Age dependency of primary tumor sites and metastases in patients with Ewing sarcoma.

BACKGROUND: The median age of patients with Ewing sarcoma (EwS) at diagnosis is around 14-15 years. Older age is associated with a worse outcome. The correlation of age at diagnosis on sites of disease has not been fully described. OBJECTIVE: The goal of this study was to evaluate the differences in sites of primary tumor and metastatic tumor involvement according to age groups. DESIGN/METHOD: EwS data from the Gesellschaft für Pädiatrische Onkologie und Hämatology (GPOH) database of the Cooperative Ewing Sarcoma Study (CESS) 81/86 and the European Intergroup Cooperative Ewing's Sarcoma Study EICESS 92 and the EUROpean Ewing tumor Working Initiative of National Groups-99-Protocol (EURO-E.W.I.N.G.-99) study were analyzed. Patient and tumor characteristics were evaluated statistically using chi square tests. RESULTS: The study population included 2,635 patients with bone EwS. Sites of primary and metastatic tumors differed according to the age groups of young children (0-9 years), early adolescence (10-14 years), late adolescence (15-19 years), young adults (20-24 years), and adults (more than 24 years). Young children demonstrated the most striking differences in site of disease with a lower proportion of pelvic primary and axial tumors. They presented less often with metastatic disease at diagnosis. CONCLUSIONS: Site of primary and metastatic tumor involvement in EwS differs according to patient age. The biological and developmental etiology for these differences requires further investigations.

Impact of Fc gamma-receptor polymorphisms on the response to rituximab treatment in children and adolescents with mature B cell lymphoma/leukemia.

Recent studies in adult lymphoma patients have indicated a correlation between polymorphisms of Fc gamma-receptors (FcγRs, encoded by the respective FCGR genes) and the response to rituximab treatment. In vitro, cells expressing FcγRIIIa-158V mediate antibody-dependent cellular cytotoxicity (ADCC) more efficiently than cells expressing FcγRIIIa-158F. The impact of the FCGR2A-131HR polymorphism is unclear. In this study, the FCGR polymorphisms FCGR3A-158VF and FCGR2A-131HR were analyzed in pediatric patients with mature aggressive B cell non-Hodgkin lymphoma/leukemia (B-NHL). Pediatric patients received a single dose of rituximab monotherapy. Response was evaluated on day 5 followed by standard chemotherapy for B-NHL. Among 105 evaluable patients, a response to rituximab was observed in 21 % of those homozygous for FcγRIIa-131RR (5/24) compared to 48 % of patients who were HH and HR FcγRIIa-131 allele carriers (18/34 and 21/47, respectively; p = 0.044). Among patients with the FCGR3A-158 polymorphism, those homozygous for the FF genotype had a significantly favorable rituximab response rate of 59 % (22/37) compared to 32 % in patients who were FcγRIIIa-158VV and FcγRIIIa-VF allele carriers (2/9 and 20/59, respectively; p = 0.022). A stringent phase II response evaluation of children and adolescents with B-NHL after one dose of rituximab monotherapy showed a significant association between the rituximab response rate and FCGR polymorphisms. These findings support the hypothesis that FCGR polymorphisms represent patient-specific parameters that influence the response to rituximab.

Immunreconstitution and infectious complications after rituximab treatment in children and adolescents: what do we know and what can we learn from adults?

Rituximab, an anti CD20 monoclonal antibody, is widely used in the treatment of B-cell malignancies in adults and increasingly in pediatric patients. By depleting B-cells, rituximab interferes with humoral immunity. This review provides a comprehensive overview of immune reconstitution and infectious complications after rituximab treatment in children and adolescents. Immune reconstitution starts usually after six months with recovery to normal between nine to twelve months. Extended rituximab treatment results in a prolonged recovery of B-cells without an increase of clinically relevant infections. The kinetic of B-cell recovery is influenced by the concomitant chemotherapy and the underlying disease. Intensive B-NHL treatment such as high-dose chemotherapy followed by rituximab bears a risk for prolonged hypogammaglobulinemia. Overall transient alteration of immune reconstitution and infections after rituximab treatment are acceptable for children and adolescent without significant differences compared to adults. However, age related disparities in the kinetic of immune reconstitution and the definitive role of rituximab in the treatment for children and adolescents with B-cell malignancies need to be evaluated in prospective controlled clinical trials.

Mature B-cell lymphoma and leukemia in children and adolescents-review of standard chemotherapy regimen and perspectives.

Mature B-cell non-Hodgkin lymphoma (B-NHL) comprises more than 50% of all non-Hodgkin lymphoma (NHL) in children and adolescents. Many B-NHL subtypes frequently observed in adults are rarely diagnosed in children and adolescents. In this age group, Burkitt lymphoma (BL), Burkitt leukemia or FAB L3 leukemia (B-AL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMLBL), follicular lymphoma (FL), and aggressive mature B-NHL not further classifiable (B-NHL nfc) are the most common subtypes. Diverse clinical trials demonstrated similar results of current combination chemotherapy regimens succeeding in overall survival rates of more than 80%. However, treatment-related toxicity and the poor prognosis of relapse are serious concerns. Furthermore, specific histological B-NHL subtypes are rare in children and optimal treatment is not established. New treatment modalities are urgently needed for these patient groups. Rituximab, a monoclonal antibody that is already established in the treatment of adults with mature B-NHL, demonstrated promising results in pediatric patients. The definitive role of rituximab in the treatment of children and adolescents with B-NHL needs to be evaluated in prospective controlled clinical trials. This review provides a comprehensive overview of chemotherapy regimens and the perspectives for children and adolescents with mature B-cell lymphoma and leukemia.

SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease.

BACKGROUND: We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s). METHODS: Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy. RESULTS: Patients with localized germinoma (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 ± 0.02 vs 0.88 ± 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 ± 0.023 event-free and overall survival. CONCLUSIONS: Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease.

Clinical features and outcomes in patients with extraskeletal Ewing sarcoma.

BACKGROUND: Ewing sarcoma can arise in either bone or soft tissue. The purpose of this study was to investigate whether patient characteristics, treatment strategies, and outcomes differ between skeletal Ewing sarcoma and extraskeletal Ewing sarcoma (EES). METHODS: Patients <40 years of age with Ewing sarcoma or peripheral primitive neuroectodermal tumor reported to the United States Surveillance, Epidemiology, and End Results Program database from 1973 to 2007 were evaluated based on skeletal (n = 1519) versus extraskeletal (n = 683) site of origin. Patient characteristics were compared using Fisher exact tests. Overall survival was estimated via the Kaplan-Meier method and compared using log-rank tests and Cox proportional hazard models. RESULTS: Patients with EES had a higher mean age (19.5 vs 16.3 years; P < .001) and were less likely to be male (53.4% vs 63.3%; P < .001) or white (84.8% vs 92.5%; P < .001) compared with patients with skeletal tumors. Extraskeletal tumors were more likely to arise in axial locations (72.9% vs 54.2%; P = .001) but were less likely to arise specifically in the pelvis (19.8% vs 26.6%; P < .001). Metastatic status or tumor size did not differ by group. Five-year overall survival was superior for localized EES compared with localized skeletal tumors (69.7% vs 62.6%; P = .02). The hazard ratio for death in patients with localized skeletal tumors compared with localized EES was 2.36 (95% confidence interval, 1.61-3.44) beyond 24 months from initial diagnosis. CONCLUSIONS: Patient characteristics and outcomes differ among patients with EES compared with patients with skeletal Ewing sarcoma. These findings may have important implications for patient care.

Racial differences in the incidence of mesenchymal tumors associated with EWSR1 translocation.

BACKGROUND: The incidence of Ewing sarcoma varies by race, with very low rates among persons of African and East Asian ancestry. The incidence by race of other mesenchymal tumors that also harbor EWSR1 translocations has not been studied. METHODS: The SEER database was queried to find cases of mesenchymal tumors associated with EWSR1 translocations: Ewing sarcoma; clear cell sarcoma; extraskeletal myxoid chondrosarcoma; myxoid liposarcoma; desmoplastic small round cell tumor; and myoepithelial tumor. Age-adjusted incidence rates were calculated for white, African American, and Asian/Native American populations and compared statistically. RESULTS: Ewing sarcoma was significantly less common in the African American and Asian/Native American populations compared with the white population, with incidence rate ratios of 0.12 (95% CI, 0.08-0.20; P<0.001) and 0.54 (95% CI, 0.41-0.69; P<0.001), respectively. Desmoplastic small round cell tumor was significantly more common in the African American population compared with the white population (incidence rate ratio=3.0; 95% CI, 1.62-5.49; P<0.001). Myxoid liposarcoma was significantly less common in the Asian/Native American population compared with the white population (incidence rate ratio=0.72; 95% CI, 0.56-0.92; P=0.006). The incidence rates for extraskeletal myxoid chondrosarcoma, myoepithelial tumors, and clear cell sarcoma did not differ significantly by race. CONCLUSIONS: Tumors associated with EWSR1 translocation are not uniformly more common in people of European ancestry. IMPACT: The relationship between race and EWSR1 somatic translocation is complex. Future studies investigating the genetic epidemiology of EWSR1 translocated tumors are required.

Life-threatening hypersplenism due to idiopathic portal hypertension in early childhood: case report and review of the literature.

BACKGROUND: Idiopathic portal hypertension (IPH) is a disorder of unknown etiology and is characterized clinically by portal hypertension, splenomegaly, and hypersplenism accompanied by pancytopenia. This study evaluates the pathogenic concept of the disease by a systematic review of the literature and illustrates novel pathologic and laboratory findings. CASE PRESENTATION: We report the first case of uncontrolled splenic hyperperfusion and enlargement with subsequent hypersplenism leading to life-threatening complications of IPH in infancy and emergent splenectomy. CONCLUSIONS: Our results suggest that splenic NO and VCAM-1, rather than ET-1, have a significant impact on the development of IPH, even at a very early stage of disease. The success of surgical interventions targeting the splenic hyperperfusion suggests that the primary defect in the regulation of splenic blood flow seems to be crucial for the development of IPH. Thus, beside other treatment options splenectomy needs to be considered as a prime therapeutic option for IPH.

Osteosarcoma in children 5 years of age or younger at initial diagnosis.

BACKGROUND: Since osteosarcoma is extremely rare in children < or =5 years of age, we sought to investigate if tumor characteristics, treatment strategies, and outcomes differ compared to older patients. PROCEDURE: Patients <20 years of age with high-grade osteosarcoma reported to national SEER database from 1973 to 2006 were separated into two groups based on age at diagnosis: < or =5 years (n = 49) and 6-19 years (n = 1,687). Patient, tumor, and treatment characteristics were compared using Fisher exact tests. Overall survival was estimated by Kaplan-Meier methods and compared using log-rank tests and Cox models. RESULTS: Patients < or =5 years had higher proportions of osteosarcoma arising from the upper limb compared to older patients (24.5% vs. 11.2%; P = 0.006). These very young patients had a significantly higher proportion of telangiectatic histology (10.2% vs. 2.9%; P = 0.017). Sex, metastatic status, race, or ethnicity did not differ by age. A higher proportion of very young patients was treated with amputation (55.2% vs. 27.3%; P = 0.002). Five-year overall survival was inferior for patients with localized osteosarcoma 5 years of age or younger compared to older children (51.9% vs. 67.3%; P = 0.03). After controlling for metastatic status, year of diagnosis, and tumor site, the hazard ratio for death in very young patients was 1.6 (95% confidence interval 1.02-2.36; P = 0.04) compared to older patients. CONCLUSIONS: Tumor characteristics, treatment, and outcomes differ among children < or =5 years of age compared to older pediatric patients. These differences may reflect differences in tumor biology.

Ethnic and racial differences in patients with Ewing sarcoma.

BACKGROUND: Ewing sarcoma (ES) was a malignant tumor of bone or soft tissue. One of the few risk factors for developing ES is race, with a higher incidence noted in populations of European rather than African or Asian ancestry. The goal of the current study was to evaluate racial and ethnic differences in presentation and overall survival (OS) among patients diagnosed with ES before age 40 years. METHODS: Data from the Surveillance, Epidemiology, and End Results database identified 1715 patients aged <40 years who were diagnosed with ES between 1973 and 2005. Racial and ethnic group differences were compared using chi-square tests. OS was estimated by Kaplan-Meier analysis and compared using log-rank tests and Cox models. RESULTS: Black patients had significantly more soft-tissue tumors compared with white non-Hispanic patients (P <.0001). Asian and white Hispanic patients were found to have an intermediate frequency of soft-tissue tumors that also differed from white non-Hispanic patients (P <.0001). White Hispanic patients presented with a higher proportion of larger tumors compared with white non-Hispanic patients (P = .042). Black patients tended to be older than white non-Hispanic patients (P = .012). Sex, frequency of pelvic tumors, and metastatic status did not appear to differ by ethnicity or race. OS was found to differ according to race and ethnicity. Even after controlling for known confounders, OS was significantly worse for black, Asian, and white Hispanic patients compared with white non-Hispanic patients (P = .0031, P = .0182, and P = .0051, respectively). CONCLUSIONS: Ethnic and racial differences in characteristics and outcomes of patients with ES do exist. Understanding the etiology of these differences will require further study.

Presentation of acute promyelocytic leukemia as granulocytic sarcoma.

Granulocytic sarcoma (GS) is a localized tumor composed of immature myeloid cells. This extramedullary tumor can present before, concurrent with or after the diagnosis of acute myeloid leukemia. GS is extremely uncommon in acute promyelocytic leukemia (APL). As a proportion of patients never develop systemic disease, correct and timely diagnosis may be rather difficult, but is a prerequisite for optimal outcome. GS should be considered in the differential diagnosis of children with unusual bone lesions. We describe a patient with GS who presented with symptoms mimicking osteomyelytis or rheumatoid disease.

The serine-threonine kinase MNK1 is post-translationally stabilized by PML-RARalpha and regulates differentiation of hematopoietic cells.

Microarray analyses were performed to identify target genes that are shared by the acute myeloid leukemia (AML) translocation products PML-RARalpha, PLZF-RARalpha and AML1-ETO in inducibly transfected U937 cell lines. The cytoplasmic serine and threonine kinase MNK1 was identified as one of the target genes. At the protein level, MNK1 was significantly induced by each of the three fusion proteins. Protein half-life analyses showed that PML-RARalpha enhanced MNK1 protein stability in U937 cells and ATRA exposure decreased MNK1 half-life in NB4 cells. EIF4E, the main MNK1 substrate, plays a role in the pathogenesis of a variety of cancers. Upon MNK1 overexpression, eIF4E phosphorylation increased as a sign of functional activation. Interestingly, MNK1 protein expression decreased during myeloid differentiation. Inhibition of MNK1 activity by a specific inhibitor (CGP57380) enhanced differentiation of HL60 and 32D cells, further suggesting a role for MNK1 in the myeloid differentiation. In addition, kinase dead mutants of MNK1 significantly impaired proliferation of 32D cells. Immunohistochemistry of primary AML bone marrow biopsies showed strong cytoplasmic MNK1 expression in 25 of 99 AML specimens (25%). MNK1 expression was associated with high levels of c-myc expression. Taken together, we identified MNK1 as a target gene of several leukemogenic fusion proteins in AML. MNK1 plays a role in myeloid differentiation. These data suggest a role for MNK1 in the AML fusion protein-associated differentiation block.