Naoko Maeda

Biomarker and morphological characteristics of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis

BACKGROUND Viruses may induce primary as well as secondary hemophagocytic lymphohistiocytosis (HLH), but it may not be possible to discriminate between these two in patients with a negative family history. Among these HLH cases, fulminant and fatal virus-associated hemophagocytic syndrome (VAHS) occurs mostly in relation to Epstein-Barr virus (EBV) infection. Although the immunological characteristics of EB-VAHS were previously reported, data on non-EB-VAHS were sporadic and fragmentary. This study has compared the clearly distinguishable groups of EBV-positive vs. EBV-negative HLH cases. PROCEDURE Among 26 patients with EBV-related HLH and 12 patients with non-EBV HLH, peripheral blood mononuclear cell (PBMC) subsets and serum concentrations of cytokines at the active phase of the disease were compared. Blood and bone marrow smears were also compared. RESULTS AND CONCLUSIONS The frequency of the CD3+HLADR+ subset in PBMC (median 34.3% vs. 4.8%), of serum concentrations of interferon (IFN)-gamma (median 105 U/ml vs. 2.4 U/ml), and of soluble interleukin-2-receptor (sIL-2R) (median 14,700 U/ml vs. 3,412 U/ml) were significantly different between these two groups. Morphological characteristics were noted for EBV-related HLH cases. Mortality also differed between these two groups, 9/26 vs. 0/12 (P = 0.05). Data indicate pronounced immunological imbalance and poor prognosis in EBV-related HLH cases. These parameters could be useful for determining an EBV involvement as well as risk factors in the early care and treatment of HLH patients.

Social outcomes and quality of life of childhood cancer survivors in Japan: a cross-sectional study on marriage, education, employment and health-related QOL (SF-36).

Social outcomes and quality of life (QOL) of childhood cancer survivors (CCSs) remain unknown in Japan. We investigated these outcomes in young adult CCSs compared to those of their siblings in Japan, and analyzed the association between social outcome and SF-36 health survey subscale scores. Between 2007 and 2009, we performed a cross-sectional survey using self-rating questionnaires. We estimated social outcomes and health-related QOL by performing the SF-36 in each group: CCSs with or without stem cell transplantation (SCT)/radiotherapy (RT) and their siblings. Adjusted odds ratios for outcomes of interest were estimated using logistic regression analysis. Questionnaires from 185 CCSs and 72 CCS’s siblings were analyzed. There were no differences in educational attainment or annual income. The SF-36 subscale scores of CCSs with SCT and RT were significantly lower than those of siblings in physical functioning (PF) (p < 0.001 and 0.003, respectively) and general health (GH) (both p = 0.001). Lower PF scores correlated with recurrence (p = 0.041) and late effects (p = 0.010), and poor GH scores with late effects (p = 0.006). The CCSs had made efforts to attain educational/vocational goals; however, a significant proportion of CCSs who had experienced late effects remain at increased risk of experiencing diminished QOL.

Pharmacokinetics and safety of voriconazole intravenous-to-oral switch regimens in immunocompromised Japanese pediatric patients.

ABSTRACT The aim of this study was to investigate the pharmacokinetics, safety, and tolerability of voriconazole following intravenous-to-oral switch regimens used with immunocompromised Japanese pediatric subjects (age 2 to <15 years) at high risk for systemic fungal infection. Twenty-one patients received intravenous-to-oral switch regimens based on a recent population pharmacokinetic modeling; they were given 9 mg/kg of body weight followed by 8 mg/kg of intravenous (i.v.) voriconazole every 12 h (q12h), and 9 mg/kg (maximum, 350 mg) of oral voriconazole q12h (for patients age 2 to <12 or 12 to <15 years and <50 kg) or 6 mg/kg followed by 4 mg/kg of i.v. voriconazole q12h and 200 mg of oral voriconazole q12h (for patients age 12 to <15 years and ≥50 kg). The steady-state area under the curve over the 12-h dosing interval (AUC0–12,ss) was calculated using the noncompartmental method and compared with the predicted exposures in Western pediatric subjects based on the abovementioned modeling. The geometric mean (coefficient of variation) AUC0–12,ss values for the intravenous and oral regimens were 51.1 μg · h/ml (68%) and 45.8 μg · h/ml (90%), respectively; there was a high correlation between AUC0–12,ss and trough concentration. Although the average exposures were higher in the Japanese patients than those in the Western pediatric subjects, the overall voriconazole exposures were comparable between these two groups due to large interindividual variability. The exposures in the 2 cytochrome P450 2C19 poor metabolizers were among the highest. Voriconazole was well tolerated. The most common treatment-related adverse events were photophobia and abnormal hepatic function. These recommended doses derived from the modeling appear to be appropriate for Japanese pediatric patients, showing no additional safety risks compared to those with adult patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01383993.)

Survey of childhood cancer survivors who stopped follow-up physician visits.

Background:  Childhood cancer cure rates have increased remarkably; however, survivors face an increased risk of morbidity and mortality. Survivors may benefit from anticipatory guidance and periodic surveillance to minimize morbidity and mortality.

Osteochondroma with metaphyseal abnormalities after total body irradiation followed by stem cell transplantation.

The occurrence of osteochondroma after total body irradiation (TBI) followed by stem cell transplantation (SCT) in our institutions was described, and its clinical significance discussed. Of 305 cases treated with SCT using TBI conditioning from 1980 to 2001, 4 cases of osteochondroma were identified on clinical examination. Mean age at the time of TBI was 4.4 years (range, 1.6 to 8.0). One patient developed multiple osteochondromas. All 4 cases showed metaphyseal abnormalities, including sclerotic metaphyseal lesion, fraying, and longitudinal striation, in the area where osteochondromas occurred. Only 1 patient required resection of the tumor due to pain. Two cases had other skeletal abnormalities including slipped capital femoral epiphysis and valgus-knee deformity, which required surgical intervention to prevent or correct these deformities. Osteochondroma is one of the complications developing after TBI, possibly concurrently with the metaphyseal abnormalities as seen on radiographs. However, clinical problems arising from osteochondroma are minimal, and surgical intervention is necessary in limited cases.

A case of NUT midline carcinoma with complete response to gemcitabine following cisplatin and docetaxel.

Background: NUT midline carcinoma (NMC) is recognized as a very rare tumor that most often occurs around the midline and shows NUT rearrangement. This tumor affects children and younger adults, progresses rapidly, and shows an extremely poor prognosis, even with intensive chemotherapy. Very few reports have described effective treatment for this tumor. Methods: A 12-year-old girl with NMC was treated using cisplatin (CDDP), docetaxel, gemcitabine, pemetrexed, and vinorelbine. Results: Imaging showed partial response with CDDP and docetaxel, and complete response with gemcitabine. After reexacerbation of the tumor, although partial response was achieved with vinorelbine, the patient died 89 weeks after onset because of reexacerbation. Conclusions: NMC is a very rare disease with poor prognosis. This study is the first to report response of NMC to gemcitabine and vinorelbine. The findings suggest that combination chemotherapies including CDDP, docetaxel, gemcitabine, and vinorelbine may be a choice in the treatment for NMC.

Medical visits of childhood cancer survivors in Japan: A cross-sectional survey

Background:  Although more children with cancer continue to be cured, these survivors experience various late effects. Details of the medical visit behaviors of childhood cancer survivors (CCS) in adulthood remain to be elucidated.

Predictors of Posttraumatic Stress Symptoms Among Adolescent and Young Adult Survivors of Childhood Cancer Importance of Monitoring Survivors’ Experiences of Family Functioning

The purpose of this study was to identify factors associated with posttraumatic stress symptoms (PTSS) among Japanese long-term childhood cancer survivors (CCSs). Subjects comprised 185 adolescent and young adult (AYA) CCSs who completed anonymous self-report questionnaires. Attending physicians also completed an anonymous disease/treatment data sheet. Mean age of survivors was approximately 8 years at diagnosis and 23 years at participation. Multiple regression analysis showed that family functioning, satisfaction with social support, being female, and interactions between family functioning and gender and age at the time of diagnosis were associated with PTSS among survivors. This study revealed family functioning as the most predictive factor of PTSS among AYA CCSs in Japan. Even when the survivor may have unchangeable risk factors, family functioning can potentially moderate the effects on PTSS. Thus, it is crucial for health professionals to carefully monitor and attend to survivors’ experiences of family functioning to mitigate PTSS.

Osteosarcoma After Bone Marrow Transplantation

Three children treated with bone marrow transplantation for acute lymphoblastic leukemia, Diamond-Blackfan anemia, and congenital amegakaryocytic thrombocytopenia developed secondary osteosarcoma in the left tibia at the age of 13, 13, and 9 years, respectively, at 51, 117, and 106 months after transplantation, respectively. Through treatment with chemotherapy and surgery, all 3 patients are alive without disease. We surveyed the literature and reviewed 10 cases of osteosarcoma after hematopoietic stem cell transplantation (SCT), including our 3 cases. Eight of the patients had received myeloablative total body irradiation before SCT. The mean interval from SCT to the onset of osteosarcoma was 6 years and 4 months, and the mean age at the onset of osteosarcoma was 14 years and 5 months. The primary site of the post-SCT osteosarcoma was the tibia in 6 of 10 cases, in contrast to de novo osteosarcoma, in which the most common site is the femur. At least 7 of the 10 patients are alive without disease. Osteosarcoma should be one of the items for surveillance in the follow-up of patients who undergo SCT.

Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia

Complete tyrosine kinase 2 (TYK2) deficiency has been previously described in patients with primary immunodeficiency diseases. The patients were infected with various pathogens, including mycobacteria and/or viruses, and one of the patients developed hyper-IgE syndrome. A detailed immunological investigation of these patients revealed impaired responses to type I IFN, IL-10, IL-12 and IL-23, which are associated with increased susceptibility to mycobacterial and/or viral infections. Herein, we report a recessive partial TYK2 deficiency in two siblings who presented with T-cell lymphopenia characterized by low naïve CD4+ T-cell counts and who developed Epstein-Barr virus (EBV)-associated B-cell lymphoma. Targeted exome-sequencing of the siblings’ genomes demonstrated that both patients carried novel compound heterozygous mutations (c.209_212delGCTT/c.691C > T, p.Cys70Serfs*21/p.Arg231Trp) in the TYK2. The TYK2 protein levels were reduced by 35% in the T cells of the patient. Unlike the response under complete TYK2 deficiency, the patient’s T cells responded normally to type I IFN, IL-6, IL-10 and IL-12, whereas the cells displayed an impaired response to IL-23. Furthermore, the level of STAT1 was low in the cells of the patient. These studies reveal a new clinical entity of a primary immunodeficiency with T-cell lymphopenia that is associated with compound heterozygous TYK2 mutations in the patients.