as metastatic.

Adolescent↗

PubMed2001

Second malignancies after ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study.

BACKGROUND: Ewing tumor treatment involves high cumulative doses of alkylating agents and topoisomerase inhibitors, drugs capable of inducing second cancers. We analyzed the second cancer risk in a large cohort of consistently treated patients. PATIENTS AND METHODS: Six hundred ninety Ewing tumor patients were treated between 1992 and 1999 with local therapy and vincristine. doxorubicin, ifosfamide and/or cyclophosphamide, and antinomycin D, with or without etoposide as a randomized question. Second cancer incidences were estimated by competing risk analyses; standardized incidence ratios (SIR) in comparison to registry data were compiled. RESULTS: After a median observation time of 56 months (32 months for survivors), 6 of 690 patients had developed second cancers: MDS/AML, two, ALL/NHL, two, squamous cell carcinoma, one, liposarcoma, one. SIR were increased 20-30 fold in comparison to the general population. The cumulative second cancer risk five years after diagnosis of the Ewing tumor was 0.0093 for the total group, zero for patients without etoposide, and 0.0118 with etoposide. Additional phase II high-dose therapy increased the risk to 0.0398 after five years. CONCLUSIONS: The second cancder risk observed was in the range to be expected in cancer survivors. High-dose therapy, and less markedly, etoposide, may contribute to the overall second cancer risk.

Adolescent↗

PubMed2001

Liposomal amphotericin B for prophylaxis of invasive fungal infections in high-risk paediatric patients with chemotherapy-related neutropenia: interim analysis of a prospective study.

Invasive fungal infections (IFI) are a major cause of morbidity and mortality in patients with cancer. A retrospective analysis of children with cancer at high risk for IFI treated at Münster University Hospital showed that the incidence (7.4% vs. 1.8%) and lethality (28.1% vs. 0) of documented IFI were lower in patients receiving systemic antifungal prophylaxis with liposomal amphotericin B (l-AmB) in comparison to a historical control group. To determine whether this decline in incidence and lethality was due to antifungal prophylaxis or was produced by advances in diagnostic procedures and early empirical antifungal therapy, a prospective study was initiated. Patients in the prophylaxis arm received thrice-weekly 1 mg kg(-1) body weight l-AmB, whilst patients in the early intervention arm received no prophylaxis. Diagnostic procedures and antifungal therapy for suspected or proven IFI were initiated as clinically indicated for all patients. The primary endpoint of the study was the incidence of IFI. Secondary endpoints were the use of therapeutic doses of l-AmB, the safety of prophylactic l-AmB, and the total consumption of l-AmB for antifungal therapy. The interim analysis after 1 year showed no differences between the two approaches with respect to the incidence of IFI and to safety issues.

Adolescent↗

PubMed2001

Establishment of an in vivo model for pediatric Ewing tumors by transplantation into NOD/scid mice.

Ewing tumors are a clinically heterogeneous group of childhood sarcomas that represent a paradigm for understanding solid tumor biology, as they are the first group of sarcomas for which a chromosome translocation has been characterized at the molecular level. However, the biologic organization of the tumor, especially the processes that govern proliferation, differentiation, and metastasis of primitive tumor stem cells is poorly understood. Therefore, to develop a biologically relevant in vivo model, five different Ewing tumor cell lines and primary tumor cells from three patients were transplanted into immune-deficient mice via intravenous injection. NOD/scid mice that carry a complex immune deficiency and thus nearly completely lack the ability to reject human cells were used as recipients. Overall, 26 of 52 mice (50%) transplanted with VH-64, WE-68, CADO-ES1, TC-71, and RM-82 cells and 4 of 10 mice (40%) transplanted with primary tumor cells engrafted. Moreover, primary cells that did not grow in vitro proliferated in mice. The pattern of metastasis was similar to that in patients with frequent metastases in lungs (62%), bone marrow (30%), and bone (23%). Using limiting dilution experiments, the frequency of the engraftment unit was estimated at 1 Ewing tumor-initiating cell in 3 x 10(5) VH-64 cells. These data demonstrate that we have been able to establish an in vivo model that recapitulates many aspects of growth and progression of human Ewing tumors. For the first time, this model provides the opportunity to identify and characterize primitive in vivo clonogenic solid tumor stem cells. This model will, therefore, be instrumental in studying many aspects of tumor cell biology, including organ-selective metastasis and tumor angiogenesis.

Animals↗

PubMed2001

Ewing tumour: incidence, prognosis and treatment options.

Ewing tumours, i.e. Ewing's sarcoma and malignant peripheral neuroectodermal tumours, are the second most common primary malignant tumours of bone in childhood and adolescence, with an annual incidence rate in Caucasians of 3 per 1 million children <15 years of age. Histopathologically small blue round cell tumours, Ewing tumours show a typical chromosomal rearrangement in >95% of cases linking the EWS gene on chromosome 22q12 to a member of the ETS transcription gene family, most commonly to Fli-1 on 11q24. This fusion contributes to the malignant potential of Ewing tumour cells, indeed antisense oligonucleotides may prevent tumour growth in vitro. After open biopsy, and histological and possibly molecular biological confirmation of the diagnosis, treatment consists of several months of multidrug cytostatic therapy and local therapy. Both surgery and radiotherapy may control local disease, but without consequent cytostatic chemotherapy all patients will eventually succumb to distant metastases. With the use of alkylating agents including doxorubicin, cyclophosphamide and/or ifosfamide, and other cytostatic drugs such as actinomycin D (dactinomycin), vincristine and etoposide, long-term survival can be achieved in >50% of patients with localised disease. Patients with clinically detectable metastases at diagnosis, patients not responding to therapy and patients with disease relapse have a significantly poorer prognosis. Maximum supportive care and local therapy managed by an experienced physician are required in all patients, and inclusion of high-risk patients in phase I and II studies is warranted. Hence, treatment of patients with Ewing tumours should be performed in experienced centres only and preferably within controlled clinical trials.

Antineoplastic Agents↗

PubMed2001

Whole-body MR imaging for detection of bone metastases in children and young adults: comparison with skeletal scintigraphy and FDG PET.

OBJECTIVE: The purpose of this study was to compare the diagnostic accuracy of whole-body MR imaging, skeletal scintigraphy, and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for the detection of bone metastases in children. SUBJECTS AND METHODS: Thirty-nine children and young adults who were 2--19 years old and who had Ewing's sarcoma, osteosarcoma, lymphoma, rhabdomyosarcoma, melanoma, and Langerhans' cell histiocytosis underwent whole-body spin-echo MR imaging, skeletal scintigraphy, and FDG PET for the initial staging of bone marrow metastases. The number and location of bone and bone marrow lesions diagnosed with each imaging modality were correlated with biopsy and clinical follow-up as the standard of reference. RESULTS: Twenty-one patients exhibited 51 bone metastases. Sensitivities for the detection of bone metastases were 90% for FDG PET, 82% for whole-body MR imaging, and 71% for skeletal scintigraphy; these data were significantly different (p < 0.05). False-negative lesions were different for the three imaging modalities, mainly depending on lesion location. Most false-positive lesions were diagnosed using FDG PET. CONCLUSION: Whole-body MR imaging has a higher sensitivity than skeletal scintigraphy for the detection of bone marrow metastases but a lower sensitivity than FDG PET.

Adolescent↗

PubMed2001

High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma.

PURPOSE: Despite highly efficacious chemotherapy, patients with osteosarcomas still have a poor prognosis if adequate surgical control cannot be obtained. These patients may benefit from therapy with radiolabeled phosphonates. PATIENTS AND METHODS: Six patients (three male, three female; seven to 41 years) with unresectable primary osteosarcoma (n = 3) or unresectable recurrent sites of osteosarcomas (n = 3) were treated with high-activity of Sm-153-EDTMP (150 MBq/kg BW). In all patients autologous peripheral blood stem cells had been collected before Sm-153-EDTMP therapy. RESULTS: No immediate adverse reactions were observed in the patients. In one patient bone pain increased during the first 48 hrs after therapy. Three patients received pain relief. Autologous peripheral blood stem cell reinfusion was performed on day +12 to +27 in all patients to overcome potentially irreversible damage to the hematopoietic stem cells. In three patient external radiotherapy of the primary tumor site was performed after Sm-153-EDTMP therapy and in two of them polychemotherapy was continued. Thirty-six months later one of these patients is still free of progression. Two further patients are still alive. However, they have developed new metastases. The three patients who had no accompanying external radiotherapy, all died of disease progression five to 20 months after therapy. CONCLUSION: These preliminary results show that high-dose Sm-153-EDTMP therapy is feasible and warrants further evaluation of efficacy. The combination with external radiation and polychemotherapy seems to be most promising. Although osteosarcoma is believed to be relatively radioresistant, the total focal dose achieved may delay local progression or even achieve permanent local tumor control in patients with surgically inaccessible primary or relapsing tumors.

Adolescent↗

PubMed2000

Apoptotic responsiveness of the Ewing's sarcoma family of tumours to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL).

We investigated the cytotoxic responsiveness of 40 cell lines derived from representatives of the Ewing's sarcoma family of tumours (ESFT), i.e., Ewing's sarcoma (ES), peripheral primitive neuroectodermal tumour (pPNET) and Askin tumour (AT), to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Incubation with TRAIL at 100 ng/ml induced cell death at 24 hr in 19 of 26 ES, 11 of 12 pPNET and 2 of 2 AT cell lines. Half-maximal cell death concentrations (IC(50) values) varied from 0.1 to 20 ng/ml. TRAIL displayed potent cytotoxic activity against freshly derived ESFT cell isolates. Cytotoxicity was associated with phosphatidylserine expression and internucleosomal DNA fragmentation, features characteristic of apoptosis. The apoptotic programme in the sensitive ESFT VH-64 cell line revealed TRAIL-induced activation of FLICE/MACH1 (caspase-8) and CPP32/Yama/apopain (caspase-3) and processing of the prototype caspase substrate poly(ADP-ribose) polymerase. In addition, TRAIL provoked a collapse of the mitochondrial transmembrane potential (DeltaPsi(m)), parallelled by a reduction in ATP levels and release of cytochrome c from mitochondria into the cytosol. Inhibition of caspase-8 and caspase-3 by zIETDfmk and zDEVDfmk, respectively, substantially prevented TRAIL-induced apoptosis. However, zIETDfmk, but not zDEVDfmk, reduced TRAIL-mediated DeltaPsi(m) dissipation, indicating that TRAIL causes mitochondrial dysfunction through caspase-8 acting upstream of mitochondria. While macromolecule synthesis inhibitors (actinomycin D, cycloheximide) augmented susceptibility to TRAIL in TRAIL-responsive cell lines, these agents did not render TRAIL-resistant cell lines susceptible to TRAIL. However, the proteasome inhibitor MG132 sensitised to TRAIL in resistant cell lines. Collectively, these results show that TRAIL initiates effective death in the vast majority (80%) of cell lines derived from ESFT. Since TRAIL provoked cell death in ESFT ex vivo, this cytokine may be a promising drug for the treatment of ESFT in vivo.

Adenosine Triphosphate↗

PubMed2000

FDG-PET for detection of osseous metastases from malignant primary bone tumours: comparison with bone scintigraphy.

The purpose of this study was to compare positron emission tomography using fluorine-18 fluorodeoxyglucose (FDG-PET) and technetium-99m methylene diphosphonate (MDP) bone scintigraphy in the detection of osseous metastases from malignant primary osseous tumours. In 70 patients with histologically proven malignant primary bone tumours (32 osteosarcomas, 38 Ewing's sarcomas), 118 FDG-PET examinations were evaluated. FDG-PET scans were analysed with regard to osseous metastases in comparison with bone scintigraphy. The reference methods for both imaging modalities were histopathological analysis, morphological imaging [additional conventional radiography, computed tomography (CT) or magnetic resonance imaging (MRI)] and/or clinical follow-up over 6-64 months (median 20 months). In 21 examinations (18%) reference methods revealed 54 osseous metastases (49 from Ewing's sarcomas, five from osteosarcomas). FDG-PET had a sensitivity of 0.90, a specificity of 0.96 and an accuracy of 0.95 on an examination-based analysis. Comparable values for bone scintigraphy were 0.71, 0.92 and 0.88. On a lesion-based analysis the sensitivity of FDG-PET and bone scintigraphy was 0.80 and 0.72, respectively. Analysing only Ewing's sarcoma patients, the sensitivity, specificity and accuracy of FDG-PET and bone scan were 1.00, 0.96 and 0.97 and 0.68, 0.87 and 0.82, respectively (examination-based analysis). None of the five osseous metastases from osteosarcoma were detected by FDG-PET, but all of them were true-positive using bone scintigraphy. In conclusion, the sensitivity, specificity and accuracy of FDG-PET in the detection of osseous metastases from Ewing's sarcomas are superior to those of bone scintigraphy. However, in the detection of osseous metastases from osteosarcoma, FDG-PET seems to be less sensitive than bone scintigraphy.

Adolescent↗

PubMed2000

Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Düsseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria.

BACKGROUND: An update of results from the High Risk Protocol of the Meta-EICESS Study, conducted at the Pediatric Stem-Cell Transplant Centers of Düsseldorf and Vienna. In order to evaluate a possible therapeutic benefit after allogeneic SCT in patients with advanced Ewing tumors (AET), we compared outcome after autologous and allogeneic stem-cell transplantation (SCT). PATIENTS AND METHODS: We analyzed 36 patients treated with the myeloablative Hyper-ME protocol (hyperfractionated total body irradiation, melphalan, etoposide +/- carboplatin) between November 1986 and December 1994. Minimal follow-up for all patients was five years. All patients underwent remission induction chemotherapy and local treatment before myeloablative therapy. Seventeen of thirty-six patients had multifocal primary Ewing's tumor, eighteen of thirty-six had early, multiple or multifocal relapse, one of thirty-six patients had unifocal late relapse. Twenty-six of thirty-six were treated with autologous and ten of thirty-six with allogeneic hematopoietic stem cells. We analyzed the following risk factors, that could possibly influence the event-free survival (EFS): number of involved bones, degree of remission at time of SCT, type of graft, indication for SCT, bone marrow infiltration, bone with concomitant lung disease, age at time of diagnosis, pelvic involvement, involved compartment radiation, histopathological diagnosis. RESULTS: EFS for the 36 patients was 0.24 (0.21) +/- 0.07. Eighteen of thirty-six patients suffered relapse or died of disease, nine of thirty-six died of treatment related toxicity (DOC). Nine of thirty-six patients are alive in CR. Age > or = 17 years at initial diagnosis (P < 0.005) significantly deteriorated outcome. According to the type of graft, EFS was 0.25 +/- 0.08 after autologous and 0.20 +/- 0.13 after allogeneic SCT. Incidence of DOC was more than twice as high after allogeneic (40%) compared to autologous (19%) SCT, even though the difference did not reach significance (P = 0.08, Fisher's exact test). CONCLUSIONS: Because of the rather short observation period. secondary malignant neoplasms (SMN) may complicate the future clinical course of some of our patients who are currently viewed as event-free survivors. EFS in AET is not improved by allogeneic SCT due to a higher complication rate. The patient group was to small to analyze for a possible graft-versus-tumor effect.

Adolescent↗

PubMed2000

Assessing permeability alterations of the blood-bone marrow barrier due to total body irradiation: in vivo quantification with contrast enhanced magnetic resonance imaging.

Our aim was to quantify irradiation-induced permeability alterations of the blood-bone marrow barrier (BMB) with dynamic contrast enhanced magnetic resonance imaging (MRI). The standard small molecular contrast agent, gadoterate meglumine, and a new macromolecular contrast agent, carboxymethyldextran-Gd-DOTA (CMD-Gd-DOTA), were compared. Twenty New Zealand white rabbits underwent MRI of the bone marrow before and 1-2 days after total body irradiation (TBI). Dynamic, repetitive T1-weighted MRI was performed before and after injection of either 0.05 mmol/kg BW CMD-Gd-DOTA (n = 10) or 0.5 mmol/kg BW gadoterate (n = 10). Bone marrow contrast enhancement was quantified as delta signal intensity: DeltaSI = |(SIpost - SIpre) / SIpre| * 100%. All MRI data were compared with the histopathologic BMB ultrastructure. Dynamic bone marrow DeltaSI data steadily increased after CMD-Gd-DOTA injection, while blood DeltaSI data slightly decreased. This bone marrow contrast enhancement, indicative of contrast agent extravasation, was significantly higher and prolonged in the irradiated group as compared to non-irradiated controls (P < 0.05) and corresponded to irradiation-induced alterations of the BMB ultrastructure seen on electron microscopy. By contrast, DeltaSI data of non-irradiated and irradiated marrow were not significantly different following gadoterate injection (P > 0.05). We conclude that irradiation-induced alterations in BMB permeability could be reliably assessed with dynamic MRI, using the new macromolecular contrast agent CMD-Gd-DOTA. Bone Marrow Transplantation (2000) 25, 71-78.

Animals↗