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  • 1
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 98, No. 6 ( 2019-6), p. 1521-1523
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 1458429-3
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  • 2
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 25, No. 3 ( 2019-03), p. S400-
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 3056525-X
    detail.hit.zdb_id: 2057605-5
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  • 3
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3093-3093
    Abstract: Abstract 3093 Allogeneic hematopoietic stem cell transplantation (allo SCT) is potentially curative treatment for relapsed follicular lymphoma (FL) that remains non-curative disease even with modern immunochemotherapy. Number of potential candidate of allo SCT for FL has been increasing with the development of reduced intensity conditioning (RIC) regimens and increased donor availability due to use of hematopoietic stem cell from unrelated donor including cord blood (CB). However, short-term and long-term transplantation-related complications are still major obstacles in applying this treatment. Recently, EBMT and CIBMTR reported a prognostic score of allo SCT for FL (Ann Oncol 2011;22 :Suppl 4, iv94). However, this score awaits validation. To elucidate prognostic factors for OS after allo SCT for FL, we conducted a retrospective study using the national registry data of the Japan Society of Hematopoietic Cell Transplantation (JSHCT). In total, 472 cases of allo SCT for FL performed from 2000 to 2008 were identified. 220 (46.6%) were male and the median age at allo SCT was 50 yo (range: 27–75). Forty six (9.7%) patients were 60 yo or older. Eighty two (17.3%) patients had previous history of autologous transplantation (ASCT). Stem cell source was BM or PB from related donor in 215 (45.5%), unrelated donor BM in 180 (38.1%), and unrelated donor umbilical cord blood (CB) in 77 (16.3%). Conditioning regimen was myeloablative (MAC) in 20.7% and reduced intensity (RIC) in 79.3%, respectively. Patients undergoing MAC were younger than those with RIC (45 vs 50 yo, P 〈 0.01). T-cell depletion with ATG or ALG was performed in 7.5%. ECOG performance status (PS) at allo SCT was ≥ 2 in 10.7%. 71.5% had chemosensitive disease at allo SCT and disease status was CR in 38.9%. With a median follow up of 47.3 mo (range: 0.9–122) among survivors, overall survival rate at 4years after allo SCT (4y OS) was 52.6%. Patients who had CB transplantation had worse OS than those transplanted from related donor or unrelated BM (30.0%, 58.5%, 54.6%, P =1.35e-6, logrank). Additionally, in univariate analysis, PS ≥2, chemoresistant disease at allo SCT, older age, male sex were adverse prognostic factors for OS, while previous history of ASCT, time from diagnosis to allo SCT ( 〈 3y vs ≥3y), disease status at allo SCT (CR vs non CR), conditioning regimen (MAC vs RIC), and year of allo SCT (2000–2 vs 2003–5 vs 2006–8) were not. 4y OS of patients undergoing MAC and RIC were 46.2% and 54.0% (P =0.28), respectively. In multivariate analysis with proportional hazard modeling, PS ≥2 (HR 3.2, P =0.00015), chemorefractory disease (HR 2.7, P =0.039), and use of CB (HR 3.8, P =0.039) were independent adverse predictors of OS. Although risk factors that are incorporated in the proposed EBMT/CIBMTR risk score other than PS were not predictive of OS in the present analysis, we applied this score to the population of the present study. In the entire population, 4y OS were 61.0% and 38.5% (P =9.5e-08) in patients with the score 〈 3 (n=294) and ≥3 (n=77), respectively. This score was predictive of OS in patients who underwent transplantation from related donor (65.4% vs 36.7%, P =3.77e-08) and from unrelated BM (59.0% vs 41.7%, P =0.0217). In conclusion, this retrospective study of JSHCT registry data showed that allo SCT for FL is a reasonable option for patients with relapsed FL when suitable donor is available. Poor PS, chemorefractory disease, and CB as donor source were adverse prognostic factors for OS. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    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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  • 4
    In: Journal of Gastroenterology and Hepatology, Wiley, Vol. 11, No. 8 ( 1996-08), p. 724-727
    Type of Medium: Online Resource
    ISSN: 0815-9319 , 1440-1746
    Language: English
    Publisher: Wiley
    Publication Date: 1996
    detail.hit.zdb_id: 2006782-3
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  • 5
    In: Bone Marrow Transplantation, Springer Science and Business Media LLC, Vol. 54, No. 9 ( 2019-9), p. 1515-1517
    Type of Medium: Online Resource
    ISSN: 0268-3369 , 1476-5365
    RVK:
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2004030-1
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  • 6
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1582-1582
    Abstract: Abstract 1582 Background: Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-1). HTLV-1 is endemic to the southwestern region of Japan, Caribbean basin, Central and South America, and western Africa. A previous report by the Japan Clinical Oncology Group-Lymphoma Study Group (JCOG-LSG) identified five prognostic factors: advanced performance status (PS), high lactic dehydrogenase (LDH), age of 40 years or older, total involved lesions, and hypercalcemia, based on an analysis of 854 patients with newly diagnosed ATL registered between 1983 and 1987. The JCOG-LSG then proposed 4 clinical subtypes: acute, lymphoma, chronic, and smoldering types. In general, the prognosis of acute and lymphoma type ATL is similarly very poor, whereas that of the chronic and smouldering types is better. It has come to the attention of clinicians that there are diverse clinical courses and treatment outcomes among patients with acute and lymphoma type ATL. Therefore, it is necessary to establish a prognostic index (PI) for a risk-adapted approach and improving the quality of clinical trials. The aim of this study was to develop the first PI for acute and lymphoma type ATL (ATL-PI). Patients and Methods: We conducted a nationwide retrospective survey of ATL patients who were newly diagnosed between January 2000 and December 2009, and 1,270 patients with acute and lymphoma type were registered. Fully eligible 807 individuals excluding patients who have received allogeneic hematopoietic stem cell transplantation were used for this analysis, and randomly split the dataset into training (n=404) and validation (n=403) samples. We applied a multivariable fractional polynomial model using continuous variables, and then developed the simplified one using dichotomizing variables. Results: The overall median survival time (MST) for 807 patients was 7.7 months. The Ann Arbor stage (I - II vs. III - IV), performance status (0–1 vs. 2–4), and the three continuous variables of age, serum albumin, and soluble interleukin-2 receptor (sIL-2R) were identified as independent prognostic factors in the training sample. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. In the validation sample, MSTs were 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively (p 〈 0.0001). ATL-PI = 0.65 (if Stage = III or IV) + 0.35 (if PS 〉 1) + 0.016 × Age (years) − 0.36 × Albumin (g/dL) + 0.37 × log10 (sIL2R (U/mL)) To make the scoring system simpler and clinically practicable, we also simplified the original ATL-PI by dichotomizing age at 70 years, serum albumin at 3.5 g/dL, and sIL-2R at 20,000 U/mL and subsequently fitted a multivariate Cox model based on these dichotomizations in the training sample. Then, we derived a simplified ATL-PI as follows: Simplified ATL-PI = 2 (if Stage = III or IV) + 1 (if PS 〉 1) + 1 (if Age 〉 70) + 1 (if Albmin 〈 3.5) + 1 (if sIL2R 〉 20,000) The scores from 0 to 2 were categorized into low risk group, 3 and 4 into intermediate risk, and from 5 to 6 into high risk group. This classification yielded a good separation of OS curves (p 〈 0.0001), and high concordance to the original ATL-PI in the validation sample. Conclusion: We identified 5 prognostic factors in acute and lymphoma type ATL using a multivariable fractional polynomial model, and further simplified it with minimal loss of the original index. The ATL-PI enables us to distinguish 3 different groups by predicting OS at the time of diagnosis. The ATL-PI, the first PI for acute and lymphoma type ATL, may be a promising platform in consideration of the choice of optimal treatment by risk-stratification and for well-controlled clinical trials. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    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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  • 7
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2011-12)
    Abstract: Emmprin, a glycoprotein containing two Ig domains, is enriched on tumor cell surfaces and stimulates matrix metalloproteinase (MMP) production by adjacent stromal cells. Its first Ig domain (ECI) contains the biologically active site. The dependence of emmprin activity on N-glycosylation is controversial. We investigated whether synthetic ECI with the shortest sugar is functionally active. Methods The whole ECI peptides carrying sugar chains, a chitobiose unit or N-linked core pentasaccharide, were synthesized by the thioester method and added to fibroblasts to examine whether they stimulate MMP-2 production. Results ECI carrying a chitobiose unit, ECI-(GlcNAc) 2 , but not ECI without a chitobiose unit or the chitobiose unit alone, dose-dependently stimulated MMP-2 production by fibroblasts. ECI with longer chitobiose units, ECI-[(Man) 3 (GlcNAc) 2 ], also stimulated MMP-2 production, but the extent of its stimulation was lower than that of ECI-(GlcNAc) 2 . Conclusions Our results indicate that ECI can mimic emmprin activity when substituted with chitobiose, the disaccharide with which N-glycosylation starts.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 2041352-X
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  • 8
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 700-700
    Abstract: Background Natural killer (NK) cell malignancies are rare lymphoid neoplasms characterized by aggressive clinical behavior and poor treatment outcomes. Clinically they are classified as extranodal NK/T-cell lymphoma, nasal type (NKTCL) and aggressive NK cell leukemia (ANKL). Both subtypes are almost invariably associated with Epstein-Barr virus (EBV). Recently, genomic studies in NKTCL have identified recurrent somatic mutations in JAK-STAT pathway molecules STAT3 and STAT5b as well as in the RNA helicase gene DDX3X in addition to previously detected chromosomal aberrations. Here, we identified somatic mutations in 4 cases of ANKL in order to understand whether these entities share common alterations at the molecular level. To further establish common patterns of deregulated oncogenic signaling pathways operating in malignant NK cells, we performed drug sensitivity profiling using NK cell lines representing ANKL, NKTCL and other malignant NK cell proliferations. We aimed to identify sensitivities to agents that selectively target components of pathways required for survival of malignant NK cells in an unbiased manner. Methods Exome sequencing was performed on peripheral blood or bone marrow of ANKL patients using the NK cell negative fraction or other healthy tissue as control. Profiling of drug responses was performed with a high-throughput drug sensitivity and resistance testing (DSRT) platform comprising 461 approved and investigational oncology drugs. The NK cell lines KAI3, KHYG-1, NKL, NK-YS, NK-92, SNK-6 and YT and IL-2-stimulated and resting NK cells from healthy donors were used as sample material. All drugs were tested on a 384-well format in 5 different concentrations over a 10,000-fold concentration range for 72 h and cell viability was measured. A Drug Sensitivity Score (DSS) was calculated for each drug using normalized dose response curve values. Results The ANKL patients displayed mutations in genes reported as recurrently mutated in NKTCL, such as FAS, TP53, NRAS, STAT3 and DDX3X. Additionally, novel alterations in genes previously implicated in the pathogenesis of NKTCL were detected. These included an inactivating mutation in INPP5D (SHIP), a negative regulator of the PI3K/mTOR pathway and a missense mutation in PTPRK, a negative regulator of STAT3 activation. Interestingly, the total number of nonsilent somatic mutations in 3 out of 4 ANKL patients (97, 82 and 45) was remarkably high compared to other hematological malignancies analyzed in our variant calling pipeline. Analysis of drug sensitivities in NK cell lines showed a close correlation between all cell lines and a markedly higher correlation with those of IL-2 stimulated than resting healthy NK cells, suggesting that malignant NK cells may share a common drug response pattern. Furthermore, in an unsupervised hierarchical clustering the NK cell lines formed a distinct group from other leukemia cell lines tested (Fig. A). Among pathway-selective compounds (namely, kinase inhibitors and rapalogs), the drugs most selective for malignant NK cells fell into two major categories: PI3K/mTOR inhibitors (e.g. temsirolimus, buparlisib) and inhibitors of aurora and polo-like kinases such as rigosertib and GSK-461364 (Fig. B). JAK inhibitors (e.g. ruxolitinib, gandotinib) and CDK inhibitors (e.g. dinaciclib) showed strong efficacy in both malignant NK cells and IL-2 activated healthy NK cells. Conclusions Our exome sequencing results suggest that candidate driver alterations affecting similar signaling pathways underlie the pathogenesis of ANKL as has been reported in NKTCL. Drug sensitivity profiling highlights the PI3K/mTOR pathway as a potential major driver of malignant NK cell proliferation, whereas JAK-STAT signaling appears to be essential in both healthy and malignant NK cells. Components of these pathways harbored mutations in our small cohort of ANKL patients and have been shown to be deregulated by mutations or other mechanisms in previous studies, underlining their importance as putative drivers. The systematic large-scale characterization of drug responses also identified these pathways as potential targets for novel therapy strategies in NK cell malignancies. Figure 1. (A) Unsupervised hierarchical clustering based on drug sensitivity scores (DSS) of NK, AML, CML and T-ALL cell lines. (B) Scatter plot comparing DSS of malignant NK cell lines (average) and healthy IL-2 stimulated NK cells. Figure 1. (A) Unsupervised hierarchical clustering based on drug sensitivity scores (DSS) of NK, AML, CML and T-ALL cell lines. (B) Scatter plot comparing DSS of malignant NK cell lines (average) and healthy IL-2 stimulated NK cells. Disclosures Mustjoki: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    In: Blood, American Society of Hematology, Vol. 118, No. 23 ( 2011-12-01), p. 6018-6022
    Abstract: Epstein-Barr virus (EBV)–DNA was prospectively analyzed in plasma and mononuclear cells (MNCs) from peripheral blood in patients with extranodal natural killer (NK)/T-cell lymphoma, nasal type, to evaluate the clinical significance for diagnosis, monitoring the tumor burden, and prognostication. Thirty-three patients were enrolled, and 32 were evaluable. Pretreatment plasma and MNC EBV-DNA was detectable in 14 (range, 50-71 000 copies/mL) and 6 patients (range, 20-780 copies/μg DNA), respectively, and both were well correlated (r = 0.8741, P 〈 .0001). Detectable plasma EBV-DNA was associated with higher clinical stage (P = .02), presence of B symptoms (P = .02), worse performance status (P = .02), and higher serum soluble IL-2 receptor level (P 〈 .0001). Twenty-two patients attained complete response. Plasma EBV-DNA level was significantly higher in nonresponders than in responders (mean, 16 472 vs 2 645 copies/mL; P = .02). Multivariate analysis showed clinical stage (hazard ratio, 9.0; 95% confidence interval, 1.8%-45.0%) and pretreatment plasma EBV-DNA (hazard ratio, 10.6; 95% confidence interval, 1.3%-87.0%) were significant prognostic factors. Three-year overall survival of plasma EBV-DNA positive and negative patients was 42.9% and 94.4%, respectively (P = .0009). Plasma was a preferable sample for this purpose in NK/T-cell lymphoma, nasal type, and EBV-DNA level was a good indicator for response and overall survival.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    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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  • 10
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4270-4270
    Abstract: Clinical impact of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is not well studied in a large series of patients with lymphoma undergoing autologous stem cell transplantation (ASCT). Retrospective analysis was performed to evaluate clinical outcomes of patients with lymphoma receiving ASCT with or without HBV and HCV infections. Patients and Methods Among 13218 adult patients registered in the Adult Lymphoma Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) database, we selected patients who had the information on HBV and HCV infection status and received ASCT from 1989 to 2010. Patients diagnosed as Hodgkin lymphoma, mature or precursor T- and B-cell lymphoma were included. Histological diagnosis of natural killer (NK)-cell lymphoma and adult T-cell leukemia/lymphoma were excluded in this analysis. Patients who had human immunodeficiency virus (HIV) infection and history of previous transplantation were also excluded. Survival analysis was performed to compare patients positive for HBV and HCV with those negative for both. Prognostic indicator for survival was also investigated in patients positive for HBV and HCV. Results A total of 4641 patients with 2819 male were analyzed. The median age of all patients was 54 years (range: 16-81 years). The patient characteristics were summarized in Table 1. HBV and HCV infections were present in 162 (3.5%) and 104 (2.2%) patients, respectively. Ten patients (0.2%) had both HBV and HCV infections. Detailed data on anti-HBV antigen or antibody and genetic data were not available in the analysis. Patients with HBV and HCV infections were older and more diagnosed with advanced stage than those without infections. With a median follow-up of 2.8 years, the 2-year overall survival (OS) rate of all patients was 75% (95%CI: 73 to 76). Cumulative incidence of treatment-related mortality (TRM) at one year after ASCT was 5.8% (95%CI: 5.2 to 6.6). According to HBV and HCV positivity, the estimated 2-year overall survival (OS) rates were 74% (95%CI: 65 to 81), 77% (95%CI: 66 to 84), 60% (95%CI: 25 to 83) and 75% (95%CI: 73 to 76) in patients with HBV-positive, HCV-positive, both virus positive and negative patients, respectively. Cumulative incidence of TRM at one year was 11% (95%CI: 6.2 to 16) 6.6% (95%CI: 2.7 to 13) and 5.7 (95%CI: 5.0 to 6.4) in patients with HBV-positive, HCV-positive and both virus negative patients, respectively. In patients with or without HBV and HCV infections, there was no statistically significant difference in rates of OS (p=0.82, Figure 1) and TRM (p=0.63). In multivariate analysis of patients infected with HBV, factors associated with shorter OS were male sex (HR: 3.1, 95%CI: 1.2 to 7.6), non-remission/relapse status at ASCT (HR: 2.7, 95%CI: 1.2 to 5.9) and ASCT before 2005 years (HR: 3.6, 95%CI: 1.6 to 8.4). ASCT before 2005 years was associated with higher TRM in patients with HBV infection (HR: 4.4, 95%CI: 1.5 to 13). In patients with HCV infection, multivariate analysis revealed that partial remission (HR: 3.5, 95%CI: 1.2 to 10.6), non-remission/relapse (HR: 5.3, 95%CI: 1.9 to 14.6) status at ASCT and age≥ 50 years at ASCT (HR: 7.0, 95%CI: 1.5 to 31.9) were significantly associated with shorter OS. Non-remission/relapse status at ASCT was associated with higher TRM in patients infected with HCV (HR: 4.4, 95%CI: 1.1 to 18.3). Difference in histology was an adverse factor for outcomes in the HBV- and HCV-negative groups, however, the factor could not be identified as adverse indicator in the HBV- and HCV-positive groups. Conclusions Prognosis of patients with HBV and HCV infections would be comparable to patients without those infections. Disease status at ASCT could be one of useful landmarks to predict outcomes in patients positive for HBV and HCV undergoing ASCT. After careful consideration, ASCT might be a feasible option for patients with HBV and HCV infections. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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