Publications by authors named "Kenichi Ishizawa"

165 Publications

Association between milk and yogurt intake and mortality: a community-based cohort study (Yamagata study).

BMC Nutr 2021 Jul 14;7(1):33. Epub 2021 Jul 14.

Department of Public Health and Hygiene, Yamagata University Graduate School of Medical Science, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.

Background: Dairy products are known as health-promoting foods. This study prospectively examined the association between milk and yogurt intake and mortality in a community-based population.

Methods: The study population comprised of 14,264 subjects aged 40-74 years who participated in an annual health checkup. The frequency of yogurt and milk intake was categorized as none (< 1/month), low (< 1/week), moderate (1-6/week), and high (> 1/day) intake. The association between yogurt and milk intake and total, cardiovascular, and cancer-related mortalities was determined using the Cox proportional hazards model.

Results: During the follow-up period, there were 265 total deaths, 40 cardiovascular deaths and 90 cancer-related deaths. Kaplan-Meier analysis showed that the total mortality in high/moderate/low yogurt intake and moderate/low milk intake groups was lower than that in none group (log-rank, P < 0.01). In the multivariate Cox proportional hazard analysis adjusted for possible confounders, the hazard ratio (HR) for total mortality significantly decreased in high/moderate yogurt intake group (HR: 0.62, 95% confidence interval [CI]: 0.42-0.91 for high intake, HR: 0.70, 95%CI: 0.49-0.99 for moderate intake) and moderate milk intake group (HR: 0.67, 95% CI: 0.46-0.97) compared with the none yogurt and milk intake groups. A similar association was observed for cancer-related mortality, but not for cardiovascular mortality.

Conclusions: Our study showed that yogurt and milk intake was independently associated with a decrease in total and cancer-related mortalities in the Japanese population.
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http://dx.doi.org/10.1186/s40795-021-00435-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278744PMC
July 2021

A unique three-way Philadelphia chromosome variant t(4;9;22)(q21;q34;q11.2) in a newly diagnosed patient with chronic phase chronic myeloid leukemia: a case report and review of the literature.

J Med Case Rep 2021 May 25;15(1):285. Epub 2021 May 25.

Department of Internal Medicine III, Division of Hematology and Cell Therapy, Yamagata University faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.

Background: Chronic myeloid leukemia is a hematologic malignancy associated with the fusion of two genes: BCR and ABL1. This fusion results from a translocation between chromosomes 9 and 22, which is called the Philadelphia chromosome. Although the Philadelphia chromosome is present in more than 90% of patients with chronic myeloid leukemia, 5-8% of patients with chronic myeloid leukemia show complex variant translocations. Herein, we report a unique case of a three-way translocation variant in chronic phase chronic myeloid leukemia.

Case Presentation: A 40-year-old Asian male who presented with leukocytosis was diagnosed with chronic phase chronic myeloid leukemia. Cytogenetic karyotyping analysis showed 46,XY,t(4;9;22)(q21;q34;q11.2). He was treated with bosutinib and then changed to dasatinib because of intolerance, and MR4.5 (BCR-ABL/ABL ≦ 0.0032%, international scale) was achieved after 17 months of continuous treatment.

Conclusion: This was the 14th case of t(4;9;22), in particular, a new variant Ph translocation involved in chromosome 4q21 and the first successful case treated with tyrosine kinase inhibitors in the world. We summarize previous case reports regarding three-way variant chromosome translocation, t(4;9;22) and discuss how this rare translocation is linked to prognosis.
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http://dx.doi.org/10.1186/s13256-021-02885-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146239PMC
May 2021

A phase 2 study of polatuzumab vedotin + bendamustine + rituximab in relapsed/refractory diffuse large B-cell lymphoma.

Cancer Sci 2021 Jul 4;112(7):2845-2854. Epub 2021 Jun 4.

Department of Hematology and Oncology, Osaka University Hospital, Osaka, Japan.

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m , rituximab 375 mg/m (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography-computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.
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http://dx.doi.org/10.1111/cas.14937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253277PMC
July 2021

[Two-year remission of a relapsed primary gastric peripheral T-cell lymphoma treated with total gastrectomy followed by adjuvant chemotherapy].

Rinsho Ketsueki 2021 ;62(2):79-84

Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology (3rd department of internal medicine), Yamagata University Hospital.

A 67-year-old man was diagnosed with a submucosal primary gastric T-cell lymphoma (PGTL) via upper gastroenteroscopy following an annual health check-up. He received six cycles of CHOP and achieved a complete remission. However, the patient relapsed 4 months post therapy. A second remission, which was maintained for years, was achieved after surgical gastrectomy followed by adjuvant chemotherapies. Prior reports have shown that surgery combined with chemotherapies was curative for patients with newly-diagnosed PGTL. In this report, surgery combined with chemotherapies was successfully applied for early-relapsed PGTL.
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http://dx.doi.org/10.11406/rinketsu.62.79DOI Listing
March 2021

A randomized phase 2/3 study of R-CHOP vs CHOP combined with dose-dense rituximab for DLBCL: the JCOG0601 trial.

Blood Adv 2021 02;5(4):984-993

Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) is the standard of care for untreated diffuse large B-cell lymphoma (DLBCL). However, the schedule for rituximab administration has not been optimized. To compare standard R-CHOP with CHOP plus dose-dense weekly rituximab (RW-CHOP) in patients with untreated DLBCL, we conducted a phase 2/3 study (JCOG0601, jRCTs031180139). Patients were randomly assigned to R-CHOP (CHOP-21 with 8 doses of rituximab once every 3 weeks [375 mg/m2]) or RW-CHOP (CHOP-21 with 8 doses of weekly rituximab [375 mg/m2]) groups. The primary end point of the phase 2 component was percent complete response (%CR) of the RW-CHOP arm, whereas that of the phase 3 component was progression-free survival (PFS). Between December 2007 and December 2014, 421 untreated patients were randomly assigned to R-CHOP (213 patients) or RW-CHOP (208 patients). The %CR in the RW-CHOP arm was 85.3% and therefore met the prespecified decision criteria for the phase 2 component. With a median follow-up of 63.4 months, the 3-year PFS and overall survival were 79.2% and 88.7% in the R-CHOP arm and 80.3% and 90.4% in the RW-CHOP arm, respectively. There was no significant difference in PFS (hazard ratio, 0.95; 90.6% confidence interval, 0.68-1.31). Although the safety profile and efficacy of RW-CHOP was comparable with R-CHOP and its tolerability was acceptable, weekly rituximab in combination with CHOP during the early treatment period did not improve PFS in untreated patients with DLBCL. This trial was registered at jrct.niph.go.jp as #jRCTs031180139.
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http://dx.doi.org/10.1182/bloodadvances.2020002567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903239PMC
February 2021

High Parity Is an Independent Risk Factor for Tooth Loss in Women: A Community-Based Takahata Study in Japan.

Tohoku J Exp Med 2021 01;253(1):77-84

Department of Dentistry, Oral and Maxillofacial Plastic and Reconstructive Surgery, Faculty of Medicine, Yamagata University.

Risk factors for tooth loss have been widely examined previously. However, no previous study has comprehensively investigated the risk factors, including lifestyle-related specific factors (parity, oral health habits, and socioeconomic status), for fewer than 20 teeth among women in the general population in Japan. This cross-sectional study explored the association of these risk factors, especially parity, with having fewer than 20 teeth among Japanese women. A self-reported questionnaire including items on lifestyle-related risk factors (parity, oral health, diet [e.g., alcohol and sucrose consumption]) and socioeconomic status was sent by post to female residents (age ≥ 40 years) of Takahata town, Yamagata Prefecture, in 2005. Multivariate logistic regression analysis including 3,854 eligible participants was performed to investigate the association between various factors (including parity) and having fewer than 20 teeth. The results indicated that, compared with nulliparous women, women with two, three, and four completed pregnancies had 2.485-, 2.844-, and 4.305-fold increased risk of having fewer than 20 teeth, respectively. Our study is the largest-scale study of the general female population in Japan and the first study to comprehensively investigate risk factors (parity, oral health status, and socioeconomic status) for fewer than 20 teeth. We thus found that higher parity, especially, two or more, was independent risk factors for having less than 20 teeth among Japanese women. In conclusion, the present study emphasizes the importance of good oral health habits in women, especially, during pregnancy and in the postpartum period, to maintain 20 or more teeth.
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http://dx.doi.org/10.1620/tjem.253.77DOI Listing
January 2021

Identification of Salivary Proteomic Biomarkers for Oral Cancer Screening.

In Vivo 2021 Jan-Feb;35(1):541-547

Department of Dentistry, Oral and Maxillofacial Plastic and Reconstructive Surgery, Faculty of Medicine, Yamagata University, Yamagata, Japan.

Background/aim: The current study aimed to identify biomarkers for differentiating between patients with oral cancer (OC) and healthy controls (HCs) on the basis of the comprehensive proteomic analyses of saliva samples by using liquid chromatography-mass spectrometry (LC-MS/MS).

Patients And Methods: Unstimulated saliva samples were collected from 39 patients with OC and from 31 HCs. Proteins in the saliva were comprehensively analyzed using LC-MS/MS. To differentiate between patients with OC and HCs, a multiple logistic regression model was developed for evaluating the discriminatory ability of a combination of multiple markers.

Results: A total of 23 proteins were significantly differentially expressed between the patients with OC and the HCs. Six out of the 23 proteins, namely α-2-macroglobulin-like protein 1, cornulin, hemoglobin subunit β, Ig k chain V-II region Vk167, kininogen-1 and transmembrane protease serine 11D, were selected using the forward-selection method and applied to the multiple logistic regression model. The area under the curve for discriminating between patients with OC and HCs was 0.957 when the combination of the six metabolites was used (95% confidence interval=0.915-0.998; p<0.001). Furthermore, these candidate proteins did not show a stage-specific difference.

Conclusion: The results of the current study showed that six salivary proteins are potential non-invasive biomarkers for OC screening.
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http://dx.doi.org/10.21873/invivo.12289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880761PMC
June 2021

Association between presence of 20 or more natural teeth and all-cause, cancer-related, and cardiovascular disease-related mortality: Yamagata (Takahata) prospective observational study.

BMC Oral Health 2020 12 2;20(1):353. Epub 2020 Dec 2.

Department of Dentistry, Oral and Maxillofacial Plastic and Reconstructive Surgery, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.

Background: Several studies have surveyed the relationship between the presence of ≥ 20 natural teeth and mortality. However, very few have evaluated this association over a long-term follow-up of more than ten years within a large population in Japan. This study aimed to prospectively confirm the associations between mortality and the presence of ≥ 20 natural teeth within a community-based population in Japan.

Methods: A prospective observational study including 2208 participants aged ≥ 40 years was conducted in Takahata Town, Japan, between May 2005 and December 2016. All participants answered a self-administered questionnaire to provide their background characteristics, including their number of teeth. The participants were classified into two categories based on their self-reported number of teeth (< 20 and ≥ 20 teeth). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional-hazards regression model to assess risk factors for all-cause, cancer-, and cardiovascular disease-related mortality.

Results: The total follow-up period was 131.4 ± 24.1 months (mean ± SD). After adjusting for covariates, the risk of all-cause mortality was significantly higher in the group with < 20 teeth than in those with ≥ 20 teeth (HR = 1.604, 95% CI 1.007-2.555, p = 0.047). However, the risk of cancer- and cardiovascular disease-related mortalities was not statistically significant between the two groups.

Conclusion: In this study, participants with < 20 teeth had a significantly higher risk of all-cause mortality, although the difference was borderline significant. These results emphasize the importance of having ≥ 20 natural teeth for a healthy life expectancy.
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http://dx.doi.org/10.1186/s12903-020-01346-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709387PMC
December 2020

Relationship between social support status and mortality in a community-based population: a prospective observational study (Yamagata study).

BMC Public Health 2020 Oct 29;20(1):1630. Epub 2020 Oct 29.

Global Center of Excellence Program Study Group, Yamagata University School of Medicine, Yamagata, Japan.

Background: Social support, defined as the exchange of support in social relationships, plays a vital role in maintaining healthy behavior and mitigating the effects of stressors. This study investigated whether functional aspect of social support is related to 5-year mortality in health checkup participants.

Methods: This study recruited 16,651 subjects (6797 males, 9854 females). Social support was evaluated using five-component questions: Do you have someone 1) whom you can consult when you are in trouble? 2) whom you can consult when your physical condition is not good? 3) who can help you with daily homework? 4) who can take you to hospital when you don't feel well? and 5) who can take care of you when you are ill in bed? The association between the component of social support and all-cause and cardiovascular mortality was examined using Cox proportional hazard analysis.

Results: The percentage of subjects without social support components was 7.7-15.0%. They were more likely to be male, non-elderly, and living alone. During the follow-up period, there were 166 all-cause and 38 cardiovascular deaths. Cox proportional analysis adjusted for confounders showed that only the lack of support for transportation to hospital was significantly associated with all-cause (hazard ratio [HR] 2.01, 95% confidence interval [CI] 1.26-3.05) and cardiovascular mortality (HR 3.30, 95% CI 1.41-6.87). These associations were stronger in males than females.

Conclusion: This study showed that the lack of social support for transportation to the hospital was independently associated with all-cause and cardiovascular mortality in a community-based population.
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http://dx.doi.org/10.1186/s12889-020-09752-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597005PMC
October 2020

Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorders, Diffuse Large B-Cell Lymphoma Type, in a Patient with Behçet's Disease Treated with Cyclosporine A.

Case Rep Oncol 2020 Sep-Dec;13(3):1145-1151. Epub 2020 Sep 21.

Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Yamagata, Japan.

A 40-year-old man had been treated for Behçet's disease (BD) with cyclosporine A (CsA) for 14 years. He presented multiple lymphadenopathies with fever. Histological examination of surgical biopsy showed other iatrogenic immunodeficiency-associated lymphoproliferative disorders, diffuse large B-cell lymphoma type with positivity for Epstein-Barr virus encoding RNA-1 (EBER-1). , , and translocations were not detected. CsA was stopped, and R-CHOP therapy was initiated. However, his lymphoma was chemotherapy resistant and rapidly progressed. To the best of our knowledge, this is the first case of diffuse large B-cell lymphoma that occurred in a BD patient treated with CsA reported in English. Both BD and CsA are associated with the pathogenesis of lymphoma. We also describe extremely rare cases in the form of a literature review.
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http://dx.doi.org/10.1159/000510362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548881PMC
September 2020

Urinary phosphate-containing nanoparticle contributes to inflammation and kidney injury in a salt-sensitive hypertension rat model.

Commun Biol 2020 10 15;3(1):575. Epub 2020 Oct 15.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, 173-8605, Japan.

Although disturbed phosphate metabolism frequently accompanies chronic kidney disease (CKD), its causal role in CKD progression remains unclear. It is also not fully understood how excess salt induces organ damage. We here show that urinary phosphate-containing nanoparticles promote kidney injury in salt-sensitive hypertension. In Dahl salt-sensitive rats, salt loading resulted in a significant increase in urinary phosphate excretion without altering serum phosphate levels. An intestinal phosphate binder sucroferric oxyhydroxide attenuated renal inflammation and proteinuria in this model, along with the suppression of phosphaturia. Using cultured proximal tubule cells, we confirmed direct pathogenic roles of phosphate-containing nanoparticles in renal tubules. Finally, transcriptome analysis revealed a potential role of complement C1q in renal inflammation associated with altered phosphate metabolism. These data demonstrate that increased phosphate excretion promotes renal inflammation in salt-sensitive hypertension and suggest a role of disturbed phosphate metabolism in the pathophysiology of hypertensive kidney disease and high salt-induced kidney injury.
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http://dx.doi.org/10.1038/s42003-020-01298-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562875PMC
October 2020

Phase I studies of darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma: a pooled analysis of two phase I studies conducted in Japan and Korea.

Jpn J Clin Oncol 2021 Feb;51(2):218-227

Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.

Objective: Two phase I studies of darinaparsin including Japanese and Korean patients with relapsed/refractory peripheral T-cell lymphoma were performed to evaluate its safety (primary purpose), efficacy and pharmacokinetic profile (ClinicalTrials.gov: NCT01435863 and NCT01689220).

Methods: Patients received intravenous darinaparsin for 5 consecutive days at 200 mg/m2/day in 4-week cycles, 300 mg/m2/day in 4-week cycles or 300 mg/m2/day in 3-week cycles.

Results: Seventeen Japanese and 6 Korean patients were enrolled and treated. Drug-related adverse events developed in 18 patients (78%). Dose-limiting toxicity, grade 3 hepatic dysfunction, was reported on Day 15 of cycle 1 in 1 Japanese patient who received 300 mg/m2/day. The most common drug-related, grade ≥ 3 adverse events were lymphopenia (9%), neutropenia (9%) and thrombocytopenia (9%). No deaths occurred. In 14 evaluable patients, 1 and 3 patients had complete response and partial response, respectively. The plasma concentration-time profiles of arsenic, a surrogate marker for darinaparsin, were similar between Japanese and Korean patients. No significant difference was found in its pharmacokinetic profile.

Conclusions: These data indicate the good tolerability and potential efficacy of darinaparsin in patients with relapsed/refractory peripheral T-cell lymphoma. Darinaparsin 300 mg/m2/day for 5 consecutive days in 3-week cycles is the recommended regimen for phase II study.
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http://dx.doi.org/10.1093/jjco/hyaa177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869082PMC
February 2021

Age-Related Changes in Astigmatism and Potential Causes.

Cornea 2020 Nov;39 Suppl 1:S34-S38

Department of Ophthalmology and Visual Sciences, Yamagata University Faculty of Medicine, Yamagata, Japan.

Astigmatism causes deterioration of the retinal image and affects vision quality. Maintenance and improvement of visual function requires an understanding of the prevalence, age-related changes, and mechanisms of astigmatism. In this article, we discuss the findings of studies that investigated astigmatism. Some of these studies showed that the prevalence of high degrees of astigmatism in childhood typically decreases with emmetropization. With-the-rule astigmatism occurs most commonly in young adults. With age, the prevalence of astigmatism increases, and the axis shifts from a predominance of with-the-rule astigmatism to a predominance of against-the-rule astigmatism. This age-related change is caused by alterations in corneal curvature. Although the cause of this change is not fully understood, alterations in the position and tension of the eyelid, corneal stromal collagen fibrils, Descemet membrane, and extraocular muscles may influence the shape of the cornea. Furthermore, genetic factors may contribute to the development of astigmatism. Technological advances in ophthalmology are expected to improve our understanding of the etiology of astigmatism and enable the maintenance of quality of vision.
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http://dx.doi.org/10.1097/ICO.0000000000002507DOI Listing
November 2020

A Rare Chromosome Abnormality with der(16)t(1;16)(q12;q11.2) in Blast Crisis of Chronic Myeloid Leukemia.

Case Rep Oncol 2020 May-Aug;13(2):1020-1025. Epub 2020 Aug 27.

Department of Internal Medicine, Nihonkai General Hospital, Sakata, Japan.

Although tyrosine kinase inhibitors markedly improve the clinical outcome of chronic myeloid leukemia (CML), blast crisis in CML (CML-BC) still has a poor prognosis. Many chromosomal abnormalities have been reported in CML-BC and may contribute to therapeutic resistance, disease progression, and prognosis. Herein, we report a rare chromosome abnormality with der(16)t(1;16)(q12;q11.2) in CML-BC. It has been demonstrated that this chromosomal abnormality is associated with disease progression and poor prognosis in other malignancies, such as Ewing sarcoma. A 70-year-old man with CML who had been treated with imatinib and dasatinib was admitted to our hospital after complaining for several weeks of fatigue and dyspnea and diagnosed with CML-BC. His tumor cells presented additional chromosomal abnormality with der(16)t(1;16)(q12;q11.2), which has never been reported in CML cases. We successfully treated him using cytotoxic agents combined with ponatinib, and this chromosome abnormality was detected via G-banding. Our patient has lived for over 8 months without any progression with ponatinib treatment alone. Although the biological function of this chromosomal abnormality remains unclear, the satellite DNA of 1q12, which induces genomic instability in other malignancies, and the loss of 16q may contribute to the disease progression of CML in this case. In conclusion, this paper is the first to report on the case of CML-BC with der(16)t(1;16)(q12;q11.2).
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http://dx.doi.org/10.1159/000509642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506380PMC
August 2020

Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study.

Cancer Sci 2020 Dec 21;111(12):4567-4580. Epub 2020 Oct 21.

Department of Hematology, International Medical Center, Saitama Medical University, Saitama, Japan.

Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983-1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010-2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow-up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016-2017. Of 770 evaluable patients, 391 (50.8%) had acute-type, 192 (24.9%) had lymphoma-type, 106 (13.8%) had chronic-type, and 81 (10.5%) had smoldering-type ATL. The initial therapy regimens used for acute/lymphoma-type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP-AMP-VECP)-like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma-type ATL patients. The 4-year survival rates (the median survival time, days) for acute-, lymphoma-, unfavorable chronic-, favorable chronic-, and smoldering-type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4-year survival rates for acute- and lymphoma-type ATL improved compared with those reported in 1991, but those for chronic- and smoldering-type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan.
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http://dx.doi.org/10.1111/cas.14658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734015PMC
December 2020

Isatuximab monotherapy in relapsed/refractory multiple myeloma: A Japanese, multicenter, phase 1/2, safety and efficacy study.

Cancer Sci 2020 Dec 15;111(12):4526-4539. Epub 2020 Oct 15.

Department of Hematology and Oncology, Nagoya City University Institute of Medical and Pharmaceutical Sciences, Nagoya, Japan.

Isatuximab, an anti-CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open-label, single-arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose-limiting toxicities occurred; the recommended dose for the single-arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high-risk cytogenetic abnormalities had comparable results. In phase 2, the median progression-free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high-risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706.
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http://dx.doi.org/10.1111/cas.14657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734004PMC
December 2020

Plasma Exchange as an Initial Treatment for Severe Bleeding Induced by Acquired Factor V Deficiency: A Case Report and Mini Literature Review.

Acta Haematol 2021 12;144(1):82-87. Epub 2020 Aug 12.

Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology (Third Internal Medicine), Yamagata University, Yamagata, Japan,

Acquired factor V deficiency (AFVD) is a rare autoimmune bleeding disorder. Unlike acquired hemophilia, bypass therapies with recombinant activated factor VII and activated prothrombin complex concentrates are ineffective for severe bleeding due to AFVD. Although several treatment strategies have been attempted, a standard of care for severe hemorrhage induced by AFVD is lacking. Herein, we report a case of AFVD with severe bleeding that responded to plasma exchange (PE) combined with immunosuppression. We also reviewed previously reported AFVD cases with severe hemorrhage and suggest that PE may be an effective initial treatment for AFVD-induced severe hemorrhage.
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http://dx.doi.org/10.1159/000505770DOI Listing
March 2021

Role of the Ubiquitin Proteasome System in the Regulation of Blood Pressure: A Review.

Int J Mol Sci 2020 Jul 28;21(15). Epub 2020 Jul 28.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan.

The kidney and the vasculature play crucial roles in regulating blood pressure. The ubiquitin proteasome system (UPS), a multienzyme process mediating covalent conjugation of the 76-amino acid polypeptide ubiquitin to a substrate protein followed by proteasomal degradation, is involved in multiple cellular processes by regulating protein turnover in various tissues. Increasing evidence demonstrates the roles of UPS in blood pressure regulation. In the kidney, filtered sodium is reabsorbed through diverse sodium transporters and channels along renal tubules, and studies conducted till date have provided insights into the complex molecular network through which ubiquitin ligases modulate sodium transport in different segments. Components of these pathways include ubiquitin ligase neuronal precursor cell-expressed developmentally downregulated 4-2, Cullin-3, and Kelch-like 3. Moreover, accumulating data indicate the roles of UPS in blood vessels, where it modulates nitric oxide bioavailability and vasoconstriction. Cullin-3 not only regulates renal salt reabsorption but also controls vascular tone using different adaptor proteins that target distinct substrates in vascular smooth muscle cells. In endothelial cells, UPS can also contribute to blood pressure regulation by modulating endothelial nitric oxide synthase. In this review, we summarize current knowledge regarding the role of UPS in blood pressure regulation, focusing on renal sodium reabsorption and vascular function.
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http://dx.doi.org/10.3390/ijms21155358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432568PMC
July 2020

Phase 2 study of bosutinib in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia.

Int J Hematol 2020 Jul 11;112(1):24-32. Epub 2020 Apr 11.

Akita University Hospital, Akita, Japan.

This open-label, single-arm, phase 2 study (ClinicalTrials.gov, NCT03128411) evaluated the efficacy, safety, and pharmacokinetics of bosutinib at a starting dose of 400 mg once daily (QD) in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). The primary endpoint was major molecular response (MMR) at Month 12 in the modified as-treated population (Philadelphia chromosome-positive [Ph+] patients with e13a2/e14a2 transcripts). Sixty Japanese patients with CP CML were treated with bosutinib; median age was 55 years (range 20-83), 60.0% were males, and all were Ph+ and had e13a2/e14a2 transcripts. After median follow-up of 16.6 months (range 11.1-21.9), 41 (68.3%) patients remained on bosutinib. The MMR rate at Month 12 was 55.0% (2-sided 90% confidence interval: 44.4-65.6). There were no on-treatment transformations to accelerated/blast phase, and no patient died on treatment or within 28 days of the last bosutinib dose. The most common treatment-emergent adverse events were diarrhea (86.7%), increased alanine aminotransferase (55.0%), and increased aspartate aminotransferase (46.7%). The primary objective of this phase 2 study was met, and there were no new safety signals for bosutinib. These data suggest bosutinib is an effective first-line treatment option for Japanese patients with newly diagnosed CP CML.
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http://dx.doi.org/10.1007/s12185-020-02878-xDOI Listing
July 2020

A case of iatrogenic immunodeficiency-associated colonic lymphoma complicating ulcerative colitis.

Diagn Pathol 2020 Apr 7;15(1):34. Epub 2020 Apr 7.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.

Background: Ulcerative colitis (UC) is one of the major types of inflammatory bowel diseases and is associated with a significantly increased risk of not only lymphoproliferative disorders but also lymphomas, of which most cases are related to the long-term usage of immunosuppressants. Here, we demonstrate a very rare case of other iatrogenic immunodeficiency-associated colonic diffuse large B-cell lymphoma (Oii-DLBCL) complicating UC and rectal perforation. In addition, we reviewed the clinicopathological features of previous cases of DLBCL related to UC.

Case Presentation: A 68-year-old man was diagnosed with left-sided UC 26 months prior. Although he was followed by immunosuppressive therapy with azathioprine and infliximab, an emergency total proctocolectomy was performed due to rectal perforation. The resected specimen exhibited irregular wall thickening and elevated multinodular lesions extending from the mid-transverse colon to the rectum, measuring up to 52 cm in length. Histologically, the lesion was diagnosed as Oii-DLBCL and crypt abscess surrounded by mixed inflammatory cell was remained.

Conclusion: Oii-DLBCL complicating UC with rectal perforation is extremely rare. Macro- and microscopic findings are important for early diagnosis of the lesion.
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http://dx.doi.org/10.1186/s13000-020-00954-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137478PMC
April 2020

Association among chronic kidney disease, airflow limitation, and mortality in a community-based population: The Yamagata (Takahata) study.

Sci Rep 2020 03 27;10(1):5570. Epub 2020 Mar 27.

Department of Public Health and Hygiene, Yamagata University, Yamagata, Japan.

Chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD) are known risk factors for mortality. In this study, we examined the overlap of CKD and airflow limitation (AFL) that characterises COPD and its effect on 10-year mortality in a community-based population. This study included 1,233 health check-up participants (mean age, 63.7 years; 46.7% men). We defined serum creatinine-based CKD (CKDcr) and serum cystatin C-based CKD (CKDcys) as glomerular filtration rate <60 mL/min/1.73 m, estimated using serum creatinine or cystatin C, and/or dipstick proteinuria ≥1+. AFL was defined as forced expiratory volume in 1 s to forced vital capacity ratio <70% on spirometry. Compared with subjects without AFL, those with AFL showed a significantly higher prevalence of CKDcys but not of CKDcr. Cox proportional hazard analysis adjusted for confounders showed that the hazard ratio (95% confidence interval) for all-cause mortality was 1.45 (0.77-2.63) in subjects with CKDcys alone, 1.29 (0.60-2.54) in those with AFL alone, and 2.94 (1.33-6.12) in those with both CKDcys and AFL, with subjects without both AFL and CKD as the reference. This study showed that AFL and CKDcys are strongly associated and that their overlap is a significant risk factor for mortality in community-based populations.
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http://dx.doi.org/10.1038/s41598-020-62540-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101320PMC
March 2020

Good prognosis for follicular lymphoma with estrogen receptor α-positive follicular dendritic cells.

Hematol Oncol 2020 Aug 13;38(3):293-300. Epub 2020 Apr 13.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata, Japan.

Follicular lymphoma (FL) has a meshwork of follicular dendritic cells (FDCs). We previously demonstrated the presence of estrogen receptor alpha (ERα) CD23 FDCs in grades 1-2 FL. The significance of FDCs as a prognostic factor in FL remains unknown. The current study aimed to compare clinicopathological features, including prognosis, between FL with and without ERα FDCs. This study evaluated the clinicopathological significance of ERα expression in 70 FL patients by immunostaining. The presence of ERα mRNA on FDCs from 5 FL patients was confirmed by CD21/ERα double staining (immunohistochemistry and in situ hybridization). We defined patients with frequent ERα expression as the ERα group and those with infrequent ERα expression as the ERα group. Thirty-two patients were assigned to the ERα group (45.7%), and 38 patients were assigned to the ERα group (54.3%). Both overall survival (OS) and progression-free survival (PFS) were significantly better in the ERα group than in the ERα group (OS, log-rank, P = .0465; PFS, log-rank, P = .0336). Moreover, high ERα expression on FDCs was an independent prognostic factor for OS in both the univariate ([hazard ratio] HR, 0.163; P = .0260) and multivariate (HR, 0.050; P = .0188) analyses and for PFS in both the univariate (HR, 0.232; P = .0213) and multivariate (HR, 0.084; P = .0243) analyses. ERα mRNA expression was detected in CD21 FDCs within the neoplastic follicles of FL patients. In conclusion, a neoplastic follicular microenvironment with ERα-positive FDCs might affect the grade and presence of the follicular pattern of FL and improve patient prognosis.
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http://dx.doi.org/10.1002/hon.2730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496718PMC
August 2020

Upregulation of renal Na-K-2Cl cotransporter 2 in obese diabetes mellitus via a vasopressin receptor 2-dependent pathway.

Biochem Biophys Res Commun 2020 04 5;524(3):710-715. Epub 2020 Feb 5.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, 173-8605, Japan. Electronic address:

Na-K-2Cl cotransporter 2 (NKCC2) in thick ascending limb (TAL) in the kidney plays a central role in tubuloglomerular feedback (TGF) system by sensing NaCl delivery to the distal tubules. Although accumulating data indicate that dysregulated TGF contributes to the progression of diabetic complications, the regulation of NKCC2 in diabetes mellitus (DM) remains unclear. We here show that NKCC2 is overactivated via a vasopressin receptor 2 (V2R)-dependent mechanism in db/db mice, a mouse model of obese DM. Compared with db/+ mice, we found that both aquaporin 2 and NKCC2 levels were significantly increased in the kidney in db/db mice. Immunohistochemical analysis of V2R and NKCC2 in the kidney demonstrated that V2R is present in the TAL, as well as in the collecting duct. Moreover, the administration of tolvaptan, a selective V2R antagonist, sharply decreased aquaporin 2 and NKCC2 in db/db mice, confirming the causal role of V2R signaling in NKCC2 induction in this model. Although tolvaptan reduced aquaporin 2 abundance also in db/+ mice, its effect on NKCC2 was modest compared with db/db mice. In total kidney lysates, uromodulin expression was not altered between db/+ and db/db mice, suggesting that V2R signaling alters NKCC2 without altering uromodulin levels. These data implicate the dysregulation of NKCC2 in the pathophysiology of type 2 DM, and underscore the complex nature of fluid volume disorders in diabetic kidney disease.
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http://dx.doi.org/10.1016/j.bbrc.2020.01.142DOI Listing
April 2020

Clinical investigation of pituitary incidentalomas: A two-center study.

Intractable Rare Dis Res 2019 Nov;8(4):239-244

Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikusino, Fukuoka, Japan.

Recent advances in imaging technology resulted in an increase in pituitary incidentalomas (PIs) detection. PIs were reported to be present in 1.6% persons with magnetic resonance imaging of the brain. Whereas, there were few studies about PIs with detailed investigation. We aimed to investigate the clinical and endocrinological characteristics of PIs. We evaluated 65 patients diagnosed with PIs who underwent detailed clinical and endocrinological evaluations. Of the 65 patients, 33 (50.8%) had non-functional pituitary adenomas (NFPAs), 11 (16.9%) had Rathke's cleft cysts (RCCs), 7 (10.8%) had functional pituitary adenomas (FPAs), 6 (9.2%) had benign extra-pituitary tumors (BEPTs), and 8 (12.3%) had malignant tumors (MTs). Compared with patients with NFPAs, those with MTs were significantly younger and had a significantly lower body mass index, lower prevalence of hypertension, and lower prevalence of dyslipidemia. Patients with MTs had significantly higher prevalence of central diabetes insipidus than those with NFPAs. In addition, patients with NFPAs had significantly higher prevalence of pituitary apoplexy than those with FPAs, BEPTs, and MTs. In conclusion, our study demonstrated clinical and endocrinological characteristics of PIs. Highly detailed clinical and endocrinological investigations should be performed for PIs. In addition, MTs should be considered in the differential diagnosis for young and lean patients with central diabetes insipidus.
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http://dx.doi.org/10.5582/irdr.2019.01083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929595PMC
November 2019

TAFRO Syndrome Presenting with Retroperitoneal Panniculitis-like Computed Tomography Findings at Disease Onset.

Intern Med 2020 Apr 13;59(7):997-1000. Epub 2019 Dec 13.

Department of Internal Medicine, Nihonkai General Hospital, Japan.

TAFRO syndrome is rare, and its pathophysiology remains unclear. We herein report the case of a 66-year-old man who presented at our emergency department with epigastric pain. Contrast-enhanced computed tomography (CT) showed high-density retroperitoneal panniculus with contrast enhancement. He was treated initially with a protease inhibitor and hydration, to little effect. Anasarca, thrombocytopenia, and renal dysfunction developed gradually, and TAFRO syndrome was diagnosed. He was treated successfully with prednisolone and cyclophosphamide, and subsequent CT findings showed improvement. Abnormal CT findings of the retroperitoneum may indicate the early stages of TAFRO syndrome before the presentation of typical ascites.
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http://dx.doi.org/10.2169/internalmedicine.3740-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184093PMC
April 2020

A Randomized, Double-Blind, Efficacy and Safety Study of PF-05280586 (a Rituximab Biosimilar) Compared with Rituximab Reference Product (MabThera) in Subjects with Previously Untreated CD20-Positive, Low-Tumor-Burden Follicular Lymphoma (LTB-FL).

BioDrugs 2020 Apr;34(2):171-181

University Hospital Centre Zagreb, Kišpatićeva ul. 12, 10000, Zagreb, Croatia.

Background: Biosimilars are highly similar to the licensed biologic ("reference product"), with no clinically meaningful differences in safety, purity, or potency between the two products.

Objective: This comparative 52-week clinical study evaluated the efficacy, safety, immunogenicity, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-05280586 (Ruxience™ [a rituximab biosimilar]) versus rituximab reference product sourced from the EU (MabThera; rituximab-EU).

Patients And Methods: Subjects with CD20-positive, low-tumor-burden follicular lymphoma (LTB-FL) and an Eastern Cooperative Oncology Group performance status 0-1 were randomized (1:1) to PF-05280586 or rituximab-EU (375 mg/m intravenously [once weekly for 4 weeks at days 1, 8, 15, and 22]), stratified using the Follicular Lymphoma International Prognostic Index 2 classification. The primary endpoint was overall response rate (ORR) at week 26 (percentage of subjects achieving complete response [CR] or partial response [PR]). Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the difference in ORR between groups was within the prespecified margin (± 16%). Secondary endpoints included progression-free survival (PFS), CR rate, safety, immunogenicity, PK, and PD.

Results: A total of 394 subjects were randomized: PF-05280586 (n = 196) or rituximab-EU (n = 198). ORR at week 26 was 75.5% (PF-05280586) versus 70.7% (rituximab-EU), for a difference of 4.66%; 95% CI (- 4.16 to 13.47), which was entirely within the prespecified equivalence margin. Rates of CR were 29.3% (PF-05280586) versus 31.0% (rituximab-EU). Estimated 1-year PFS rates were 78.2% (95% CI 70.2-84.2) and 83.0% (95% CI 75.0-88.6) for PF-05280586 and rituximab-EU, respectively. Safety, immunogenicity, and mean serum concentrations were similar between groups.

Conclusions: The efficacy, safety, immunogenicity, PK, and PD of PF-05280586 and rituximab-EU were similar up to week 52 in subjects with previously untreated CD20-positive LTB-FL.

Clinical Trial Registration: ClinicalTrials.gov, NCT02213263 and EudraCT (2014-000132-41).
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http://dx.doi.org/10.1007/s40259-019-00398-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113218PMC
April 2020

A case of myeloid sarcoma of the mandibular gingiva as extramedullary relapse of acute myeloid leukemia.

Oral Maxillofac Surg 2020 Mar 1;24(1):121-126. Epub 2019 Dec 1.

Department of Dentistry, Oral and Maxillofacial-Plastic and Reconstructive Surgery, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.

Purpose: Myeloid sarcoma (MS) is defined as a tumorous mass of myeloblasts or immature myeloid cells involving an extramedullary anatomic site. MS occurs in 3 to 8% of patients with acute myeloid leukemia. The overwhelming majority of MS occurs in the skin, bones, and gastrointestinal tract; intraoral MS (IMS) is extremely rare.

Methods: We describe a case of MS of the mandibular gingiva in a patient with acute myeloid leukemia that was in remission. We also present a review of the English and Japanese literature with a special focus on the management and prognosis of intraoral MS.

Results: The patient was discharged while in remission 8 months after the initial examination.

Conclusion: The prognosis of IMS is extremely poor in general, and a diagnostic delay can prevent adequate therapy by hematologists and oncologists. All dental clinicians must keep the possibility of IMS in mind and carefully examine all patients with AML.
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http://dx.doi.org/10.1007/s10006-019-00812-yDOI Listing
March 2020

Efficiency score from data envelopment analysis can predict the future onset of hypertension and dyslipidemia: A cohort study.

Sci Rep 2019 11 8;9(1):16309. Epub 2019 Nov 8.

Department of Clinical Oncology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, Yamagata, 990-9585, Japan.

Primary prevention focuses on ensuring that healthy people remain healthy. As it is practically difficult to provide intervention for an entire healthy population, it is essential to identify and target the at risk of risks population. We aimed to distinguish at risk of risks population using data envelopment analysis (DEA). Efficiency score was calculated from the DEA using a cohort sample and its association with the onset of hypertension and dyslipidemia was analyzed. A stratification analysis was performed according to the number of conventional risk factors in participants. The adjusted odds ratios (aORs) of the incidence of hypertension and dyslipidemia according to a 0.1-point increase in efficiency score were 0.66 (90% confidence interval [CI] 0.55-0.78, p < 0.0001) and 0.84 (90% CI 0.75-0.94, p = 0.01), respectively. In the stratification analysis, aOR of the incidence of hypertension according to a 0.1-point increase in efficiency score was 0.57 (90% CI 0.37-0.89, p = 0.04) in participants with no conventional risk factors. Participants with lower efficiency score were suggested to be at high risk for future onset of hypertension and dyslipidemia. The DEA might enable us to identify the risk of hypertension where conventional methods might fail.
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http://dx.doi.org/10.1038/s41598-019-52898-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841950PMC
November 2019
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