Tandem High-Dose Chemotherapy Increases the Risk of Secondary Malignant Neoplasm in Pediatric Solid Tumors.

PURPOSE: This study aimed to investigate the incidence and risk factors for secondary malignant neoplasms (SMN) in pediatric solid tumors, focusing on the effects of tandem high-dose chemotherapy (HDCT). MATERIALS AND METHODS: Patients (aged < 19 years) diagnosed with or treated for pediatric solid tumors between 1994 and 2014 were retrospectively analyzed. The cumulative incidence of SMN was estimated using competing risk methods by considering death as a competing risk. RESULTS: A total of 1,435 patients (413 with brain tumors and 1,022 with extracranial solid tumors) were enrolled. Seventy-one patients developed 74 SMNs, with a 10-year and 20-year cumulative incidence of 2.680±0.002% and 10.193±0.024%, respectively. The types of SMN included carcinoma in 28 (37.8%), sarcoma in 24 (32.4%), and hematologic malignancy in 15 (20.3%) cases. Osteosarcoma and thyroid carcinoma were the most frequently diagnosed tumors. Multivariate analysis showed that radiotherapy (RT) > 2, 340 cGy, and tandem HDCT were significant risk factors for SMN development. The SMN types varied according to the primary tumor type; carcinoma was the most frequent SMN in brain tumors and neuroblastoma, whereas hematologic malignancy and sarcomas developed more frequently in patients with sarcoma and retinoblastoma, respectively. CONCLUSION: The cumulative incidence of SMN in pediatric patients with solid tumors was considerably high, especially in patients who underwent tandem HDCT or in those who received RT > 2,340 cGy. Therefore, the treatment intensity should be optimized based on individual risk assessment and the long-term follow-up of pediatric cancer survivors.

Postchemotherapy gross residual tumor in non-high-risk neuroblastoma: Clinical significance and the role of adjuvant therapy.

BACKGROUND: Although survival rate among patients with non-high-risk neuroblastoma is excellent, a gross residual tumor (GRT) is often present at the end of treatment. However, reliable data do not exist on the relevance of a GRT for the risk of progression and the role of adjuvant therapy for patients with GRT. METHODS: A retrospective review of 131 patients with non-high-risk neuroblastoma who underwent chemotherapy was performed. GRT was defined as >1 cm3 residual soft tissue density on end-of-chemotherapy scans. Progression-free survival (PFS) and overall survival (OS) rates were compared between patients with GRT and those without GRT. A proportional hazards model was also used to assess the effects of GRT and adjuvant therapies, including radiation and isotretinoin therapy on outcomes. RESULTS: GRT was found in 52 (40%) patients in the study cohort. Correlation was not found between GRT and outcomes (PFS; p = .954, OS; p = .222). In multivariable analysis, GRT remained a nonsignificant predictor of outcome after adjusting for confounders. Local radiation and isotretinoin therapy did not affect outcome for patients with GRT. However, within GRT subgroups, the degree of volume reduction, as well as absolute residual volume in the primary tumor after induction treatment, were significantly associated with outcomes. CONCLUSION: GRT in non-high-risk neuroblastoma may not indicate active disease that requires additional treatment. However, risk of progression is increased in patients with GRT whose response to treatment was less prominent, thus adjuvant therapy should be reserved only for those patients.

Clinical implication of residual MIBG-positive disease in the follow-up of high-risk neuroblastoma treated with tandem high-dose chemotherapy and autologous stem cell transplantation.

BACKGROUND: The implication of residual metaiodobenzylguanidine (MIBG)-positive disease in the era of tandem high-dose chemotherapy (HDCT) with autologous stem cell transplantation (auto-SCT) has not yet been established in neuroblastoma. Moreover, most published studies have not evaluated the long-term prognosis of patients with residual MIBG-positive disease following treatment completion. Therefore, we investigated the prognostic significance of residual MIBG-positive disease at each treatment phase and after treatment completion. METHODS: We assessed MIBG scans labeled with either iodine-123 (123 I) or 131 I from 150 patients with MIBG-avid and high-risk neuroblastoma enrolled in the NB-2004, -2009, and -2014 trials at postinduction, posttandem HDCT/auto-SCT, and completion of treatment. RESULTS: The residual MIBG-positive disease at postinduction and posttandem HDCT/auto-SCT evaluation was highly correlated with the risk of progression. However, at treatment completion, there was no significant difference in survival and risk of progression between patients with residual MIBG-positive disease and MIBG-negative patients. Patients with persistent MIBG-positive disease at the end of treatment were more likely to have indolent tumor characteristics, such as favorable histology at diagnosis, lower incidence of MYCN amplification, and slow response to chemotherapy. CONCLUSION: Residual MIBG-positive disease during treatment predicted unfavorable outcomes for patients with high-risk neuroblastoma, even under tandem HDCT/auto-SCT. However, persistent MIBG uptake at the completion of all treatments may not always indicate an active disease.

Metastatic Burden Defines Clinically and Biologically Distinct Subgroups of Stage 4 High-Risk Neuroblastoma.

This study aimed to identify the prognostic subgroups of stage 4 high-risk neuroblastoma based on metastatic burden and explore their distinct clinical and genomic features. Patients aged ≥18 months with stage 4 and metaiodobenzylguanidine-avid neuroblastoma were enrolled. One hundred and thirty eligible patients were treated under the tandem high-dose chemotherapy scheme. Prognostic significance of metastatic burden measured by the modified Curie score was analyzed using a competing risk approach, and the optimal cut-point was determined. Metastasis-specific subgroups (cut-point: 26) were compared using clinicopathological variables, and differential gene expression analysis and gene set variation analysis (GSVA) were performed using RNA sequencing (RNA-seq). Metastatic burden at diagnosis showed a progressive association with relapse/progression. After applying the cut-point, patients with high metastatic burden showed >3-fold higher risk of relapse/progression than those with low metastatic burden. Moreover, patients with high metastatic burden showed smaller primary tumors and higher biochemical marker levels than those with low metastatic burden. In the genomic analysis, 51 genes were found to be differentially expressed based on the set criteria. GSVA revealed 55 gene sets, which significantly distinguished patients with high metastatic burden from those with low metastatic burden at a false discovery rate <0.25. The results indicated the prognostic significance of metastatic burden in stage 4 high-risk neuroblastoma, and we identified the distinct clinicopathological and genomic features based on metastatic burden. This study may aid in the better understanding and risk-stratification of stage 4 high-risk neuroblastoma patients.

Changes in Serum Creatinine Levels and Natural Evolution of Acute Kidney Injury with Conservative Management of Hemodynamically Significant Patent Ductus Arteriosus in Extremely Preterm Infants at 23-26 Weeks of Gestation.

Changes in kidney function in extremely preterm infants (EPT) with conservatively managed hemodynamically significant (HS) patent ductus arteriosus (PDA) are not known well. We aimed to present the postnatal course in serum creatinine levels (sCr), prevalence of acute kidney injury (AKI), then relevance between AKI and adverse outcomes in EPT with conservatively managed HS PDA. By review of medical records, we analyzed the postnatal course of sCr and prevalence of stage 3 AKI defined by the modified Kidney Disease Improving Global Outcome (KDIGO) in EPT at gestational age of 23 to 26 weeks with conservatively treated HS PDA. We investigated if the presence and/or prolonged duration of stage 3 AKI elevated the risk of adverse outcomes. The results showed that, neither factor was associated with adverse outcomes. While the average PDA closure date was at postnatal day (P) 41 and 53, sCr peaked at P 10 and 14 and the cumulative prevalence of stage 3 AKI was 57% and 72% in the EPT of 25-26 and 23-24 weeks' gestation, respectively. The high prevalence of stage 3 AKI without adverse outcomes in EPT with conservatively managed HS PDA suggests that it might reflect renal immaturity rather than pathologic conditions.