ABSTRACT
OBJECTIVE: To study the risk factors for the development of moyamoya syndrome after cranial irradiation for primary brain tumors in children. METHODS: We reviewed neuroimaging studies and dosimetry data for 456 children who were treated with radiation for a primary brain tumor and who were prospectively evaluated with serial neuroimaging studies and neurologic evaluations. A total of 345 patients had both adequate neuroimaging and radiation dosimetry data for further analysis. We used survival analysis techniques to examine the relationship of clinically important variables as risk factors for the development of moyamoya over time. RESULTS: Overall, 12 patients (3.5%) developed evidence of moyamoya. The onset of moyamoya was more rapid for patients with neurofibromatosis type 1 (NF1) (median of 38 vs 55 months) and for patients who received >5,000 cGy of radiation (median of 42 vs 67 months). In a multiple Cox proportional hazards regression analysis controlling for age at start of radiation, each 100-cGy increase in radiation dose increased the rate of moyamoya by 7% (hazard ratio [HR] = 1.07, 95% CI: 1.02 to 1.13, p = 0.01) and the presence of NF1 increased the rate of moyamoya threefold (HR = 3.07, 95% CI: 0.90 to 10.46, p = 0.07). CONCLUSIONS: Moyamoya syndrome is a potentially serious complication of cranial irradiation in children, particularly for those patients with tumors in close proximity to the circle of Willis, such as optic pathway glioma. Patients who received higher doses of radiation to the circle of Willis and with neurofibromatosis type 1 have increased risk of the development of moyamoya syndrome.
Subject(s)
Brain Neoplasms/radiotherapy , Cerebral Arteries/radiation effects , Moyamoya Disease/epidemiology , Radiation Injuries/epidemiology , Radiotherapy/adverse effects , Boston/epidemiology , Cerebral Arteries/pathology , Cerebral Arteries/physiopathology , Child , Child, Preschool , Circle of Willis/pathology , Circle of Willis/physiopathology , Circle of Willis/radiation effects , Comorbidity , Dose-Response Relationship, Radiation , Female , Humans , Incidence , Infant , Male , Neurofibromatosis 1/radiotherapy , Optic Chiasm/pathology , Optic Chiasm/physiopathology , Optic Chiasm/radiation effects , Prospective Studies , Risk Factors , Survival AnalysisABSTRACT
The SSX genes are members of the family of cancer/testis antigens that encode tumor-associated antigens recognizable by autologous cytolytic T lymphocytes. Their expression is common in tumors of diverse lineages and absent in normal tissues except testis and thyroid. In this study, sixty-seven neuroblastomas (NB) (12 stage 1, 13 stage 2, 12 stage 3, 12 stage 4S and 13 stage 4) were examined by RT-PCR and a sensitive chemiluminescent detection method for SSX-2 and SSX-4 expression. Seventy-two percent (13/18) of stage 4 NB expressed SSX-2 and 67% (12/18) expressed SSX-4. SSX-2 and SSX-4 positivity correlated with metastatic NB stage 4 (p=0.02 and p=0.006, respectively). Sensitivity experiments showed SSX-2 detection was one tumor cell in 10(6) normal cells, and one in 10(4) for SSX-4. All normal tissues (n=6), with the exception of testis, normal bone marrow (BM, n=12) and normal peripheral blood (PBL, n=10) were negative for SSX-2 and SSX-4 expression. Thirty-two BM and 14 PBL obtained from 35 stage 4 NB patients at 24 months from their diagnosis were evaluated for SSX-2 expression. Unlike another cancer/testis antigen, GAGE, only one BM sample was positive, and no prognostic utility could be established. Further investigation of SSX expression at other relevant time points is warranted.
Subject(s)
Antigens, Neoplasm/genetics , Biomarkers, Tumor/genetics , Neoplasm Proteins/genetics , Neuroblastoma/metabolism , Repressor Proteins/genetics , Bone Marrow/metabolism , Gene Expression , Humans , Neoplasm Staging , Neuroblastoma/pathology , Reverse Transcriptase Polymerase Chain Reaction , Sensitivity and SpecificityABSTRACT
BACKGROUND: Previously, we reported the utility of GAGE as a molecular marker for neuroblastoma (NB) and malignant melanoma in blood and bone marrow (BM). Among patients with stage III melanoma rendered disease-free by surgery, GAGE expression was a strong prognostic factor for patient survival. PROCEDURE: All patients with advanced NB diagnosed at > 1 year of age initially treated with protocol N6 (n = 24) and N7 (n = 38) at Memorial Sloan-Kettering Cancer Center were included in this study. Their BM cells at 12, 18, and 24 months (median time after diagnosis) were evaluated for the presence of GAGE. RESULTS: GAGE positivity at 12 months (25%), when patients were still on treatment, did not predict progression-free survival (PFS) and overall survival from the time of sampling. Positivity at 18 months (29%) was associated with poorer PFS and survival (but P > 0.05). By 24 months, the presence of GAGE (26%) was a very strong predictor of out-come (P < 0.001). When only remission marrows at 24 months were analyzed, PFS was 4.7-fold lower among GAGE-positive patients. Thirty-seven percent of N6 patients were positive for GAGE, in contrast to 17% of the patients in the more current regimen N7. CONCLUSIONS: The detection of GAGE by RT-PCR in marrow may have utility in molecular staging of patients in clinical remission. It may allow earlier identification of patients at risk, such that appropriate intervention can be given before clinical relapse. GAGE may also serve as a surrogate endpoint for adjuvant treatment strategies, and to determine the duration of therapy.
