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  • 1
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    Factors Associated with Breakthrough Fungemia Caused by Candida , Trichosporon , or Fusarium Species in Patients with Hematological Disorders
    American Society for Microbiology ; 2022
    In:  Antimicrobial Agents and Chemotherapy Vol. 66, No. 3 ( 2022-03-15)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 66, No. 3 ( 2022-03-15)
    Abstract: Limited data are available on breakthrough fungemia, defined as fungemia that develops on administration of antifungal agents, in patients with hematological disorders. We reviewed the medical and microbiological records of adult patients with hematological diseases who had breakthrough fungemia between January 2008 and July 2019 at Toranomon Hospital and Toranomon Hospital Kajigaya in Japan. A total of 121 cases of breakthrough fungemia were identified. Of the 121 involved patients, 83, 11, 5, and 22 were receiving micafungin, voriconazole, itraconazole, and liposomal amphotericin B, respectively, when the breakthrough occurred. Of the 121 causative breakthrough fungal strains, 96 were Candida species, and the rest were 13 cases of Trichosporon species, 7 of Fusarium species, 2 of Rhodotorula mucilaginosa , and 1 each of Cryptococcus neoformans , Exophiala dermatitidis , and Magnusiomyces capitatus . The crude 14-day mortality rate of breakthrough fungemia was 36%. Significant independent factors associated with the crude 14-day mortality rate were age of ≥60 years ( P =  0.011), chronic renal failure ( P =  0.0087), septic shock ( P  〈   0.0001), steroid administration ( P =  0.0085), and liposomal amphotericin B breakthrough fungemia ( P =  0.0011). An absolute neutrophil count of 〉 500/μL was significantly more common in candidemia in the multivariate analysis ( P = 0.0065), neutropenia and nonallogeneic hematopoietic stem cell transplants were significantly more common in Trichosporon fungemia ( P =  0.036 and P =  0.033, respectively), and voriconazole breakthrough fungemia and neutropenia were significantly more common in Fusarium fungemia ( P =  0.016 and P =  0.016, respectively). The epidemiological and clinical characteristics of breakthrough fungemia of patients with hematological disorders were demonstrated. Some useful factors to predict candidemia, Trichosporon fungemia, and Fusarium fungemia were identified.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/aac.02081-21
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
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  • 2
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    Invasive Fungal Infections in Reduced Intensity Cord Blood Transplantation (RICBT).
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 3226-3226
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 3226-3226
    Abstract: & lt;Background & gt; Invasive fungal infection is one of the most fatal complications after stem cell transplantation (SCT). EBMT group reported the risk factors of invasive fungal infections were delayed neutrophile engraftment and steroid use for acute graft versus host disease (GVHD) in cord blood transplantation with myeloablative regimens. However it has not been clear about invasive fungal infections after RICBT. & lt;Objective & gt; The 1st purpose of this report was to investigate the incidence and pathogens of invasive fungal infections and the 2nd was to identify the risk factors for fungal infections after RICBT. & lt;Patients and Methods & gt; We reviewed medical records of 103 patients with hematological diseases who had received RICBT between March 2002 and May 2005 at Toranomon Hospital, Tokyo, Japan. Median age was 57 years (17–79). Primary diseases were advanced (n=81) or standard (n=22). Median follow-up was 14 months (0.5–27). Conditioning regimen was fludarabine 125 mg/m2, melphalan 80 mg/m2 and TBI 4 Gy. GVHD prophylaxis was cyclosporine (n=67) or tacrolimus (n=43). Median total nucleated cells (TNC): 2.8 x 10^7 cells (1.7–5.2); Median CD34+: 0.78 x 10^5 cells (0.01–3.28); HLA match: 6/6 (n=2), 5/6 (n=16), 4/6 (n=88), 3/6 (n=1). Fluconazole 200mg/day was used as prophylaxis of fungal infections. Diagnosis of invasive fungal infection was made with the following EORTC/MSG criteria. The following factors were considered potential predictors of outcomes about 2nd purpose: patient’s age, infused TNC dose, disease status at transplantation, speed of netrophile engraftment, pre-engraftment reactions (PER) which we reported (Clin Cancer Res.10:3586–92, 2004), and acute GVHD. & lt;Results & gt; Neutrophile ( & gt;500/μL) and platelet recovery ( & gt;20,000/μL) were observed in 83% at day 60 (median; 22 day), 55% at day 100 (43day), respectively. Cumulative incidence of acute GVHD (II-IV) was 33%. OS were 39% (95% CI: 29–50) in all cases, 67% (95% CI: 47–87) in standard, and 32% (95% CI: 20–43) in advanced (p & lt;0.05), respectively. Incidence of invasive fungal infections was 12% (95% CI: 6–20) and median onset day was 23 days (1–84) after RICBT. Pathogens of invasive fungal infections comprised 9 cases of probable invasive pulmonary aspergillosis, and one case each of Candida pneumonia and Trichosporon sepsis. Incidence of invasive fungal infections in patients with PER+/steroids + (n=22) was 28% (95% CI: 9–43), in patients without PER (n=80) was 7% (95% CI: 1–14). In multivariate analysis, the most important risk factor of invasive fungal infections was steroid use for PER (p & lt;0.05), while other factors did not influence. & lt;Discussion/Conclusion & gt; In our experience with reduced intensity cord blood transplantation, the only risk factor for invasive fungal infections was steroid use for PER within 30 days. Invasive fungal infections, especially invasive aspergillosis, remain an important complication after allogeneic stem cell transplantation, regardless of the type of conditioning regimens and the sources of stem cells. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.3226.3226
    RVK:
    XA 33000
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 3
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    Reduced-Intensity Cord Blood Transplantation (RICBT) Is a Feasible Approach for Advanced Adult T-Cell Leukemia (ATL).
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 5448-5448
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 5448-5448
    Abstract: Introduction: ATL in advanced stage is a lymphoid malignancy with poor prognosis, its mean survival time being a few months. Allogeneic hematopoietic stem cell transplantation has been shown to be potentially curative approach, but the availability of HLA-matched donor, either of related or unrelated, limits its application to many of the patients. Cord blood has been widely used as an alternative donor cells. We report here the feasibility of RICBT for patients with advanced ATL. Patients and Methods: Eighteen patients with advanced ATL, including 11 acute type and 7 lymphoma type, who underwent RICBT between March 2002 and June 2005 at our institution, were retrospectively analyzed. Eighty percent of them were chemo-refractory at the time of transplant. Median age of the patients was 59 years (27–79). Pretransplant conditioning regimen consisted of fludarabine 125 mg/m2, melphalan 80 mg/m2 and TBI 4 Gy. GVHD prophylaxis was either cyclosporine (CSP, n=11) or tacrolimus (TAC, n=7) alone. The median number of infused nucleated cells and CD34 positive cells were 2.83 (1.95–4.83) x 107 and 1.00 (0.40–2.91) x 105, respectively. All the patients received CB units with HLA mismatches at 1 (n=8) or 2 (n=10) loci. Results: Neutrophil and platelet engraftment were observed in 15 (83.3%, median 16 days) and 14 patients (77.8 %, median 42 days). Two died before engraftment. Five of the engrafted patients (30%) developed acute GVHD (grade II–IV). Although 14 out of 15 patients who survived over 30 days achieved complete remission, 6 died of non-relapse mortality (NRM) within 100 days post-transplant (5 sepsis, 1 encephalitis), and another 6 died of relapse (median 225 days post-transplant). Five of the 7 patients who were alive beyond 100 days developed chronic GVHD (4 limited, 1 extensive). One patient experienced rapid tumor regression along with the chronic GVHD after cessation of TAC at day 146 post-transplant, indicating possible GvATL effect. Estimated 1-year overall and progression-free survival rates were 27.9 +/− 9.0 % and 17.2 +/− 12.8 %, respectively. Among 9 survivors beyond 100 days post-transplant, 5 remain alive at median follow-up of 17 months but only 2 of them remain progression free. Univariate analyses revealed high age (over 60), poor ECOG performance status (over 2) and high sIL-2R level (over 10000IU/L) as poor factors for survival. TAC dramatically decreased the day 100 mortality (14.3%) compared with CSP (45.5%). Conclusion: This pilot study indicates that our RICBT is feasible even for the ATL patients in advanced stage. Day 100 mortality was improved by using TAC but eventually the overall survival decreased to comparable level with CSP. To further improve the outcome, RICBT should be investigated for patients in early stage of the disease, or new approach to prevent late relapse should be explored.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.5448.5448
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 4
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    Comparison among Related Peripheral Blood Stem Cell Transplantation (R-PBSCT), Unrelated Bone Marrow Transplantation (U-BMT), and Unrelated Cord Blood Transplantation (U-CBT) with Reduced Intensity Regimens for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS).
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 5441-5441
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 5441-5441
    Abstract: & lt;Background & gt; Previous reports about comparison between unrelated donor and cord blood for acute leukemia with myeloablative regimens showed that at least relapse rate (RR) and overall survival (OS) were not significantly different in the two groups. However we have not yet understood comparison among R-PBSCT, U-BMT, and U-CBT with reduced intensity regimens for elderly AML/MDS patients. & lt;Objective & gt; The 1st purpose of this report was to investigate OS and causes of death and the 2nd was to investigate engraftment, incidence of acute/chronic GVHD, and RR for AML/MDS patients received R-PBSCT, U-BMT, and U-CBT with reduced intensity regimens. & lt;Patients/Methods & gt; We reviewed medical records of 62 AML/MDS patients who had received RIST between June 2001 and March 2005 at Toranomon Hospital, Tokyo, Japan. 20 patients received R-PBSCT, 19 patients U-BMT, and 23 patients U-CBT. Median age was 56 years (17–70). Primary diseases were de novo AML (n=34) and MDS overt leukemia (n=11), and MDS (n=17) including advanced (n=47) or standard (n=15). Median follow-up was 7.2 months (1.5–37). Conditioning regimen consisted of Fludarabine (Flu) + Busulfan (BU) with cyclosporine (CyA) + MTX in R-PBSCT, Flu + BU + TBI 4Gy with CyA or tacrolimus +MTX in U-BMT, and Flu + Melphalane (Mel) + TBI 4Gy with tacrolimus only in U-CBT, respectively. G-CSF was used after RIST until neutrophile engraftment. & lt;Results & gt; HLA disparities were 6/6 match (n=18) and 5/6 (n=2) in R-PBSCT, 6/6 (n=18) and 5/6 (n=1) in U-BMT, and 5/6 (n=2) and 4/6 (n=21) in U-CBT, respectively (P & lt;0.001) and infused CD34 cell counts were 3.6, 1.53, and 0.081 ×10E6/kg, respectively (P & lt;0.001). Neutrophile ( & gt;500/μL)/platelet recovery ( & gt;20,000/μL) were observed 100% (median 16.5 days) and 90% (13.5) in R-PBSCT, 90% (20) and 79% (26) in U-BMT, and 91% (21.5) and 70% (41.5) in U-CBT, respectively (P & lt;0.05). In R-PBSCT, U-BMT, and U-CBT cumulative incidence of acute GVHD (II-IV) was 50%, 59% and 30%, and chronic GVHD was 30%, 29%, and 25%, respectively (NS). Causes of death included infections (n=5), GVHD (n=8), TRM (n=1) and progressive disease (n=16) in total cases after RIST and there was no difference among three groups. OS was 43% (95% CI: 26–59) in all cases, 69% (95% CI: 26–59) in standard, and 39% (95% CI: 24–54) in advanced, respectively (p & lt;0.05). According to stem cell sources, OS and RR was 64%, 34% in R-PBSCT, 68%, 35% in U-BMT, and 59%, 45% in U-CBT, respectively (NS). & lt;Discussion/Conclusion & gt; In this report, the differences were followings; HLA disparities, infused CD34 cell dose, conditioning regimen with GVHD prophylaxis, neutorphile and platelet engraftment. The incidence of acute/chronic GVHD, OS, RR, and causes of death were same among three groups. This Flu+Mel+TBI 4Gy + tacrolimus with U-CBT would be feasible and acceptable for elderly patients with AML/MDS. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.5441.5441
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 5
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    Hemophagocytic Syndrome (HPS) Post Reduced Intensity Cord Blood Transplantation (RI-CBT) in Adult Patients with Hematological Diseases.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2743-2743
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2743-2743
    Abstract: & lt;Introduction & gt; HPS are rare but often-fatal conditions characterized by an inappropriate and sustained activation of the cellular immune system leading to accumulation of activated macrophages and a cytokine storm. HPS consists of primary and secondary Hemophagocytic Lymphohistiocytosis (HLH). Secondary HLH occurs at any age and the genetic contribution remains uncertain. Clinical features in patients with HLH are fever, cytopenias, liver dysfunction, hepato-splenomegaly, and the presence of hemophagocytosis in the bone marrow as well as other reticuloendothelical tissues. We will report on the hematological abnormalities and the clinical course of 20/152 patients who received RI-CBT and developed secondary HLH in adult patients with hematological disease in early phase after RI-CBT. & lt;Object & gt; The 1st purpose was to investigate the incidence of HLH and pattern of chimerism. The 2nd was to identify the risk factors after UCBT. & lt;Patients and Methods & gt; We reviewed medical records of 152 patients with hematological diseases who had received RI-CBT between January 2002 and April 2005 at Toranomon Hospital, Tokyo, Japan. Diagnosis of HLH was made with the followings; high fever, cytopenias, and hemophagocytic findings in bone marrow examination. Time to event curves were plotted by using the actuarial method of Kaplan-Meier, and differences between curves were analyzed by log-rank tests. The following factors were considered potential predictors of outcomes about 2nd purpose: patient’s age, HLA disparity, infused TNC dose/CD34 dose, disease/disease status at transplantation, GVHD prophylaxis and sepsis which coincided with HLH. All factors were tested for the proportional hazards assumption. & lt;Results & gt; Patient’s median age was 55 years (17–79), Primary diseases consisted of standard (n=31) and advanced (n=121). HLA disparities were 4/6 match (n=123), 5/6 (n=22), and others (n=7). Total nucleated cell/CD34 cell dose were 3.46×10E7/kg (1.6–5.2) and 0.78×10E5/kg (0.1–3.3), respectively. Main conditioning regimen was Fludarabine (125mg/m2) +Melphalan (80mg/m2) or Busulfan (8mg/kg) +TBI 4Gy with cyclospoline (n=89) and tacrolimus (n=63) as GVHD prophylaxis and received single cord blood unit. Twenty patients were diagnosis with HLH and the incidence of HLH was 13% (95%CI; 8–18) and median onset day was 18.5 days (range; 10–29). In patients with sepsis (n=46) and without sepsis (n=106), the incidence of HLH was 28% (95%CI; 15–41) and 7% (95%CI; 3–12), respectively (P & lt;0.0002). All patients who were diagnosis with HLH using bone marrow examination achieved 100% of donor chimerism. In multivariate analysis, the most important risk factor of HLH after RI-CBT was sepsis which coincided with HLH at the same times (p & lt;0.05), while other factors did not influence. & lt;Discussion/Conclusion & gt; HLH is fatal complication after allogeneic peripheral stem cell and unrelated bone marrow transplantation. However in RI-CBT, the incidence would be higher and earlier onset than other sources. The most of HLH patients died by multi-organ failure. In this report the most important risk factor was sepsis which coincided with HLH. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2743.2743
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 6
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    Identification of Patient-Specific Anti-Apoptotic Molecules As Therapeutic Targets in Poor Prognosis Acute Lymphoblastic Leukemia (ALL)
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1236-1236
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1236-1236
    Abstract: Relapse and refractory ALL shows dismal prognosis despite recent progress in intensive chemotherapy and development of molecular targeting agents. In this study, we aimed to identify vulnerabilities in genetically-diverse ALL and to find additional therapeutic targets in Philadelphia chromosome-positive (Ph+) ALL and chronic myeloid myeloid leukemia (CML) to overcome BCR-ABL tyrosine kinase inhibitor (TKI) resistance. To this end, we performed in vitro drug screening using 23 human ALL samples (9 Ph+ ALL, 5 MLL-ALL, 1 ALL with ETV-RUNX1, 5 B-ALL, not otherwise specified and 4 T-ALL), 10 CML samples and eight mixed phenotype acute leukemia (MPAL) samples (four B-Myeloid and four T-Myeloid). Based on our recent findings in AML (Hashimoto, Saito et al., Nature Cancer 2021), we treated leukemia-engrafting cells with small molecules targeting anti-apoptotic molecules (BCL-2, MCL-1 or BIRC) or molecules associated with cell division (AURKB) in addition to tyrosine kinase inhibitors. Among these compounds, BIRC inhibitor and venetoclax exhibited great efficacy. Responsiveness to each compound was: 28 of 41 for BIRC inhibitor (68.3%), 24 of 40 for venetoclax (60%), 11 of 37 for MCL-1 inhibitor (29.7%) and 4 of 37 for AURKB inhibitor (10.8%). We found differential sensitivity between T-ALL/MPAL T-myeloid and CML. Seven out of eight T-ALL and MPAL T-myeloid samples were highly sensitive to venetoclax (87.5%), while nine out of 10 CML samples were responsive to BIRC inhibition (90%). On the other hand, among Ph+ ALL/MPAL and Ph- B-ALL/MPAL B-myeloid samples, sensitivities to BIRC inhibitor and venetoclax were variable. To identify determinants of sensitivity to compounds, we examined the relation between mutational profile and in vitro leukemia elimination through targeted DNA sequencing for 79 lymphoid and myeloid malignancy-associated somatic mutations. Consistent with our previous study, CBL-mutated leukemia showed higher sensitivity to BIRC inhibitor (four of five cases) compared with venetoclax (two of five cases). Among genes related to RAS signaling pathway, KRAS mutations were most frequent (n=6). While five of six KRAS-mutated cases were BIRC inhibitor sensitive (83.3%), three of six cases were sensitive to venetoclax (50%). For cases with mutations in BCR-ABL1 kinase domain, the sensitivity to BIRC inhibitor and venetoclax was variable. Finally, we went on to setup in vivo experiments to elucidate if targeting the patient-specific vulnerabilities resulted in potent therapeutic efficacy against patient leukemic cells. We created patient-derived xenograft (PDX) models of 5 Ph+ ALL/MPAL, 2 Ph- B-ALL/MPAL, 2 T-ALL/MPAL and 2 CML cases. For Ph+ ALL/MPAL and CML, BIRC inhibitor and/or venetoclax combined with dexamethasone (DEX) and TKI achieved effective in vivo elimination of leukemic cells as predicted by in vitro experiments. Combination therapy showed almost complete elimination of Ph+ leukemic cells even in the presence of T315I mutation. For Ph- B-ALL/MPAL and T-ALL/MPAL, preliminary in vivo experiments showed additional inhibition of BIRC and BCL-2 resulted in more profound reduction of leukemic cells in BM compared with DEX alone (Combination: 2.1% [0.25-8] of hCD45+ leukemic cells, n=13 vs. DEX alone: 67.2% [59-76.5] , n=11, median [IQR], p & lt;0.001). We found targeting anti-apoptotic molecules in combination with DEX and/or TKI eradicated human genetically-diverse ALL, MPAL and CML cells both in vitro and in vivo. Inhibition of BIRC and BCL-2 overcame glucocorticoid resistance of Ph- ALL. Altogether, our results may offer precision medicine approach and contribute to improvement of clinical outcome in treatment-resistant ALL, CML and MPAL. Disclosures Uchida: Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma Inc.: Honoraria. Harigae: Ono pharma: Honoraria, Other: Subsidies or Donations; Astellas Pharma: Other: Subsidies or Donations; Kyowakirin: Other: Subsidies or Donations; Janssen Pharma: Honoraria; Chugai Pharma: Honoraria; Novartis Pharma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-147625
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 7
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    HHV6-Associated Limbic Encephalitis after Reduced-Intensity Umbilical Cord Blood Transplantation.
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 2208-2208
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2208-2208
    Abstract: Background: HHV6 reactivation has been increasingly recognized in allogeneic haematopoietic stem cell transplant recipients, particularly in umbilical cord blood transplantation. In adult recipients, HHV6 has been associated with limbic encephalitis (HHV6-LE), which causes anterograde amnesia and epilepsy. The CNS disorder confined to the hippocampal regions; the presence of abnormal MRI signals involving the hippocampus, and detection of HHV6 DNA inCSF. However, the clinical features of the syndrome have not been well characterized. Methods: In this study we retrospectively reviewed the medical records of 139 umbilical cord blood transplantation recipients with reduced-intensity conditioning between January 2006 and December 2007 at Toranomon Hospital in Japan to determine the incidence of HHV6-LE among these patients. The diagnosis was based on the acute development of retrograde amnesia, confusion, coma and seizures accompanied by charascteristic MRI findings of abnormal high signal intensity on flair and T2 weighted images in the hippocampus and mesial temporal lobes, and the detection of HHV6 DNA in CSF. Eighty-six were received foscarnet before the onset of HHV6-LE as prophylaxis. All the patients who manifested suspicious symptoms of HHV6-LE were treated with foscarnet. Results: HHV6-LE was diagnosed in 11/139 for a cumulative incidence of 7.2%. The median age was 49 years (range 36–82), 3 were female. Diseases treated were AML/MDS (8), ALL (1), diffuse large B-cell lymphoma (1), and aplastic anemia (1). All 11 were conditioned with fludarabine-based reduced-intensity regimen, and tacrolimus alone (5) or tacrolimus+mycophenolate mofetil (6) were used as GVHD prophylaxis. Five of them had started foscarnet before the onset of HHV6-LE as a prophylaxis. Median symptom onset was on day +20 (range, 12–50). Initial symptoms included confusion in 9, retrograde amnesia in 8, and seizures in 5. MRI demonstrated hyppocampal and mesial temporal lobe FLAIR/T2 high signal intensity in 8/11. Initial CSF analysis demonstrated a median WBC count was 7 (range, 1–21)/μl, median protein was 49 (range, 44–337) mg/dl, median glucose was 107 (range, 62–269) mg/dl. No positive results of bacterial or viral cultures were observed in any of the patients. Median HHV6 DNA levels in the CSF was 20000 (range, 200–80000) copies/ml. Median HHV6 DNA levels in peripheral blood was 200 (range, 0–300000) copies/ml. Remarkably, 7 patients were negative for HHV6 in peripheral blood even within 6 days prior to the onset of CNS symptoms. All were treated with foscarnet at 50–100mg/kg of body weight, and clinical symptoms improved in 9 evaluable patients (2 were not evaluable due to severe pulmonary complications). The virus was cleared in the CSF successfully in 7 patients evaluated. Seven died with the median survival of 32 days (range, 7–346) from diagnosis of limbic encephalitis. HHV6-LE was not a direct cause of death in any of them (2 were from infection, 2 from IP, 2 from relapse, and 1 from MOF). Four were alive as of July 31, 2008, and what is of extreme interest is that all were those who received foscarnet as a prophylaxis. None of the factors analysed failed to reach statistical significance regarding the impact on the onset of HHV6-LE. Conclusions: High incidence of HHV6-LE as well as reactivation of the virus was observed in CB recipients. HHV6 DNA monitoring in peripheral blood may not be sufficient to predict the development of HHV6-LE. Although clinical manifestations were severe in some cases, foscarnet therapy was effective in all evaluable cases. Possible positive impact of prophylactic foscarnet therapy on better survival was suggested, which needs further evaluation by prospective study.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.2208.2208
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 8
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    Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation
    American Society of Hematology ; 2012
    In:  Blood Vol. 119, No. 12 ( 2012-03-22), p. 2768-2777
    Details
    In: Blood, American Society of Hematology, Vol. 119, No. 12 ( 2012-03-22), p. 2768-2777
    Abstract: In recent years, advances in the humanized mouse system have led to significantly increased levels of human hematopoietic stem cell (HSC) engraftment. The remaining limitations in human HSC engraftment and function include lymphoid-skewed differentiation and inefficient myeloid development in the recipients. Limited human HSC function may partially be attributed to the inability of the host mouse microenvironment to provide sufficient support to human hematopoiesis. To address this problem, we created membrane-bound human stem cell factor (SCF)/KIT ligand (KL)–expressing NOD/SCID/IL2rgKO (hSCF Tg NSG) mice. hSCF Tg NSG recipients of human HSCs showed higher levels of both human CD45+ cell engraftment and human CD45+CD33+ myeloid development compared with NSG recipients. Expression of hSCF/hKL accelerated the differentiation of the human granulocyte lineage cells in the recipient bone marrow. Human mast cells were identified in bone marrow, spleen, and gastrointestinal tissues of the hSCF Tg NSG recipients. This novel in vivo humanized mouse model demonstrates the essential role of membrane-bound hSCF in human myeloid development. Moreover, the hSCF Tg NSG humanized recipients may facilitate investigation of in vivo differentiation, migration, function, and pathology of human mast cells.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2011-05-353201
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
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    Clinical Characteristics and GVL Effect of Chronic Graft-Versus-Host disease Following Reduced-Intensity Umbilical Cord Blood Transplantation (RICBT).
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1162-1162
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    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1162-1162
    Abstract: Abstract 1162 Poster Board I-184 Backgrounds Umbilical cord blood can be an alternative stem cell source for the patients of hematological diseases. However, little is known about chronic GVHD (cGVHD) and graft versus leukemia/lymphoma (GVL) effect in reduced-intensity cord blood transplantation (RICBT). We had been demonstrated that cGVHD in CBT is tolerable compared with that in BMT and that the occurrence of cGVHD could result in good prognosis. Here, we analyzed the clinical picture of chronic GVHD following RICBT and the GVL effect. Methods We reviewed medical records of 192 patients with hematological diseases who had received CBT between Jan. 2004 and Dec. 2008 who had been free from disease progression for more than 100 days after RICBT at Toranomon Hospital, Tokyo, Japan. Median age was 54 years (17-82). Most of them had diseases in advanced status (n=168). Most of the pre-transplant conditioning were reduced intensity consisted of fludarabine, melphalan and TBI 4Gy (n=157). GVHD prophylaxis were tacrolimus (Tac) alone (n=99) and Tac plus mycophenolate mofetil (MMF) (n=93). HLA disparities were as follows; 6/6 (n=9), 5/6 (n=38), 4/6 (n=142), and 3/6 (n=3). Underlying diseases were AML (n=58), myelodysplastic syndrome (n=36), ALL (n=23), lymphoma (n=64) and others (n=11). Results The Median observation period after the transplantation was 924 days (range, 109–1944). Chronic GVHD was admitted in 114 patients (59.4%) consisted of limited type 88 (45.8%) and extensive type 26 (13.5%) in classical criteria, and mild type 96 (50.0%), moderate type 15 (7.8%), and severe type 3 (1.6%) in NIH consensus criteria of cGVHD. The target organs of cGVHD were skin 87.5%, liver 40.6%, and mouth mucous membranes 32.8 %, eye 23.4%, and the lungs only 7.8% (COP3 and BOS2). Except 21 cases ( 10.9%) required systemic steroid or MMF therapy. The median of Karnofsky score of cGVHD was 90%(40-100). During observation period, no patients except one patient caused by heart failure were died of cGVHD. In multivariate analysis, high-risk disease (p=0.019) and preceding acute GVHD (p=0.026) are related to the occurrence of cGVHD, and cGVHD increased overall survival (p 〈 0.01) and suppressed recurrence of the disease (p 〈 0.01). Conclusion Although the frequency of cGVHD was not low, the severity was mild, and the death related to cGVHD is rare in RICBT. NIH consensus criteria is useful for the evaluation of cGVHD severity. Some effect of GVL may play a role on better survival and lower relapse rate in RICBT. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1162.1162
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Membrane-Bound Human Stem Cell Factor Promotes Differentiation of Human Granulocytes and Mast Cells In Vivo,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3419-3419
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3419-3419
    Abstract: Abstract 3419 Recently, advances in xenograft models for human hemamtopoietic stem cells (HSCs), or the humanized mice, have begun to allow investigators to examine the differentiation of human hematopoietic and immune cells in vivo. However, lymphoid-skewed human hematopoietic development in the mouse bone marrow is one of the remaining limitations in the humanized mouse models. The inefficient human myeloid development could at least partly be attributed to the mouse microenvironment not fully supporting differentiation and maturation of human myeloid lineage. To overcome this problem, we focused on the role of membrane-bound human stem cell factor in supporting the maintenance of human HSCs and inducing the development of human myeloid cells and created human stem cell factor transgenic NOD/SCID/IL2rgKO (hSCF Tg NSG) mice. Transplantation of 5000–50000 cord blood-derived Lin-CD34+CD38- cells resulted in significantly higher engraftment of human CD45+ leukocytes at 3–6 months post-transplantation in the bone marrow, spleen, and peripheral blood of hSCF Tg NSG recipients compared with those of non-transgenic NSG recipients. The enhanced human CD45+ engraftment was most prominent in the bone marrow (hSCF Tg recipients: 98.0 +/− 1.3%, n= 15, non-Tg NSG controls: 75.3 +/− 7.3%, n=7). In the bone marrow, the frequency of human CD33+ myeloid cells within the total human CD45+ population was significantly higher in the hSCF Tg NSG recipients than in the non-Tg NSG recipients and constituted the majority of human hematopoietic cells (hSCF Tg recipients: 54.6 +/− 4.5%, n=15 and non-Tg NSG controls: 29.3 +/− 4.0%, n=7). Flow cytometric analysis demonstrated that the majority of engrafted human myeloid cells in the hSCF Tg recipient bone marrow were side-scatter high, HLA-DR negative granulocytes. Reflecting the effect of human SCF on the development of human mast cells, human c-Kit+CD203c+ mast cells were identified in the bone marrow, spleen, and gastrointestinal tracts of the hSCF Tg NSG recipients. Altogether, the in vivo humanized mouse model demonstrates the essential role of membrane-bound SCF in human myeloid development. The hSCF Tg NSG humanized mice may facilitate the in vivo investigation of human HSCs, myeloid progenitors and mature myeloid lineage. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3419.3419
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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