Congenital deficiency of protein C (PC) is a rare disease that causes thrombophilia during the neonatal and infantile periods. Despite anticoagulative treatments, purpura fulminans and major vessel ...thrombosis often occur. We report a 7-year-old girl with congenital PC deficiency who underwent deceased donor liver transplantation (LT) and experienced complications accompanied by initial poor graft function (IPGF). Before LT, she had cerebral and ophthalmic hemorrhage, and seven episodes of purpura fulminans. The operation was successfully performed; however, the liver graft developed IPGF. Hyperammonemia and coagulopathy required continuous hemodiafiltration and infusion of fresh frozen plasma. It took 22 days for PC activity to reach reference levels. The changes in clotting and anticlotting activities in the patient’s plasma were revealed using clot waveform analysis and the HemosIL ThromboPath
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assay. PC activity remained normal for 5 years after LT. Even when IPGF occurs, liver function including PC activity can remain normal for a long time after recovery from IPGF. LT can be a curative treatment for congenital PC deficiency.
Human herpes virus 6 (HHV‐6) is known to cause primary encephalitis in the frontal lobes/cerebral hemisphere or reactivated encephalitis in the hippocampus, but the pathogenesis remains unclear. ...HHV‐6B has also been detected in hippocampal samples in patients with mesial temporal lobe epilepsy. A 1 year and 3 months old female, who had been clinically diagnosed with exanthema subitum and febrile convulsion, was found dead on the third day after onset. Macroscopic findings showed massive brain edema. Microscopic examination revealed gemistocytic astrocytes and ballooned oligodendrocytes in the frontal white matter, along with neuronal cell death with microglial infiltration in the frontal cortex. Polymerase chain reaction detected HHV‐6B in the cerebrospinal fluid and necropsy brain samples. The hippocampus showed a 4–5‐fold increase in virus copy number of HHV‐6B compared to samples from other brain sites. Immunostaining indicated that HHV‐6B had infected vascular endothelial cells, neurons and oligodendrocytes but not astrocytes or microglia. Hippocampal neurons were infected with highly concentrated HHV‐6B, but the hippocampus had neither neuronal loss nor reactive glial response. Silent and abundant HHV‐6B infection in the hippocampus might be associated with latent infection, reactivation and some hippocampus‐oriented disorders, including mesial temporal lobe epilepsy.
ETV6-RUNX1-positive B precursor acute lymphoblastic leukemia (B-ALL) is a common subtype of pediatric B-ALL that has shown excellent outcomes in contemporary clinical trials for pediatric B-ALL. ...Examinations of the possibility of reducing therapeutic intensity may thus be explored. This prospective study examined outcomes in 205 pediatric patients with ETV6-RUNX1-positive B-ALL uniformly treated following the Japan Association of Childhood Leukemia Study Group (JACLS) ALL-02 protocol. The JACLS ALL-02 protocol does not employ minimal residual disease detected by polymerase chain reaction (PCR-MRD)-based risk stratification; however, 4-year event-free survival (EFS) and overall survival (OS) were 94.4 ± 1.6 and 97.5 ± 1.1%, respectively. In particular, 92 of 205 (44.9%) patients were successfully treated with a less intensive regimen involving only two cycles of high dose methotrexate and one course of re-induction therapy comprising vincristine,
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-asparaginase (L-asp), pirarubicin, and prednisolone. Multivariate analysis revealed that discontinuation of L-asp and poor response to prednisolone was, respectively, associated with poor EFS (HR 6.3; 95% CI 1.3–27.0) and OS (HR 17.5; 95% CI 2.3–130), suggesting that the majority of ETV6-RUNX1-positive B-ALL cases may be cured by a less-intensive chemotherapy regimen if the risk stratification system including PCR-MRD monitoring and insufficient use of L-asp is avoided.
Unrelated cord blood transplantation (CBT) was performed for the treatment of pyruvate kinase (PK) deficiency in a female pediatric patient at the age of 1 year 7 months, who had been in severe and ...frequent transfusion‐dependent hemolytic anemia, despite red blood cell (RBC) PK activity 5.52 IU/gHb. pyruvate kinase‐liver and RBC (PK‐LR) had a compound heterozygous mutation located on exon 8: c.1044G > T/c.1076G > A (K348N/R359H). Hemoglobin and RBC PK corrected to 13.5 g/dL and 9.00 IU/gHb, respectively, with gene correction at 6 months after CBT. CBT should be considered as an option for useful treatment in children with severe PK deficiency in the absence of HLA identical sibling with normal RBC PK activity.
This study was a second multicenter trial on childhood ALL by the Japan Childhood Leukemia Study Group (JACLS) to improve outcomes in non-T ALL. Between April 2002 and March 2008, 1138 children with ...non-T ALL were enrolled in the JACLS ALL-02 trial. Patients were stratified into three groups using age, white blood cell count, unfavorable genetic abnormalities, and treatment response: standard risk (SR), high risk (HR), and extremely high risk (ER). Prophylactic cranial radiation therapy (PCRT) was abolished except for CNS leukemia. Four-year event-free survival (4yr-EFS) and 4-year overall survival (4yr-OS) rates for all patients were 85.4% ± 1.1% and 91.2% ± 0.9%, respectively. Risk-adjusted therapy resulted in 4yr-EFS rates of 90.4% ± 1.4% for SR, 84.9% ± 1.6% for HR, and 66.5% ± 4.0% for ER. Based on NCI risk classification, 4yr-EFS rates were 88.2% in NCI-SR and 76.4% in NCI-HR patients, respectively. Compared to previous trial ALL-97, 4yr-EFS of NCI-SR patients was significantly improved (88.2% vs 81.2%, log rank p = 0.0004). The 4-year cumulative incidence of isolated (0.9%) and total (1.5%) CNS relapse were significantly lower than those reported previously. In conclusion, improved EFS in NCI-SR patients and abolish of PCRT was achieved in ALL-02.
TEN is a rare and critical disease mostly caused by drugs. It is mediated by activated CD8+ T cells that cause keratinocyte apoptosis with the assistance of cytokines/chemokines. We herein report a ...pediatric case of TEN after allogeneic HSCT with precursor B‐cell acute lymphoblastic leukemia (pre‐B‐ALL) in second complete remission. Although we did not evaluate the T‐cell subpopulation in blood or skin lesion of the patient, an imbalanced immune reconstitution after HSCT might additively contribute to the development of TEN.
Genetic alterations of Ikaros family zinc finger protein 1 (IKZF1), point mutations in Janus kinase 2 (JAK2), and overexpression of cytokine receptor‐like factor 2 (CRLF2) were recently reported to ...be associated with poor outcomes in pediatric B‐cell precursor (BCP)‐ALL. Herein, we conducted genetic analyses of IKZF1 deletion, point mutation of JAK2 exon 16, 17, and 21, CRLF2 expression, the presence of P2RY8‐CRLF2 fusion and F232C mutation in CRLF2 in 202 pediatric BCP‐ALL patients newly diagnosed and registered in Japan Childhood Leukemia Study ALL02 protocol to find out if alterations in these genes are determinants of poor outcome. All patients showed good response to initial prednisolone (PSL) treatment. Ph+, infantile, and Down syndrome–associated ALL were excluded. Deletion of IKZF1 occurred in 19/202 patients (9.4%) and CRLF2 overexpression occurred in 16/107 (15.0%), which are similar to previous reports. Patients with IKZF1 deletion had reduced event‐free survival (EFS) and overall survival (OS) compared to those in patients without IKZF1 deletion (5‐year EFS, 62.7% vs. 88.8%, 5‐year OS, 71.8% vs. 90.2%). Our data also showed significantly inferior 5‐year EFS (48.6% vs. 84.7%, log rank P = 0.0003) and 5‐year OS (62.3% vs. 85.4%, log rank P = 0.009) in NCI‐HR patients (n = 97). JAK2 mutations and P2RY8‐CRLF2 fusion were rarely detected. IKZF1 deletion was identified as adverse prognostic factor even in pediatric BCP‐ALL in NCI‐HR showing good response to PSL.
We conducted genetic analyses of IKZF1 deletion, point mutation of JAK2 exon 16, 17, and 21, CRLF2 expression, the presence of P2RY8‐CRLF2 fusion and F232C mutation in CRLF2 in 202 pediatric BCP‐ALL patients newly diagnosed and registered in Japan Childhood Leukemia Study ALL02 protocol to find out if IKZF1 deletion had reduced event‐free survival and overall survival. JAK2 mutations and P2RY8‐CRLF2 fusion were rarely detected. IKZF1 deletion was identified as adverse prognostic factor even in pediatric BCP‐ALL showing good response to PSL.
We describe our experience with a 12 year-old girl with kaposiform hemangioendothelioma accompanied by Kasabach–Merritt phenomenon with exacerbation of the disease 10 years after the initial ...diagnosis. Kaposiform hemangioendothelioma infiltrated into the subcutaneous tissue of the facial skin with deterioration of coagulopathy despite conventional therapies including corticosteroid, vincristine, and propranolol. Sirolimus, a mammalian target of rapamycin inhibitor, produced rapid and dramatic improvement of the Kasabach–Merritt phenomenon and kaposiform hemangioendothelioma shrinkage. Eventually, multifocal lesions of kaposiform hemangioendothelioma disappeared on the images of magnetic resonance imaging and have remained in remission for 27 months after sirolimus cessation. We demonstrated that the AKT/mammalian target of rapamycin signaling pathway played a pivotal role in the kaposiform hemangioendothelioma growth. Sirolimus must be a strong candidate for molecular therapy targeting kaposiform hemangioendothelioma.
This study reviewed the clinical characteristics of 112 pediatric B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) patients with TCF3‐PBX1 fusion treated according to the Japan Association of ...Childhood Leukemia Study (JACLS) ALL02 protocol (n = 82) and Children's Cancer and Leukemia Study Group (CCLSG) ALL 2004 protocol (n = 30). The 3‐year event‐free survival (EFS) and overall survival (OS) rates were 85.4 ± 3.9% and 89.0 ± 3.5% in JACLS cohort, and the 5‐year EFS and OS were 82.8 ± 7.0% and 86.3 ± 6.4% in CCLSG cohort, respectively, which are comparable to those reported in western countries. Conventional prognostic factors such as age at onset, initial white blood cell count, and National Cancer Institute risk have also no impact on OS in both cohorts. Surprisingly, the pattern of relapse in JACLS cohort, 9 of 82 patients, was unique: eight of nine patients relapsed during the maintenance phase and one patient had primary induction failure. However, bone marrow status and assessment of minimal residual disease on days 15 and 33 did not identify those patients. Interestingly, the two patients with IKZF1 deletion eventually relapsed in JACLS cohort, as did one patient in CCLSG cohort. International collaborative study of larger cohort is warranted to clarify the impact of the IKZF1 deletion on the poor outcome of TCF3‐PBX1 positive BCP‐ALL.
This study reviewed the clinical characteristics of 112 pediatric B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) patients with TCF3‐PBX1 fusion treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL02 and Children's Cancer and Leukemia Study Group (CCLSG) ALL 2004 protocol. Conventional prognostic factors such as age at onset, initial white blood cell count, and National Cancer Institute risk have no impact on prognosis. Interestingly, the two patients with IKZF1 deletion eventually relapsed, as did one patient in the independent cohort of 22 BCP‐ALL patients with TCF3‐PBX1 fusion CCLSG ALL 2004 protocol who harbored the IKZF1 deletion.
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