Successful Outcome of Mother and Baby in a Woman With Severe COVID-19 Pneumonia in the Third Trimester of Pregnancy Who Required Extracorporeal Membrane Oxygenation Therapy.

Some studies have reported increased severe coronavirus disease (COVID-19) infection in the third trimester of pregnancy. Therefore, prenatal care in the third trimester requires careful judgment. It has been reported that extracorporeal membrane oxygenation (ECMO) therapy is useful for severe coronavirus disease 2019 (COVID-19) pneumonia; however, the optimal timing for the initiation of ECMO is controversial because the risks and benefits to the mother and fetus require careful consideration. We report a good outcome for mother and baby in a pregnant woman with severe COVID-19 pneumonia at 29 weeks gestation, who underwent urgent delivery and required ECMO therapy. A 34-year-old woman tested positive for COVID-19 at 27 weeks gestation. Despite treatment with remdesivir and prednisolone, her respiratory condition worsened. Consequently, she underwent emergent endotracheal intubation at 28 weeks and 2 days. Although the PaO2/FiO2 (P/F ratio) improved temporarily after endotracheal intubation, her respiratory condition progressively worsened. At 29 weeks gestation, an emergency cesarean section was performed and ECMO was initiated the next day. Although hematoma was observed after ECMO initiation, her respiratory condition improved. She was discharged home 54 days after the cesarean delivery without any complications. The neonate was intubated and transferred to the neonatal intensive care unit and was ultimately discharged home without any complications. Considering the risks and benefits of ECMO for the mother and fetus in the third trimester, ECMO should be initiated after delivery for better outcomes. The P/F ratio may be useful for an appropriate decision regarding delivery and the initiation of ECMO.

Effect of Germline MEFV Polymorphisms on the Prognosis of Japanese Children with Cancer: A Regional Analysis.

INTRODUCTION: MEFV is the gene responsible for familial Mediterranean fever. It encodes pyrin, which controls inflammation. Besides, previous studies have reported that some germline MEFV variants were associated with tumour susceptibility. MATERIALS AND METHODS: The loci of 12 germline MEFV variants were genotyped in 153 Japanese children with cancer, and the frequencies of these variants among the patient groups were compared with those in the general Japanese population. Additionally, the relationship between these variants and clinical data, including relapse and death, was investigated. RESULTS: Minor allele frequencies did not differ between patients and the general population, or between sex, age at diagnosis, and diagnosis among patients. P369S/R408Q associated with significantly lower relapse-free survival in all patient analyses and in patients with solid tumours. Additionally, although the results were not significant, E148Q/L110P was likely to associate with worse relapse-free survival in patients with solid tumours. DISCUSSION/CONCLUSION: Despite several limitations, this study provided the novel insight that the germline MEFV variants are associated with the clinical outcome of paediatric cancer.

Preemptive hematopoietic cell transplantation for asymptomatic patients with X-linked lymphoproliferative syndrome type 1.

Few reports have examined whether prophylactic allogeneic hematopoietic cell transplantation (HCT) for X-linked lymphoproliferative syndrome type 1 (XLP1) improves the prognosis. We compared the prognosis of symptomatic probands and affected siblings in the same family. Twenty-two cases (10 probands and 12 affected siblings) in Japan, the United Kingdom, and the United States were analyzed. The overall survival (OS) rate at 5 years after diagnosis was 70.0% in probands and 91.7% in affected siblings (p = 0.0789). The prognosis of patients who developed symptoms of XLP1 before HCT and those who did not was also compared. The 5-year probability of OS from the time of diagnosis in asymptomatic patients (100%) was significantly better than that in symptomatic patients (66.7%). These results suggested that early HCT as soon as the diagnosis is made improves the prognosis in asymptomatic XLP1 patients.

Prenatal diagnosis of MAGED2 gene mutation causing transient antenatal Bartter syndrome.

Transient antenatal Bartter syndrome due to melanoma-associated antigen D2 gene mutation is a newly reported type of Bartter syndrome. Its characteristics include an X-linked inheritance pattern, early-onset hydramnios, and spontaneous disappearance of symptoms after childbirth. To date, there have been no reports of prenatally diagnosed cases. We herein present the case of a preterm male born to a mother with early-onset hydramnios and a family history of X-linked idiopathic hydramnios. We suspected melanoma-associated antigen D2 gene mutation and performed direct sequencing. As a result, we were able to prenatally establish a diagnosis of transient Bartter syndrome due to a melanoma-associated antigen D2 gene mutation.

Dysregulation of the Intestinal Microbiome in Patients With Haploinsufficiency of A20.

INTRODUCTION: Haploinsufficiency of A20 (HA20) is a form of inborn errors of immunity (IEI). IEIs are genetically occurring diseases, some of which cause intestinal dysbiosis. Due to the dysregulation of regulatory T cells (Tregs) observed in patients with HA20, gut dysbiosis was associated with Tregs in intestinal lamina propria. METHODS: Stool samples were obtained from 16 patients with HA20 and 15 of their family members. Infant samples and/or samples with recent antibiotics use were excluded; hence, 26 samples from 13 patients and 13 family members were analyzed. The 16S sequencing process was conducted to assess the microbial composition of samples. Combined with clinical information, the relationship between the microbiome and the disease activity was statistically analyzed. RESULTS: The composition of gut microbiota in patients with HA20 was disturbed compared with that in healthy family members. Age, disease severity, and use of immunosuppressants corresponded to dysbiosis. However, other explanatory factors, such as abdominal symptoms and probiotic treatment, were not associated. The overall composition at the phylum level was stable, but some genera were significantly increased or decreased. Furthermore, among the seven operational taxonomic units (OTUs) that increased, two OTUs, Streptococcus mutans and Lactobacillus salivarius, considerably increased in patients with autoantibodies than those without autoantibodies. DISCUSSION: Detailed interaction on intestinal epithelium remains unknown; the relationship between the disease and stool composition change helps us understand the mechanism of an immunological reaction to microorganisms.

Immunophenotyping of A20 haploinsufficiency by multicolor flow cytometry.

Haploinsufficiency of A20 (HA20) causes inflammatory disease resembling Behçet's disease; many cases have been reported, including some that are complicated with autoimmune diseases. This study aims to clarify the immunophenotype of patients with HA20 by analyzing lymphocyte subsets using multicolor flow cytometry. The patients with HA20 previously diagnosed in a nationwide survey were compared by their cell subpopulations. In total, 27 parameters including regulatory T cells (Tregs), double-negative T cells (DNTs), and follicular helper T cells (TFHs) were analyzed and compared with the reference values in four age groups: 0-1, 2-6, 7-19, and ≥20 years. The Tregs of patients with HA20 tended to increase in tandem with age-matched controls at all ages. In addition, patients ≥20 years had increased DNTs compared with controls, whereas TFHs significantly increased in younger patients. In HA20 patients, the increase in DNTs and TFHs may contribute to the development of autoimmune diseases.

Establishment of immunity against Epstein-Barr virus infection in a patient with CHARGE/complete DiGeorge syndrome after peripheral blood lymphocyte transfusion.

CHARGE syndrome is a rare congenital malformation syndrome which may share symptoms with DiGeorge syndrome. Complete DiGeorge syndrome (cDGS) is a severe form of DiGeorge syndrome, characterized by a CD3+ T-cell count of <50/mm3 due to athymia, and is fatal without immunologic intervention. We performed peripheral blood lymphocyte transfusion (PBLT) from an HLA-identical sibling without pretransplant conditioning in a CHARGE/cDGS patient with a novel CHD7 splice site mutation. Cyclosporine and short-term methotrexate were used for graft versus host disease (GVHD) prophylaxis, and neither acute nor chronic GVHD was observed. After PBLT, T-cell proliferative response to phytohemagglutinin and concanavalin A recovered, and intractable diarrhea improved. EBV infection, evidenced by a gradual increase in the viral genome copy number to a maximum of 2861 copies/µgDNA on day 42 after PBLT, resolved spontaneously. HLA A2402 restricted, EBV-specific CTLs were detected from peripheral blood on day 148, and EBV seroconversion was observed on day 181. Thus, EBV-specific immunity was successfully established by PBLT. Our results indicate that PBLT is a simple and effective therapy to reconstitute immune systems in CHARGE/DiGeorge syndrome.

Interinstitutional patient transfers between rapid chemotherapy cycles were feasible to utilize proton beam therapy for pediatric Ewing sarcoma family of tumors.

AIM: To assess the feasibility of transferring to the University of Tsukuba Hospital for proton beam therapy (PBT) during intensive chemotherapy in children with Ewing sarcoma family of tumors (ESFT) who had been diagnosed and started their first-line treatment at prefectural or regional centers for pediatric oncology. BACKGROUND: The treatment of ESFT relies on a multidisciplinary approach using intensive neoadjuvant and adjuvant chemotherapies with surgery and radiotherapy. Multi-agent chemotherapy comprising vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC-IE) is widely used for ESFT, and the interval between each course is very important for maintaining the intensity and effect of chemotherapy. MATERIALS AND METHODS: Clinical information of patients who received PBT and VDC-IE between April 2009 and May 2016 was collected retrospectively. The intervals between each course of VDC-IE and adverse events were assessed. RESULTS: Fifteen patients were evaluated. No delays in the intervals of chemotherapy due to transfer were observed. There were no adverse events caused during/just after transfer and no increases in adverse events. The estimated 4-year overall and event-free survival rates were 94.6% and 84.8%, respectively. DISCUSSION: Although the results of efficacy are preliminary, survival rates were comparable with past studies. More experience and follow-up are required to further assess the efficacy of PBT for patients with ESFT. CONCLUSION: Multidisciplinary therapy for children with ESFT involving transfer to our hospital for PBT during VDC-IE was feasible without treatment delay or an increase in adverse events.

Haploidentical peripheral blood stem cell transplantation without irradiation or busulfan after reduced-intensity conditioning for KMT2A(MLL)-rearranged infant B-cell precursor acute lymphoblastic leukemia: Report of two cases.

We present two infants with KMT2A(MLL)-gene-R-associated BCP-ALL, who received HLA haploidentical PBSCT after RIC. The patients developed ALL at age 6 months and 3 months, respectively. Case 1 underwent PBSCT at the second CR with detectable KMT2A-AFF1(MLL-AF4) fusion gene transcript at 11 months of age, and Case 2 at the first CR without KMT2A-MLLT1(MLL-ENL) fusion gene transcript at 8 months of age. Both patients received G-CSF-mobilized unmanipulated peripheral blood mononuclear cells from their HLA haploidentical mothers after administration of FLU, MEL, and ATG. Tacrolimus, methotrexate, and mPSL were administered as prophylaxis against GVHD. Engraftment was rapidly obtained with complete chimerism in both patients. Acute adverse events included acute GVHD in Case 1 and bacterial sepsis in Case 2. At last clinical check at age 5 years and 4 years, respectively, both patients were recurrence-free and attained normal growth and development. We conclude that PBSCT from an HLA haploidentical mother with non-TBI and non-BU regimen seems feasible and efficacious, offering favorable life quality for infants.

Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age.

The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.

Molecular genetic and cytogenetic analysis of a primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma.

We performed cytogenetic and molecular cytogenetic analyses of a primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, a rare type of primary cutaneous T-cell lymphoma. G-banded analysis at initial diagnosis and recurrence revealed complex karyotype and clonal evolution reflecting genomic instability that parallels the aggressive clinical course observed. Spectral karyotyping revealed numerous structural abnormalities. SNP array-based analysis of an initial diagnostic sample revealed numerous gains and losses of chromosomal material, including loss of short arm of the chromosome 17, to which TP53 is mapped. The molecular cytogenetics and array data of this case suggest genomic instability, particularly chromosomal instability and haploinsufficiency for TP53, the latter possibly giving rise to alteration of p14ARF-Mdm2-p53 tumor suppressor protein pathway, likely to be associated with unfavorable clinical course.

Lack of Impact of High Dietary Vitamin A on T Helper 2-Dependent Contact Hypersensitivity to Fluorescein Isothiocyanate in Mice.

Overuse of vitamin A as a dietary supplement is a concern in industrialized countries. High-level dietary vitamin A is thought to shift immunity to a T helper 2 (Th2)-dominant one, resulting in the promotion of allergies. We have been studying a fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS) mouse model that involves Th2-type immunity. We fed a diet with a high retinyl palmitate content (250 international units (IU)/g diet) or a control diet (4 IU/g diet) to BALB/c mice for three weeks. No augmentation of FITC-induced CHS was found in mice fed the diet with a high vitamin A content, although accumulation of the vitamin was confirmed in the livers of these animals. The results indicated that relatively short-term feeding of the high-level vitamin A diet did not influence the Th2-driven response at a stage with significant retinol accumulation in the liver. The results were in contrast to the high-dose pyridoxine diets that produced a reduced response in FITC-induced CHS.

Bullous pemphigoid after allogeneic hematopoietic stem cell transplantation.

Bullous pemphigoid (BP) is an autoimmune skin disorder characterized by subepidermal blisters due to deposit of autoantibody against dermal basement membrane protein. It has been reported that BP can occur after allogeneic hematopoietic stem cell transplantation (HSCT). We describe a patient with BP having autoantibody against BP180 after unrelated-donor HSCT against T lymphoblastic leukemia. The patient was treated with steroid leading to complete resolution of BP, but T lymphoblastic leukemia progressed rapidly after steroid hormone treatment. Given that immunosuppressant may reduce graft-versus-tumor effect, immunomodulatory agents such as nicotinamide and tetracycline, erythromycin, and immunoglobulin may be appropriate as soon as typical blister lesions are seen after HSCT.

Tailor-made treatment combined with proton beam therapy for children with genitourinary/pelvic rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas among children. Patients who developed genitourinary/pelvic rhabdomyosarcoma (GU/P-RMS) have a higher complication ratio and relatively poorer event free survival, with local therapy being very important. While proton beam therapy (PBT) is expected to reduce co-morbidity, especially for children, this lacks firm evidence and analysis. We analyzed GU/P-RMS children who had undergone multimodal therapy combined with PBT at a single institution. METHOD: We retrospectively reviewed charts of children with GU/P-RMS treated from January 2007 to May 2013 at the University of Tsukuba Hospital who had undergone multimodal therapy with PBT. RESULTS: There were 5 children and their median age at diagnosis was 2.8 years (0.6-4.4 years). Primary sites were the bladder (2) and the prostate (3). All received neo-adjuvant chemotherapy and 3 underwent chemotherapy during PBT (Group Cx). All patients of Group Cx developed leukocytopenia (WBC <1000/µL). The median dose of PBT was 47.7 GyE (41.4-50.4 GyE). All patients survived by their last hospital visit (median, 36 months). CONCLUSIONS: We analyzed multimodal treatment combined with PBT applied for GU/P-RMS. PBT was well tolerated and could be a plausible choice instead of photon therapy for this population.

Influence of SLCO1B1 polymorphism on maintenance therapy for childhood leukemia.

BACKGROUND: Management of the adverse effects of chemotherapy is essential to improve outcome of children with leukemia. Some genetic polymorphisms can predict treatment-related toxicity, and be used individually in dose modification of 6-mercaptopurine (6-MP) and methotrexate (MTX) in maintenance therapy for childhood acute lymphoblastic leukemia (ALL). We investigated associations between clinical course and candidate gene polymorphisms less evaluated in Japanese patients. METHODS: Fifty-three children who received maintenance chemotherapy were enrolled in this study. The scheduled dose of oral 6-MP was 40 mg/m(2) daily and that of oral MTX was 25 mg/m(2) weekly. The doses were adjusted according to white blood cell count (target range, 2.5-3.5 × 10(9) /L) and aspartate aminotransferase and alanine aminotransferase level (< 750 IU/L). Eight polymorphisms in six candidate genes, TPMT, ITPA, MRP4, MTHFR, RFC1, and SLCO1B1, were genotyped using the Taqman PCR method. Clinical course was reviewed retrospectively from medical records. RESULTS: The average dose of 6-MP was lower in the patients with at least one variant allele at SLCO1B1 c.521 T > C than in the patients with wild homozygous genotype. The other analyzed polymorphisms were not associated with toxicity, 6-MP, or MTX dose. CONCLUSIONS: Polymorphism of SLCO1B1 c.521 T > C could be a strong predictor of 6-MP dose reduction in maintenance chemotherapy in childhood ALL.

Imatinib-induced Severe Hepatitis in a 9-Year-old Girl With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.

Imatinib mesylate has dramatically improved the outcome of children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph* ALL) and is now included as first-line therapy. Uncommon adverse effects of this drug for pediatric use, however, are largely unknown. We report the first case of a 9-year-old child who developed severe acute hepatitis with grade 4 transaminases and bilirubin elevation during imatinib treatment for Ph* ALL. Liver biopsy showed extensive lobular and pericentral necrosis of hepatocytes. Liver function recovered after discontinuing imatinib with a 4-week prednisolone. Extensive hepatic necrosis should be considered not only in adults but also in children under imatinib administration.

Safety and Effectiveness of Micafungin in Japanese Pediatric Patients: Results of a Postmarketing Surveillance Study.

Limited data are available about the safety and efficacy of micafungin in children. A postmarketing surveillance study was conducted to assess the safety and effectiveness of micafungin, an echinocandin antifungal, in pediatric patients. A prospective multicenter postmarketing observational study was carried out between October 2006 and September 2008 in Japan. Pediatric patients under 16 years received an intravenous infusion of micafungin at a dose of 1 mg/kg for candidiasis and 1 to 3 mg/kg for aspergillosis, with the option of increasing the dose if required to 6 mg/kg once daily. All adverse events were recorded. A total of 201 pediatric patients were enrolled. There were 55 adverse drug reactions reported among 42 of 190 patients evaluated for safety (22.1%); the most frequently reported adverse drug reaction was hepatobiliary disorders. No adverse drug reactions were reported in 18 neonates (aged below 4 wk). The overall clinical response rate in 91 patients evaluated for efficacy was 86.8%. The response rate in neonates was 90.0%, and there were no differences in the response rate by age. Micafungin was found to have sufficient safety and effectiveness for the treatment of fungal infections in pediatric patients with various backgrounds.

Safety and efficacy of micafungin for prophylaxis against invasive fungal infections in Japanese patients undergoing hematopoietic stem cell transplantation: Results of a post-marketing surveillance study.

Invasive fungal infections are a major cause of morbidity and mortality in patients with hematopoietic stem cell transplantation. A prospective multicenter post-marketing observational surveillance study was conducted from July 2007 to June 2010 to assess the safety and efficacy of micafungin, an echinocandin antifungal, for prophylaxis against invasive fungal infections in Japanese patients undergoing hematopoietic stem cell transplantation. Among 241 patients evaluated for safety, 143 adverse drug reactions were reported in 86 patients (35.7%), with hepatobiliary disorders the most frequently reported adverse drug reactions. The success rate for prophylaxis at the end of observation was 72.8% (131/180 patients), and the incidence of breakthrough infections was only 4.4% (8/180 patients). In conclusion, micafungin had sufficient safety and efficacy for prophylaxis against invasive fungal infections in Japanese patients with various backgrounds undergoing hematopoietic stem cell transplantation.