Biomedical subjects

Kaoru Uchimaru

Publications and source records attributed to Kaoru Uchimaru.

At least 19 recordsLinked to original sources

PubMed2025

A viral clonality evenness score to predict progression to adult T-cell leukaemia in asymptomatic carriers of human T-lymphotropic virus type 1 in Japan: a retrospective longitudinal cohort study.

BACKGROUND: Adult T-cell leukaemia/lymphoma (ATL) is a highly aggressive T-cell malignancy that occurs in approximately 2-7% of individuals with human T-lymphotropic virus type 1 (HTLV-1), after decades of asymptomatic infection. To address the urgent need for predictive biomarkers to identify asymptomatic carriers of HTLV-1 at high risk of progression to ATL, we aimed to evaluate viral clonality sequencing as a potential tool for risk stratification. METHODS: This retrospective longitudinal cohort study involved HTLV-1 carriers enrolled in the Joint Study on Predisposing Factors of ATL Development, a nationwide cohort study initiated in Japan in 2002. Participants were selected from this cohort on the basis of their baseline proviral load at the time of enrolment as an asymptomatic carrier, length of follow-up, and clinical outcome. The cohort was subdivided into three subgroups: the first comprising HTLV-1 carriers who developed ATL, the second comprising carriers with high proviral load (≥4%) who did not progress to ATL, and the third comprising carriers with low proviral load (<4%) who did not progress to ATL. DNA extracted from peripheral blood mononuclear cells collected at enrolment and at least one follow-up visit was analysed by HTLV-1 clonality sequencing and the proviral load was quantified. We calculated a viral clonality evenness (VCE) score, based on the Shannon Evenness Index, to quantify the uniformity of the clonal distribution of samples, for which 0 represents a perfectly monoclonal architecture and 1 indicates a completely polyclonal landscape. We then estimated the performance of proviral load thresholds and VCE scoring to classify the risk of progression to ATL using the area under the receiver operating characteristic curve (AUC), the accuracy, and Matthews correlation coefficient. VCEs were compared between participant subgroups with the Wilcoxon rank sum test. FINDINGS: 56 participants followed up by JSPFAD between Feb 6, 2003, and July 19, 2022, were included in this study: 17 who progressed to ATL (mean follow-up 8·3 years [SD 4·0]), 18 who had a high proviral load and did not progress to ATL (9·7 years [3·4]), and 21 who had a low proviral load and did not progress to ATL (7·5 years [3·0]). Clonality sequencing of samples from 39 participants who did not progress to ATL revealed hundreds to thousands of HTLV-1 integration sites at both timepoints, corresponding to multiple clones of low and uniform abundance, and these participants had high VCE scores (≥0·694) at baseline. By contrast, most participants (14 of 17) who progressed to ATL had a single predominant clone or two to four predominant clones at both timepoints, and lower VCE scores (<0·694) at baseline than those who did not progress (p<0·0001). AUCs were very similar for proviral load thresholds (91 [95% CI 80-98]) and VCE scoring (91 [78-100]), although when using methods that give equal weight to every individual, VCE scoring outperformed proviral load thresholds in predicting progression to ATL (accuracy: proviral load 0·76 [95% CI 0·76-0·77], VCE scoring 1·00 [0·99-1·00]; Matthews correlation coefficient: proviral load 0·23 [95% CI 0·19-0·24], VCE scoring 0·91 [0·80-1·00]). Prediction based on VCE scoring indicated no false positives, compared with 20% when using proviral load, although VCE scoring yields a greater number of false negatives (0·3% vs 0·1%). INTERPRETATION: The implementation of VCE scoring in clinical practice could inform early pre-emptive therapeutic interventions, exclusively targeting individuals with HTLV-1 at high risk and aiming to prevent progression to aggressive, treatment-refractory disease. Further validation, including independent confirmation of the performance of VCE scoring in multiple populations and the characterisation of its temporal dynamics, will be crucial to determine its clinical utility and potential integration into care pathways. FUNDING: Association Jules Bordet, FNRS-Télévie, FCC, WALInnov, FLF, JSPS-KAKENHI, and CoBiA.

Humans↗

PubMed2006

Hemorrhagic cystitis in adults after unrelated cord blood transplantation: a single-institution experience in Japan.

Hemorrhagic cystitis (HC) is the main complication after hematopoietic stem cell transplantation (SCT). Adenovirus (AdV) is the leading cause of late-onset HC after SCT in Japan. The incidence and outcome of HC were studied in 77 adults who underwent unrelated cord blood transplantation (CBT). Thirty-two patients developed HC in a median of 19 days (range, 11-170 days) after CBT. The cumulative incidence of HC was 41.8% at 1 year. Ten patients developed gross hematuria. The cumulative incidence of moderate-to-severe HC was 13.2% at 1 year. Only 1 patient developed severe HC; AdV was detected in a urine sample from that patient. AdV was also detected in a urine sample from another patient with moderate HC after CBT. AdV in both patients was identified as AdV type 11. The cumulative incidence of AdV-induced HC was 2.8% at 1 year. The incidence of AdV-induced severe HC after CBT may be relatively low among Japanese adults. The role of other viruses, including BK virus, in the pathogenesis of HC after CBT needs to be examined.

Adenoviridae↗

PubMed2005

Human herpesvirus 6 variant B infection in adult patients after unrelated cord blood transplantation.

Human herpesvirus 6 variant B (HHV-6B) infection was studied in 23 adult patients who underwent cord blood transplantation (CBT). HHV-6B DNA was detected by quantitative polymerase chain reaction analysis after CBT in the sera from 15 patients (65%) at day 14 or 15 (week 2), from 16 patients (70%) at day 21 or 22 (week 3), and from 3 patients (13%) at day 28 or 29 (week 4). HHV-6B DNAemia was found in none of the 20 patients examined at day 7 or 8 (week 1). The overall incidence of HHV-6B DNAemia reached 87% (20 of 23 patients). This incidence was much higher than after unrelated bone marrow transplantation (19%, P < .0001). In CBT patients, positive HHV-6B DNAemia at week 3 was significantly associated with early skin rash (88% versus 14%, P < .005) and grade II-IV acute graft-versus-host disease (aGVHD) (69% versus 14%, P < .05). In contrast, positive HHV-6B DNAemia at week 2 was associated with neither skin rash nor aGVHD. Prospective large-scale studies are needed to determine the role of HHV-6 infection in CBT patients.

Adolescent↗

PubMed2005

Unrelated cord blood transplantation after myeloablative conditioning for adult patients with refractory anemia.

We report the results of unrelated cord blood transplantation (CBT) after myeloablative conditioning in 3 patients with myelodysplastic syndrome-refractory anemia (MDS-RA). All patients were treated with total body irradiation, cytosine arabinoside (Ara-C), and cyclophosphamide, followed by unrelated HLA-mismatched CBT. Granulocyte colony-stimulating factor was infused continuously, starting 12 hours before Ara-C therapy and continuing until the end of Ara-C therapy. All patients received standard cyclosporine and methotrexate therapy as graft-versus-host disease prophylaxis. All patients had myeloid reconstitution, and the times to reach an absolute neutrophil count >0.5 x 10(9)/L were 23, 20, and 26 days. All patients showed full donor chimerism at the time of the first bone marrow examination (on day +42, +43, and +62) after CBT. All patients are alive and free of disease at between 17 and 39 months after CBT. These results suggest that adult MDS-RA patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.

Adult↗

PubMed2005

Atypical hypersensitivity to mosquito bites without natural killer cell proliferative disease in an adult patient.

Hypersensitivity to mosquito bites (HMB) is a rare disorder that occurs in the first 2 decades of life and is considered to be associated with chronic Epstein-Barr virus (EBV) infection and natural killer (NK) cell leukemia/lymphoma. EBV-encoded small nuclear RNA (EBER)-positive NK cells infiltrate the skin lesion at the site of the mosquito bite. In this report, we present the case of an adult patient with mantle cell lymphoma complicated by atypical HMB. The anti-EBV antibody titer of the patient indicated reactivation of chronic infection with this virus, and EBV DNA in the peripheral blood mononuclear cells was detected after chemotherapy by quantitative polymerase chain reaction analysis. However, an in situ hybridization analysis did not detect EBER-positive cells in the skin lesion at the bite site or in the lymph node. Peripheral NK cell lymphocytosis and EBV-associated lymphoproliferative disease did not develop. These findings suggest that some patients with chronic EBV infection may develop HMB without NK cell proliferative disease.

Animals↗

PubMed2004

Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies.

Unrelated cord blood transplantation (CBT) has now become more common, but as yet there have been only a few reports on its outcome compared with bone marrow transplantation (BMT), especially for adults. We studied the clinical outcomes of 113 adult patients with hematologic malignancies who received unrelated BM transplants (n = 45) or unrelated CB transplants (n = 68). We analyzed the hematopoietic recovery, rates of graft-versus-host disease (GVHD), risks of transplantation-related mortality (TRM) and relapse, and disease-free survival (DFS) using Cox proportional hazards models. The time from donor search to transplantation was significantly shorter among CB transplant recipients (median, 2 months) than BM transplant recipients (median, 11 months; P < .01). Multivariate analysis demonstrated slow neutrophil (P < .01) and platelet (P < .01) recoveries in CBT patients compared with BMT patients. Despite rapid tapering of immunosuppressants after transplantation and infrequent use of steroids to treat severe acute GVHD, there were no GVHD-related deaths among CB transplant recipients compared with 10 deaths of 24 among BM transplant recipients. Unrelated CBT showed better TRM and DFS results compared with BMT (P = .02 and P < .01, respectively), despite the higher human leukocyte antigen mismatching rate and lower number of infused cells. These data strongly suggest that CBT could be safely and effectively used for adult patients with hematologic malignancies.

Adolescent↗

PubMed2004

Ganciclovir-related neutropenia after preemptive therapy for cytomegalovirus infection: comparison between cord blood and bone marrow transplantation.

We studied ganciclovir (GCV)-related neutropenia after preemptive therapy for cytomegalovirus infection: 9 of 17 (53%) cord blood transplantation (CBT) patients and 18 of 20 (90%) bone marrow transplantation (BMT) patients developed GCV-related neutropenia with an absolute neutrophil count (ANC) of less than 1,000/microl. Among the patients who did not receive granulocyte colony-stimulating factor, 2 (13%) and 1 (7%) CBT patients, and 10 (56%) and 8 (44%) BMT patients, developed neutropenia with an ANC of less than 500 and 250/microl, respectively. The incidences of neutropenia in patients with an ANC of less than 1,000, 500, and 250/microl were significantly lower after CBT in comparison with BMT. Two BMT patients, but no CBT patients, developed neutropenic fever, and both patients recovered after antibiotic therapy. In CBT patients, a creatinine clearance rate of less than 50 ml/min and an absence of steroid therapy were associated with a greater incidence of GCV-related neutropenia. No risk factors for GCV-related neutropenia were found in BMT patients. These results suggest that GCV may be less toxic to myeloid progenitor cells from cord blood than those from bone marrow.

Adolescent↗

PubMed2004

CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells.

Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) have poor prognosis despite intensive therapeutic intervention. Recently, imatinib, a BCR-ABL tyrosine kinase inhibitor, has been proven to be an effective treatment for Ph(+) ALL, but nearly all patients rapidly acquire resistance. High-dose imatinib administration might overcome this resistance; however, systemic toxicities would likely limit this approach. Therefore, a new delivery system allowing for the specific targeting of imatinib is urgently needed. Because almost all Ph(+) ALL cells express CD19 on their surface, we have developed an immunoliposome carrying anti-CD19 antibody (CD19-liposomes). The internalization efficiency of the CD19-liposomes approached 100% in all Ph(+) ALL cells but was very low in CD19(-) cells. The cytocidal effect of imatinib-encapsulated CD19-liposomes (imatinib-CD19-liposomes) on Ph(+) ALL cell lines and primary leukemia cells from patients with Ph(+) ALL was much greater than that of imatinib with or without control liposomes. Importantly, the imatinib-CD19-liposomes did not affect the colony formation of CD34(+) hematopoietic cells, even at inhibitory concentration of free imatinib. Taken together, these data clearly demonstrate that the imatinib-CD19-liposomes induced specific and efficient death of Ph(+) ALL cells. This new therapeutic approach might be a useful treatment for Ph(+) ALL with fewer side effects than free imatinib.

Antigens, CD19↗

PubMed2004

A novel maxizyme vector targeting a bcr-abl fusion gene induced specific cell death in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Patients with Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) generally have a poor prognosis and would benefit from the development of new therapeutic approaches. We previously demonstrated that an allosterically controllable ribozyme, maxizyme (Mz), can induce apoptosis in chronic myelogenous leukemia (CML) cells. Ph(+) ALL cells harbor a bcrabl fusion gene (e1a2) encoding a 190-kDa fusion protein (p190) involved in disease pathogenesis. In this study, we have designed a Mz that specifically cleaves e1a2 mRNA and transduced this e1a2Mz into Ph(+) ALL cells using a third-generation lentiviral vector system. In 3 of 5 Ph(+) ALL cell lines, e1a2Mz transduction resulted in a significant decrease in viability and increased cell apoptosis. We observed a decrease in e1a2 mRNA in all Ph(+) ALL cells transduced with e1a2Mz, and the e1a2 mRNA level was higher in e1a2Mz-resistant cells than in e1a2Mz-sensitive cells. All samples of primary Ph(+) ALL cells tested showed e1a2Mz-induced growth inhibition and apoptosis. Importantly, e1a2Mz did not influence the colony formation of normal CD34(+) cord blood cells. These results indicate that e1a2Mz kills Ph(+) ALL cells specifically, suggesting that it may be used as a novel gene therapy strategy for Ph(+) ALL.

Apoptosis↗

PubMed2004

Anti-NK cell treatment induces stable mixed chimerism in MHC-mismatched, T cell-depleted, nonmyeloablative bone marrow transplantation.

OBJECTIVE: To clarify natural killer (NK) cell-mediated resistance under cytoreductive conditioning and T cell-depleted bone marrow transplantation, we investigated the effects of host NK cell depletion on engraftment and induction of stable mixed chimerism. METHODS: BALB/c mice (H-2kd) were injected intraperitoneally with anti-asialoGM1 antibody (anti-NK Ab) on day -1. On day 0, they received total body irradiation (TBI) at a dose of 500 cGy, followed by intravenous infusion of 2 x 10(7) T cell-depleted (TCD) bone marrow cells from C57BL/6 mice (H-2kb). Early engraftment and chimerism were determined by the relative ratio of peripheral blood (PB) lymphocytes expressing either H-2kd or H-2kb on day +21. Long-term engraftment and chimerism were evaluated on PB and spleen by multicolor flow cytometry. RESULTS: Although no recipients treated with TBI alone showed engraftment, all the recipients conditioned with anti-NK Ab and TBI showed successful engraftment as well as a donor-dominant pattern of mixed chimerism in both PB and spleen. Spleen cells from recipients with mixed chimerism showed specific tolerance to both host and donor strains, but not to a third party (C3H/He). None of the reconstituted mice showed signs of graft vs host disease, and all survived up to day +330. CONCLUSION: These observations indicate that host NK cell depletion may be used to reduce the intensity of conditioning regimens for engraftment of TCD grafts, and can contribute to establishment of stable mixed chimerism in major histocompatibility complex-mismatched nonmyeloablative transplantation.

Animals↗

PubMed2004

Unrelated cord blood transplantation after myeloablative conditioning in patients over the age of 45 years.

We report the results of unrelated cord blood transplantation (CBT) after myeloablative conditioning in 21 patients over the age of 45 years. Among the patients the median age was 48 years (range, 45-53 years), the median weight was 58.6 kg (range, 43.6-76.2 kg) and the median number of cryopreserved nucleated cells was 2.45 x 10(7)/kg (range, 1.63-3.71 x 10(7)/kg). Nineteen patients had myeloid reconstitution and the median time to more than 0.5 x 10(9)/l absolute neutrophil count was 22 d. A self-sustained platelet count more than 50 x 10(9)/l was achieved in 17 patients at a median time of 49 d. Acute graft-versus-host disease (GVHD) above grade II occurred in 7 of 19 evaluable patients and chronic GVHD occurred in 14 of 16 evaluable patients. Among 14 chronic GVHD patients, in seven patients the disease was extensive. Fifteen patients were alive and free of disease at between 217 and 1798 d after transplantation. With a median follow-up of 847 d, the probability of disease-free survival at 2 years was 71.4%. These results suggest that patients over 45 years of age without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.

Chronic Disease↗

PubMed2004

Unrelated cord blood transplantation with a reduced-intensity conditioning regimen following autologous transplantation for multiple myeloma.

Two patients, 51- and 45-year-old men with stage III immunoglobulin G multiple myeloma, achieved partial and complete remissions, respectively, after conventional chemotherapy. They both received high-dose melphalan (200 mg/m2) with autologous stem cell transplantation (ASCT). Eighty-four and 78 days after ASCT, the patients underwent unrelated cord blood transplantation (CBT) following treatment with total-body irradiation (2 Gy), fludarabine (90 mg/m2), and melphalan (140 mg/m2). Neutrophil engraftment was attained on day +27 in patient 1 and day +15 in patient 2. Full donor chimerism of the marrow cells was confirmed. Regimen-related toxicity in both patients remained within grade I. Grades I and II acute graft-versus-host disease (GVHD) occurred in patients I and 2, respectively, but improved without steroid therapy. Both patients developed limited chronic GVHD of the skin but needed no treatment. The serum paraprotein level in patient 1 decreased further after ASCT and CBT but remained at minimally detectable levels. The serum and urine paraprotein levels in patient 2 remained below detectable limits. These results suggested that CBT with a reduced-intensity conditioning regimen after high-dose chemotherapy with ASCT is a new promising approach for the treatment of multiple myeloma.

Cord Blood Stem Cell Transplantation↗

PubMed2004

Thyroglobulin-pulsed human monocyte-derived dendritic cells induce CD4+ T cell activation.

Although thyroglobulin (Tg) would be expected to act as a tumor-associated antigen that might be exploitable by immunotherapy against thyroid cancers, it remains unclear how to effectively enhance the immune response to Tg in human since it is a self-component glycoprotein. We therefore tested whether and how human peripheral blood (PB) monocyte-derived dendritic cells (DCs) pulsed with human (h)Tg would induce activation of hTg-specific T cells. We found that immature DCs (iDCs) exhibited a higher endocytic capacity for fluorescein isothiocyanate-conjugated hTg than did mature DCs (mDCs). Although freshly isolated T cells responded poorly to mDCs, hTg-primed T cells responded much more strongly to hTg pulsed mDCs, which selectively induced IFN-gamma-secreting T cells. These results suggest that hTg-pulsed mDCs enhance the responses of Tg-specific T cells, raising the possibility that vaccination with hTg-pulsed mDCs may be an effective approach as immunotherapy to potentiate thyroid cancer specific therapy.

CD4-Positive T-Lymphocytes↗

PubMed2004

[Vitamin B12 absorption test].

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Absorption↗

PubMed2003

Resolution of Behçet's disease after HLA-mismatched unrelated cord blood transplantation for myelodysplastic syndrome.

In 1991, a 27-year-old woman who presented with recurrent oral and genital ulcers, fever, and erythema nodosum was diagnosed with Behçet's disease (BD). Her symptoms were refractory to conventional therapy. In 1999, pancytopenia was noticed in this patient for the first time, and in 2000, her white blood cell count decreased to 0.94x10(9)/l with 1% myeloblasts and 24% neutrophils. Bone marrow examination showed mild hypocellularity with 8% myeloblasts and 6% mature neutrophils with dysplastic features. A diagnosis of myelodysplastic syndrome (MDS)-refractory anemia with excess blasts was made. Despite marked neutropenia, the BD symptoms continued. Since her neutropenia worsened to 0.24x10(9)/l with 21% neutrophils, the patient underwent cord blood transplantation (CBT) from an unrelated donor in July 2001. Myeloid engraftment was documented on day 26. Grade I acute graft-versus-host disease occurred, but resolved spontaneously. Cyclosporin treatment was reduced gradually and discontinued 6 months after CBT. Twenty-three months after CBT, the patient is doing well and has no signs or symptoms of BD or MDS. These observations suggest that allogeneic hematopoietic stem cell transplantation, which encompasses CBT, may be an effective therapy in patients with high-risk aggressive BD.

Adult↗

PubMed2003

One allele deletion of the RB1 gene in a case of refractory anemia with del(13)(q12q14): a fluorescence in situ hybridization study of the RB1 gene.

The tumor suppressor gene RB1 is known to be located on chromosome band 13q14. We investigated the involvement of the RB1 gene in a case of refractory anemia with del(13)(q12q14) by florescence in situ hybridization (FISH) analysis using the RB1 locus (13q14) DNA probe. Bone marrow cells derived from this patient exhibited a single signal of the RB1 gene in 58 of 100 bone marrow cells, as determined by interphase FISH analysis. Hematopoietic colony-forming assays showed that the absolute number of erythroid, myeloid, and mixed colonies was comparable to that of normal subjects. FISH analysis of selected colonies revealed that only a single signal for the RB1 gene was detected in five of five granulocyte macrophage-colony-forming units (CFUs), four of five erythroid burst-forming units, and two of four mixed CFUs (total 11/14: 78.6%). Thus, the majority of hematopoietic progenitor cells lacked one allele of the RB1 gene, suggesting that in this particular case the RB1 gene played an important role in abnormal hematopoiesis.

Aged↗

PubMed2003

Unrelated cord blood transplantation for adult patients with de novo acute myeloid leukemia.

We report the results of unrelated cord blood transplantation (CBT) for 18 adult patients with de novo acute myeloid leukemia (AML). The median age was 43 years, the median weight was 55.2 kg, and the median number of cryopreserved nucleated cells was 2.51 x 107/kg. Seventeen patients had myeloid reconstitution and the median time to more than 0.5 x 109/L absolute neutrophil count was 23 days. A self-sustained platelet count more than 50 x 109/L was achieved in 16 patients at a median time of 49 days. Acute graft-versus-host disease (GVHD) above grade II occurred in 11 of 17 evaluable patients and chronic GVHD occurred in 14 of 17 evaluable patients. Fourteen patients are alive and free of disease at between 185 and 1332 days after transplantation. The probability of disease-free survival at 2 years was 76.6%. These results suggest that adult AML patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.

Acute Disease↗

PubMed2003

Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome.

We report the results of unrelated cord blood transplantation (CBT) for 13 adult patients with advanced myelodysplastic syndrome (MDS). The median age was 40 years, the median weight was 51 kg, and the median number of infused nucleated cells was 2.43 x 107/kg. Twelve patients had myeloid reconstitution, and the median time to more than 0.5 x 109/L (5 x 108/L) absolute neutrophil count was 22.5 days. A self-sustained platelet count more than 50 x 109/L was achieved in 11 patients at a median time of 49 days. Acute graft versus host disease (GVHD) occurred in 9 of 12 evaluable patients and chronic GVHD in 8 of 11 evaluable patients. Ten patients are alive and free of disease at between 171 and 1558 days after transplantation. The probability of disease-free survival at 2 years was 76.2%. These results suggest that adult advanced MDS patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.

Adult↗