Health-related quality of life in Japanese children with acute lymphoblastic leukemia during and after chemotherapy.

BACKGROUND: Quality of life (QOL) as a treatment outcome has not yet been evaluated among patients receiving a specific treatment regimen by treatment phase in a consistent manner. This exploratory cross-sectional study evaluated the QOL of children with acute lymphoblastic leukemia (ALL) receiving one of the most popular treatment regimens in Japan (Japan Association of Childhood Leukemia Study ALL-02 revised protocol). METHODS: Children aged 5-18 years with newly diagnosed B-cell precursor ALL were included. The Pediatric Quality of Life Inventory™ 4.0 Generic Core Scales (PedsQL-J) were completed by children with ALL and their siblings, as well as by age- and sex-matched healthy controls. PedsQL Cancer Module (PedsQL-C) scores were also collected from children with ALL. RESULTS: QOL in children with ALL of the consolidation phase group was significantly decreased compared with that of healthy controls, except in the area of emotional functioning. Regarding the maintenance phase group, QOL impairment was noted in the physical and school functioning, but no differences were noted in social functioning. The off-treatment group had a large effect size only for physical functioning, and the social functioning score was even better in children with ALL than in matched controls. QOL of children with ALL differed with treatment phase. Effect size varied with function and treatment phase. CONCLUSIONS: QOL may change with the progression of treatment, and the timing of these changes varied according to function and problem.

A comprehensive study of the distressing experiences and support needs of parents of children with intractable cancer.

OBJECTIVE: The primary endpoints of this study were: (1) to explore the distressing experiences of parents of patients with intractable pediatric cancer in Japan from disclosure of poor prognosis to the present and (2) to explore support they regarded as necessary. METHODS: A multi-center questionnaire survey was conducted that included 135 bereaved parents of patients with pediatric cancer in Japan. RESULTS: The top five distressing experiences shared by over half of the bereaved parents were: 'Realize that the child's disease was getting worse' (96.7%), 'Witness the child's suffering' (96.7%), 'Make many decisions on the basis that the child will die in the not-so-distant future' (83.6%), 'Feel anxious and nervous about the child's acute deterioration' (82.0%) and 'Realize that there was nothing that I could do for the child' (78.7%). The top five support regarded as necessary were: 'Visit the room and speak to the sick child every day' (90.2%), 'Provide up-to-date information' (80.3%), 'Sufficiently explain the disadvantages of each treatment option' (80.3%), 'Show a never-give-up attitude until the end' (78.7%) and 'Make arrangements to allow the sick child to spend time with his/her siblings' (73.8%). CONCLUSIONS: This study identified the common distressing experiences of parents and the support regarded as necessary by them. To provide efficient support with limited manpower in pediatric setting, healthcare professionals should recognize these tasks as high priorities when engage parents of intractable pediatric cancer patients.

Efficacy of micafungin in pediatric immunocompromised patients with invasive fungal infection.

BACKGROUND: Micafungin, an antifungal echinocandin, has been indicated for pediatric patients with invasive fungal infection (IFI) in Japan and Europe. Its efficacy in immunocompromised pediatric patients with IFI, however, has not been fully investigated. METHODS: The safety and efficacy of micafungin as an antifungal therapy were analyzed in nine consecutive severe immunocompromised patients with IFI. RESULTS: Three patients with proven or probable Candida infections had complete response to micafungin therapy. Of the other six patients with proven, probable or possible Aspergillus infection, four had complete response and one had partial response to micafungin treatment. No severe adverse events were observed. CONCLUSIONS: In this small series, micafungin was effective for IFI caused by both Candida and Aspergillus species and no severe adverse events were observed in these immunocompromised patients.

Mycobacterium avium complex-associated peritonitis with CAPD after unrelated bone marrow transplantation.

Peritonitis remains an important complication of peritoneal dialysis and is mostly caused by aerobic enteric bacteria. Non-tuberculous mycobacteria (NTM)-associated peritonitis is an unusual but serious infection, requiring special culture techniques to avoid delay in diagnosis. We report the case of an 11-year-old girl with aplastic anemia on ambulatory peritoneal dialysis who had Mycobacterium avium complex-associated peritonitis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This case emphasizes that we should be constantly cautious about NTM infection in allo-HSCT recipients, especially when standard cultures are negative and the infection is refractory to empirical antibiotic therapy.

PBSCT is associated with poorer survival and increased chronic GvHD than BMT in Japanese paediatric patients with acute leukaemia and an HLA-matched sibling donor.

BACKGROUND: Peripheral blood stem cells (PBSC) may be used as an alternative to bone marrow (BM) for allogeneic transplantation. Since peripheral blood stem cell bank from unrelated volunteer donor has been started in Japan, use of PBSC allografts may be increased. Therefore we surveyed the outcomes of Japanese leukemia children after PBSC and BM transplantation. PROCEDURE: This retrospective study compared the outcomes of 661 children (0-18 years) with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) who received their first allogeneic peripheral blood stem cell transplantation (PBSCT; n = 90) or bone marrow transplantation (BMT; n = 571) from HLA-matched siblings between January 1996 and December 2007. RESULT: Neutrophil recovery was faster after PBSCT than after BMT (ALL: P < 0.0001; AML: P = 0.0002), as was platelet recovery (ALL: P = 0.0008; AML: P = 0.0848). However, the cumulative incidence of chronic graft-versus-host disease (GvHD) was higher after PBSCT than after BMT (ALL: 26.0% vs. 9.9%, P = 0.0066; AML: 41.6% vs. 11.1%, P < 0.0001). The 5-year disease-free survival (DFS) was lower after PBSCT than after BMT for ALL (40.6% vs. 57.1%, P = 0.0257). The 5-year overall survival (OS) was lower after PBSCT than after BMT for ALL (42.4% vs. 63.7%, P = 0.0032) and AML (49.8% vs. 71.8%, P = 0.0163). Multivariate analysis revealed the use of PBSC was a significant risk factor for DFS and OS. PBSCT and BMT did not differ in relapse rate, acute GvHD for ALL and AML, or in DFS for AML. CONCLUSION: PBSC allografts in Japanese children engraft faster but are associated with poorer survival and increased chronic GvHD.

Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia.

The Additional sex combs like 1 (Asxl1) gene is 1 of 3 mammalian homologs of the Additional sex combs (Asx) gene of Drosophila. Asx is unusual because it is required to maintain both activation and silencing of Hox genes in flies and mice. Asxl proteins are characterized by an amino terminal homology domain, by interaction domains for nuclear receptors, and by a C-terminal plant homeodomain protein-protein interaction domain. A recent study of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) revealed a high incidence of truncation mutations that would delete the PHD domain of ASXL1. Here, we show that Asxl1 is expressed in all hematopoietic cell fractions analyzed. Asxl1 knockout mice exhibit defects in frequency of differentiation of lymphoid and myeloid progenitors, but not in multipotent progenitors. We do not detect effects on hematopoietic stem cells, or in peripheral blood. Notably, we do not detect severe myelodysplastic phenotypes or leukemia in this loss-of-function model. We conclude that Asxl1 is needed for normal hematopoiesis. The mild phenotypes observed may be because other Asxl genes have redundant function with Asxl1, or alternatively, MDS or oncogenic phenotypes may result from gain-of-function Asxl mutations caused by genomic amplification, gene fusion, or truncation of Asxl1.

Supplementation of highly concentrated ß-cryptoxanthin in a satsuma mandarin beverage improves adipocytokine profiles in obese Japanese women.

BACKGROUND: Serum ß-cryptoxanthin levels are lower in overweight subjects than in normal subjects. Abnormalities of adipocytokine profiles in obesity subjects have been reported. There are several reports that serum ß-cryptoxanthin levels in them were relatively lower than normal subjects. OBJECTIVE: We hypothesize that supplementation of highly concentrated ß-cryptoxanthin improves serum adipocytokine profiles in obese subjects. This study tested the association between ß-cryptoxanthin intake and serum adipocytokine levels. METHODS: An intervention study consisted of a 3-week long before-and-after controlled trial, where ß-cryptoxanthin (4.7 mg/day) was given to 17 moderately obese postmenopausal women. RESULTS: The results indicated no significant changes in body weight or body mass index (BMI). Serum ß-cryptoxanthin levels increased significantly by 4-fold. Serum high molecular weight (HMW)-adiponectin levels increased significantly, while serum plasminogen activator inhibitor (PAI)-1 levels decreased. CONCLUSIONS: We concluded that increasing the intake of ß-cryptoxanthin to approximately 4 mg per day for 3 weeks may have beneficial effects on the serum adipocytokine status and consequently alleviate progression of metabolic syndrome.

Allogeneic hematopoietic stem cell transplantation against recurrent rhabdomyosarcoma.

The prognosis of high-risk rhabdomyosarcoma (RMS) with metastatic or recurrent disease remains poor. We report a 6-year-old girl who successfully underwent allogeneic hematopoietic stem cell transplantation against recurrent metastatic alveolar RMS. The disease recurred at distant lymph node metastasis with bone marrow involvement. After chemotherapy and radiotherapy for the metastatic site, she underwent allogeneic bone marrow transplantation during complete remission from her 5/8 HLA-matched father. She developed acute graft-versus-host disease after preemptive donor lymphocyte infusion and remains in a disease-free condition for 31 months after transplantation. A graft-versus-tumor effect through allogeneic immune cells might produce a beneficial effect for high-risk RMS.

In vitro metabolism of nobiletin, a polymethoxy-flavonoid, by human liver microsomes and cytochrome P450.

Cytochrome P450 enzymes (CYPs) in the liver metabolize drugs prior to excretion, with different enzymes acting at different molecular motifs. At present, the human CYPs responsible for the metabolism of the flavonoid, nobiletin (NBL), are unidentified. We investigated which enzymes were involved using human liver microsomes and 12 cDNA-expressed human CYPs. Human liver microsomes metabolized NBL to three mono-demethylated metabolites (4'-OH-, 7-OH- and 6-OH-NBL) with a relative ratio of 1:4.1:0.5, respectively, by aerobic incubation with nicotinamide adenine dinucleotide phosphate (NADPH). Of 12 human CYPs, CYP1A1, CYP1A2 and CYP1B1 showed high activity for the formation of 4'-OH-NBL. CYP3A4 catalyzed the formation of 7-OH-NBL with the highest activity and of 6-OH-NBL with lower activity. CYP3A5 also catalyzed the formation of both metabolites but considerably more slowly than CYP3A4. In contrast, seven CYPs (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1) were inactive for NBL. Both ketoconazole and troleandomycin (CYP3A inhibitors) almost completely inhibited the formation of 7-OH- and 6-OH-NBL. Similarly, α-naphthoflavone (CYP1A1 inhibitor) and furafylline (CYP1A2 inhibitor) significantly decreased the formation of 4'-OH-NBL. These results suggest that CYP1A2 and CYP3A4 are the key enzymes in human liver mediating the oxidative demethylation of NBL in the B-ring and A-ring, respectively.

Polycomb group gene rae28 is required for sustaining activity of hematopoietic stem cells.

The rae28 gene (rae28), also designated as mph1, is a mammalian ortholog of the Drosophila polyhomeotic gene, a member of Polycomb group genes (PcG). rae28 constitutes PcG complex 1 for maintaining transcriptional states which have been once initiated, presumably through modulation of the chromatin structure. Hematopoietic activity was impaired in the fetal liver of rae28-deficient animals (rae28-/-), as demonstrated by progressive reduction of hematopoietic progenitors of multilineages and poor expansion of colony forming units in spleen (CFU-S(12)) during embryonic development. An in vitro long-term culture-initiating cell assay suggested a reduction in hematopoietic stem cells (HSCs), which was confirmed in vivo by reconstitution experiments in lethally irradiated congenic recipient mice. The competitive repopulating units (CRUs) reflect HSCs supporting multilineage blood-cell production. CRUs were generated, whereas the number of CRUs was reduced by a factor of 20 in the rae28-/- fetal liver. We also performed serial transplantation experiments to semiquantitatively measure self-renewal activity of CRUs in vivo. Self-renewal activity of CRUs was 15-fold decreased in rae28-/-. Thus the compromised HSCs were presumed to reduce hematopoietic activity in the rae28-/- fetal liver. This is the first report to suggest that rae28 has a crucial role in sustaining the activity of HSCs to maintain hematopoiesis.

WT1 peptide immunotherapy for cancer in children and young adults.

Wilms tumor gene (WT1) can be overexpressed in childhood cancers. We evaluated the efficacy of WT1 vaccination for five children with solid cancer or acute leukemia. WT1 vaccine was administered to HLA-A*2402-positive patients with WT1-overexpressing residual tumor despite prior conventional treatment. One patient showed complete response and one patient showed stable disease according to the Response Evaluation Criteria in Solid Tumors; the remaining three showed progressive disease. Treatment-related adverse effects were limited to local injection site erythema. These results suggest that WT1 vaccination has therapeutic potential, but any beneficial effect may be insufficient in the presence of gross residual disease.

Hemophagocytosis after bone marrow transplantation for JAK3-deficient severe combined immunodeficiency.

HSCT is the optimal treatment for patients with SCID. In particular, HSCT from a HLA-identical donor gives rise to successful engraftment with long survival. We report a six-month-old girl with JAK3-deficient SCID who developed hemophagocytosis after BMT without conditioning from her HLA-identical father. She had suffered from pneumonia and hepatitis before BMT. Prophylaxis for GVHD was short-term methotrexate and tacrolimus. On day 18 after BMT, the patient developed hemophagocytosis in bone marrow when donor lymphocytes were increasing in peripheral blood. Analysis of chimerism confirmed host origin of macrophages and donor origin of lymphocytes. Thus, host macrophage activation was presumably induced in response to donor lymphocytes through immunoreaction to infections and/or alloantigens. HSCT for SCID necessitates caution with respect to hemophagocytosis.

Retropharyngeal neuroblastoma in an infant: management without surgery.

SUMMARY: Retropharyngeal neuroblastoma is rare. We report a 3-month-old infant with retropharyngeal neuroblastoma presenting with airway compression, which had an unresectable localized tumor without N-myc amplification. He was promptly treated with chemotherapy, resulting in a dramatic resolution. Subsequently, he received no surgical intervention and is well without evidence of recurrence 10 months after completion of chemotherapy. A review of the literature reveals that retropharyngeal neuroblastoma in infants has a good prognosis, but with some risk of surgical complication. Thus, it might be better to treat unresectable, localized disease accompanied by life-threatening symptoms with chemotherapy alone.

Clinical aspects and adrenal functions in eleven Japanese children with X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a genetic disease associated with demyelination of the central nervous system, adrenocortical insufficiency and accumulation of very long chain fatty acids. It is a clinically heterogeneous disorder ranging from a severe childhood cerebral form to an asymptomatic form. The incidence in Japan is estimated to be between 1:30,000 and 1:50,000 boys as determined by a nationwide retrospective survey between 1990 and 1999, which found no cases with Addison's form. We reviewed the medical records of eleven Japanese boys with X-ALD from 1990 to 2010 in our institute. Eight patients were detected by neuropsychological abnormalities, whereas a higher prevalence of unrecognized adrenocortical insufficiency (5/11: 45%) was observed than previously recognized. While no neurological abnormalities were demonstrated in two brothers, the elder brother had moderate Addison's disease at diagnosis and the presymptomatic younger brother progressed to Addison's disease six months after the diagnosis of X-ALD. Early detection of impaired adrenal function as well as early identification of neurologically presymptomatic patients by genetic analysis is essential for better prognosis. Addison's form might be overlooked in Japan; therefore, X-ALD should be suspected in patients with adrenocortical insufficiency.

Localized donor cells in brain of a Hunter disease patient after cord blood stem cell transplantation.

The efficacy of hematopoietic stem cell transplantation (HSCT) for Hunter disease (deficiency of iduronate-2-sulfatase, IDS) remains unclear. We treated a 6-year-old male suffering from a severe type of Hunter disease with cord blood stem cell transplantation (CBSCT); however, he died at 10 months post-therapy due to a laryngeal post-transplantation lymphoproliferative disorder. During the follow-up period after CBSCT, his hyperactivity, estimated mental age, and brain MR findings had not improved. We assessed the efficacy of CBSCT by biochemical and pathological analyses of the autopsied tissues. There were many distended cells with accumulated substrate in the brain, but not in the liver. IDS enzyme activity in the cerebrum remained very low, although that in the liver reached about 40% of the normal control level. However, a variable number of tandem repeats analyses demonstrated a weak donor-derived band not only in the liver but also in the cerebrum. Furthermore, IDS-immunoreactivity in the liver was recognized broadly not only in Kupffer cells but also in hepatocytes. On the other hand, IDS-immunoreactivity was recognized exclusively in CD68-positive microglia/monocytes in the patient's brain; whereas that in the normal brain was also detected in neurons and oligodendrocytes. These donor-derived IDS-positive cells were predominantly localized in perivascular spaces and some of them were evidently present in the brain parenchyma. The efficacy of CBSCT was judged to be insufficient for the brain at 10 months post-therapy. However, the pathological detection of donor-derived cells in the brain parenchyma suggests the potential of HSCT for treatment of neurological symptoms in Hunter disease. This is the first neuropathological report documenting the distribution of donor-derived cells in the brain after CBSCT into a Hunter disease patient.

Intermittent oral trimethoprim/sulfamethoxazole on two non-consecutive days per week is effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation.

Pneumocystis jiroveci pneumonia (PCP) is a serious complication in patients receiving chemotherapy or hematopoietic stem cell transplantation. Current recommendations for trimethoprim-sulfamethoxazole (TMP-SMZ) dosing as PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing three consecutive days per week. We report our experience of prophylaxis with TMP-SMZ twice daily on two non-consecutive days per week in 145 immunocompromised children with hematologic disorders, cancer, or metabolic disorders following chemotherapy or hematopoietic stem cell transplantation. There were no breakthrough cases of PCP. We therefore conclude our prophylaxis regimen is effective against PCP in immunocompromised children.

Ex vivo-expanded donor CD4(+) lymphocyte infusion against relapsing neuroblastoma: A transient graft-versus-tumor effect.

High-risk neuroblastoma has a poor prognosis despite multimodal treatment including high-dose chemotherapy. A 7-year-old male with neuroblastoma received ex vivo-expanded donor CD4(+) T lymphocyte infusion (CD4(+) DLI) after recurrence in the bone marrow following allogeneic hematopoietic stem cell transplantation from his HLA-identical mother. The disease transiently responded to CD4(+) DLI with reduction of tumor cells and a decrease of serum neuron-specific enolase. The response was associated with development of continued high fever and an increase of cytotoxic T lymphocytes in peripheral blood. This case suggests a possibility of a graft-versus-tumor effect against neuroblastoma.

Antifungal prophylaxis with micafungin in patients treated for childhood cancer.

BACKGROUND: Invasive fungal infections (IFIs) remain a major cause of infectious morality in neutropenic patients receiving chemotherapy or hematopoietic stem cell transplantation (HSCT). Micafungin exhibits broad antifungal activity against both Aspergillus and Candida species. We performed a retrospective study to determine the efficacy and safety of prophylactic micafungin against IFI in pediatric neutropenic patients during chemotherapy or HSCT. PROCEDURE: Forty patients were given micafungin (3 mg/kg/day) intravenously for neutropenia: 131 patient-cycles (39 patients) after chemotherapy and 15 patient-cycles (14 patients) after HSCT. Median duration of neutropenia and micafungin prophylaxis was 13 and 23 days after chemotherapy and HSCT, respectively. RESULTS: Treatment success rate, defined as absence of proven, probable, possible, or suspected IFIs, was 93.9% (121/131) and 80.0% (12/15) for chemotherapy and HSCT, respectively. Proven or probable IFI was documented in only one patient after HSCT. No adverse events were observed that could be related to micafungin prophylaxis. CONCLUSIONS: These results suggest that prophylactic micafungin is well tolerated and may prevent IFIs in pediatric patients with neutropenia receiving chemotherapy or HSCT.

WT1 (Wilms tumor 1) peptide immunotherapy for childhood rhabdomyosarcoma: a case report.

Immunotherapy using a Wilms tumor (WT1) peptide has been undergoing clinical trials for adulthood leukemia and solid cancer with promising results. In this study, the authors used WT1 peptide vaccination to treat a 6-year-old girl with metastatic alveolar rhabdomyosarcoma. She received weekly intradermal injection with HLA-A*2404-restricted, 9-mer WT1 peptide against residual bone disease. After 3 months her bone disease disappeared, concurrent with an increase in the frequency of WT1-specific cytotoxic T lymphocytes (CTLs). A high proportion of WT1-specific CTLs with effector or effector memory phenotype were detected in peripheral blood of this patient. She is currently still on continued WT1 peptide immunotherapy in a disease-free condition for 22 months. WT1 peptide-based immunotherapy should be a promising option for high-risk rhabdomyosarcoma in childhood.

Umbilical cord-blood transplantations from unrelated donors in patients with inherited metabolic diseases: Single-institute experience.

We evaluated the feasibility of UCBT from unrelated donors and a myeloablative preparative regimen that did not involve anti-thymocyte globulin in five children with lysosomal and peroxisomal diseases. Patients with MPS II (n = 1), adrenoleukodystrophy (n = 1), metachromatic leukodystrophy (n = 2), and Krabbe disease (n = 1) received UCBT between December 2001 and September 2005. All patients received oral Bu (600 mg/m2), CY (200 mg/kg IV), and fludarabine (180 mg/m2 IV). Prophylaxis for GVHD consisted of a combination of tacrolimus and a short methotrexate course. Neutrophil engraftment occurred a median of 24 days (range, 21-25) after transplantation. None had graft rejection. One patient developed grade III acute GVHD and the other four patients had grade I acute GVHD; none had extensive chronic GVHD. One patient developed hemorrhagic cystitis. There were no treatment-related deaths. Although one child with MPS II died of PTLD 10 months after the UCBT, four of the five children are alive 14, 20, 31, and 55 months after transplantation with complete donor chimerism. These results suggest the feasibility of the UCBT with Bu, fludarabine, and CY-preparative regimen for patients with inherited metabolic diseases.