Long-term outcomes of hematopoietic stem cell transplantation for severe treatment-resistant autoimmune cytopenia in children.

We analyzed the long-term outcomes of pediatric patients registered in the European Group for Blood and Marrow Transplantation database who underwent hematopoietic stem cell transplantation (HSCT) for severe treatment refractory autoimmune cytopenia. With a median follow-up of 100 months, event-free survival was 54% overall, with no significant difference between allogeneic HSCT (n = 15) and autologous HSCT (n = 7) recipients (58% versus 42%; P = .50). Despite a trend toward failure of response or relapse after autologous HSCT compared with allogeneic HSCT, the difference was not significant (43% versus 13%; P = .30). Treatment-related mortality was high in both HSCT groups (29% and 16%; P = .09). Based on the limited numbers of subjects in this retrospective analysis, both allogeneic and autologous HSCT may induce complete and persistent responses in approximately one-half of pediatric patients with severe refractory autoimmune cytopenia, although treatment-related toxicity is high.

Survival is influenced by approaches to local treatment of Ewing sarcoma within an international randomised controlled trial: analysis of EICESS-92.

BACKGROUND: Two national clinical trial groups, United Kingdom Children's Cancer and Leukaemia Group (CCLG) and the German Paediatric Oncology and Haematology Group (GPOH) together undertook a randomised trial, EICESS-92, which addressed chemotherapy options for Ewing's sarcoma. We sought the causes of unexpected survival differences between the study groups. METHODS: 647 patients were randomised. Cox regression analyses were used to compare event-free survival (EFS) and overall survival (OS) between the two study groups. RESULTS: 5-year EFS rates were 43% (95% CI 36-50%) and 57% (95% CI 52-62) in the CCLG and GPOH patients, respectively; corresponding 5-year OS rates were 52% (95% CI 45-59%) and 66% (95% CI 61-71). CCLG patients were less likely to have both surgery and radiotherapy (18 vs. 59%), and more likely to have a single local therapy modality compared to the GPOH patients (72 vs. 35%). Forty-five percent of GPOH patients had pre-operative radiotherapy compared to 3% of CCLG patients. In the CCLG group local recurrence (either with or without metastases) was the first event in 22% of patients compared with 7% in the GPOH group. After allowing for the effects of age, metastases, primary site, histology and local treatment modality, the risk of an EFS event was 44% greater in the CCLG cohort (95% CI 10-89%, p = 0.009), and the risk of dying was 30% greater, but not statistically significant (95% CI 3-74%, p = 0.08). CONCLUSIONS: Unexpected differences in EFS and OS occurred between two patient cohorts recruited within an international randomised trial. Failure to select or deliver appropriate local treatment modalities for Ewing's sarcoma may compromise chances of cure.Trial registration Supported by Deutsche Krebshilfe (Grants No. DKH M43/92/Jü2 and DKH 70-2551 Jü3), and European Union Biomedicine and Health Programme (Grants No. BMH1-CT92-1341 and BMH4-983956), and Cancer Research United Kingdom. Clinical trial information can be found for the following: NCT0000251.

Comparative expression analysis of Pax3 and Pax7 during mouse myogenesis.

Pax3 and Pax7 are closely related transcription factors involved in the commitment of myogenic precursors in the developing trunk. However, it is not yet clear whether these genes are required for myogenic cell specification in the head and for post-somitic myogensis per se. In part, this uncertainty is due to the scarce information about their normal time course and pattern of expression. Here, we present a systematic immunohistochemical in situ analysis of spatiotemporal characteristics of Pax3 and Pax7 protein expression in comparison to that of MyoD and myogenin in the developing trunk and head muscles. The observed patterns of expression suggest that Pax3 is not involved in myogenesis in the head and its post-somitic expression in the trunk and limb muscles is mostly repressed after stage E13.5. In contrast, Pax7 expression is shared among all striated muscles and exhibits a uniform pattern. Pax7 is expressed only in mononucleated cells that either differentiate into myotubes or later form satellite cells. During development of head muscles, expression of Pax7 follows expression of MyoD and myogenin, implying that Pax7 is not required to induce the initial steps of the myogenic program in the head. In Pax7 homozygous mutants, in which muscle development proceeds normally, expression of Pax3 is indistinguishable from its wild-type pattern (i. e. absent), suggesting that after stage E13.5 myogenesis does not require Pax3 and Pax7. These data challenge the concept that Pax3 and Pax7 determine a persistent lineage of myogenic precursors in pre-natal and post-natal muscle development.

Quality of Survivorship in a Rare Disease: Clinicofunctional Outcome and Physical Activity in an Observational Cohort Study of 618 Long-Term Survivors of Ewing Sarcoma.

Purpose Significantly improved survival rates in patients with Ewing sarcoma have raised interest in accessing the quality of long-term survivorship. In this study, subjective and objective measurement tools, preclassified as physical or mental scores, were used to assess clinicofunctional outcome and physical activity after intensive bone tumor treatment. Methods Long-term outcome of 618 survivors from consecutive Ewing sarcoma trials was assessed by the Toronto Extremity Salvage Score, Short-Form Health Survey (SF-36), Brief Symptom Inventory (BSI), and Rosenberg Self-Esteem Scale questionnaires and by the accelerometric StepWatch 3 Activity Monitor. Prospective measurements were correlated retrospectively with standardized primary trial data. Results were compared with 316 nonrandom healthy peers by using effect sizes ( d). Median observation time was 12.9 years from primary diagnosis (range, 3.7 to 31.2 years). Results Absolute subjective scores were moderate to good for survivors. Compared with control subjects, unfavorable outcome was shown on physical Toronto Extremity Salvage Score, SF-36 Physical Component Summary, and BSI-Somatization scales (| d| ≥ 0.50; P < .01), in contrast to SF-36 Mental Component Summary, BSI-Anxiety, BSI-Depression, and Rosenberg Self-Esteem Scale mental scales (| d| ≤ 0.31). Survivors were less active than control subjects, as demonstrated by a step count difference of 1,742 steps per day ( d = -0.43; P < .01); however, on average, the recommended level for an active lifestyle was achieved (≥ 10,000 steps). Location of pelvic tumor was the major inferior disease-specific prognostic factor in physical scores ( P < .01), whereas nondisease-specific inferior factors in questionnaires were older age and female sex ( P < .01). Conclusion Survivors of Ewing sarcoma apparently returned to a normal life with minor limitations. Observed reductions in physical scores should be a focus in future research to optimize treatment strategies to reduce a negative impact on the quality of survivorship.

Ewing's sarcoma and primitive neuroectodermal tumor of hand and forearm. Experience of the Cooperative Ewing's Sarcoma Study Group.

PURPOSE: Because Ewing's sarcoma (EWS) is extremely rare in the hand and forearm, only limited data are available for planning treatment or predicting prognosis. METHODS: Data of 33 patients with EWS of the forearm or hand who were enrolled in studies of the German Association for Paediatric Oncology/Haematology and the European Intergroup Cooperative Ewing's Sarcoma Study Group were analyzed. Patients received neoadjuvant multi-agent chemotherapy according to the valid protocol. Local treatment consisted of surgery (n=7), radiotherapy (n=7), or a combination of both (n=19). RESULTS: The 5/10-year overall survival rate was 84.1% (95% CI: 71.2-96.9)/74.1% (95% CI: 56.8-91.5), and both 5/10-year event-free survival rate were 71.3% (95% CI: 55.4-87.1). Only one of seven patients with secondary metastases was in remission at the time of analysis. One patient with local recurrence and another with primary metastases died. Altogether, eight of 33 patients died of their disease. The event-free survival rate was 80.6% in patients with good response to chemotherapy and 33.3% in patients with poor response. Surgery in combination with radiotherapy achieved a higher survival rate compared with radiotherapy or surgery alone. One out of two patients with non-wide margins of resection died of disease. CONCLUSIONS: The results demonstrate a remarkably high survival rate for patients with EWS of the hand and forearm.

Ewing's sarcoma family of tumors: current management.

Ewing's sarcoma is the second most frequent primary bone cancer, with approximately 225 new cases diagnosed each year in patients less than 20 years of age in North America. It is one of the pediatric small round blue cell tumors, characterized by strong membrane expression of CD99 in a chain-mail pattern and negativity for lymphoid (CD45), rhabdomyosarcoma (myogenin, desmin, actin) and neuroblastoma (neurofilament protein) markers. Pathognomonic translocations involving the ews gene on chromosome 22 and an ets-type gene, most commonly the fli1 gene on chromosome 11, are implicated in the great majority of cases. Clinical presentation is usually dominated by local bone pain and a mass. Imaging reveals a technetium pyrophosphate avid lesion that, on plain radiograph, is destructive, diaphyseal and classically causes layered periosteal calcification. Magnetic resonance best defines the extent of the lesion. Biopsy should be undertaken by an experienced orthopedic oncologist. Approximately three quarters of patients have initially localized disease. About two thirds survive disease-free. Management, preferably at a specialist center with a multi-disciplinary team, includes both local control-either surgery, radiation or a combination-and systemic chemotherapy. Chemotherapy includes cyclic combinations, incorporating vincristine, doxorubicin, cyclophosphamide, etoposide, ifosfamide and occasionally actinomycin D. Topotecan in combination with cyclophosphamide has shown preliminary activity. Patients with initially metastatic disease fare less well, with about one quarter surviving. Studies incorporating intensive therapy followed by stem cell infusion show no clear benefit. New approaches include anti-angiogenic therapy, particularly since vascular endothelial growth factor is an apparent downstream target of the ews-fli1 oncogene.

Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial.

BACKGROUND: The EUROpean Ewing tumour Working Initiative of National Groups 1999 (EURO-E.W.I.N.G. 99) protocol prescribes six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy for Ewing tumors (ET). Granulocyte-colony stimulating factor (G-CSF) is recommended. Adverse reactions (AR) were evaluated; quality assurance of data collection reviewed. PROCEDURE: Safety data from 4,746 courses of VIDE in 851 patients less than 50 years with ET were collected using a checklist and evaluated using descriptive statistics with sub-groups including gender, age, and tumor volume, analyzed by Wilcoxon and Kruskal-Wallis tests. RESULTS: Myelosuppression and infections were the major AR but with appropriate supportive therapy targeted dose intensity was maintained. Five VIDE-related deaths with three due to sepsis were reported. Renal and cardiac toxicity were reflected by glomerular filtration rate (GFR) <39 ml/min/1.73 m2 in 0.1%, tubular phosphate reabsorption < or = 0.80 in 1.9%, and left ventricular shortening fracture <28% in 2.5% VIDE courses. Statistically significant gender-associated AR concerning hemoglobin and platelets were observed with females > males as were age-associated AR concerning hemoglobin, WBC, platelets, stomatitis, and vomiting with AR decreasing with age, that is, children > adolescents > adults. No association of AR to tumor volume was found. In VIDE courses with and without G-CSF, neutropenia-related fever in 60.8% and 65.8%, and infection in 54.7% and 61.0% courses, respectively, were recorded. CONCLUSIONS: AR under VIDE remained within the expected range. Some AR, for example, hematotoxicity were significantly influenced by age and gender but not by tumor volume. G-CSF did not significantly influence neutropenia-related fever and infection. Solicited safety collection with checklists adequately reflects the burden per course.