Panel‑based next‑generation sequencing facilitates the characterization of childhood acute myeloid leukemia in clinical settings

Acute myeloid leukemia (AML) accounts for ~20% of pediatric leukemia cases. The prognosis of pediatric AML has been improved in recent decades, but it trails that of most other types of pediatric cancer, with mortality rates of 30‑40%. Consequently, newer more targeted drugs are required for incorporation into treatment plans. These newer drugs selectively target AML cells with specific gene alterations. However, there are significant differences in genetic alterations between adult and pediatric patients with AML. In the present study, inexpensive and rapid next‑generation sequencing (NGS) of >150 cancer‑related genes was performed for matched diagnostic, remission and relapse (if any) samples from 27 pediatric patients with AML. In this analysis, seven genes were recurrently mutated. KRAS was mutated in seven patients, NRAS was mutated in three patients, and KIT, GATA1, WT1, PTPN11, JAK3 and FLT3 were each mutated in two patients. Among patients with relapsed AML, six harbored KRAS mutations at diagnosis; however, four of these patients lost these mutations at relapse. Additionally, two genetic alterations (FLT3‑ITD and TP53 alterations) were detected among patients who eventually relapsed, and these mutations are reported to be adverse prognostic factors for adult patients with AML. This panel‑based, targeted sequencing approach may be useful in determining the genetic background of pediatric AML and improving the prediction of treatment response and detection of potentially targetable gene alterations. RAS pathway mutations were highly unstable at relapse; therefore, these mutations should be chosen as a target with caution. Incorporating this panel‑based NGS approach into the clinical setting may allow for a patient‑oriented strategy of precision treatment for childhood AML

Ventriculoperitoneal Shunt Outcomes among Infants

Ventriculoperitoneal shunts (VPSs) are used for the treatment of hydrocephalus. Here we analyzed the outcomes of VPS placements in 24 infants to determine the risk factors for shunt failure. The infants had undergone the initial VPS operation in our hospital between March 2005 and December 2013. They were observed until the end of January 2014. We obtained Kaplan-Meier curves and performed a multivariate Cox regression analysis of shunt failure. Of the 24 cases, the median (range) values for gestational age, birth weight, and birth head circumference (HC) were 37 (27-39) wks, 2,736 (686-3,788) g, and 35.3 (23.0-45.3) cm, respectively. The total number of shunt procedures was 45. Shunt failure rates were 0.51/shunt and 0.0053/shunt/year. Shunt infection rates were 0.13/shunt and 0.0014/shunt/year. The Kaplan-Meier analysis revealed an increased risk for shunt failure in infants ＜1 month old or in the HC ＞90ｵtile. The Cox regression analysis yielded hazard ratios (HRs) of 2.93 (95ｵ confidence interval (CI), 0.96-10.95, p＝0.059) for age ＜1 month, and 4.46 (95ｵCI:1.20-28.91,p＝0.023) for the HC ＞90ｵtile. The multivariate Cox regression analysis showed adjusted HRs of 17.56 (95ｵCI:2.69-202.8, p＝0.001) for age ＜1 month, and 2.95 (95ｵCI:0.52-24.84, p＝0.228) for the HC ＞90ｵtile. Our findings thus revealed that the risk factors for shunt failure in infants include age ＜1 month at the initial VPS placement

Changes in the Features of Invasive Pneumococcal Disease after Introduction of the Seven-valent Pneumococcal Conjugate Vaccine in a Regional Core Hospital of Kochi, Japan

Since the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) in 2007, invasive pneumococcal disease has declined, but the incidence of Streptococcus pneumoniae serotype 19A has risen worldwide. The present study examined changes in the features of invasive pneumococcal disease since the introduction of the PCV7 in Kochi, Japan. Pediatric cases of invasive pneumococcal disease were investigated before and after vaccine introduction (January 2008 to December 2013). Cases of invasive pneumococcal disease tended to decrease after PCV7 introduction. In addition, before introduction of the vaccine, most serotypes causing invasive pneumococcal disease were those included in the vaccine. However, after the introduction, we found cases infected by serotypes not covered by vaccine. Penicillin-resistant S. pneumoniae was the predominant serotype causing invasive pneumococcal disease before introduction of the PCV7, and the susceptibility of this serotype to antibiotics improved after vaccine introduction. Serotype isolates identified after vaccine introduction were also relatively susceptible to antibiotic therapy, but decreased susceptibility is expected

Long-term efficacy of bevacizumab and irinotecan in recurrent pediatric glioblastoma.

A 5-year-old boy with glioblastoma relapsed soon after postoperative irradiation in combination with temozolomide. Second-line chemotherapy was also ineffective; therefore, the bevacizumab and irinotecan were given after a third gross-total resection of the tumor. Treatment was interrupted for 1 month due to development of posterior reversible encephalopathy syndrome, but was re-initiated at a lower dose of bevacizumab with prolonged intervals between treatments. The patient was alive and disease free 2 years after initial diagnosis. Bevacizumab and irinotecan are a promising regimen for pediatric cases of recurrent glioblastoma after gross-total resection, although the optimal treatment schedule must be determined on a patient-by-patient basis

PAX5 alterations in an infant case of KMT2A-rearranged leukemia with lineage switch

Lineage switch is a rare event at leukemic relapse. While mostly known to occur in KMT2A-rearranged infant leukemia, the underlying mechanism is yet to be depicted. This case report describes a female infant who achieved remission of KMT2A-MLLT3-rearranged acute monocytic leukemia, but 6 months thereafter, relapsed as KMT2A-MLLT3-rearranged acute lymphocytic leukemia. Whole exome sequencing of the bone marrow obtained pre-post lineage switch revealed two somatic mutations of PAX5 in the relapse sample. These two PAX5 alterations were suggested to be loss of function, thus to have played the driver role in the lineage switch from acute monocytic leukemia to acute lymphocytic leukemia

Changes in the Incidence of Infantile Spinal Muscular Atrophy in Shikoku, Japan between 2011 and 2020

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. Al-though there was no cure for SMA, newly developed therapeutic drugs (nusinersen, onasemnogene abeparvovec, and risdiplam) have been proven effective for the improvement of motor function and prevention of respiratory insufficiency of infants with SMA. Nusinersen was introduced in Japan in 2017 and onasemnogene abeparvovec in 2020. We hypothesized that the introduction of these drugs might influence the incidence of SMA (more precisely, increase the diagnosis rate of SMA) in Japan. To test this hypothesis, we conducted a second epidemiological study of infantile SMA using questionnaires in Shikoku, Japan between October 2021 and February 2022. The incidence of infantile SMA during the period 2016–2020 was 7.08 (95% confidence interval [CI] 2.45–11.71) per 100,000 live births. According to our previous epidemiological study, the incidence of infantile SMA during 2011–2015 was 2.70 (95% CI 0.05–5.35) per 100,000 live births. The increased incidence of infantile SMA suggests that the widespread news in Japan regarding the introduction of therapeutic agents, nusinersen and onasemnogene abeparvovec, raised clinicians’ awareness about SMA, leading to increased and earlier diagnosis of SMA in Shikoku