MYCN amplification plus 1p36 loss of heterozygosity predicts ultra high risk in bone marrow metastatic neuroblastoma.

BACKGROUND: This study aimed to better understand the prognostic effect of multiple genetic markers and identify more subpopulations at ultra high risk of poor outcome in bone marrow (BM) metastatic neuroblastoma (NB). METHODS: We screened the MYCN, 1p36 and 11q23 loss of heterozygosity (LOH) statuses of 154 patients by interphase fluorescence in situ hybridization of BM cells. The clinical characteristics of patients with the three markers and their associations with prognosis were analysed. RESULTS: MYCN amplification and LOH at 1p36 and 11q23 were identified in 16.2%, 33.1% and 30.5% of patients, respectively. There were strong associations between MYCN amplification and 1p36 LOH as well as 11q23 LOH. Both MYCN amplification and 1p36 LOH were strongly associated with high levels of lactate dehydrogenase (LDH) and neuron-specific enolase, more than 3 metastatic organs, and more events. 11q23 LOH occurred mainly in patients older than 18 months, and those who had high LDH levels. In univariate analysis, patients with MYCN amplification had poorer prognosis than those without. Patients with 1p36 LOH had a 3-year event-free survival (EFS) and overall survival lower than those without. 11q23 LOH was associated with poorer EFS only for patients without MYCN amplification. In a multivariate model, MYCN amplification was independently associated with decreased EFS in all cohorts. 11q23 LOH was an independent prognostic factor for patients without MYCN amplification, whereas 1p36 LOH was not an independent marker regardless of MYCN amplification. Compared with all cohorts, patients with both MYCN amplification and 1p36 LOH had the worst outcome and clinical features. CONCLUSIONS: Patients with both MYCN amplification and 1p36LOH had the worst survival rate, indicating an ultra high-risk group. Our results may be applied in clinical practice for accurate risk stratification in future studies.

Central nervous system relapse in a pediatric anaplastic large cell lymphoma patient with CLTC/ALK translocation treated with alectinib: A case report.

BACKGROUND: The aberrant expression of the anaplastic lymphoma kinase (ALK) gene in ALK-positive (ALK+) anaplastic large cell lymphoma (ALCL) is usually due to t(2;5)/NPM-ALK. However, rarely, aberrant ALK expression can also result from a rearrangement of the ALK gene with various partner genes. Central nervous system (CNS) metastasis is very rare in ALK+ALCL. Patients with CNS involvement show an inferior prognosis. CASE SUMMARY: Here, we present the case of an 8-year-old girl diagnosed with ALK+ALCL. She presented with fever, skin nodules, leg swelling, and abdominal pain over the preceding 6 mo. She had extensive involvement and showed an extraordinary rare translocation, t(2;17)/CLTC-ALK, as demonstrated by RNA-seq. She underwent chemotherapy as per ALCL99, followed by vinblastine (VBL) maintenance treatment, and achieved complete remission. However, she developed CNS relapse during VBL monotherapy. The patient achieved a durable second remission with high-dose chemotherapy (including methotrexate 8 g/m2) and continuous treatment with alectinib and VBL. CONCLUSION: Alectinib showed significant and durable CNS effects in this patient. However, more cases are needed to prove the efficacy and safety of alectinib for pediatric ALK+ALCL patients.

Chromosome band 11q23 deletion predicts poor prognosis in bone marrow metastatic neuroblastoma patients without MYCN amplification.

BACKGROUND: Interphase fluorescence in situ hybridization (FISH) of bone marrow cells has been confirmed to be a direct and valid method to assess the v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) amplification in patients with bone marrow metastatic neuroblastoma. MYCN amplification alone, however, is insufficient for pretreatment risk stratification. Chromosome band 11q23 deletion has recently been included in the risk stratification of neuroblastoma. In the present study, we aimed to evaluate the biological characteristics and prognostic impact of 11q23 deletion and MYCN amplification in patients with bone marrow metastatic neuroblastoma. METHODS: We analyzed the MYCN and 11q23 statuses of 101 patients with bone marrow metastatic neuroblastoma using interphase FISH of bone marrow cells. We specifically compared the biological characteristics and prognostic impact of both aberrations. RESULTS: MYCN amplification and 11q23 deletion were seen in 12 (11.9%) and 40 (39.6%) patients. The two markers were mutually exclusive. MYCN amplification occurred mainly in patients with high lactate dehydrogenase (LDH) and high neuron-specific enolase (NSE) levels (both P < 0.001), and MYCN-amplified patients had more events (tumor relapse, progression, or death) than MYCN-normal patients (P = 0.004). 11q23 deletion was associated only with age (P = 0.001). Patients with MYCN amplification had poorer outcomes than those with normal MYCN (3-year event-free survival [EFS] rate: 8.3 ± 8.0% vs. 43.8 ± 8.5%, P < 0.001; 3-year overall survival [OS] rate: 10.4 ± 9.7% vs. 63.5% ± 5.7%, P < 0.001). 11q23 deletion reflected a poor prognosis only for patients with normal MYCN (3-year EFS rate: 34.3 ± 9.5% vs. 53.4 ± 10.3%, P = 0.037; 3-year OS rate: 42.9 ± 10.4% vs. 75.9 ± 6.1%, P = 0.048). Those with both MYCN amplification and 11q23 deletion had the worst outcome (P < 0.001). CONCLUSIONS: Chromosome band 11q23 deletion predicts poor prognosis only in bone marrow metastatic neuroblastoma patients without MYCN amplification. Combined assessment of the two markers was much superior to single-marker assessment in recognizing the patients at a high risk of disease progression.

Serum Interleukin-6 Level and the rs1800795 Polymorphism in its Gene Associated with Neuroblastoma Risk in Chinese Children.

BACKGROUND: The pro-inflammatory cytokine, interleukin-6 (IL-6), stimulates the metastasis of several neoplasms. An association of its serum level and the single nucleotide polymorphism (SNP) rs1800795 with neuroblastoma (NB) has been reported in American and Italian cohorts. This study was to clarify whether the same association exists in Chinese children. METHODS: A total of 130 NB patients, with 77 boys (59%), 53 girls (41%), mean age 41 ± 5 months, were assigned to two groups: high risk (HR) versus intermediate-low risk (non-HR), and 50 healthy children were randomly selected as the age- and gender-matched controls. Peripheral blood samples were analyzed to determine serum IL-6 level using enzyme linked immunosorbent assay and rs1800795 SNPs phenotype using polymerase chain reaction and gene sequencing. RESULTS: There were 87 NB patients in the HR group and 43 NB patients in the non-HR group. A comparison of allele and genotype frequencies of the rs1800795 polymorphism between patients and controls found no association with NB risk (P > 0.05). The frequency of GG+GC genotype was higher in HR-NB patients than in non-HR-NB patients (64.4% vs. 48.8%, P = 0.02), and serum IL-6 level was much higher in HR-NB patients with GG+GC genotype than in HR-NB patients with CC genotype (4.36 ± 1.1 pg/ml vs. 1.83 ± 0.5 pg/ml; P = 0.02), but not in Non-HR-NB patients. CONCLUSIONS: The polymorphism rs1800795 is associated with serum IL-6 level and level of NB risk. GG genotype might indicate that the tumor is highly malignant (prone to metastasis) and associated with poor prognosis.

MYCN amplification predicts poor prognosis based on interphase fluorescence in situ hybridization analysis of bone marrow cells in bone marrow metastases of neuroblastoma.

BACKGROUND: MYCN gene amplification is related to risk stratification. Therefore it is important to identify accurately the level of the MYCN gene as early as possible in neuroblastoma (NB); however, for patients with bone marrow (BM) metastasis who need chemotherapy before surgery, timely detection of the MYCN gene is not possible due to the unavailability of primary tumors. METHODS: MYCN gene status was evaluated in 81 BM metastases of NB by interphase fluorescence in situ hybridization (FISH) analysis of BM cells. The clinicobiological characteristics and prognostic impact of MYCN amplification in NB metastatic to BM were analyzed. RESULTS: MYCN amplification was found in 16% of patients with metastases, and the results were consistent with the primary tumors detected by pathological tissue FISH. MYCN amplification was associated with age, lactate dehydrogenase (LDH) levels and prognosis (P = 0.038, P < 0.001, P = 0.026). Clinical outcome was poorer in patients with MYCN amplification than in those without amplification (3-year EFS 28.8 ± 13.1 vs. 69.7 ± 5.7%, P = 0.005; 3-year OS 41.5 ± 14.7 vs. 76.7 ± 5.5%, P = 0.005). CONCLUSIONS: MYCN amplification predicts a poor outcome in NB metastatic to BM, and interphase FISH of bone marrow cells provides a timely direct and valid method to evaluate the MYCN gene status.

[Allogeneic stem cell transplantation for 8 patients with malignant infantile osteopetrosis in China].

OBJECTIVE: Osteopetrosis is a rare genetic disorder and the malignant infantile osteopetrosis (MIOP) is the worst subtype of this disease. Seventy percent of patients die in six years of life without proper treatment. Hematopoietic stem cell transplantation (HSCT) offers the only chance of cure for MIOP. METHOD: Retrospective analysis was performed on 8 patients with MIOP who underwent HSCT in Beijing Children's Hospital during the period from 2006 to 2011. RESULT: Eight cases (4 male and 4 female, mean age at HSCT 13.5 months) were diagnosed as malignant infantile osteopetrosis. Conditioning regimen included fludarabine, busulfan and cyclophosphamide. All patients received cyclosporin for prophylaxis of graft vs. host disease (GvHD). A UMD recipient underwent CD34(+) cell selection. ATG/ALG, mycophenolate mofetil (MMF) and methotrexate (MTX) used for recipients with unrelated cord donor (2) and recipients with haplo-identical donors (5). Average time for neutrophil engraftment was 15.7 day (9 - 36), platelet engraftment was 43.3 day (10 - 68). The patients were followed up from 47 days to 5 years, 1 patient died of post-transplant complications. Seven cases presented better in clinical manifestation. Acute GvHD I°-II° was observed in 6 patients, III°-IV° in 2 patients. It was controlled by anti-GvHD therapy. CONCLUSION: Non-allogenic stem cell transplantation treatment of infantile MIOP showed high survival rate and restoration of hematopoiesis in haploid transplant patients, therefore, non-allogenic HSCT may be an option to treat MIOP in children.