Publications by authors named "Takashi Miyagi"

36 Publications

Clinicopathological features of adult T-cell leukemia/lymphoma with HTLV-1-infected Hodgkin and Reed-Sternberg-like cells.

Blood Adv 2021 01;5(1):198-206

Laboratory of Hematoimmunology, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, Nishihara, Japan.

Hodgkin and Reed-Sternberg (HRS) cells, a hallmark of classic Hodgkin lymphoma (CHL), are occasionally detected in non-Hodgkin lymphomas, including adult T-cell leukemia/lymphoma (ATLL), a lymphoid neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). HRS-like cells associated with ATLL have been described to be of B-cell lineage and infected with Epstein-Barr virus (EBV), not HTLV-1. We herein describe clinicopathological findings in 8 cases (4 males and 4 females; median age, 73 years [range, 55-81 years]) of ATLL with HTLV-1-infected HRS-like cells identified by ultrasensitive RNA in situ hybridization for HTLV-1 basic leucine zipper factor (HBZ-ISH), a specific viral transcript of HTLV-1. All patients showed nodal or mediastinal lesions, and 5 of the 8 patients were at an advanced disease stage. HRS-like cells were positive for CD30, CD15, MUM1, CD25, and HBZ-ISH and negative for B-cell markers, including PAX5, pan-T-cell antigens, and EBV in all cases. Five cases were positive for CD4, and 6 cases were positive for fascin. HBZ was identified in both HRS-like cells and surrounding lymphoid cells in 1 case with an aggressive clinical course and only HRS-like cells in 7 cases, most of whom showed a clinical response regardless of the chemotherapeutic regimen. Even though the definitive lineage typing of the HTLV-1-infected HRS cells is one of the limitations of this study in the absence of single-cell microdissection for polymerase chain reaction analysis, the combination of diffuse HBZ-ISH positivity and negativity for PAX5 and EBV deemed these cases distinct from CHL arising in HTLV-1 carriers.
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http://dx.doi.org/10.1182/bloodadvances.2020003201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805330PMC
January 2021

Genetic profile of adult T-cell leukemia/lymphoma in Okinawa: Association with prognosis, ethnicity, and HTLV-1 strains.

Cancer Sci 2021 Mar 31;112(3):1300-1309. Epub 2021 Jan 31.

Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

Genetic alterations in adult T-cell leukemia/lymphoma (ATLL), a T-cell malignancy associated with HTLV-1, and their clinical impacts, especially from the perspective of viral strains, are not fully elucidated. We employed targeted next-generation sequencing and single nucleotide polymorphism array for 89 patients with ATLL in Okinawa, the southernmost islands in Japan, where the frequency of HTLV-1 tax subgroup-A (HTLV-1-taxA) is notably higher than that in mainland Japan, where most ATLL cases have HTLV-1-taxB, and compared the results with previously reported genomic landscapes of ATLL in mainland Japan and the USA. Okinawan patients exhibited similar mutation profiles to mainland Japanese patients, with frequent alterations in TCR/NF-ĸB (eg, PRKCB, PLCG1, and CARD11) and T-cell trafficking pathways (CCR4 and CCR7), in contrast with North American patients who exhibited a predominance of epigenome-associated gene mutations. Some mutations, especially GATA3 and RHOA, were detected more frequently in Okinawan patients than in mainland Japanese patients. Compared to HTLV-1-taxB, HTLV-1-taxA was significantly dominant in Okinawan patients with these mutations (GATA3, 34.1% vs 14.6%, P = .044; RHOA, 24.4% vs 6.3%, P = .032), suggesting the contribution of viral strains to these mutation frequencies. From a clinical viewpoint, we identified a significant negative impact of biallelic inactivation of PRDM1 (P = .027) in addition to the previously reported PRKCB mutations, indicating the importance of integrated genetic analysis. This study suggests that heterogeneous genetic abnormalities in ATLL depend on the viral strain as well as on the ethnic background. This warrants the need to develop therapeutic interventions considering regional characteristics.
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http://dx.doi.org/10.1111/cas.14806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935801PMC
March 2021

Autistic traits are associated with the functional connectivity of between-but not within-attention systems in the general population.

BMC Neurosci 2020 11 23;21(1):49. Epub 2020 Nov 23.

Department of Neuropsychiatry, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-Ku, Kyoto, 606-8507, Japan.

Background: Previous studies have demonstrated that individuals with autism spectrum disorder (ASD) exhibit dysfunction in the three attention systems (i.e., alerting, orienting, and executive control) as well as atypical relationships among these systems. Additionally, other studies have reported that individuals with subclinical but high levels of autistic traits show similar attentional tendencies to those observed in ASD. Based on these findings, it was hypothesized that autistic traits would affect the functions and relationships of the three attention systems in a general population. Resting-state functional magnetic resonance imaging (fMRI) was performed in 119 healthy adults to investigate relationships between autistic traits and within- and between-system functional connectivity (FC) among the three attention systems. Twenty-six regions of interest that were defined as components of the three attention systems by a previous task-based fMRI study were examined in terms of within- and between-system FC. We assessed autistic traits using the Autism-Spectrum Quotient.

Results: Correlational analyses revealed that autistic traits were significantly correlated with between-system FC, but not with within-system FC.

Conclusions: Our results imply that a high autistic trait level, even when subclinical, is associated with the way the three attention systems interact.
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http://dx.doi.org/10.1186/s12868-020-00603-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686764PMC
November 2020

Relationship between media multitasking and functional connectivity in the dorsal attention network.

Sci Rep 2020 10 22;10(1):17992. Epub 2020 Oct 22.

Department of Neuropsychiatry, Faculty of Medicine, Kyoto University, Kyoto, Japan.

With the development of digital technology, media multitasking behaviour, which is using two or more media simultaneously, has become more commonplace. There are two opposing hypotheses of media multitasking with regard to its impact on attention. One hypothesis claims that media multitasking can strengthen attention control, and the other claims heavy media multitaskers are less able to focus on relevant tasks in the presence of distractors. A total of 103 healthy subjects took part in this study. We measured the Media Multitasking Index (MMI) and subjects performed the continuous performance test. Resting state and oddball task functional MRI were conducted to analyse functional connectivity in the dorsal attention network, and the degree centrality (DC) was calculated using graph theory analysis. We found that the DCs in the dorsal attention network were higher during resting state than during the oddball task. Furthermore, the DCs during the task were positively correlated with the MMI. These results indicated that the DC reduction from resting state to the oddball task in high media multitaskers was attenuated compared with low media multitaskers. This study not only reveals more about the neurophysiology of media multitasking, but could also indicate brain biomarkers of media multitasking behaviour.
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http://dx.doi.org/10.1038/s41598-020-75091-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582949PMC
October 2020

Psychological resilience is correlated with dynamic changes in functional connectivity within the default mode network during a cognitive task.

Sci Rep 2020 10 20;10(1):17760. Epub 2020 Oct 20.

Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Resilience is a dynamic process that enables organisms to cope with demanding environments. Resting-state functional MRI (fMRI) studies have demonstrated a negative correlation between resilience and functional connectivities (FCs) within the default mode network (DMN). Considering the on-demand recruitment process of resilience, dynamic changes in FCs during cognitive load increases may reflect essential aspects of resilience. We compared DMN FC changes in resting and task states and their association with resilience. Eighty-nine healthy volunteers completed the Connor-Davidson Resilience Scale (CD-RISC) and an fMRI with an auditory oddball task. The fMRI time series was divided into resting and task periods. We focused on FC changes between the latter half of the resting period and the former half of the task phase (switching), and between the former and latter half of the task phase (sustaining). FCs within the ventral DMN significantly increased during "switching" and decreased during "sustaining". For FCs between the retrosplenial/posterior cingulate and the parahippocampal cortex, increased FC during switching was negatively correlated with CD-RISC scores. In individuals with higher resilience, ventral DMN connectivities were more stable and homeostatic in the face of cognitive demand. The dynamic profile of DMN FCs may represent a novel biomarker of resilience.
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http://dx.doi.org/10.1038/s41598-020-74283-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576164PMC
October 2020

A new diagnostic algorithm using biopsy specimens in adult T-cell leukemia/lymphoma: combination of RNA in situ hybridization and quantitative PCR for HTLV-1.

Mod Pathol 2021 01 17;34(1):51-58. Epub 2020 Aug 17.

Department of Pathology and Cell Biology, Graduate School of Medicine and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.

Histopathological distinction between adult T-cell leukemia/lymphoma (ATLL) and other T-cell neoplasms is often challenging. The current gold standard for the accurate diagnosis of ATLL is the Southern blot hybridization (SBH) assay, which detects clonal integration of human T-cell leukemia virus type I (HTLV-1) provirus. However, SBH cannot be performed with small biopsy or formalin-fixed paraffin-embedded (FFPE) tissue samples because this assay requires a large amount of DNA without degradation. Here we developed a new diagnostic algorithm for the accurate diagnosis of ATLL using FFPE samples. This method combines two HTLV-1 detection assays, namely, ultrasensitive RNA in situ hybridization using RNAscope for HTLV-1 bZIP factor (HBZ-RNAscope), and quantitative PCR targeting the tax gene (tax-qPCR). We analyzed 119 FFPE tissue specimens (62 ATLL, and 57 non-ATLL, including 41 HTLV-1 carriers) and compared them with the SBH results using the corresponding fresh-frozen samples. As a result, tax-qPCR had a higher ATLL identification rate than HBZ-RNAscope (88% [52/59], and 63% [39/62], respectively). However, HBZ-RNAscope clearly visualized the localization of HTLV-1-infected tumor cells and its identification rate increased to 94% (17/18) when the analysis was limited to samples up to 2 years old, indicating its usefulness in the daily diagnosis. The diagnostic algorithm combining these two assays successfully evaluated 94% (112/119) of samples and distinguished ATLL from non-ATLL cases including HTLV-1 carriers with 100% sensitivity and specificity. This method is expected to replace SBH and increase the accuracy of the diagnosis of ATLL.
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http://dx.doi.org/10.1038/s41379-020-0635-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806504PMC
January 2021

[EFFICACY, PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF INTRAVENOUS C1 INHIBITOR FOR LONG-TERM PROPHYLAXIS AND TREATMENT OF BREAKTHROUGH ATTACKS IN JAPANESE SUBJECTS WITH HEREDITARY ANGIOEDEMA: A PHASE 3 OPEN-LABEL STUDY].

Arerugi 2020 ;69(3):192-203

Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University.

Background: Hereditary angioedema (HAE) is associated with recurrent, painful, and potentially lifethreatening attacks characterized by swelling of subcutaneous or submucosal tissues.

Purpose: To investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of repeat-use C1 inhibitor (C1-INH) replacement therapy for long-term prophylaxis and treatment of breakthrough attacks in the management of Japanese patients with HAE type I or II.

Methods: An open-label, single-arm, Phase 3 study was conducted in Japanese patients with HAE (NCT02865720). For patients 6 years of age or older, 1000U were administered biweekly (by a healthcare professional or self-administered) via intravenous infusion.

Results: In 8 enrolled patients, the mean number of attacks normalized per month was lower during C1-INH treatment than during the 3 months prior (1.826 vs. 3.375). Clinically meaningful mean change from baseline in the angioedema-quality of life (AE-QoL) total score was shown during treatment with C1-INH. Pharmacokinetic data showed markedly higher and enduring post-baseline plasma levels of C1-INH functional activity and C1-INH antigen concentration, starting from 0.5h after first dose of C1-INH and lasting up to 72 hours. C1-INH was well tolerated with no new safety signals identified in this population of Japanese patients with HAE.

Conclusion: C1-INH was effective for long-term prophylaxis and treatment of breakthrough attacks with favourable safety profile in Japanese patients with HAE.
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http://dx.doi.org/10.15036/arerugi.69.192DOI Listing
August 2020

Proteomic profiling of HTLV-1 carriers and ATL patients reveals sTNFR2 as a novel diagnostic biomarker for acute ATL.

Blood Adv 2020 03;4(6):1062-1071

Laboratory of Hematoimmunology, Graduate School of Health Sciences, University of the Ryukyus, Nishihara, Japan.

Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type 1 (HTLV-1)-associated T-cell malignancy with generally poor prognosis. Although only ∼5% of HTLV-1 carriers progress to ATL, early diagnosis is challenging because of the lack of ATL biomarkers. In this study, we analyzed blood plasma profiles of asymptomatic HTLV-1 carriers (ACs); untreated ATL patients, including acute, lymphoma, smoldering, and chronic types; and ATL patients in remission. Through SOMAscan, expression levels of 1305 plasma proteins were analyzed in 85 samples (AC, n = 40; ATL, n = 40; remission, n = 5). Using gene set enrichment analysis and gene ontology, overrepresented pathways in ATL vs AC included angiogenesis, inflammation by cytokines and chemokines, interleukin-6 (IL-6)/JAK/STAT3, and notch signaling. In selecting candidate biomarkers, we focused on soluble tumor necrosis factor 2 (sTNFR2) because of its active role in enriched pathways, extreme significance (Welch's t test P < .00001), high discrimination capacity (area under the curve >0.90), and novelty in ATL research. Quantification of sTNFR2 in 102 plasma samples (AC, n = 30; ATL, n = 68; remission, n = 4) using enzyme-linked immunosorbent assay showed remarkable elevations in acute ATL, at least 10 times those of AC samples, and return of sTNFR2 to AC state levels after achieving remission. Flow cytometry and immunostaining validated the expression of TNFR2 in ATL cells. No correlation between sIL-2 and sTNFR2 levels in acute ATL was found, suggesting the possibility of sTNFR2 as an independent biomarker. Our findings represent the first extensive blood-based proteomic analysis of ATL, suggesting the potential clinical utility of sTNFR2 in diagnosing acute ATL.
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http://dx.doi.org/10.1182/bloodadvances.2019001429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094015PMC
March 2020

Transplant-related complications are impediments to the success of allogeneic hematopoietic stem cell transplantation for adult T cell leukemia patients in non-complete remission.

Bone Marrow Transplant 2020 01 18;55(1):233-241. Epub 2019 Sep 18.

Division of Endocrinology, Diabetes and Metabolism, Hematology and Rheumatology, (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.

Outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with adult T cell leukemia/lymphoma (ATL) are not satisfactory, particularly in patients in non-complete remission at transplantation (Pt-non-CR). We conducted a regional retrospective study in the ATL endemic area of Okinawa, Japan. Of 62 ATL patients, 21 received allo-HSCT in CR and 41 in non-CR. The 3-year overall survival (3yOS) rate and median survival time for the whole cohort was 25.6% and 7.7 months, respectively. The 3yOS of Pt-non-CR was significantly lower than that of patients in CR (Pt-CR) (16.8% vs. 43.6%, P = 0.005). Transplant-related mortality (TRM) was significantly higher in Pt-non-CR than in Pt-CR (46.3% vs. 15.7%, P = 0.025), while there was no significant difference in disease-associated mortality (DAM) between Pt-non-CR and Pt-CR. Multivariable analysis for Pt-non-CR revealed that poor performance status (poor-PS) and higher sIL-2R level (high sIL-2R) adversely affected OS. Poor-PS was associated with higher TRM, but not with higher DAM in Pt-non-CR. High sIL-2R did not affect TRM or DAM in Pt-non-CR. Overall, high TRM rates rather than DAM contribute to the poor outcomes of Pt-non-CR, suggesting that not only disease control but also management of transplant-related complications is required for allo-HSCT in ATL patients.
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http://dx.doi.org/10.1038/s41409-019-0669-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7091703PMC
January 2020

Martial Arts "" and the Motivation Network During Attention Processing: An fMRI Study.

Front Hum Neurosci 2019 22;13:170. Epub 2019 May 22.

Department of Neuropsychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Japanese martial arts, , have been reported to improve cognitive function, especially attention. However, the underlying neural mechanisms of the effect of on attention processing has not yet been investigated. , a type of fencing using bamboo swords, is one of the most popular forms of worldwide. We investigated the difference in functional connectivity (FC) between players (KPs) and non-KPs (NKPs) during an attention-related auditory oddball paradigm and during rest. The analyses focused on the brain network related to "motivation." Resting-state functional magnetic resonance imaging (rs-fMRI) and task-based fMRI using the oddball paradigm were performed in healthy male volunteers (14 KPs and 11 NKPs). Group differences in FC were tested using CONN-software within the motivation network, which consisted of 22 brain regions defined by a previous response-conflict task-based fMRI study with a reward cue. Daily general physical activities were assessed using the International Physical Activity Questionnaire (IPAQ). We also investigated the impact of major confounders, namely, smoking habits, alcohol consumption, IPAQ score, body mass index (BMI), and reaction time (RT) in the oddball paradigm. Resting-state fMRI revealed that KPs had a significantly lower FC than NKPs between the right nucleus accumbens and right frontal eye field (FEF) within the motivation network. Conversely, KPs exhibited a significantly higher FC than NKPs between the left intraparietal sulcus (IPS) and the left precentral gyrus (PCG) within the network during the auditory oddball paradigm [statistical thresholds, False Discovery Rate (FDR) < 0.05]. These results remained significant after controlling for major covariates. Our results suggest that attenuated motivation network integrity at rest together with enhanced motivation network integrity during attentional demands might underlie the instantaneous concentration abilities of KPs.
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http://dx.doi.org/10.3389/fnhum.2019.00170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539200PMC
May 2019

VCAP-AMP-VECP as a preferable induction chemotherapy in transplant-eligible patients with aggressive adult T-cell leukemia-lymphoma: a propensity score analysis.

Bone Marrow Transplant 2019 09 21;54(9):1399-1405. Epub 2019 Jan 21.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.

A dose-intensified multi-agent chemotherapy regimen called VCAP-AMP-VECP was investigated in Japan as front-line therapy for patients with adult T-cell leukemia-lymphoma (ATL). Although a prospective randomized controlled study showed that VCAP-AMP-VECP was superior to CHOP, the trial was rather small and no subsequent studies confirmed the benefit of VCAP-AMP-VECP over CHOP. We conducted a retrospective analysis of transplant-eligible patients with ATL who received only VCAP-AMP-VECP or CHOP, incorporating inverse probability of treatment weighting (IPTW) using propensity scoring. Overall, 947 and 513 patients were treated with VCAP-AMP-VECP and CHOP, respectively. The median follow-up of surviving patients was 1006 days. The crude probabilities of 2-year overall survival (OS) for patients in the VCAP-AMP-VECP and CHOP groups were 31.2% and 24.6%, respectively (P < 0.001). Stratified by risk group according to the modified ATL-prognostic index score at diagnosis, the crude probabilities of 2-year OS in the VCAP-AMP-VECP and CHOP groups were 39.8 and 45.0% in the low-risk group (P = 0.69), 32.2 and 21.6% in the intermediate-risk group (P < 0.001), and 17.2 and 6.2% in the high-risk group (P = 0.005). Our current analysis suggests that VCAP-AMP-VECP regimen is a preferable front-line therapy in patients with aggressive ATL in intermediate- and high-risk groups.
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http://dx.doi.org/10.1038/s41409-019-0446-zDOI Listing
September 2019

Evaluation of two prognostic indices for adult T-cell leukemia/lymphoma in the subtropical endemic area, Okinawa, Japan.

Cancer Sci 2018 Jul 16;109(7):2286-2293. Epub 2018 Jun 16.

Division of Endocrinology, Diabetes and Metabolism, Hematology and Rheumatology, Second Department of Internal Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

Aggressive adult T-cell leukemia/lymphoma (ATL) has an extremely poor prognosis and is hyperendemic in Okinawa, Japan. This study evaluated two prognostic indices (PIs) for aggressive ATL, the ATL-PI and Japan Clinical Oncology Group (JCOG)-PI, in a cohort from Okinawa. The PIs were originally developed using two different Japanese cohorts that included few patients from Okinawa. The endpoint was overall survival (OS). Multivariable Cox regression analyses in the cohort of 433 patients revealed that all seven factors for calculating each PI were statistically significant prognostic predictors. Three-year OS rates for ATL-PI were 35.9% (low-risk, n = 66), 10.4% (intermediate-risk, n = 256), and 1.6% (high-risk, n = 111), and those for JCOG-PI were 22.4% (moderate-risk, n = 176) and 5.3% (high-risk, n = 257). The JCOG-PI moderate-risk group included both the ATL-PI low- and intermediate-risk groups. ATL-PI more clearly identified the low-risk patient subgroup than JCOG-PI. To evaluate the external validity of the two PIs, we also assessed prognostic discriminability among 159 patients who loosely met the eligibility criteria of a previous clinical trial. Three-year OS rates for ATL-PI were 34.5% (low-risk, n = 42), 9.2% (intermediate-risk, n = 109), and 12.5% (high-risk, n = 8). Those for JCOG-PI were 22.4% (moderate-risk, n = 95) and 7.6% (high-risk, n = 64). The low-risk ATL-PI group had a better prognosis than the JCOG-PI moderate-risk group, suggesting that ATL-PI would be more useful than JCOG-PI for establishing and examining novel treatment strategies for ATL patients with a better prognosis. In addition, strongyloidiasis, previously suggested to be associated with ATL-related deaths in Okinawa, was not a prognostic factor in this study.
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http://dx.doi.org/10.1111/cas.13641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029833PMC
July 2018

Human T-cell leukemia virus type I Tax genotype analysis in Okinawa, the southernmost and remotest islands of Japan: Different distributions compared with mainland Japan and the potential value for the prognosis of aggressive adult T-cell leukemia/lymphoma.

Leuk Res 2017 10 18;61:18-24. Epub 2017 Aug 18.

Laboratory of Hematoimmunology, Graduate School of Health Sciences, University of the Ryukyus, Nishihara, Japan. Electronic address:

Okinawa, comprising remote islands off the mainland of Japan, is an endemic area of human T-cell leukemia virus type I (HTLV-1), the causative virus of adult T-cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). We investigated the tax genotype of HTLV-1 among 29 HTLV-1 carriers, 74 ATL patients, and 33 HAM patients in Okinawa. The genotype distribution-60 (44%) taxA cases and 76 (56%) taxB cases-differed from that of a previous report from Kagoshima Prefecture in mainland Japan (taxA, 10%; taxB, 90%). A comparison of the clinical outcomes of 45 patients (taxA, 14; taxB, 31) with aggressive ATL revealed that the overall response and 1-year overall survival rates for taxA (50% and 35%, respectively) were lower than those for taxB (71% and 49%, respectively). In a multivariate analysis of two prognostic indices for aggressive ATL, Japan Clinical Oncology Group-Prognostic Index and Prognostic Index for acute and lymphoma ATL, with respect to age, performance status, corrected calcium, soluble interleukin-2 receptor, and tax genotype, the estimated hazard ratio of taxA compared with taxB was 2.68 (95% confidence interval, 0.87-8.25; P=0.086). Our results suggest that the tax genotype has clinical value as a prognostic factor for aggressive ATL.
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http://dx.doi.org/10.1016/j.leukres.2017.08.006DOI Listing
October 2017

Development of a modified prognostic index for patients with aggressive adult T-cell leukemia-lymphoma aged 70 years or younger: possible risk-adapted management strategies including allogeneic transplantation.

Haematologica 2017 07 24;102(7):1258-1265. Epub 2017 Mar 24.

Department of Hematology, Nagasaki University Hospital, Fukuoka, Japan.

Adult T-cell leukemia-lymphoma is a distinct type of peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I. Although allogeneic stem cell transplantation after chemotherapy is a recommended treatment option for patients with aggressive adult T-cell leukemia-lymphoma, there is no consensus about indications for allogeneic stem cell transplantation because there is no established risk stratification system for transplant eligible patients. We conducted a nationwide survey of patients with aggressive adult T-cell leukemia-lymphoma in order to construct a new, large database that includes 1,792 patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who were diagnosed between 2000 and 2013 and received intensive first-line chemotherapy. We randomly divided patients into two groups (training and validation sets). Acute type, poor performance status, high soluble interleukin-2 receptor levels (> 5,000 U/mL), high adjusted calcium levels (≥ 12 mg/dL), and high C-reactive protein levels (≥ 2.5 mg/dL) were independent adverse prognostic factors used in the training set. We used these five variables to divide patients into three risk groups. In the validation set, median overall survival for the low-, intermediate-, and high-risk groups was 626 days, 322 days, and 197 days, respectively. In the intermediate- and high-risk groups, transplanted recipients had significantly better overall survival than non-transplanted patients. We developed a promising new risk stratification system to identify patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who may benefit from upfront allogeneic stem cell transplantation. Prospective studies are warranted to confirm the benefit of this treatment strategy.
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http://dx.doi.org/10.3324/haematol.2017.164996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566038PMC
July 2017

Synthesis and structure-activity relationships of 1-benzylindane derivatives as selective agonists for estrogen receptor beta.

Bioorg Med Chem 2016 11 20;24(22):5895-5910. Epub 2016 Sep 20.

Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1, Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.

The estrogen receptor beta (ERβ) selective agonist is considered a promising candidate for the treatment of estrogen deficiency symptoms in ERβ-expressing tissues, without the risk of breast cancer, and multiple classes of compounds have been reported as ERβ selective agonists. Among them, 6-6 bicyclic ring-containing structures (e.g., isoflavone phytoestrogens) are regarded as one of the cyclized analogues of isobutestrol 5b, and suggest that other cyclized scaffolds comprising 5-6 bicyclic rings could also act as selective ERβ ligands. In this study, we evaluated the selective ERβ agonistic activity of 1-(4-hydroxybenzyl)indan-5-ol 7a and studied structure-activity relationship (SAR) of its derivatives. Some functional groups improved the properties of 7a; introduction of a nitrile group on the indane-1-position resulted in higher selectivity for ERβ (12a), and further substitution with a fluoro or a methyl group to the pendant phenyl ring was also preferable (12b, d, and e). Subsequent chiral resolution of 12a identified that R-12a has a superior profile over S-12a. This is comparable to diarylpropionitrile (DPN) 5c, one of the promising selective ERβ agonists and indicates that this indane-based scaffold has the potential to provide better ERβ agonistic probes.
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http://dx.doi.org/10.1016/j.bmc.2016.09.047DOI Listing
November 2016

Characterization of patients with aggressive adult T-cell leukemia-lymphoma in Okinawa, Japan: a retrospective analysis of a large cohort.

Int J Hematol 2016 Oct 21;104(4):468-75. Epub 2016 Jun 21.

Division of Endocrinology, Diabetes and Metabolism, Hematology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

Okinawa Prefecture, located in the subtropics, is an area of endemic adult T-cell leukemia-lymphoma (ATL) in Japan. We retrospectively analyzed 659 patients with aggressive ATL in seven institutions in Okinawa between 2002 and 2011. The median patient age was 68 years. More patients were aged ≥90 years (2.6 %), in this study, than in a nationwide survey (<1 %). The median survival time (MST) of the entire cohort was 6.5 months. Of the 217 patients who had a clinical status similar to that stated in the eligibility criteria of JCOG9801 (a randomized phase III study comparing VCAP-AMP-VECP with CHOP-14), 147 who received the CHOP regimen had a poorer MST than those in the CHOP-14 arm of JCOG9801 (8 vs 11 months). The prevalence of strongyloidiasis in the ATL patients was much higher (12.4 %) than in the historical cohort who visited the University of the Ryukyus Hospital (3.4 %). Furthermore, strongyloidiasis may be associated with ATL-related deaths. These findings suggest that, compared with other areas in Japan, in Okinawa, the proportion of patients aged ≥90 years with clinical features of aggressive ATL is higher, outcomes are poorer, and the disease is associated with a higher prevalence of strongyloidiasis.
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http://dx.doi.org/10.1007/s12185-016-2042-yDOI Listing
October 2016

Characterization of patients with aggressive adult T-cell leukemia-lymphoma in Okinawa, Japan: a retrospective analysis of a large cohort.

Int J Hematol 2016 Oct 21;104(4):468-75. Epub 2016 Jun 21.

Division of Endocrinology, Diabetes and Metabolism, Hematology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

Okinawa Prefecture, located in the subtropics, is an area of endemic adult T-cell leukemia-lymphoma (ATL) in Japan. We retrospectively analyzed 659 patients with aggressive ATL in seven institutions in Okinawa between 2002 and 2011. The median patient age was 68 years. More patients were aged ≥90 years (2.6 %), in this study, than in a nationwide survey (<1 %). The median survival time (MST) of the entire cohort was 6.5 months. Of the 217 patients who had a clinical status similar to that stated in the eligibility criteria of JCOG9801 (a randomized phase III study comparing VCAP-AMP-VECP with CHOP-14), 147 who received the CHOP regimen had a poorer MST than those in the CHOP-14 arm of JCOG9801 (8 vs 11 months). The prevalence of strongyloidiasis in the ATL patients was much higher (12.4 %) than in the historical cohort who visited the University of the Ryukyus Hospital (3.4 %). Furthermore, strongyloidiasis may be associated with ATL-related deaths. These findings suggest that, compared with other areas in Japan, in Okinawa, the proportion of patients aged ≥90 years with clinical features of aggressive ATL is higher, outcomes are poorer, and the disease is associated with a higher prevalence of strongyloidiasis.
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http://dx.doi.org/10.1007/s12185-016-2042-yDOI Listing
October 2016

Design, synthesis, and structure-activity relationships of a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-D-glycopyranosides substituted with novel hydrophilic groups as highly potent inhibitors of sodium glucose co-transporter 1 (SGLT1).

Bioorg Med Chem 2013 Feb 5;21(3):748-65. Epub 2012 Dec 5.

Central Research Laboratory, Kissei Pharmaceutical Company, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano Prefecture 399-8304, Japan.

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a). To further improve SGLT1 inhibitory activity and reduce aglycone permeability, a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-D-glycopyranoside derivatives bearing novel hydrophilic substitution groups on the phenyl ring were synthesized and their inhibitory activity toward SGLTs was evaluated. Optimized compound 14c showed an improved profile satisfying both higher activity and lower permeability of its aglycone (22f) compared with initial leads 1 and 2. Moreover, the superior efficacy of 14c in various carbohydrate tolerance tests in diabetic rat models was confirmed compared with acarbose, an α-glucosidase inhibitor (α-GI) widely used in the clinic.
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http://dx.doi.org/10.1016/j.bmc.2012.11.041DOI Listing
February 2013

Structure-activity relationship studies of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia.

Bioorg Med Chem 2012 Nov 24;20(22):6598-612. Epub 2012 Sep 24.

Central Research Laboratory, Kissei Pharmaceutical Company, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano Prefecture, Japan.

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure-activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors. Representative derivatives showed a dose-dependent suppressing effect on the escalation of blood glucose levels in oral mixed carbohydrate tolerance tests (OCTT) in streptozotocin-nicotinamide-induced diabetic rats (NA-STZ rats).
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http://dx.doi.org/10.1016/j.bmc.2012.09.037DOI Listing
November 2012

[Cauda equina relapse after autologous stem cell transplantation in a patient with primary plasma cell leukemia].

Gan To Kagaku Ryoho 2010 Apr;37(4):743-6

Department of Endocrinology and Metabolism, Internal Medicine, University of The Ryukyus School of Medicine.

We report a rare case showing involvement with the cauda equina after autologous peripheral blood stem cell transplantation for primary plasma cell leukemia (PCL). A 55-year-old man was diagnosed with PCL(IgA-k type, stage III)in November of 2006. He was treated with VAD chemotherapy consisting of vincristine, doxorubicin, and dexamethasone. After achieving hematological remission, he received tandem high-dose melphalan supported by autologous peripheral blood stem cell transplantation. Five months after his second transplant, he complained of lumbago and bilateral leg pain. M-protein and Bence-Jones protein were not detected in serum or urine. An axial magnetic resonance imaging study revealed enlargement of the cauda equina nerve roots on T-1 weighted image. A sagittal T-1 weighted gadolinium-enhanced imaging study showed hyperintensities along the cauda equina. Leptomeningeal enhancement was also seen below the level of Th6. A cytological examination of the cerebrospinal fluid (CSF) with May-Giemsa stain showed atypical plasma cells. Immunoelectrophoresis of the CSF revealed monoclonal IgA-k type protein. A diagnosis of central nervous system (CNS)relapse was made. The patient died of pneumonia two months after relapse. It should be kept in mind that CNS relapse can occur during hematological remission in patients with multiple myeloma including PCL.
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April 2010

Treatment-related Burkitt's lymphoma: literature review and case report of successful treatment with rituximab monotherapy.

Acta Haematol 2009 29;122(4):211-5. Epub 2009 Oct 29.

Department of Endocrinology and Metabolism, Internal Medicine, University of the Ryukyus School of Medicine, Okinawa, Japan.

The development of Burkitt's lymphoma (BL) is uncommon in elderly people. Most treatment-related hematological malignancies are of a myeloid lineage. Only a few cases with BL secondary to cancer treatment have been described. We report a rare case of an elderly patient with radiotherapy-related BL. A 71-year-old Japanese man, who had a past history of oropharyngeal cancer treated with local irradiation 15 years ago, presented with a left mandibular mass in December 2004. A partial mandibulectomy disclosed pathological features consistent with BL. Although the patient was initially treated with intensive chemotherapy, the development of complications precluded further anticancer drug treatment. Rituximab was administered once weekly for 5 consecutive weeks, with resolution of the mandibular mass. He remained in remission without further lymphoma treatment for more than 3 years after diagnosis. Rituximab monotherapy should be considered as a therapeutic option for elderly patients with BL.
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http://dx.doi.org/10.1159/000253028DOI Listing
December 2009

[HIV- and HHV-8-negative primary effusion lymphoma-like lymphoma presenting with lymphomatous effusions complicated by cardiac tamponade-a case report].

Gan To Kagaku Ryoho 2009 Jul;36(7):1195-8

Dept. of Endocrinology and Metabolism, Internal Medicine, University of The Ryukyus School of Medicine.

We report a rare case of human immunodeficiency virus (HIV)- and human herpes virus-8 (HHV-8)-negative primary effusion lymphoma (PEL)-like lymphoma presenting with lymphomatous effusions complicated by cardiac tamponade. A 68-year-old woman was hospitalized with generalized weakness in June 2006. Echocardiogram revealed the presence of pericardial effusion and she had the signs of cardiac tamponade. Urgent pericardial drainage relieved her symptoms. Chest computed tomography showed bilateral pleural effusions along with pericardial effusion. Cytologic findings of both effusions were suggestive of malignancies, including malignant lymphoma. Immunocytochemical studies with a panel of antibodies, including CD20 and CD79a, could not provide a definite diagnosis. Flow cytometric analysis of pleural effusion revealed that tumor cells were positive for CD10 and CD19, but negative for CD20, CD23, surface immunoglobulin, and T-cell associated antigens. Clonal rearrangement of the immunoglobulin heavy chain gene was detected by Southern blot analysis. Polymerase chain reaction proved to be negative for HHV-8. The serology test for HIV was negative. After a diagnosis of HHV-8-negative PEL-like lymphoma, she was treated with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone). However, she died of progressive lymphoma 7 months after the diagnosis. PEL-like lymphomas are of B-cell origin. In some cases of PEL-like lymphoma, tumor cells may be negative for representative markers of B-cell phenotype such as CD20 and CD79a.
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July 2009

Intensive chemotherapy for a patient with primary cutaneous diffuse large B-cell lymphoma with Burkitt-like morphology.

Intern Med 2009 16;48(6):475-8. Epub 2009 Mar 16.

Department of Endocrinology and Metabolism, Internal Medicine, University of The Ryukyus School of Medicine, Okinawa.

We report a rare case of primary cutaneous diffuse large B-cell lymphoma (DLBCL) with Burkitt-like morphology. A 54-year-old man presented with multiple subcutaneous tumors. Pathological examination showed morphological features resembling Burkitt or Burkitt-like lymphoma (BL/BLL) with high MIB-1 positivity. Cytogenetic studies revealed no 8q24/c-myc translocation. After the diagnosis of Burkitt-like DLBCL, the patient was treated with CODOX-M chemotherapy (cyclophosphamide, doxorubicin, vincristine, cytarabine and methotrexate), which led to durable remission. The present case suggests that short-term, high-intensity chemotherapy used for BL/BLL may be appropriate for primary cutaneous Burkitt-like DLBCL, as well as systemic lymphoma with Burkitt-like morphology.
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http://dx.doi.org/10.2169/internalmedicine.48.1791DOI Listing
August 2009

Extranodal adult T-cell leukemia/lymphoma of the head and neck: a clinicopathological study of nine cases and a review of the literature.

Leuk Lymphoma 2009 Feb;50(2):187-95

Department of Endocrinology and Metabolism, Internal Medicine, University of The Ryukyus School of Medicine, Okinawa, Japan.

Extranodal adult T-cell leukemia/lymphoma (ATLL) of the head and neck is a rare disease. We studied the clinicopathological features of nine patients with ATLL involving extranodal head and neck sites and conducted a literature review. Six patients presented with extranodal mass of the head and neck, whereas three had disseminated diseases. Tumors involved the parotid gland, sinonasal tract, masseter muscle, mandible and skull. Histopathology included diffuse pleomorphic-type (with angiocentric features), Hodgkin-like and anaplastic large cell-type. Five patients with localised disease showed prolonged survival regardless of unfavourable histology and/or aberrant provirus status, including integration of multiple copies or defective provirus. Patients with localised disease documented in the literature, including our study series, had a reduced frequency of elevated lactate dehydrogenase, no hypercalcemia and longer survival. ATLL should be included in the differential diagnosis of extranodal head and neck lymphoma. Localised extranodal ATLL of the head and neck may exhibit indolent clinical behaviours.
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http://dx.doi.org/10.1080/10428190802702383DOI Listing
February 2009

[A Japanese case of human herpes virus-8-associated multicentric castleman disease complicated by hemophagocytic syndrome].

Gan To Kagaku Ryoho 2008 Aug;35(8):1431-4

Dept. of Endocrinology and Metabolism, Internal Medicine, University of The Ryukyus School of Medicine.

We report a Japanese case of human herpes virus-8 (HHV-8)-associated multicentric Castleman disease(MCD) complicated by hemophagocytic syndrome(HPS). A 60-year-old man presented with persistent fever and progressive pancytopenia in June 2004. On physical examination, anemia, icterus, hepatosplenomegaly, and generalized lymphadenopathy were detected. Laboratory findings showed elevated levels of serum ferritin and soluble interleukin-2 receptor. Anti-human immunodeficiency virus (HIV) antibody was negative. Bone marrow aspiration revealed a normocellular marrow with an increased number of hemophagocytic histiocytes. Biopsy of cervical lymph node disclosed pathological features compatible with the plasmablastic variant of Castleman disease. HHV-8 DNA was detected in the specimen from lymph node by polymerase chain reaction. Thus, the diagnosis of HHV-8-associated MCD complicated by HPS was made. The patient was treated with immunotherapy and subsequent chemotherapy. However, he died of bacterial sepsis after one-month therapy. This case report provides some evidence that HHV-8 may be a causative agent of MCD even in HIV-seronegative Japanese patients.
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August 2008

[Primary diffuse large B-cell lymphoma of the uterine cervix--a case report].

Gan To Kagaku Ryoho 2008 Aug;35(8):1423-5

Dept. of Endocrinology and Metabolism, Internal Medicine, University of The Ryukyus School of Medicine.

Primary malignant lymphoma of the female genital tract is an extremely rare clinical entity. We report a case of primary non-Hodgkin lymphoma of the uterine cervix. A 68-year-old woman presented with abnormal genital bleeding in May 2002. A coloposcopic examination revealed a mass in the uterine cervix. Magnetic resonance imaging showed a bulky cervical tumor(7.5 x 8 cm)invading the right parametrium and adjacent levator ani muscle. Involvement of pelvic lymph nodes was also observed. The uterine lesion exhibited homogenous hypointensity on T1 weight image and isointense to hyperintense on T2-weight image. No other lesions were detected by the whole-body computed tomography, gallium scintigraphy, and bone marrow examination. Although cytology of the smear from the uterine cervix was nondiagnostic, the histologic examination of the punch biopsy material showed a diffuse proliferation of atypical lymphoid cells. Immunophenotypic studies revealed tumor cells were positive for CD19, CD20, CD30, and k-chain. A diagnosis of diffuse large B-cell lymphoma of the uterine cervix, clinical stage IIE was made. The patient was treated with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone(CHOP)chemotherapy followed by the involved field irradiation. She remains alive and free of disease more than 5 years after the diagnosis.
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August 2008

[Primary pulmonary Hodgkin lymphoma--two case reports and a review of the literature].

Gan To Kagaku Ryoho 2007 Dec;34(13):2279-82

Dept. of Endocrinology and Metabolism, Internal Medicine, University of the Ryukyus School of Medicine.

Primary extranodal involvement of Hodgkin lymphoma (HL) is rare. We report two HL patients presenting with exclusive or predominant lung involvement. In both cases, the results of transbronchial and/or CT-guided lung needle biopsy were indicative of granulomatous disease. Eventually, lymph node biopsy specimens revealed HL with nodular sclerosis type and lymphocyte-rich type, respectively. There were no specific symptoms, laboratory and imaging findings for pulmonary HL. A histological examination was required to confirm the diagnosis. Lung biopsy techniques such as transbronchial or percutaneous biopsy may be insufficient to allow diagnosis of HL. Pulmonary HL should be included in the differential diagnosis of lung involvement, even when the pathological evaluation of nonspecific inflammation was made from the biopsied specimens.
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December 2007

Adult T-cell leukemia/lymphoma with multiple integration of HTLV-1 provirus presenting as an isolated paranasal sinus tumor: a case report.

Head Neck 2008 Jun;30(6):815-20

Department of Endocrinology and Metabolism, Internal Medicine, University of the Ryukyus School of Medicine, Okinawa, Japan.

Background: Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoma and etiologically associated with human T-lymphotropic virus type 1 (HTLV-1). Patients with ATLL commonly present with leukemic changes, systemic lymphadenopathy, and/or extranodal lesion and have very poor prognosis.

Methods And Results: We describe a rare case of ATLL presenting as an isolated paranasal mass. Southern blot analysis of the biopsied specimens demonstrated multiple integration bands of HTLV-1 provirus of different intensities. Chemotherapy resulted in complete resolution of the paranasal mass. Thereafter, the patient showed an indolent clinical course with leukemic changes and pulmonary and cutaneous ATLL lesions and remains alive more than 5 years from diagnosis.

Conclusion: ATLL should be included in the differential diagnosis of sinonasal lymphoma, although the event is rare. Multiple HTLV-1 provirus integrations of different intensities may be indicative of good prognosis for ATLL.
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http://dx.doi.org/10.1002/hed.20730DOI Listing
June 2008

[Interdigitating dendritic cell sarcoma/tumor--a case report].

Gan To Kagaku Ryoho 2007 Mar;34(3):469-71

Dept. of Endocrinology and Metabolism, University of The Ryukyus School of Medicine.

We report an extremely rare case of interdigitating dendritic cell sarcoma/tumor (IDCS). A 52-year-old man presented with a 2-week history of fever in January 2002. Physical examination revealed enlarged, painless right axillary lymph nodes, and hepatosplenomegaly. Whole-body computerized tomography showed enlarged lymph nodes in mediastinal, right axillary, abdominal para-aortic, ileum, and inguinal regions. Hepatosplenomegaly was also detected. In addition to abnormal liver function tests, serum levels of soluble interleukin-2 receptor and ferritin were elevated. Excisional biopsy of right axillary lymph node was performed in February 2002. Histological examination showed a diffuse proliferation of medium-to large-sized cells with round or oval nuclei and abundant cytoplasm. Spindle shape cells and Hodgkin-like giant cells were also seen. Immunohistochemically, the tumor cells expressed S-100 protein, CD 68, and CD 45 RO. They were negative for CD 1, CD 3, CD 15, CD 20, CD 21, CD 23, FDC, DRC, and p80. These findings were compatible with the diagnosis of IDCS. The patient was treated with polychemotherapy consisting of doxorubicin,cyclophosphamide, vincristine, and prednisone. However, he developed fungal pneumonia and died of respiratory failure 1 month after the start of treatment.
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March 2007
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