A phase III clinical trial of a mixture agent of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors.

INTRODUCTION: MC710, a 1:10 protein weight ratio mixture of plasma-derived activated factor VII (FVIIa) and factor X (FX), is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. We evaluated the haemostatic efficacy and safety of one to two administrations of MC710 in 21 joint, muscle, and subcutaneous bleeding episodes in 14 male patients, in a multi-centre, open-label, non-randomized clinical trial. METHODS: Subjects were intravenously administered one or two doses of 60 or 120 µg kg-1 MC710 (as FVIIa) once or twice (to a maximum of 180 µg kg-1 ) over up to five bleeding episodes per subject. The haemostatic efficacy of MC710 was determined for each episode by investigator evaluation, using changes in visual analogue scale (VAS) for pain relief, and/or knee joint or muscle circumference for swelling reduction, and range of motion (ROM) for improvement of joint mobility. RESULTS: In 21 treatments for bleeding episodes, 19 were rated "excellent" or "effective" 8 h after the last treatment. VAS significantly decreased over time, and ROM significantly improved over time compared with the values before treatment. One mild adverse reaction, decreased blood potassium, and two serious adverse events, both knee joint bleeding, were observed within 1 week after first administration, with no significant effect on safety. Furthermore, diagnostic markers did not show any signs of disseminated intravascular coagulation (DIC). CONCLUSION: These results show that MC710 has sufficient haemostatic efficacy and safety, and can be used as a potential bypassing agent to control bleeding in haemophilia patients with inhibitors.

Survival of HER2-positive primary breast cancer patients treated by neoadjuvant chemotherapy plus trastuzumab: a multicenter retrospective observational study (JBCRG-C03 study).

We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87 % [95 % confidence interval (CI) 85-90]. The pathologic complete response (pCR: ypT0/is + ypN0) rate was 51 %. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36 %, P < 0.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82 %, P < 0.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage [hazard ratio (HR) 2.63, 95 % CI 1.36-5.21, P = 0.004 for cN2-3 vs. cN0], histological/nuclear grade 3 (HR 1.81, 95 % CI 1.15-2.91, P = 0.011), and non-pCR (HR 1.98, 95 % CI 1.22-3.24, P = 0.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95 % CI 1.43-4.90, P = 0.002) and clinical tumor stage (HR 2.20, 95 % CI 1.16-4.20, P = 0.017 for cT3-4 vs. cT1-2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95 % CI 1.48-6.62, P = 0.003), clinical nodal stage (HR 4.26, 95 % CI 1.53-13.14, P = 0.005 for cN2-3 vs. cN0), and young age (HR 2.40, 95 % CI 1.12-4.94, P = 0.026 for ≤40 vs. >40) were negative predictors for DFS. Strict pCR (ypT0 + ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95 % CI 1.31-5.97, P = 0.006 and HR 3.86, 95 % CI 1.13-24.21, P = 0.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients.

A Phase II clinical trial of a mixture of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors: haemostatic efficacy, safety and pharmacokinetics/pharmacodynamics.

MC710, a mixture of plasma-derived activated factor VII and factor X at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In a Phase II trial, we evaluated the haemostatic efficacy and safety of single doses of MC710, and investigated pharmacokinetic and pharmacodynamic parameters in nine joint bleeding episodes in six male haemophilia patients with inhibitors. This trial was a multi-centre, open-label, non-randomized study of two doses (60 and 120 µg kg(-1) as FVIIa dose), allowing the re-administration of different MC710 dosages to the same subjects. Haemostatic efficacy was assessed by evaluating reduction in pain and swelling, as well as increase in range of motion in a bleeding joint. The results of the study showed that in nine bleeding episodes, seven treatments were rated as 'excellent' or 'effective' according to investigator's rating system of efficacy at 8 h after administration. No serious or severe adverse events were observed after administration; furthermore, measurement of several diagnostic markers revealed no signs or symptoms of disseminated intravascular coagulation (DIC). The haemostatic potential of MC710 was confirmed at doses of 60 and 120 µg kg(-1) in this trial. MC710 is thus expected to be a safe and efficacious novel bypassing agent for controlling bleeding in haemophilia patients with inhibitors.

Lineage-restricted function of nuclear factor kappaB-inducing kinase (NIK) in transducing signals via CD40.

CD40 signaling in B cells and dendritic cells (DCs) is critical for the development of humoral and cell-mediated immunity, respectively. Nuclear factor kappaB (NF-kappaB)-inducing kinase (NIK) has been implicated as a central transducing kinase in CD40-dependent activation. Here, we show that although NIK is essential for B cell activation, it is dispensable for activation of DCs. Such data provide compelling evidence that different intermediary kinases are used by different cellular lineages to trigger NF-kappaB activation via CD40.

Assembly and regulation of the CD40 receptor complex in human B cells.

CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily. Studies with human B cells show that the binding of CD154 (gp39, CD40L) to CD40 recruits TNF receptor- associated factor 2 (TRAF2) and TRAF3 to the receptor complex, induces the downregulation of the nonreceptor-associated TRAFs in the cell and induces an increased expression of Fas on the cell surface. Combined signaling through the interluekin 4 receptor and CD40 induces an increased expression of Fas with a commensurate increase in the level of TRAF2, but not TRAF3, that is recruited to the receptor complex. In contrast, engagement of the membrane immunoglobulin and CD40 limits Fas upregulation and reduces the recruitment of TRAF2, relative to TRAF3, to the CD40 receptor complex. These studies show that the TRAF composition of the CD40 receptor complex can be altered by signals that influence B cell differentiation.

Expression of uPAR mRNA in peripheral blood is a favourite marker for metastasis in gastric cancer cases.

Urokinase-type plasminogen activator receptor (uPAR) plays a central role in the plasminogen activation cascade and participates in extracellular matrix degradation, cell migration and invasion. We evaluated the expression level of uPAR mRNA and the presence of isolated tumour cells (ITCs) in bone marrow (BM) and peripheral blood (PB) in gastric cancer patients and clarified its clinical significance. We assessed specific uPAR mRNA expression by quantitative real-time reverse transcriptase- polymerase chain reaction (RT-PCR) in BM and PB in 846 gastric cancer patients as well as three epithelial cell markers, carcinoembryonic antigen (CEA), cytokeratin (CK)-19 and CK-7. The uPAR mRNA expression in bone marrow and peripheral blood expressed significantly higher than normal controls (P<0.0001). The uPAR mRNA in BM showed concordant expression with the depth of tumour invasion, distant metastasis, and the postoperative recurrence (P=0.015, 0.044 and 0.010, respectively); whereas in PB, we observed more intimate significant association between uPAR expression and clinicopathologic variables, such as depth of tumour invasion, the distant metastasis, the venous invasion and the clinical stage (P=0.009, 0.002, 0.039 and 0.008, respectively). In addition, the uPAR mRNA expression in PB was an independent prognostic factor for distant metastasis by multivariate analysis. We disclosed that it was possible to identify high-risk patients for distant metastasis by measuring uPAR mRNA especially in peripheral blood at the timing of operation in gastric cancer patients.

Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group.

We evaluated the efficacy of a treatment strategy in which infants with acute lymphoblastic leukemia (ALL) were stratified by their MLL gene status and then assigned to different risk-based therapies. A total of 102 patients were registered on two consecutive multicenter trials, designated MLL96 and MLL98, between 1995 and 2001. Those with a rearranged MLL gene (MLL-R, n=80) were assigned to receive intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT), while those with germline MLL (MLL-G, n=22) were treated with chemotherapy alone. The 5-year event-free survival (EFS) rate for all 102 infants was 50.9% (95% confidence interval, 41.0-60.8%). The most prominent late effect was growth impairment, observed in 58.9% of all evaluable patients in the MLL-R group. This plan of risk-based therapy appears to have improved the overall prognosis for infants with ALL, compared with previously reported results. However, over half the events in patients with MLL rearrangement occurred before the instigation of HSCT, and that HSCT-related toxic events comprised 36.3% (8/22) of post-transplantation events, suggesting that further stratification within the MLL-R group and the development of more effective early-phase intensification chemotherapy will be needed before the full potential of this strategy is realized.

Prophylactic fresh frozen plasma may prevent development of hepatic VOD after stem cell transplantation via ADAMTS13-mediated restoration of von Willebrand factor plasma levels.

We initially conducted a multicenter, randomized trial (n=43), and subsequently a questionnaire study (n=209) of participating hospitals, to evaluate whether infused fresh frozen plasma (FFP) could prevent the occurrence of hepatic veno-occlusive disease (VOD) after stem cell transplantation (SCT). Forty-three patients were divided into two groups: 23 receiving FFP infusions and 20 not receiving it. VOD developed in three patients not receiving FFP. Plasma von Willebrand factor (VWF) antigen levels were lower at days 0, 7 and 28 after SCT in patients receiving FFP than in those not receiving it, whereas plasma ADAMTS13 activity (ADAMTS13:AC) did not differ between them. Plasma VWF multimer (VWFM) was demonstrated to be defective in the high approximately intermediate VWFM during the early post-SCT phase, but there was a significant increase in high VWFM just before VOD onset. This suggests that a relative enzyme-to-substrate (ADAMTS13/high-VWFM) imbalance is involved in the pathogenesis of VOD. To strengthen this hypothesis, the incidence of VOD was apparently lower in patients receiving FFP infusions than in those not receiving it (0/23 vs 3/20) in the randomized trial. Further, the results combined with the subsequent questionnaire study (0/36 vs 11/173) clearly showed the incidence to be statistically significant (0/59 vs 14/193, P=0.033).

Sensitivity to dexamethasone and absence of bcl-2 protein in Burkitt's lymphoma cell line (Black93) derived from a patient with acute tumor lysis syndrome: comparative study with other BL and non-BL lines.

An Epstein-Barr virus (EBV)-negative Burkitt's lymphoma (BL) cell line, designated Black93, was established in culture from a patient who developed acute tumor lysis syndrome (ATLS). Growth inhibition in vitro by dexamethasone (DXM) and the expression of bcl-2 protein (Bcl-2) were investigated in Black93 and 17 other cell lines derived from EBV-negative or -positive BL, pre-B acute lymphoblastic leukemia (ALL), follicular lymphoma (FL), and EBV-positive lymphoblastoid cell lines of normal B cell origin (B-LCL), assuming an inherent susceptibility of Black93 to cell death. The most marked growth inhibition by DXM was observed in Black93, two other BL, two pre-B-ALL and two FL lines. The other cell lines were less sensitive or were resistant. DNA extracted from the Black93 cells treated with DXM showed a ladder of oligo-nucleosomal DNA on electrophoresis. On testing of fixed smears by indirect immunofluorescence, bcl-2 protein (Bcl-2) was undetectable in Black93 and three BL lines but was detected in all the other cell lines at varying intensity. Western blot analysis showed mostly the same results. In the BL lines, the most DXM-sensitive cell lines lacked Bcl-2 expression, and the DXM-resistant cell lines always expressed Bcl-2. While none of the DXM-resistant cell lines lacked Bcl-2 expression, several pre-B or FL lines that expressed [correction of expessed] Bcl-2 were sensitive to DXM. Black93 is the first reported cell line established from a patient with ATLS. The positive sensitivity to DXM and the lack of Bcl-2 expression observed in Black93 are a major characteristic exhibited frequently by BL lines and, probably, by fresh BL cells. These properties may contribute to the precipitation of ATLS.

Coexpression of cell-surface immunoglobulin (sIg), terminal deoxynucleotidyl transferase (TdT) and recombination activating gene 1 (RAG-1): two cases and derived cell lines.

While it is generally agreed that in the lymphoid differentiation of B lineage cells there is no stage in which cell-surface immunoglobulin (sIg) and terminal deoxynucleotidyl transferase (TdT) are expressed simultaneously, a few B cell acute lymphoblastic leukemia (B-ALL) cases with this phenotype have been reported. Two such cases and the derived cell lines are reported here, in which the expression of recombination activating gene-1 (RAG-1) was also detected. One case was a CD19+ CD22+ HLA-DR+ sIg+ (gamma, kappa) B-ALL. The cell line (Bay9I) also expressed CD10. Karyotypic analysis revealed t(14;18)(q32;q21) and additional aberrations. In the other case, the fresh leukemia cells expressed CD19, CD24 and HLA-DR antigen. The derived cell line (Tree92) also expressed CD22 and sIg (mu, lambda). The karyotype of the Tree92 cells was t(8;14)(q24;q32) with additional aberrations. Tree92 is the first established cell line having both t(8;14)(q24;q32) and TdT. TdT was detected by Northern blotting as well as indirect immunofluorescence analysis. In addition, both Bay9I and Tree92 expressed RAG-1, as detected by Northern blot analysis. Cross-linking of sIg on Tree92 cells with anti-mu antibody led to significant down-regulation of RAG-1 expression. It seems that there is a sIg+ TdT+ RAG-1+ B lineage differentiation stage, and that signaling through sIg can modulate RAG-1 expression.

A new CYP2D6 allele with a nine base insertion in exon 9 in a Japanese population associated with poor metabolizer phenotype.

The CYP2D6 gene of a Japanese sparteine poor metabolizer (PM, proband) showing a urinary sparteine metabolic ratio of 31.6 was analysed, and a heterozygous CYP2D6(D), a deletional type, was found by restriction fragment length polymorphism analysis with Xba I enzyme. The PM did not have any other previously described mutations in the CYP2D6 gene causing the loss of catalytic activity of the CYP2D6 enzyme. Thus, a possible new allele(s) responsible for the PM phenotype was analysed. The results indicated that the PM possessed a new 9-base insertion in exon 9, designated CYP2D6(J9). The CYP2D6(J9) and CYP2D6(D) alleles were clarified to be inherited from the mother [2D6(W)/2D6(J9)] and the father [2D6(W)/2D6(D)], respectively. The 9-base insertion caused a large increase in the apparent K(m) value for bufuralol 1'-hydroxylation as examined by expression of the enzyme protein in yeast. Four of 300 Japanese carried a heterozygous CYP2D6(J9) allele (0.7%, 4/600 chromosomes) as determined by a polymerase chain reaction analysis.

Genetic polymorphism of CYP2D6 in the Japanese population.

The frequencies of CYP2D6 mutations in a Japanese population were investigated. Individuals were classified into three groups: control individuals, cancer patients and Parkinsonians. Genotyping for CYP2D6*3, CYP2D6*4 and CYP2D6*18 was carried out using the polymerase chain reaction, and that for CYP2D6*5 was also carried out using XbaI restriction fragment length polymorphism. The frequencies of the CYP2D6*3, CYP2D6*4, CYP2D6*5 and CYP2D6*18 mutant alleles were 0%, 0.77%, 4.10% and 0.53% in more than 256 Japanese control individuals, respectively. Based on these data, the population frequency of the CYP2D6 poor metabolizer phenotype was estimated to be 0.29%. The distribution of the four mutated alleles was not significantly different between control individuals and cancer patients or Parkinsonians.

Activation of a brain-specific protein kinase C subspecies in the presence of phosphatidylethanol.

Protein kinase C (PKC) is normally activated by diacylglycerol in the presence of Ca2+ and phosphatidylserine. At physiological concentrations of Ca2+, however, phosphatidylethanol, a product of the phospholipase D-catalyzed transphosphatidylation reaction between membrane phospholipids and ethanol, can replace phosphatidylserine, and activate PKC. This mode of activation is most effective for the gamma-subspecies, which is expressed only in central nervous tissue. Phosphatidylmethanol is also effective to some extent. Consideration of these results suggests the possibility that ethanol may exert some effect on signal transduction in this tissue via changes in protein phosphorylation.

Identification of the structures of multiple subspecies of protein kinase C expressed in rat brain.

Rat brain protein kinase C purified to apparent homogeneity [(1986) Biochem. Biophys. Res. Commun. 135, 636-643] was resolved into three distinct fractions, type I, II and III, upon chromatography on a hydroxyapatite column connected to high-performance liquid chromatography. Comparison of each fraction with the four subspecies of protein kinase C, that were separately expressed in COS cells transfected by the respective cDNAs, alpha, beta I, beta II and d gamma, identified the primary structures of these three fractions of protein kinase C. Type I corresponded to the enzyme encoded by the gamma-sequence; type II was a mixture of the two subspecies determined by the beta I- and beta II-sequences; and type III had the structure encoded by the alpha-sequence. The structures and properties of these subspecies of protein kinase C were similar to each other.

Intrathecal prostaglandin E1 produces a long-lasting allodynic state.

The existence of prostaglandin (PG) receptors in the spinal cord has been demonstrated, but their role in sensory processing is not yet well defined. PGE1 is widely used clinically as a vasodilator. The present study was designed to investigate the effects of intrathecally administered PGE1 on the transmission of different types to sensory information, including that associated with noxious somatic, noxious visceral, and non-noxious somatic stimulation. The tail-flick (TF) test was employed to measure responses to noxious somatic stimuli, and the colorectal distension test was used to examine responses to noxious visceral stimuli. Withdrawal response to mechanical pressure produced by Semmes-Weinstein mono-filaments (SWMs) was measured as an assessment of sensitivity to non-noxious mechanical somatic stimulation. TF latencies and colorectal distension thresholds decreased for a short time (10-20 min) following the intrathecal (i.t.) administration of both 100 ng or 500 ng of PGE1. In sharp contrast to these short duration effects, there was a long-lasting increase in agitation scores (allodynia) produced by 3 different intensities of SWMs (0.217, 0.745 and 2.35 g) after administration of PGE1. The changes in agitation scores to SWMs were dependent on the dose of PGE1 and the intensity of stimulation. This increase of agitation score was seen when PGE1 was administered through the i.t. catheter or by direct i.t. puncture and the increase lasted for at least 2 days after drug administration. Intrathecal administration of saline, however, did not produce any changes in TF latencies, colorectal distension thresholds, or agitation scores produced by SWMs. No significant histological difference was seen between spinal cords exposed to 500 ng PGE1 and saline 48 h after drug administration. These results demonstrate that PGE1 may trigger a hypersensitive (allodynic and/or hyperalgesic) state in sensory processing pathways at the spinal level. They also indicate that long-lasting changes in processing of non-noxious, but not noxious, information produced by PGE1 continues after the disappearance of the direct action of PGE1.

Rapid determination of hepatitis B surface antigen (HBsAg) by latex agglutination using an integrating sphere turbidimetric assay.

A method for determining levels of serum HBs antigen has been developed, applying the principles of the integrating sphere turbidimetric assay (ISTA). Using this method, the minimum detectable level of HBs antigen is 15 ng/ml, i.e., it is three times more sensitive than the reversed passive hemagglutination (RPHA) method. Reproducibility and specificity are also excellent with ISTA. With a cut-off level of 20 ng/ml, the highest reading possible with this method is 1000 ng/ml. Serum HBs antigen can readily be measured by this method if a fully automated EL-1000 analyzer is used. This rapid and simple method of measurement should be clinically useful.

Tissue-engineered vascular autograft: inferior vena cava replacement in a dog model.

Tissue-engineered vascular autografts (TEVAs) were made by seeding 4-6 x 10(6) of mixed cells obtained from femoral veins of mongrel dogs onto tube-shaped biodegradable polymer scaffolds composed of a polyglycolid acid (PGA) nonwoven fabric sheet and a copolymer of L-lactide and caprolactone (n = 4). After 7 days, the inferior vena cavas (IVCs) of the same dogs were replaced with TEVAs. After 3, 4, 5, and 6 months, angiographies were performed, and the dogs were sacrificed. The implanted TEVAs were examined both grossly and immunohistologically. The implanted TEVAs showed no evidence of stenosis or dilatation. No thrombus was found inside the TEVAs, even without any anticoagulation therapy. Remnants of the polymer scaffolds were not observed in all specimens, and the overall gross appearance similar to that of native IVCs. Immunohistological staining revealed the presence of factor VIII positive nucleated cells at the luminal surface of the TEVAs. In addition, lesions were observed where alpha-smooth muscle actin and desmin positive cells existed. Implanted TEVAs contained a sufficient amount of extracellular matrix, and showed neither occlusion nor aneurysmal formation. In addition, endothelial cells were found to line the luminal surface of each TEVA. These results strongly suggest that "ideal" venous grafts with antithrombogenicity can be produced.

A case of hemophagocytic lymphohistiocytosis with prolonged remission after syngeneic bone marrow transplantation.

We report a 7-year-old girl with hemophagocytic lymphohistiocytosis who received a syngeneic bone marrow transplant from her twin sister. She presented with high fever and cough. Laboratory findings revealed pancytopenia, elevation of liver enzymes, and hyperferritinemia. Bone marrow examination revealed histiocytic hemophagocytes and lymphoblastoid cells. Southern blot analysis of the bone marrow cells revealed a monoclonal proliferation of EBV-infected lymphocytes. Although she underwent combined chemotherapy according to the HLH-94 protocol, she developed severe pancytopenia. Following myeloablative conditioning with busulfan (16 mg/kg), cyclophosphamide (120 mg/kg), and etoposide (1.5 g/m2), she was transplanted with 6.6 x 10(8)/kg mononuclear cells from the twin sister. She remains in complete remission 23 months after transplantation.

Lack of clinical utility of minimal residual disease detection in allogeneic stem cell recipients with childhood acute lymphoblastic leukemia: multi-institutional collaborative study in Japan.

The clinical utility of minimal residual disease (MRD) measurements following allogeneic stem cell transplantation (SCT) in childhood ALL is controversial. We therefore performed a multi-institutional study of MRD in bone marrow samples taken before SCT and at 1, 3, 6 and 12 months after SCT. Case-specific clonal rearrangements of IgH and TCR genes and expression levels of Wilms' tumor 1 (WT1) mRNA were determined by PCR or RT-PCR methods. In total, 95 cases met all criteria for analysis of informative IgH/TCR markers and quantitative WT1 mRNA expression levels. During the 2-year (median 414 days) study period, 20 patients relapsed. Although the proportion of patients with a positive IgH/TCR result before SCT was significantly reduced at 1 month after treatment (P<0.001), attesting the efficacy of SCT, serial measurements of IgH/TCR rearrangements did not correlate with leukemic relapse. Clonal switch was demonstrated in 11 of the 14 patients with bone marrow relapse, indicating that the poor predictive power of the MRD assay most likely reflected the loss of PCR targets. WT1 expression was not related to either MRD detection by IgH/TCR assays or to clinical leukemic relapse. The clinical value of serial MRD monitoring would be limited in ALL patients undergoing SCT.

Allogeneic hematopoietic stem cell transplantation for patients with hemophagocytic syndrome (HPS) in Japan.

Seventeen cases (age at onset, 1 month to 18 years; M/F, 9/8) of hemophagocytic syndrome which received allogeneic hematopoietic stem cell transplantation (SCT) in Japan during the period 1988-1998 are reported. The patients consisted of six familial inheritance-proven erythrophagocytic lymphohistiocytosis (FEL), five familial inheritance-unknown and infective agents-unknown HLH (of which two were highly likely to have been FEL with characteristic CNS signs), and six aggressive Epstein-Barr virus (EBV)-related HLH (of which two were natural killer cell-type large granular leukemia/lymphoma-associated hemophagocytic syndrome, EBV-NK-LGLL-HPS). All cases were treated intensively with immuno-chemotherapy, or with chemotherapy before SCT. As sources of SCT, 12 cases received bone marrow cells (sibling six, father one, URD five), two cord blood, two purified CD34-positive cells, and one PBSC. SCTs were successful in all 17 cases, apart from one receiving CD34-positive SCT. Following SCT, four patients relapsed and five died with a median follow-up of 23 months. Among the relapsed cases, the two EBV-NK-LGLL-HPS previously published as successfully transplanted were included. Among the fatal cases, three patients died from relapsed active disease and the remaining two from fatal post-SCT EBV-positive T cell lymphoma and extensive chronic GVHD, respectively. As of the end of September 1998, 10 patients are alive without disease for 3.5 months to 147 months, while two post-SCT patients are still having therapy for residual/recurrent disease. The Kaplan-Meier analysis showed a 2-year event-free survival after SCT as 54.0+/-13.0%.