Myeloablative therapy with autologous stem cell rescue for patients with Ewing sarcoma.

The aim of this study was to identify risk factors associated with PFS in patients with Ewing sarcoma undergoing ASCT; 116 patients underwent ASCT in 1989-2000 and reported to the Center for International Blood and Marrow Transplant Research. Eighty patients (69%) received ASCT as first-line therapy and 36 (31%), for recurrent disease. Risk factors affecting ASCT were analyzed with use of the Cox regression method. Metastatic disease at diagnosis, recurrence prior to ASCT and performance score <90 were associated with higher rates of disease recurrence/progression. Five-year probabilities of PFS in patients with localized and metastatic disease at diagnosis who received ASCT as first-line therapy were 49% (95% CI 30-69) and 34% (95% CI 22-47) respectively. The 5-year probability of PFS in patients with localized disease at diagnosis, and received ASCT after recurrence was 14% (95% CI 3-30). PFS rates after ASCT are comparable to published rates in patients with similar disease characteristics treated with conventional chemotherapy, surgery and irradiation suggesting a limited role for ASCT in these patients. Therefore, ASCT if considered should be for high-risk patients in the setting of carefully controlled clinical trials.

Progress in the diagnosis and treatment of rhabdomyosarcoma and related soft tissue sarcomas.

Advances in the diagnosis and treatment of rhabdomyosarcoma and related soft tissue sarcomas continue in the Intergroup Rhabdomyosarcoma Study Group (IRSG) and European cooperative groups. The use of molecular biology techniques in soft tissue sarcomas are redefining the classic pathology of these small blue cell tumors. Improvements in imaging, radiotherapy, and surgery, in part, deserve credit for the better survival seen in all cooperative trials. These advances confound the interpretation of consecutively run chemotherapy trials using historical comparisons. The IRSG has reported improvement in the prognosis of both nonmetastatic and metastatic embryonal rhabdomyosarcoma as attributable to three, three-drug regimens that use cyclophosphamide at 2.2 g/m2 in either maintenance or induction and maintenance therapy. Patients of any age with metastatic, nonembryonal, and those over 10 years of age with metastatic embryonal rhabdomyosarcoma continue to have a poor prognosis, which even megatherapy has failed to change. The doublet of ifosfamide and etoposide in combination with vincristine, actinomycin D, and cyclophosphamide at 2.2 g/m2 achieved a remarkable 3-year survival of 58% in patients with metastatic rhabdomyosarcoma and undifferentiated soft tissue sarcoma. The topoisomerase I inhibitor, topotecan, has recently been found by the IRSG to have a 57% overall response rate in patients with metastatic alveolar rhabdomyosarcoma. Topotecan has completed testing with cyclophosphamide in a phase II window study in newly diagnosed patients with metastatic disease and has been incorporated into a randomized trial in intermediate risk patients in IRSG-V. Molecular studies in IRSG-V will be applied in the detection of occult bone marrow metastases and the evaluation of resection margins at initial and second-look surgery. Long-term follow-up will be required in patients with gross residual sarcoma randomized to conventional and hyperfractionated radiotherapy in IRSG-IV to assess late effects. Although older patients with unfavorable histology and metastatic disease continue to have a poor prognosis, the overall 5-year survival of children and adolescents with nonmetastatic and metastatic rhabdomyosarcoma is approaching 80%. As molecular discoveries advance the diagnosis and detection of rhabdomyosarcoma, it is hoped that the futuristic molecular based treatment strategies in development and early testing will further improve survival in high-risk patients with metastatic soft tissue sarcoma.

Bone marrow transplantation in adolescents.

This paper reviews bone marrow transplantation in adolescents. The primary indications for bone marrow transplantation are malignancies, usually relapsed lymphomas or acute/chronic leukemias. Autologous bone marrow transplantation is used as a high-dose consolidation therapy in some solid tumor patients with varied success. Peripheral blood stem cells are a feasible source of autologous stem cells in adolescents. The process of stem cell transplantation and the complications are the same in adolescents as in younger children and adults. Adolescents face the same biologic barriers to allogeneic transplant (minimal residual disease, availability of donor), but may also face more problems with their insurance status. The psychological and social aspects of bone marrow transplantation during adolescence are unique to their developmental stage. With appropriate medical, nursing, and psychosocial support, bone marrow transplantation offers cure for the adolescent with high-risk disease.

An SEM examination of granule cell migration in the mouse cerebellum.

The inward migration of external granule cells (EGC) from the pial surface of the developing cerebellum to form the (internal) granule cell layer was examined using SEM. Cerebella from male mice ranging in age from days 1-20 were fixed, then fractured through the developing pyramid region. EGC were initially unspecialized cells, forming 2-3 layers at the pial surface. EGC layers increased to 6-8, granule cells in the deeper regions elongated, and a prominent space formed between superficial and deep (premigratory) strata. During peak migration (days 8-12), nests of 4-6 EGC were associated with Bergmann glial fibers (BF) of the Golgi epithelial cells, which crossed molecular and EGC layers to terminate as spiny endfeet at the pial surface. Fibrils of extracellular material (ECM) often linked both premigratory and migrating EGC with a nearby BF. The molecular layer thickened considerably and the parallel fibers were traversed by an increasing number of Bergmann fibers and Purkinje cell processes during this period. As active migration slowed (days 13-20) and EGC reached their destination below the Purkinje cell layer, they lost their polarity and were enmeshed in ECM. The role of the Bergmann fibers and extracellular material in granule cell migration is considered.

Regimen-related toxicity of myeloablative chemotherapy with BCNU, thiotepa, and etoposide followed by autologous stem cell rescue for children with newly diagnosed glioblastoma multiforme: report from the Children's Cancer Group.

BACKGROUND: The survival of children with glioblastoma multiforme (GBM) remains poor. In an effort to improve the cure rate of children with this disease, high-dose chemotherapy followed by autologous stem cell rescue (ASCR) has been evaluated. We report the regimen-related toxicity (RRT) and survival seen in 11 children with newly diagnosed GBM treated with high-dose chemotherapy on a Children's Cancer Group study (CCG-9922). PROCEDURES: This phase II pilot study, intended to treat 30 patients, accrued 11 patients from July, 1993, to April, 1995. The pre-ASCR preparative regimen included BCNU 100 mg/m2 every 12 hr for a total of six doses on days -8, -7, -6; thiotepa 300 mg/m2/day on days -5, -4, -3; and etoposide 250 mg/m2/day on days -5, -4, -3. All patients received delayed radiotherapy at a dose of 5,400 cGy to the primary site commencing on approximately day +42 after ASCR. RESULTS: Five patients (45%) developed significant, nonfatal (grade III or IV) pulmonary and/or neurological toxicities. Three patients developed signs and/or symptoms of idiopathic interstitial pneumonitis. Eight patients (73%) have died, two (18%) of toxicity, and six (55%) of disease progression. Three patients (27%) achieved and remain in complete radiographic remission 2.9, 3.9, and 5.1 years from ASCR. One of these three, developed a lymphoblastic non-Hodgkins lymphoma (NHL) 3. 5 years post-ASCR. The survival rates for these 11 children at 1 year and 2 years are 73% +/- 13% and 46% +/- 14%, respectively. The progression-free survival rates at 1 year and at 2 years are 64% +/- 14% and 46% +/- 14%, respectively. CONCLUSIONS: We conclude that high-dose chemotherapeutic regimens followed by ASCR is a feasible treatment of childhood GBM. The BCNU-based preparative regimen utilized in this study was associated with prohibitive pulmonary toxicity.

Mobilization of peripheral blood stem cells in children using G-CSF after carboplatin containing myelosuppressive chemotherapy.

PURPOSE: Peripheral blood stem cell (PBSC) apheresis provides an alternative to autologous marrow harvest as a source of hematologic stem cells for transplantation in children with solid tumors. PATIENTS AND METHODS: Eight children with metastatic or recurrent solid tumors underwent 27 apheresis procedures. Recovery from myelosuppressive chemotherapy occurred without continuous daily growth factor support prior to mobilization. Granulocyte colony stimulating factor (G-CSF) at 16 microgs/kg/day was used to increase stem cells in the peripheral circulation. CD 34 positive cells, mononuclear cells (MNC), and CFU-GM were measured in the apheresis products. Prior chemotherapy was examined as a clinical factor that affected PBSC yield. RESULTS: A significant correlation was found between CD 34+/kg and CFU-GM/kg of the products (r = 0.758, P < 0.001). Patients receiving cumulative doses of carboplatin over 1,600 mg/m2 produced adequate MNC (1 x 10(8)/kg) but yielded significantly less CD 34+ cells or CFU-GM than those patients receiving less carboplatin. Prior doses of etoposide and ifosfamide did not effect PBSC yield. CONCLUSIONS: The mobilization technique was well tolerated, and the products obtained produced trilineage engraftment in the patients that underwent peripheral blood stem cell transplantation. Peripheral blood stem cell apheresis in children can be optimized by selection of appropriate candidates and mobilization with G-CSF after an absence of hematopoietic growth factor support.