[Molecular subgrouping and characterization analysis of medulloblastomas in a cohort of Japanese patients].

Medulloblastoma is the most common solid malignancy and cause of oncologic death among children. Recent advances in genomic analysis obtained through international large-scale collaborations, Medulloblastoma Advanced Genomics International Consortium(MAGIC), have revealed that medulloblastomas can be classified into at least four distinct subgroups depending on their molecular expression profiles. These studies showed that the prognosis, age distributions, and molecular mechanisms of these subgroups of medulloblastomas completely differ from each other. Here we report the first analysis of molecular subgroups of medulloblastoma in Japanese patients(Shizuoka cohort). Molecular subgroups were predicted for 18 medulloblastomas;and age distributions, radiographic features, and histological characteristics were analyzed. It was predicted that 11% of the medulloblastomas were of the WNT type, 50% of the SHH type, 6% of the group 3 type, and 33% of the group 4 type. The percentage of group 3 type medulloblastomas was smaller than in the MAGIC study, while the percentage of the SHH type was larger. However, age distribution, recurrence-free survival, and overall survival for each group were quite similar to the MAGIC study. In addition, in an imaging study, 78% of patients with medulloblastomas of the SHH type presented tumors in the cerebellar hemispheres. The classical pathohistological hallmarks that may predict medulloblastoma prognosis were mainly seen in tumors of the SHH type. Molecular subgrouping of medulloblastomas could be important in the future, not only for prediction of prognosis, but also for decision making regarding the use of future new treatments such as molecular targeting therapy. The establishment of a public molecular analysis system of medulloblastomas in Japan is greatly desired, and it is currently under development;this database will help establish the molecular diagnosis of medulloblastomas in Japan.

Identification of therapy-sensitive and therapy-resistant neuroblastoma subtypes in stages III, IVs and IV.

The aim was to present a new model of risk stratification with high predictive sensitivity for non-localized neuroblastomas (NBs). "MYCN amplification", "unfavorable histology of the International Neuroblastoma Pathology Classification (INPC) system" and "low Ha-ras/trk A expression" could be defined as an independent predictor for high-risk NBs. A risk stratification flow chart was applied to 103 advanced NBs in which all three factors were examined and 69 were grouped as high-risk NBs of which 38 patients died. The predictive sensitivity for poor patient outcome was 86%, which included 38 of the 44 total deaths in this analysis. Using the number of the three independent risk factors in each tumor, the 69 high-risk NBs were classified into three subgroups. NBs with the three risk factors (triple risk) represented the most aggressive character and survival of the affected patients was only 10% ("therapy-resistant NBs"). Survivals of the patients with NBs possessed the two (double) risk factors or the one (single) risk factor were 29% and 66%, respectively. This stratification also elucidated a subgroup in which patient survival was 90% ("therapy-sensitive"). There were 21 NBs with "high Ha-ras/trk A expression", "favorable INPC histology" and "unamplified MYCN" (no risk NBs). Among the four subgroups without a risk factor, with a single risk factor, with double risk and with triple risk, Kaplan-Meier analysis showed a significant difference in NB patient outcome (p<0.0001). Risk stratification might improve the therapeutic efficacy for the high-risk NBs and might decrease therapy-related sequelae in the lower risk NBs.

Results for 79 patients with neuroblastoma detected through mass screening at 6 months of age in a single institute.

BACKGROUND: In Japan, mass screening for neuroblastoma has been performed at 6 months of age to improve the prognosis of this condition for more than 20 years. In recent years, most neuroblastomas detected by mass screening were considered to have favorable biological features and sometimes tend to regress spontaneously. METHODS: The authors established non-treated observation criteria in 1997 and criteria for observation of residual tumor after first-line chemotherapy in 1999, and have made an effort to reduce the intensity of medical treatment for neuroblastoma. The authors examined outcomes of 79 patients who were found in the Shizuoka neuroblastoma mass screening at 6 months of age and who received medical treatment or underwent observation in Shizuoka Children's Hospital, Shizuoka, Japan, between December 1981 and December 2004. RESULTS: A total of 77 patients survived but the remaining two patients died from complications of medical treatment. None of the patients died due to progression of neuroblastoma. In the cases, non-treated observation was performed in 17. Of those, 12 patients are now under non-treated observation. Of their tumors, two have disappeared, nine have become smaller and another one has not change in size. Observation of residual tumor after first-line chemotherapy was performed in 15 cases, and three disappeared and the other 12 cases became smaller. Medical treatment-related complications were observed in 20 of 67 patients who received medical treatment, and 18 of the 20 patients were seen before establishing non-treated observation criteria. CONCLUSION: Non-treated observation and observation of residual tumor after first-line chemotherapy were useful to reduce medical treatment-related complications.

Spontaneous regression of metastases including meningeal metastasis after gross resection of primary tumor in an infant with stage 4 neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor in childhood. Spontaneous regression has been well described in infants, especially in those with stage 4S and those with low-stage neuroblastoma detected by screening. However, neuroblastoma presenting with intracranial metastasis is generally considered to need a postoperative chemotherapy. Here, we report a 3-month-old girl with stage 4 neuroblastoma presenting with spontaneous regression of metastatic tumor including meningeal metastasis after gross resection of primary tumor. Further investigation may be required to detect patients of this kind without the need of postoperative chemotherapy regardless of their stage at diagnosis.

Diversity in neuroblastomas and discrimination of the risk to progress.

The clinical diversity of Neuroblastomas (NBs) was discriminated into three groups with high sensitivity and specificity to patient's outcome. The 'high risk' NB is defined with any of following conditions, MYCN amplification or unfavorable histology of International Neuroblastoma Pathological Classification (INPC) or low Ha-ras/trk A expression. The 'low risk' NB is defined with all following conditions, single copy of MYCN and INPC favorable histology and high Ha-ras/trk A expression and localized tumor. The remaining NBs were classified into 'intermediate risk' ones. According to these criteria, the diversity of the 248 mass-screening NBs was shown with variety progressive risk; 40% were classified in low risk group, 25% were in high risk group and 35% were in intermediate risk group.