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Biomedical subjects

Shigeru Ohta

Publications and source records attributed to Shigeru Ohta.

At least 19 recordsLinked to original sources
PubMed2003

TRAIL/Apo2L ligands induce apoptosis in malignant rhabdoid tumor cell lines.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a potent inducer of apoptosis in various cancer cells, whereas normal cells are not sensitive to TRAIL-mediated apoptosis. Four TRAIL/Apo2L receptors (DR4, DR5, DcR1, and DcR2) have been identified. DR4 and DR5 have a death domain, whereas DcR1 and DcR2 are called decoy receptors because of their incomplete or lack of a death domain. Malignant rhabdoid tumor (MRT) is an aggressive neoplasm showing a poor prognosis because of its resistance to chemotherapeutic agents. In this study, we examined whether TRAIL could induce apoptotic cell death in MRT cell lines. We found that although half of the MRT cell lines examined were sensitive to TRAIL/Apo2L, Western blot analysis revealed that the expression of DcR2 was low in TRAIL-sensitive MRT cells. We examined the effect of doxorubicin on the expression levels of TRAIL receptors and its enhancement on the susceptibility of MRT cell lines to TRAIL. Western blot and flow cytometric analyses revealed that doxorubicin significantly increased the expression of DR5, and somewhat up-regulated the expression of DR4 and DcR2. Moreover, doxorubicin, NF-kappaB inhibitor (SN50), and PI3-kinase/Akt inhibitor (wortmannin, LY294002) enhanced the susceptibility of MRT cell lines to TRAIL/Apo2L-induced apoptosis. These results suggest that TRAIL/Apo2L may provide the basis for clinical trials of TRAIL-based treatment to improve the outcome of MRT patients.

Animals↗
PubMed2003

Estrogenic activity of an environmental pollutant, 2-nitrofluorene, after metabolic activation by rat liver microsomes.

In this study, the metabolic activation of 2-nitrofluorene (NF) to estrogenic compounds was examined. NF was negative in estrogen reporter assays using estrogen-responsive yeast and human breast cancer cell line MCF-7. However, the compound exhibited estrogenic activity after incubation with liver microsomes of 3-methylcholanthrene-treated rats in the presence of NADPH. Minor estrogenic activity was observed when liver microsomes of untreated or phenobarbital-treated rats were used instead of those from 3-methylcholanthrene-treated rats. When the compound was incubated with the liver microsomes of 3-methylcholanthrene-treated rats in the presence of NADPH, 7-hydroxy-2-nitrofluorene (7-OH-NF) was formed as a major metabolite. However, little of the metabolite was formed by liver microsomes of untreated or phenobarbital-treated rats. Rat recombinant cytochrome P450 1A1 exhibited a significant oxidase activity toward NF, affording 7-OH-NF. Liver microsomes of phenobarbital-treated rats also enhanced oxidase activity toward NF. In this case, 9-hydroxy-2-nitrofluorene was formed. 7-OH-NF exhibited a significant estrogenic activity, while the activity of 9-hydroxy-2-nitrofluorene was much lower. These results suggest that the estrogenic activity of NF was due to formation of the 7-hydroxylated metabolite by liver microsomes.

Air Pollutants↗
PubMed2003

Kawasaki disease complicated by cerebral infarction.

An 8-month-old boy presented with right hemiplegia of sudden onset after 20 days of Kawasaki disease, which was not initially treated by gamma globulin. Cranial X-ray computed tomography confirmed cerebral infarction as the cause of the right hemiplegia. In subsequent weeks, he developed multiple thromboses in coronary aneurysms. He successfully underwent intracoronary thrombolysis using tissue plasminogen activator without haemorrhagic complications. Cerebral infarction as a complication of Kawasaki disease is rare, and is a difficult clinical situation to manage.

Cerebral Infarction↗
PubMed2003

Malignant rhabdoid tumor shows a unique neural differentiation as distinct from neuroblastoma.

Malignant rhabdoid tumors (MRT) show a multiphenotypic diversity, including a neural phenotype. To elucidate the difference in neural characteristics between MRT and neuroblastoma, we examined the expression of synapsin I, neuron-restrictive silencer factor (NRSF), neurofilament medium-size (NF-M) and chromogranin A (CGA) in five MRT cell lines (TM87-16, STM91-01, TTC549, TTC642 and YAM-RTK1) and five neuroblastoma cell lines under differentiation-induction with 12-O-tetradecanoylphorbol-13-acetate (TPA). Our results showed TM87-16 and TTC642 cells, expressed synapsin I and NF-M before TPA induction, had a neural phenotype. After differentiation-induction, only TM87-16 cells expressed CGA. Among all neuroblastoma cells, expression of NF-M and CGA was stable at a high level throughout TPA-induced differentiation. In TM87-16 and TTC642 MRT cells, synapsin I mRNA promptly increased after TPA differentiation, with the peak level at 6 h, and thereafter, synapsin I mRNA rapidly decreased in a time-dependent manner. The decreased expression of synapsin I correlated with an increased expression of NRSF during differentiation-induction. In contrast, in some neuroblastoma cells, a significant up-regulation of synapsin I was observed concurrently with a down-regulation of NRSF. The inverse relationship between NRSF and synapsin I expression in TM87-16 and TTC642 MRT cells was opposite to that of neuroblastoma cells. Our results showed that the neural characteristics of these MRT cells are fairly distinct from those of neuroblastoma cells. These MRT cells appeared to have only limited capability for neural differentiation, and were still in an extremely early stage of neural differentiation.

Cell Differentiation↗
PubMed2003

In vitro metabolism of fenthion and fenthion sulfoxide by liver preparations of sea bream, goldfish, and rats.

The in vitro metabolism of fenthion and its sulfoxide (fenthion sulfoxide) in sea bream (Pagrus major) and goldfish (Carassius auratus) was investigated and compared with that in rats. Fenthion was oxidized to fenthion sulfoxide and the oxon derivative, but not to its sulfone, in the presence of NADPH by liver microsomes of sea bream, goldfish, and rats. These liver microsomal activities of the fish were lower than those of rats but were of the same order of magnitude. The NADPH-linked oxon- and sulfoxide-forming activities of liver microsomes of the fish and rats were inhibited by SKF 525-A, metyrapone, alpha-naphthoflavone, and carbon monoxide. The oxidizing activity to fenthion sulfoxide was also inhibited by alpha-naphthylthiourea. Several cytochrome P450 isoforms and flavin-containing monooxygenase 1 exhibited these oxidase activities. Fenthion sulfoxide was reduced to fenthion with liver cytosol of the fish and rats upon addition of 2-hydroxypyrimidine, N(1)-methylnicotinamide, or butyraldehyde, each of which is an electron donor of aldehyde oxidase, under anaerobic conditions. The activity was inhibited by menadione, beta-estradiol, and chlorpromazine, which are inhibitors of aldehyde oxidase. The activities in the fish livers were similar to those of rat liver. Aldehyde oxidase purified from the livers of sea bream and rats exhibited the reducing activity. Thus, fenthion and fenthion sulfoxide are interconvertible in fish and rats through the activities of cytochrome P450, flavin-containing monooxygenase, and aldehyde oxidase.

Animals↗
PubMed2003

Xanthine oxidase-catalyzed metabolism of 2-nitrofluorene, a carcinogenic air pollutant, in rat skin.

The reductive metabolism of 2-nitrofluorene, a carcinogenic air pollutant, in rat skin microsomes and cytosol was investigated. 2-Nitrofluorene was reduced to the corresponding amine by the microsomes with NADPH and by the cytosol with 2-hydroxypyrimidine or 4-hydroxypyrimidine under anaerobic conditions. The cytosolic activity was much higher than that of skin microsomes. The 2- or 4-hydroxypyrimidine-linked nitroreductase activity was inhibited by oxypurinol and (+/-)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one (BOF-4272), inhibitors of xanthine oxidase, but not by menadione, chlorpromazine and isovanillin, inhibitors of aldehyde oxidase. When skin cytosol was applied to a DEAE-cellulose column, the fractions containing xanthine oxidase exhibited a marked 2-hydroxypyrimidine-linked nitroreductase activity. In contrast, the aldehyde oxidase fraction showed little activity. Nitroreductase fractions obtained by ion exchange chromatography showed a band in Western blotting analysis using anti-rat xanthine oxidase. Moreover, the xanthine oxidase fraction exhibited a significant nitroreductase activity in the presence of 2-hydroxypyrimidine, 4-hydroxypyrimidine or hypoxanthine, and these activities were inhibited by inhibitors of xanthine oxidase. These results indicated that reduction of 2-nitrofluorene in the skin was mainly catalyzed by xanthine oxidase.

Air Pollutants↗
PubMed2003

Relationship between cord blood level of IgE specific for Dermatophagoides pteronyssinus and allergic manifestations in infancy.

The relationship between the cord blood level of IgE specific for Dermatophagoides pteronyssinus (Dp-IgE) and the development of allergic disorders in infants was investigated. None of the 10 infants who had no family history of allergic disorders and a cord blood Dp-IgE level of <0.07 IU/ml developed atopic dermatitis by 10 months of age. Among the infants whose mothers had atopy, those with a cord blood Dp-IgE level of > or =0.07 IU/ml showed a higher prevalence of allergic disorders at 3 years of age than those with a cord blood Dp-IgE level of <0.07 IU/ml. These observations suggest that the cord blood Dp-IgE level may be related to allergic manifestations in infancy.

Age Distribution↗
PubMed2003

Estrogenic activity of styrene oligomers after metabolic activation by rat liver microsomes.

In this study we examined estrogenic activity of styrene oligomers after metabolic activation by rat liver microsomes. Trans-1,2-diphenylcyclobutane (TCB), cis-1,2-diphenylcyclobutane (CCB), 1,3-diphenylpropane, 2,4-diphenyl-1-butene, 2,4,6-triphenyl-1-hexene, and 1-alpha-phenyl-4ss-(1 -phenylethyl)tetralin were negative in the yeast estrogen screening assay and estrogen reporter assay using estrogen-responsive human breast cancer cell line MCF-7. However, TCB exhibited estrogenic activity after incubation with liver microsomes of phenobarbital-treated rats in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH). Minor activity was observed when liver microsomes of untreated or 3-methylcholanthrene-treated rats were used instead of those from phenobarbital-treated rats. CCB, 1,3-diphenylpropane, and 2,4-diphenyl-1-butene also exhibited estrogenic activity after metabolic activation by liver microsomes, but the activity was lower than that of TCB. 2,4,6-Triphenyl-1-hexene and 1-alpha-phenyl-4ss-(1 -phenylethyl)tetralin did not show estrogenic activity after such incubation. When TCB was incubated with liver microsomes of phenobarbital-treated rats in the presence of NADPH, three metabolites were detected by high-performance liquid chromatography (HPLC). One metabolite isolated by HPLC exhibited a significant estrogenic activity. The active metabolite was identified as trans-1-(4-hydroxyphenyl)-2-phenylcyclobutane by mass and nuclear magnetic resonance spectral analysis. These results suggest that the estrogenic activity of TCB was caused by the formation of the 4-hydroxylated metabolite.

Animals↗
PubMed2003

Antiandrogenic activity and metabolism of the organophosphorus pesticide fenthion and related compounds.

We investigated the endocrine-disrupting actions of the organophosphorus pesticide fenthion and related compounds and the influence of metabolic transformation on the activities of these compounds. Fenthion acted as an antagonist of the androgenic activity of dihydrotestosterone (10(-7)M) in the concentration range of 10(-6)-10(-4)M in an androgen-responsive element-luciferase reporter-responsive assay using NIH3T3 cells. The antiandrogenic activity of fenthion was similar in magnitude to that of flutamide. Fenthion also tested positive in the Hershberger assay using castrated male rats. Marked estrogenic and antiestrogenic activities of fenthion and related compounds were not observed in MCF-7 cells. When fenthion was incubated with rat liver microsomes in the presence of NADPH, the antiandrogenic activity markedly decreased, and fenthion sulfoxide was detected as a major metabolite. The oxidase activity toward fenthion was exhibited by cytochrome P450 and flavin-containing monooxygenase. Fenthion sulfoxide was negative in the screening test for antiandrogens, as was fenthion sulfone. However, when fenthion sulfoxide was incubated with liver cytosol in the presence of 2-hydroxypyrimidine, an electron donor of aldehyde oxidase, the extract of the incubation mixture exhibited antiandrogenic activity. In this case, fenthion was detected as a major metabolite of the sulfoxide. Metabolic interconversion between fenthion and fenthion sulfoxide in the body seems to maintain the antiandrogenic activity.

Androgen Antagonists↗
PubMed2002

Malignant rhabdoid tumor shows incomplete neural characteristics as revealed by expression of SNARE complex.

To elucidate the biological differences in neural phenotype between malignant rhabdoid tumor (MRT) and neuroblastoma cell lines, we examined the expression of solube N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) complex proteins in MRT cell lines under differentiation induction with 12-O-tetradecanoylphorbol-13-acetate (TPA). Six MRT cell lines (TM87-16, STM91-01, TTC642, TTC549, YAM-RTK1, and TTC1240) and six neuroblastoma cell lines (IMR-32, NH12, SCCH26, TGW, NB-1, and NB-NR) were used in this study. Expression of SNAREs: the vesicle SNARE (synaptotagmin, synaptophysin, and synaptobrevin-2) and the target SNARE (syntaxin 1A, SNAP-25A/B) was examined. Our results showed that in MRT cells, only two cell lines (TM87-16, TTC642) expressed the vesicle SNARE and the target SNARE with the exception of SNAP-25B, while all neuroblastoma cells expressed the entire SNARE complex. During differentiation, synaptotagmin was upregulated in these two MRT cell lines. Interestingly, synaptophysin was downregulated in these MRT cell lines in contrast with the neuroblastoma cell lines. SNAP-25B was not expressed in MRT cells after differentiation with TPA. MRT cells having a neural phenotype morphologically looked like neuroblastoma cells after treatment with TPA. However, the expression of SNARE complex was incomplete in MRT cells. Our results suggest that the biological characteristics of MRT cells with neural phenotype are distinct from those of neuroblastoma cells.

Blotting, Western↗
PubMed2002

Outcome of infants with neuroblastoma detected by mass screening and surgically treated in Shiga Prefecture, Japan: what is the role of surgery?

To investigate retrospectively the clinical and biological features that influence the outcome of infants with neuroblastoma (NB) detected by mass screening (NBMS), and to construct surgical strategies to deal with NBMS, 20 infants diagnosed as having either NB or ganglioneuroblastoma (GNB) between 1986 and 1998 were enrolled in a study. They comprised 15 boys and 5 girls ranging in age from 7 to 14 months. The following factors were analyzed by multivariate analysis: age, stage according to the Japanese staging system at the time of diagnosis, site of the primary tumor, histologic findings, preoperative urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels, VMA/HVA ratio, lactate dehydrogenase, neuron-specific enolase, Shimada's histologic classification, amplification of the N- myc oncogene by Southern blot analysis, nuclear content, and chromosomal abnormality. The 2-year survival was 95.0% (19/20). The site of the primary tumor was the adrenal gland in 12 cases, retroperitoneum in 6, and retrothoracic space in 2. Four infants had stage I, 6 stage II, 3 stage III, 3 stage IVB, and 4 stage IV disease. Complete resection was achieved in all cases except for 1 retroperitoneal GNB. Histologic examination showed that 8 patients had NB. Of the 12 GNBs, 8 were poorly-differentiated and 1 was well-differentiated. Only 1 of the 14 examined tumors showed amplification of N- myc (20 copies). The infant with N- myc-positive NB (stage II) died 23 months after surgery in spite of aggressive postoperative chemotherapy. Multivariate analysis revealed the plasma NSE level to be a significant predictor of survival (p < 0.0143). This suggests that N- myc amplification and plasma NSE level could be closely related to the survival of infants with NBMS. The N- myc-positive NB case implies that even in locoregional NB detected by NBMS, surgical excision should play a central role in the diagnosis of its oncogenic characteristics and indicate any subsequent therapy.

Adrenal Gland Neoplasms↗
PubMed2002

Determination method of 1-methyl-1,2,3, 4-tetrahydroisoquinoline, an endogenous parkinsonism-preventing substance, by radioimmunoassay.

To develop a sensitive and simple assay method for 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), an endogenous parkinsonism-preventing substance, we designed two kinds of 1MeTIQ-bovine serum albumin (BSA) conjugates to recognize the methyl group at the 1 position of 1MeTIQ since this is the critical structural difference between 1MeTIQ and parkinsonism-inducing substances. These hapten antigens were synthesized from 1MeTIQ analogues and BSA. A specific antiserum against 1MeTIQ was obtained from a rabbit immunized with one of the hapten antigens. To utilize this antiserum for radioimmunoassay, detailed studies were carried out to establish optimum conditions. The antiserum recognized 1MeTIQ and showed little cross-reactivity with endogenous 1MeTIQ analogues and proteins. It was confirmed to be suitable for radioimmunoassay, and a standard curve was prepared in the range of 0.5 to 100 pmol of 1MeTIQ. This method was sensitive enough to measure endogenous 1MeTIQ in rat brain. This method should be applicable for evaluation of the progression or prognosis of Parkinson's disease (PD).

Animals↗
PubMed2002

Thyroid hormonal activity of the flame retardants tetrabromobisphenol A and tetrachlorobisphenol A.

The thyroid hormonal-disrupting activity of the flame retardants tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) was examined and compared with that of bisphenol A, a typical estrogenic xenobiotic. TBBPA and TCBPA, halogenated derivatives of bisphenol A, markedly inhibited the binding of triiodothyronine (T(3); 1 x 10(-10) M) to thyroid hormone receptor in the concentration range of 1 x 10(-6) to 1 x 10(-4) M, but bisphenol A did not. The thyroid hormonal activity of TBBPA and TCBPA was also examined using rat pituitary cell line GH3 cells, which grow and release growth hormone (GH) depending on thyroid hormone. TBBPA and TCBPA enhanced the proliferation of GH3 cells and stimulated their production of GH in the concentration range of 1 x 10(-6) to 1 x 10(-4) M, while bisphenol A was inactive. TBBPA, TCBPA, and bisphenol A did not show antagonistic action, i.e., these compounds did not inhibit the hormonal activity of T(3) to induce growth and GH production of GH3 cells. TBBPA and TCBPA, as well as bisphenol A, enhanced the proliferation of MtT/E-2 cells, whose growth is estrogen-dependent. These results suggest that TBBPA and TCBPA act as thyroid hormone agonists, as well as estrogens.

Animals↗
PubMed2002

Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson's disease: studies using heterologous expression systems of the dopamine transporter.

Endogenous isoquinoline (IQ) derivatives structurally related to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridine (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease. We addressed the importance of the DAT molecule for selective dopaminergic toxicity by testing the differential cytotoxicity of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (3, IQs; 4,3,4-dihydroisoquinolines and 15, 1,2,3,4-tetrahydroisoquinolines) as well as MPP(+) in non-neuronal and neuronal heterologous expression systems of the DAT gene (human embryonic kidney HEK-293 and mouse neuroblastoma Neuro-2A cells, respectively). Cell death was estimated using the MTT assay and the Trypan blue exclusion method. Nine isoquinolines and MPP(+) showed general cytotoxicity in both parental cell lines after 72hr with half-maximal toxic concentrations (TC(50) values) in the micromolar range. The rank order of toxic potency was: papaverine>salsolinol=tetrahydropapaveroline=1-benzyl-TIQ=norsalsolinol>tetrahydropapaverine>2[N]-methyl-salsolinol>2[N]-methyl-norsalsolinol>2[N]-Me-IQ(+)=MPP(+). Besides MPP(+), only the 2[N]-methylated compounds 2[N]-methyl-IQ(+), 2[N]-methyl-norsalsolinol and 2[N]-methyl-salsolinol showed enhanced cytotoxicity in both DAT expressing cell lines with 2- to 14-fold reduction of TC(50) values compared to parental cell lines. The rank order of selectivity in both cell systems was: MPP(+)>>2[N]-Me-IQ(+)>2[N]-methyl-norsalsolinol=2[N]-methyl-salsolinol. Our results suggest that 2[N]-methylated isoquinoline derivatives structurally related to MPTP/MPP(+) are selectively toxic to dopaminergic cells via uptake by the DAT, and therefore may play a role in the pathogenesis of Parkinson's disease.

Animals↗
PubMed2002

Marginal decrease in mortality and marked increase in incidence as a result of neuroblastoma screening at 6 months of age: cohort study in seven prefectures in Japan.

PURPOSE: To determine the usefulness of 6-month screening for neuroblastoma. PATIENTS AND METHODS: The cumulative incidence rates (IRs) and cumulative mortality rates (MRs) of neuroblastoma in children younger than 60 months of age were analyzed for control (n = 713,025), qualitative screening (Qual Screen, n = 1,142,519), and quantitative screening (Quan Screen, n = 550,331) cohorts, and for Screened and Unscreened subgroups within screening cohorts. RESULTS: IRs (per 100,000) for infants aged 6 to 11 months were 1.12 in Control, 5.69 in Qual Screen (P <.0001), and 17.81 in Quan Screen (P <.0001); IRs for children aged 12 to 59 months were 7.29 in Control, 5.86 in Qual Screen (P =.28), and 6.36 in Quan Screen (P =.60). IRs for children aged 12 to 59 months in Unscreened or Screened subgroups remained at the same level. When patients diagnosed at younger than 6 months of age were excluded, the MR (per 100,000) under 60 months for Control was 4.21; those in Unscreened and Screened subgroups were 3.84 and 2.53 in Qual Screen (P =.30), and 3.20 and 1.97 in Quan Screen (P =.73), respectively; MRs between Control and Unscreened subgroups revealed no significant differences (P =.89 in Qual Screen, P =.85 in Quan Screen). CONCLUSION: Six-month screening resulted in a marked increase in incidence for infants with no significant decrease in incidence for children older than 1 year of age. A decrease in mortality was observed, but it was not significant. The usefulness of screening is questionable, because the decrease of mortality should be balanced against the adverse effect of overdiagnosis and the psychological burden on parents and children.

Age Factors↗
PubMed2002

Aberrations of the hSNF5/INI1 gene are restricted to malignant rhabdoid tumors or atypical teratoid/rhabdoid tumors in pediatric solid tumors.

The hSNF5/INI1 gene, which encodes a subunit of the SWI/SNF family of chromatin-remodeling complexes and is located at 22q11.2, has been reported as a tumor suppressor gene inactivated in malignant rhabdoid tumors (MRTs). We analyzed this gene in varieties of pediatric solid tumors including MRTs, using the reverse transcription-polymerase chain reaction (PCR) and PCR-single strand conformation polymorphism method. We found 5 homozygous deletions, 2 truncated mutations, one missense mutation, and one silent mutation of the hSNF5/INI1 gene in 7 MRT cell lines, and one homozygous deletion, one microdeletion, one splicing acceptor site mutation, and one absence of expression in 7 fresh tumor tissues of MRT and atypical teratoid (AT)/rhabdoid tumors (RTs). Homozygous deletions were also found in one (KYM-1) of 8 rhabdomyosarcoma (RMS) cell lines. To investigate characteristics of the KYM-1 cell line, we have established KYM-1 tumors in nude mice into which KYM-1 cells were transplanted. Notably, we found that MyoD1, known as a marker for RMS, was not expressed in the KYM-1 cell line as well as MRT cell lines and fresh tumors. Histopathologic, cytogenetic, and molecular studies of the KYM-1 cell line and KYM-1 tumors in nude mice have revealed that this RMS cell line should be MRT rather than RMS. RMS-carrying aberrations of the hSNF5/INI1 gene should be reevaluated. No aberrations of this gene were found in the other 34 cell lines or 80 fresh tumor specimens except the single nucleotide polymorphisms in the 3' noncoding region. These results suggest that alterations of the hSNF5/INI1 gene were restricted to MRTs or AT/RTs in pediatric solid tumors.

Adult↗
PubMed2002

HLA-identical sibling peripheral blood stem cell transplantation in children and adolescents.

Allogeneic peripheral blood stem cell transplantation (PBSCT) was performed in children and adolescents for the treatment of malignant (n = 49) and nonmalignant hematological disease (n = 8). Granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCs were apheresed from 57 HLA-matched siblings aged 9 months to 24 years (median, 8 years) without any serious adverse, effects. No abnormalities were found in these donors for a median follow-up of 25 months (range, 6-56 months). Patients were conditioned with a TBI-containing regimen (n = 17) or a non-TBI regimen (n = 40). GVHD prophylaxis consisted of methotrexate (MTX) plus cyclosporine A (CSP) for 23 patients, CSP plus methylprednisolone (mPDN) for 22 patients, MTX only for 7 patients, CSP only for 4 patients, and MTX plus CSP plus mPDN for 1 patient. Engraftment was prompt, with a median number of days to reach an absolute neutrophil count (ANC) above 0.5 x 10(9)/L of 13 days (range, 8-23 days), with 1 graft failure. Acute GVHD (grades II-IV) occurred in 8 (16%) of 49 evaluable patients, and chronic GVHD developed in 23 (64%) of 36 evaluable patients. Notably, two thirds of chronic GVHD was extensive. The Kaplan-Meier estimate of 3-year disease-free survival was 0% for refractory disease (n = 6), 37.2% +/- 11.8% for high-risk malignancies (n = 25), 81.4% +/- 9.7% for standard-risk malignancies (n = 18), and 100% for nonmalignant disease (n = 8). The estimated 100-day nonrelapse mortality rate was 9.9% +/- 4.2%. In conclusion, allogeneic PBSCT is feasible in a pediatric population. Although the grade of acute GVHD was set low, as in Japanese BMT studies, the incidence and severity of chronic GVHD appears to be relatively high. For nonmalignant disease, the question arises of whether the higher incidence and severity of chronic GVHD is a drawback of this procedure. For high-risk malignancies, whether or not a graft-versus-leukemia effect prevents relapse needs to be clarified in future comparative studies with BMT.

Adolescent↗