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.

Seo E, et al. J Korean Med Sci. 2019 Sep;34(39):e254. https://doi.org/10.3346/jkms.2019.34.e254

Background: Tandem high‐dose chemotherapy and autologous stem cell transplantation (HDCT/auto‐SCT) and incorporation of ¹³¹I‐metaiodobenzylguanidine (¹³¹I‐MIBG) treatment have shown positive outcomes in high‐risk neuroblastoma. However, more optimized treatment strategies are still needed.Procedure: The NB‐2014 study was a nonrandomized, prospective trial that examined survival outcomes in metastatic high‐risk neuroblastoma patients using response‐adapted consolidation therapy. We used post‐induction residual ¹²³I‐MIBG status at metastatic sites as a treatment response marker. Patients achieving complete resolution of MIBG uptake at metastatic sites underwent a reduced first HDCT/auto‐SCT with a 20% dose reduction in HDCT. After the first HDCT/auto‐SCT, patients with remaining MIBG uptake received dose‐escalated (18 mCi/kg) ¹³¹I‐MIBG treatment. In contrast, those with complete resolution of MIBG at metastatic sites received a standard dose (12 mCi/kg) of ¹³¹I‐MIBG. We compared survival and toxicity outcomes with a historical control group from the NB‐2009.Results: Of 65 patients treated, 63% achieved complete resolution of MIBG uptake at metastatic sites following induction chemotherapy, while 29% of patients still had MIBG uptake at metastatic sites after the first HDCT/auto‐SCT. The 3‐year event‐free survival (EFS) and overall survival (OS) rates were 68.2% ± 6.0% and 86.5% ± 4.5%, respectively. Compared to NB‐2009, EFS was similar (p = .855); however, NB‐2014 had a higher OS (p = .031), a lower cumulative incidence of treatment‐related mortality (p = .036), and fewer acute and late toxicities.Conclusions: Our results suggest that response‐adaptive consolidation therapy based on chemotherapy response at metastatic sites facilitates better treatment tailoring, and appears promising for patients with metastatic high‐risk neuroblastoma.

Germline genetic context may play a significant role in the development and evolution of cancer, particularly in childhood cancers such as neuroblastoma. This study investigates the role of putatively functional germline variants in neuroblastoma, even if they do not directly increase disease risk. Our whole-exome sequencing analysis of 125 patients with neuroblastoma reveals a positive correlation between germline variant burden and somatic mutations. Moreover, patients with higher germline variant burden exhibit worse outcomes. Similar findings are observed in the independent neuroblastoma cohort where a higher germline variant burden correlates with a higher somatic mutational burden and a worse overall survival outcome. However, contrasting results emerge in adult-onset cancer, emphasizing the importance of germline genetics in neuroblastoma. The enrichment of putatively functional germline variants in cancer predisposition genes is borderline significant when compared to healthy populations (P = 0.077; Odds Ratio, 1.45; 95% confidence intervals, 0.94−2.21) and significantly more pronounced against adult-onset cancers (P = 0.016; Odds Ratio, 2.13; 95% confidence intervals, 1.10−3.91). Additionally, the presence of these variants proves to have prognostic significance in neuroblastoma (log-rank P < 0.001), and combining germline with clinical risk factors notably improves survival predictions.

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.