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.

High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis.

PURPOSE: To determine whether consolidation therapy with high-dose melphalan, etoposide, and total-body irradiation (TBI) with autologous stem-cell support would improve the prognosis for patients with newly diagnosed metastatic Ewing's sarcoma (ES). PATIENTS AND METHODS: Thirty-two eligible patients with newly diagnosed ES metastatic to bone and/or bone marrow were enrolled onto this study. Treatment was initially comprised of five cycles of induction chemotherapy (cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide) and local control. Peripheral-blood stem-cell collection was performed after the second cycle of chemotherapy, with delay if the bone marrow was persistently involved. If patients had a good response to initial therapy, they proceeded to consolidation therapy with melphalan, etoposide, TBI, and stem-cell support. RESULTS: Of the 32 eligible patients, 23 proceeded to high-dose therapy consolidation. Of the nine patients who did not proceed to consolidation, four were secondary to progressive disease and two were secondary to toxicity. Three patients died from toxicity during the high-dose phase of the therapy. The majority of the patients who underwent high-dose consolidation therapy experienced relapse and died with progressive disease. Two-year event-free survival (EFS) for all eligible patients is 20%. The 2-year post-stem-cell reconstitution EFS for the subset of 23 patients who received consolidation therapy is 24%. Analysis of peripheral-blood stem-cell collections by molecular techniques for minimal residual disease showed contamination of at least some samples by tumor cells in all three patients with available data. CONCLUSION: Consolidation with high-dose melphalan, etoposide, TBI, and autologous stem-cell support failed to improve the probability of EFS in this cohort of patients with newly diagnosed metastatic ES.

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.

Possible association of retinoic acid with bone marrow transplant nephropathy.

Bone marrow transplant (BMT) nephropathy is characterized by the acute onset of nephritis more than 100 days after BMT. The renal lesion in BMT nephropathy is similar to radiation nephritis, but BMT nephropathy occurs earlier and with lower radiation doses than radiation nephritis. The combined effects of chemotherapeutic agents and nephrotoxic drugs given before and after BMT appear to sensitize or unmask radiation nephritis. Reporting of drugs that may contribute to BMT nephropathy is critical for the development of optimal treatment regimens. Herein, we report two cases of BMT nephropathy that developed coincident with retinoic acid therapy. Both patients received autologous BMT for neuroblastoma after preparative therapy with total body irradiation/melphalan/carboplatin/etoposide. They were randomized to receive cis-retinoic acid as part of a clinical trial. Both patients developed acute nephritis during their second 2-week course of retinoic acid on post-BMT days 105 and day 139. The nephritis was associated with hypertension, anemia, thrombocytopenia, azotemia, hematuria, and proteinuria. Clinical features, laboratory evaluation, and renal biopsy indicated that these two patients developed radiation-induced BMT nephropathy. The fact that both patients developed nephritis concurrent with retinoic acid therapy raises a concern that retinoic acid may have unmasked radiation injury and triggered BMT nephropathy.

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.

Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors.

PURPOSE: To evaluate a strategy that avoids radiotherapy in children less than 6 years of age with newly diagnosed malignant brain tumors, by administering myeloablative consolidation chemotherapy with autologous bone marrow reconstitution (ABMR) after maximal surgical resection and conventional induction chemotherapy. PATIENTS AND METHODS: Between March 1991 and April 1995, 62 children (median age, 30 months) with newly diagnosed malignant brain tumors were enrolled onto this trial. Children received conventional induction chemotherapy with vincristine, cisplatin, cyclophosphamide, and etoposide, repeated every 3 weeks for five cycles. Children without disease progression on induction chemotherapy were offered consolidation with myeloablative chemotherapy that incorporated carboplatin, thiotepa, and etoposide followed by ABMR. Irradiation was used only for residual tumor at consolidation or for progressive/recurrent disease. RESULTS: Induction chemotherapy was well tolerated by most patients; however, progression was noted in 17 children (27%) and four (6%) died of treatment complications. Of 37 children who received consolidation chemotherapy with ABMR, 15 are free of disease progression (median post-ABMR without further treatment, >44 months). The remaining 22 all progressed within 15 months of ABMR; three of 37 (8%) died of treatment-related complications. The 3-year overall survival (OS) and event-free survival (EFS) rates from diagnosis for all children are 40% (95% confidence interval [CI], 28% to 52%) and 25% (95% CI, 13% to 37%), respectively. Radiotherapy was administered to 19 of 62 children: 17 for progressive disease (PD) and two for residual disease at the time of ABMR. CONCLUSION: A significant proportion of children with malignant brain tumors can avoid radiotherapy and prolonged maintenance chemotherapy yet still achieve durable remission with this brief intensive chemotherapy regimen.

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.

The National Cancer Data Base report on patterns of childhood cancers in the United States.

BACKGROUND: Patterns of and progress against childhood cancer have been reported on multi-institution, regional, national, and international bases by several sources in the past. These sources have included clinical cooperative group trials and population-based registries. In general, the population-based surveys have excluded brain tumors of either benign or uncertain behavior. The authors of this article investigated the patterns of data reported for the period 1985-1993, motivated by their interest in assessing the potential of National Cancer Data Base (NCDB) data to 1) facilitate individual institution review and 2) cover institutions that are not members of the Pediatric Oncology Group or the Children's Cancer Group, which are both national clinical cooperative groups. METHODS: Six annual calls for data, starting with a call for 1985 and 1988 cases, were issued to approximately 2100 hospitals with cancer programs (1340 programs approved by the Commission on Cancer of the American College of Surgeons and 760 other programs). The baseline data items of the NCDB included patient demography, tumor characteristics, initial treatment, and follow-up. The data for each patient were coded in the traditional manner by trained cancer registrars before being transmitted to the NCDB in standard format. RESULTS: In the most recent year for which data were reported, the NCDB included 42% of all estimated U.S. childhood cancers. The cases were reported by institutions that were members of the Pediatric Oncology Group and the Children's Cancer Group as well as nonmember institutions. The distribution of diagnostic groups reported to the NCDB was generally similar to that reported to SEER, except for lymphomas and brain cancer (the NCDB series included benign as well as malignant brain tumors). The distribution of diagnostic groups reported to the NCDB did not change over the 9-year reporting period (1985-1993). With regard to ethnicity, the most varied distribution of diagnostic groups was found among African American patients. For many types of cancer, the survival of those patients reported to the NCDB was similar to that of patients included in the SEER population-based series. These cancers included Wilms' tumor (NCDB 89% vs. SEER 88%), non-Hodgkin's lymphoma (NCDB 74% vs. SEER 70%), soft tissue sarcomas (NCDB rhabdomyosarcomas 70% and sarcomas 79% vs. SEER soft tissue sarcomas 71%), and neuroblastoma (NCDB 58% vs. SEER 57%). CONCLUSIONS: The authors concluded that the number of brain tumors of benign and uncertain behavior being diagnosed were significant enough in number that they should be included in regional and national cancer registries that report data for clinical purposes. They further concluded that for reasons of data inclusion and institutional coverage, the NCDB will be an important data base for pediatric cancers that will warrant increased use by pediatric investigators.

Unrelated donor bone marrow transplants in children.

Only a small proportion of children who might benefit from bone marrow transplant (BMT) have an HLA-identical sibling. To provide this potentially curative therapy to patients without a matched related donor, marrow transplants using less well matched related donors or unrelated donors (identified through computerized donor registries) have been performed. We report the outcome of 24 consecutive unrelated donor BMT's performed on children. Eligible diagnosis included acute leukemia (AL) (n = 15), chronic myelogenous leukemia (CML) (n = 4), myelodysplastic syndrome (MDS) (n = 3), and severe aplastic anemia (SAA) (n = 2). All donor/recipient pairs were sero-matched at 5 or 6 of the 6 HLA A, B, and DR antigens. Several different preparative regimens were used, but fractionated total body irradiation (TBI) was used in 20 patients. All recipients received graft-versus-host-disease (GVHD) prophylaxis with cyclosporine-A (CSA), four with short course methotrexate (MTX), 14 in combination with short course MTX and methylprednisolone (MPS), and five in combination with a mouse monoclonal antibody to CD5, coupled to the A-chain of ricin (Xomazyme-65). One patient received CSA and MPS alone after a T-cell depleted marrow transplant. Twenty of 23 evaluable recipients engrafted (87%). Two patients with CML never engrafted and had autologous marrow recovery, one patient with SAA died at 128 days without evidence of engraftment, and there was one early death at day + 9. Fourteen of 20 patients (70%) with stable donor-derived hematopoiesis developed significant acute GVHD > or = grade II). Eleven of 15 engrafted patients who survived > 100 days after BMT developed chronic GVHD (73%).(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of human myelopoiesis by human gangliosides.

Cell surface gangliosides are potent modulators of cellular proliferation. We hypothesize that gangliosides shed by tumor cells modulate hematopoiesis and contribute to human tumor-associated suppression of hematopoiesis. To test this hypothesis, we determined the effects on myeloid colony formation by human bone marrow mononuclear cells of total gangliosides isolated from human brain and of seven highly purified individual ganglioside species (GM1, GM2, GD1a, GD1b, GD2, GD3, and GT1b). Total human brain gangliosides and certain individual species, GD1a, GD1b, and GT1b, significantly inhibited myeloid colony formation (number as well as size). The most complex molecules, GD1a, GD1b, and GT1b, were the most inhibitory, suggesting that the degree of inhibition is related to ganglioside structural complexity. To extend these findings, we also investigated certain tumor-derived (neuroblastoma) gangliosides, which we found inhibited both myeloid colony formation and 3H-thymidine incorporation by human bone marrow mononuclear cells. These data suggest a role for gangliosides, which are shed by proliferating cells, in the regulation of human hematopoiesis and may explain the bone marrow hypoplasia observed in association with many human malignancies.

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.