Publications by authors named "Yasuo Ohashi"

436 Publications

[Investigating the relationship between higher life functions, overall mortality, and incidence of care needs in long-term follow-up study of the local population: The Kamogawa Cohort Study].

Nihon Koshu Eisei Zasshi 2021 Aug 6. Epub 2021 Aug 6.

Unit of Public Health and Preventive Medicine, Yokohama City University School of Medicine.

Objectives In addition to physical independence such as ADLs, higher-level functional capacity ("instrumental self-maintenance," "intellectual activity," and "social role") are necessary to lead the final stage of life as independently and for as long as possible. Accordingly, in a long-term follow-up study of the local population, we examined the association of health status (total mortality and incidence of care needs) with instrumental independence, intellectual activity, and social role.Methods We used participant data from the Kamogawa cohort study, which included surveyed use of health service, health status, disease prevalence, and use of long-term care insurance service for Kamogawa citizens in Chiba prefecture from 2003 to 2013. We compared the differences in lifestyle and higher-level functional capacity, by status of death and using the Long-term Care Insurance service. Higher-level functional capacity was assessed with the Tokyo Metropolitan Institute of Gerontology-Index of Competence (TMIG-IC); answer to each question, each domain score, and total score were examined.Results During the follow-up period to the end of March 2013, 810 deaths and 917 care needs were observed among the 6,503 people who consented to be followed up. The adjusted HR of higher-level functional capacity for all-cause mortality was "instrumental self-maintenance," score 4 or 5 to less than 3: 2.03 (95%CI: 1.59-2.60), "intellectual activity," score 4 to less than 3: 1.39 (95%CI: 1.09-1.77), and "social role," score 4 to less than 3: 1.28 (95%CI: 1.03-1.59). In subgroup analyses by sex, "instrumental self-maintenance" was associated with both men and women, but "intellectual activity" and "social roles" were associated with women only. The adjusted HRs for the incidence of care needs were 1.93 (95%CI: 1.55-2.40) for "instrumental self-maintenance" and 1.30 (95%CI: 1.07-1.58) for "social role." In subgroup analyses by sex, "instrumental self-maintenance" was associated with both genders, but "social role" was observed only for women.Conclusion Higher-level functional capacity ("instrumental self-maintenance," "intellectual activity," and "social role") was significantly associated with total mortality and incidence of care needs.
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http://dx.doi.org/10.11236/jph.20-113DOI Listing
August 2021

Association Between Kidney Function Decline and Baseline TNFR Levels or Change Ratio in TNFR by Febuxostat Chiefly in Non-diabetic CKD Patients With Asymptomatic Hyperuricemia.

Front Med (Lausanne) 2021 12;8:634932. Epub 2021 Jul 12.

Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.

The levels of circulating tumor necrosis factor receptor (TNFR) 1 and 2 help predict the future decline of estimated glomerular filtration rate (eGFR) chiefly in patients with diabetes. It has been recently reported that the change ratio in TNFR1 by SGLT2 inhibitor treatment is also related with future GFR decline in patients with diabetes. The aims of this study are to investigate the association between baseline TNFR levels and early change in TNFR levels by the non-purine selective xanthine oxidase inhibitor, febuxostat, and future eGFR decline chiefly in chronic kidney disease (CKD) patients without diabetes. We conducted a analysis of the FEATHER study on patients with asymptomatic hyperuricemia and CKD stage 3, who were randomly assigned febuxostat 40 mg/day or matched placebo. This analysis included 426 patients in whom baseline stored samples were available. Serum TNFR levels at baseline were measured using enzyme-linked immunosorbent assay. Those levels were also measured using 12-week stored samples from 197 randomly selected patients. Compared with placebo, short-term febuxostat treatment significantly decreased the median percent change from baseline in serum uric acid (-45.05, 95% CI -48.90 to -41.24 mg/dL), TNFR1 (1.10, 95% CI-2.25 to 4.40), and TNFR2 (1.66, 95% CI -1.72 to 4.93), but not TNFR levels. Over a median follow-up of 105 weeks, 30 patients (7.0%) experienced 30% eGFR decline from baseline. In the Cox multivariate model, high levels of baseline TNFR predicted a 30% eGFR decline, even after adjusting for age, sex, systolic blood pressure, high sensitivity C-reactive protein, uric acid, and presence or absence of febuxostat treatment and diabetes, in addition to baseline albumin to creatinine ratio and eGFR. Early change in circulating TNFR levels failed to predict future eGFR decline; however, regardless of febuxostat treatment, the elevated baseline level of TNFR was a strong predictor of 30% eGFR decline even in chiefly non-diabetic CKD patients with asymptomatic hyperuricemia.
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http://dx.doi.org/10.3389/fmed.2021.634932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310915PMC
July 2021

Impact of chemotherapy on cognitive functioning in older patients with HER2-positive breast cancer: a sub-study in the RESPECT trial.

Breast Cancer Res Treat 2021 Aug 2;188(3):675-683. Epub 2021 Jun 2.

Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan.

Purpose: To investigate whether postoperative adjuvant trastuzumab plus chemotherapy negatively affected cognitive functioning during the post-chemotherapy period compared with trastuzumab monotherapy in older patients with HER2-positive breast cancer.

Methods: In the randomized RESPECT trial, women aged between 70 and 80 years with HER2-positive, stage I to IIIA invasive breast cancer who underwent curative operation were randomly assigned to receive either 1-year trastuzumab monotherapy or 1-year trastuzumab plus chemotherapy. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) test at enrollment and 1 and 3 years after initiation of the protocol treatment. The primary outcome was change in the MMSE total score from baseline. Secondary outcomes included prevalence of suspected mild cognitive impairment (MMSE total score < 28) and suspected dementia (MMSE total score < 24).

Results: The analytical population consisted of 29 and 26 patients in the trastuzumab monotherapy and trastuzumab plus chemotherapy groups, respectively. The group differences in mean changes of the MMSE total score were 0.6 (95% confidence interval [CI] - 0.3 to 1.6) at 1 year and 0.9 (95% CI - 1.0 to 2.8) at 3 years (P = 0.136 for the group difference pooling the two visits). The prevalence of suspected mild cognitive impairment at 3 years was 41.7% in the trastuzumab monotherapy group and 28.6% in the trastuzumab plus chemotherapy group (P = 0.548).

Conclusion: This randomized sub-study did not show worse cognitive functioning during the post-chemotherapy period with trastuzumab plus chemotherapy than with trastuzumab monotherapy in older patients with HER2-positive breast cancer.

Trial Registration Number: NCT01104935 (first posted April 16, 2010).
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http://dx.doi.org/10.1007/s10549-021-06253-0DOI Listing
August 2021

Sustained Neutralizing Antibodies 6 Months Following Infection in 376 Japanese COVID-19 Survivors.

Front Microbiol 2021 7;12:661187. Epub 2021 May 7.

Department of Health Data Science, Yokohama City University Graduate School of Data Science, Yokohama, Japan.

There is scarce evidence regarding the long-term persistence of neutralizing antibodies among coronavirus disease 2019 (COVID-19) survivors. This study determined neutralizing antibody titers (NT) and antibodies against spike protein (SP) or nucleocapsid protein (NP) antigens approximately 6 months after the diagnosis of COVID-19. COVID-19 survivors in Japan were recruited. Serum samples and data related to patients' characteristics and COVID-19 history were collected. NT and titers of antibodies against NP and SP antigens were measured at 20-32 weeks after the first positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results. Factors associated with NT were identified using the multivariable linear regression and the correlations among NT and titers of immunoglobulin G (IgG) and total immunoglobulins (Igs) against NP and SP were assessed by Spearman's correlation. Among 376 participants (median [range] days after testing positive for SARS-CoV-2, 180 (147-224); median [range] years of age, 50 (20-78); 188 [50%] male), most tested positive for NT ( = 367, 98%), SP-IgG ( = 344, 91%), SP-total Ig ( = 369, 98%), NP-IgG ( = 314, 84%), and NP-total Ig ( = 365, 97%). Regression analysis indicated that higher BMI, fever, and the requirement of mechanical ventilation or extracorporeal membrane oxygenation were significantly associated with higher NT. Anti-SP antibodies correlated moderately with NT (Spearman's correlation: 0.63 for SP IgG; 0.57 for SP-total Ig), while the correlation was weak for anti-NP antibodies (0.37 for NP IgG; 0.32 for NP-total Ig). Most COVID-19 survivors had sustained neutralizing antibodies and tested positive for SP-total Ig and NP-total Ig approximately 6 months after infection.
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http://dx.doi.org/10.3389/fmicb.2021.661187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137897PMC
May 2021

Patient-reported outcomes following neoadjuvant endocrine therapy, external beam radiation, and adjuvant continuous/intermittent endocrine therapy for locally advanced prostate cancer: A randomized phase III trial.

Cancer Med 2021 05 1;10(10):3240-3248. Epub 2021 May 1.

Kotake Clinic, Osaka, Japan.

Background: We evaluated patient-reported outcomes (PRO) during neoadjuvant androgen deprivation therapy (ADT) plus external beam radiation therapy (EBRT) followed by either adjuvant continuous ADT (CADT) or intermittent ADT (IADT) for patients with locally advanced prostate cancer (Pca).

Methods: A multicenter, randomized phase III trial enrolled 303 patients with locally advanced Pca. The patients were treated with 6 months (M) of ADT followed by 72 Gy of EBRT, and were randomly assigned to CADT or IADT after 14 M. The PROs were evaluated at sic points: baseline, 6 M, 8 M, 14 M, 20 M, and 38 M using FACT-P questionnaires and EPIC urinary, bowel, and sexual bother subscales.

Results: The FACT-P total scores were significantly better (p < 0.05) in IADT versus CADT at 20 M (121.6 vs.115.4) and at 38 M (119.9 vs. 115.2). The physical well-being scores (PWB) were significantly better (p < 0.05) in IADT versus CADT at 38 M (25.4 vs. 24.0). The functional scores were significantly better in IADT than those in CADT at 14 M (20.2 vs18.7, p < 0.05) and at 20 M (21.0 vs.18.9, p < 0.05).

Conclusion: The PRO was significantly favorable in IADT on FACT-P total score at 20 M and 38 M, PWB and functional scores at 38 M.
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http://dx.doi.org/10.1002/cam4.3895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124125PMC
May 2021

Functional categories based on cognition and activities of daily living predict all-cause mortality in older adults with diabetes mellitus: The Japanese Elderly Diabetes Intervention Trial.

Geriatr Gerontol Int 2021 Jun 22;21(6):512-518. Epub 2021 Apr 22.

Department of Diabetes, Metabolism and Endocrinology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.

Aim: Although the glycemic target in older diabetes patients is based on cognition, activities of daily living and multimorbidity in the Japanese guideline, evidence of the relationships is limited. Thus, we aimed to assess the relationship between functional category and mortality in older people with diabetes.

Methods: We evaluated the data of 843 older diabetes patients in a 6-year prospective study, and the association between functional categories and all-cause mortality. The patients were divided into three functional categories based on cognition, instrumental activities of daily living and basic activities of daily living using the Mini-Mental State Examination, Tokyo Metropolitan Institute of Gerontology Index of Competence and Barthel Index at baseline, respectively (model 1). Those with multimorbidity (≥4 of 8 morbidities) were classified into category III (model 2). The functional category assessed using eight items from the Tokyo Metropolitan Institute of Gerontology Index of Competence and Barthel Index was also constructed (model 3). Hazard ratios and 95% confidence intervals were calculated in the Cox regression analysis using age, sex, body mass index, glycated hemoglobin level, total cholesterol level, estimated glomerular filtration rate and frequency of severe hypoglycemia as covariates.

Results: During the 6-year follow up, 64 incident mortalities occurred. The hazard ratios for mortality in categories II and III (as the reference of category I) were 1.83 (95% confidence interval 1.06-3.14, P = 0.030) and 3.05 (95% confidence interval 1.12-8.26, P = 0.029) after adjustment for covariates, respectively (model 1). Models 2 and 3 showed similar associations between functional category and mortality.

Conclusions: The functional categories predicted all-cause mortality in older adults with diabetes. Geriatr Gerontol Int 2021; 21: 512-518.
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http://dx.doi.org/10.1111/ggi.14171DOI Listing
June 2021

Health-Related Quality of Life With Trastuzumab Monotherapy Versus Trastuzumab Plus Standard Chemotherapy as Adjuvant Therapy in Older Patients With HER2-Positive Breast Cancer.

J Clin Oncol 2021 08 9;39(22):2452-2462. Epub 2021 Apr 9.

Biostatistics Division, Clinical Research Support Center, The University of Tokyo Hospital, Tokyo, Japan.

Purpose: We report findings on quality of life (QoL) in the RESPECT trial, which compared adjuvant trastuzumab monotherapy with trastuzumab plus chemotherapy in older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC).

Patients And Methods: Patients age 70-80 years with human epidermal growth factor receptor 2-positive surgically treated breast cancer were randomly assigned to receive trastuzumab (T) or trastuzumab plus chemotherapy (T + C). QoL was assessed using the Functional Assessment of Cancer Therapy-General (FACT-G), Philadelphia Geriatric Center Morale Scale, Hospital Anxiety and Depression Scale, Patient Neurotoxicity Questionnaire, and Tokyo Metropolitan Institute of Gerontology Index of Competence at baseline and after 2, 12, and 36 months. Comparisons were based on individual changes from baseline and were performed by Fisher's test or mixed-model repeated-measures.

Results: Among 275 patients in the parent study, 231 (84%) (average age: 74 years) were included in the analysis. At 2, 12, and 36 months, 198, 177, and 178 patients completed surveys, and the mean FACT-G scores at each survey point were 78.9, 80.4, 82.7, and 79.1 in group T and 79.5, 74.5, 78.4, and 78.5 in group T + C. Compared with group T + C, the proportion of patients showing QoL deterioration (≥ 5 points decrease from baseline in FACT-G) was significantly lower at 2 months (31% 48%; = .016) and 12 months (19% 38%; = .009). In group T, the Hospital Anxiety and Depression Scale score ( = .003) and the proportion of severe sensory peripheral neuropathy ( = .001) were significantly lower at 2 months, and Philadelphia Geriatric Center Morale Scale and Tokyo Metropolitan Institute of Gerontology Index of Competence scores were significantly higher ( = .024, .042) at 12 months. At 36 months, there were no significant differences in any QoL items.

Conclusion: Detrimental effects of adjuvant chemotherapy on global QoL, morale, and activity capacity lasted for at least 12 months but were not observed at 36 months.
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http://dx.doi.org/10.1200/JCO.20.02751DOI Listing
August 2021

A Correlation Analysis Between Metabolism-related Genes and Treatment Response to S-1 as First-line Chemotherapy for Metastatic Breast Cancer: The SELECT BC-EURECA Study.

Clin Breast Cancer 2021 10 1;21(5):450-457. Epub 2021 Feb 1.

National Cancer Center Hospital East, Kashiwa, Japan.

Introduction: The previous randomized phase 3 trial (SELECT BC) showed that S-1 as a first-line chemotherapy for metastatic breast cancer (MBC) is non-inferior to taxane with respect to overall survival. This study aimed to identify the usefulness of metabolism-related genes as predictive biomarkers for the response to S-1 compared with taxane using tumor tissue samples from the previous trial.   PATIENTS AND METHODS: In this SELECT BC-EURECA study, 147 patients with human epidermal growth factor 2 (HER2)-negative MBC who received either S-1 or taxane were evaluated. Formalin-fixed paraffin-embedded specimens were collected, and 14 genes involved in the pyrimidine metabolic pathway, estrogen receptor, progesterone receptor, HER2, Ki67, and beta-tubulin were measured using reverse transcription polymerase chain reaction in microdissected tumor specimens. The expression of each gene was categorized as low, intermediate, and high by tertile values.   RESULTS: Interaction tests to identify biomarkers for the response to S-1 compared with taxane, revealed the following as the top 3 biomarkers: RRM1 (P value = 0.24), GGH (P value = 0.25), and MTHFR (P value = 0.28). In the S-1 group, lower GGH and higher MTHFR expression were significantly correlated with better time to treatment failure. In the taxane group, there was no gene that was identified as a significant indicator of treatment failure.

Conclusion: This biomarker analysis from SELECT BC did not identify any predictive biomarkers for the response to S-1 compared with taxane. Future studies with larger sample size and information on not only mRNA, but also protein and DNA for broad functional analyses are needed.
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http://dx.doi.org/10.1016/j.clbc.2021.01.018DOI Listing
October 2021

A follow-up study of a randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-month depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer.

Breast Cancer 2021 May 27;28(3):684-697. Epub 2021 Feb 27.

Department of Integrated Science and Technology, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, TokyoTokyo, 112-8551, Japan.

Background: Previously, we conducted the 5-year open-label, randomized controlled trial (RCT) of leuprorelin adjuvant therapy in post-operative premenopausal patients with endocrine-responsive breast cancer, which was a pilot study to investigate the optimal duration of leuprorelin treatment. Since, however, long-term outcomes became required for the adjuvant endocrine therapy, we performed this follow-up observation study.

Methods: Follow-up observation study was performed up to 10th year after randomization, continuing RCT to evaluate the efficacy and safety of leuprorelin every 3 months for ≥ 3 versus 2 years, with daily tamoxifen for 5 years. Primary endpoints were disease-free survival (DFS) and 2-year landmark DFS.

Results: Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or ≥ 3 years (N = 110) with tamoxifen. Leuprorelin treatment for ≥ 3 years versus 2 years provided no significant difference in DFS (HR 0.944, 95% CI 0.486-1.8392) or 2-year landmark DFS (N = 99 and 102 in 2-year and ≥ 3-year groups, HR 0.834, 0.397-1.753). In small, higher-risk subgroup (n = 17); however, 2-year landmark DFS in ≥ 3-year group was significantly longer (HR 0.095, 0.011-0.850) than that in 2-year group. The incidence of bone-related adverse events was around 5% in both groups.

Conclusions: Adjuvant leuprorelin treatment for ≥ 3 years with tamoxifen only showed similar efficacy and safety profiles to those for 2 years in analyses among all patients but suggested greater benefit in higher-risk patients. No new safety signal was identified for long-term leuprorelin treatment.

Trial Registration Number: Not applicable. This was an observational study.
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http://dx.doi.org/10.1007/s12282-020-01205-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064970PMC
May 2021

Effect of a Multifactorial Intervention on Fracture in Patients With Type 2 Diabetes: Subanalysis of the J-DOIT3 Study.

J Clin Endocrinol Metab 2021 04;106(5):e2116-e2128

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Aims: To evaluate the effects of an intensified multifactorial intervention and patient characteristics on the incidence of fractures comorbid with type 2 diabetes.

Methods: Fracture events were identified and analyzed among adverse events reported in the J-DOIT3 study, a multicenter, open-label, randomized, parallel-group trial that was conducted in Japan, in which patients with type 2 diabetes were randomly assigned to receive conventional therapy for glucose, blood pressure, and lipids (targets: HbA1c < 6.9%, blood pressure <130/80 mm Hg, LDL-cholesterol <120mg/dL) or intensive therapy (HbA1c < 6.2%, blood pressure <120/75 mm Hg, LDL-cholesterol <80mg/dL) (ClinicalTrials.gov registration no. NCT00300976).

Results: The cumulative incidence of fractures did not differ between those receiving conventional therapy and those receiving intensive therapy (hazard ratio (HR) 1.15; 95% CI, 0.91-1.47; P = 0.241). Among the potential risk factors, only history of smoking at baseline was significantly associated with the incidence of fractures in men (HR 1.96; 95% CI, 1.04-3.07; P = 0.038). In contrast, the incidence of fractures in women was associated with the FRAX score [%/10 years] at baseline (HR 1.04; 95% CI, 1.02-1.07; P < 0.001) and administration of pioglitazone at 1 year after randomization (HR 1.59; 95% CI, 1.06-2.38; P = 0.025).

Conclusions: Intensified multifactorial intervention may be implemented without increasing the fracture risk in patients with type 2 diabetes. The fracture risk is elevated in those with a history of smoking in men, whereas it is predicted by the FRAX score and is independently elevated with administration of pioglitazone in women.
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http://dx.doi.org/10.1210/clinem/dgab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063245PMC
April 2021

High-Density Lipoprotein Cholesterol and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Statins: An Observation from the REAL-CAD Study.

J Atheroscler Thromb 2021 Jan 9. Epub 2021 Jan 9.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University.

Aim: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients.

Methods: From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) <120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months-at baseline) and (absolute difference/baseline)×100, respectively.

Results: During a median follow-up period of 4.0 (IQR 3.2-4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, HR 1.03, 95% CI 0.94-1.12, HR 1.05, 95% CI 0.98-1.12, and HR 1.08, 95% CI 0.94-1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months.

Conclusions: After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.
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http://dx.doi.org/10.5551/jat.59881DOI Listing
January 2021

Renal prognoses by different target hemoglobin levels achieved by epoetin beta pegol dosing to chronic kidney disease patients with hyporesponsive anemia to erythropoiesis-stimulating agent: a multicenter open-label randomized controlled study.

Clin Exp Nephrol 2021 May 7;25(5):456-466. Epub 2021 Jan 7.

Fukuoka Renal Clinic, Fukuoka, Japan.

Background: There is no evidence regarding appropriate target hemoglobin levels in chronic kidney disease (CKD) patients with an erythropoiesis-stimulating agent (ESA)-hyporesponsiveness. Therefore, we conducted a randomized controlled study in non-dialysis dependent CKD (NDD-CKD) patients with ESA-hyporesponsiveness, comparing results of intensive versus conservative treatment to maintain hemoglobin levels.

Methods: This was a multicenter, open-label, randomized, parallel-group study conducted at 89 institutions. Among NDD-CKD patients, those with ESA-hyporesponsive renal anemia were randomly assigned to an intensive treatment group, to which epoetin beta pegol was administered with target hemoglobin level of 11 g/dL or higher, or conservative treatment group, in which the hemoglobin levels at enrollment (within ± 1 g/dL) were maintained. The primary endpoint was the time to the first kidney composite event defined as (1) transition to renal replacement therapy (dialysis or renal transplantation); (2) reduction of estimated glomerular filtration rate (eGFR) to less than 6.0 mL/min/1.73 m; or (3) reduction of eGFR by 30% or more. Secondary endpoints were kidney function (change rate in eGFR), cardiovascular (CV) events, and safety.

Results: Between August 2012 and December 2015, 385 patients were registered, and 362 patients who met the eligibility criteria were enrolled. There was no significant difference in kidney survival or in CV events between the two groups. However, the incidences of the 3 types of kidney composite events tended to differ.

Conclusions: In NDD-CKD patients with ESA-hyporesponsive renal anemia, the aggressive administration of ESA did not clearly extend kidney survival or result in a significant difference in the incidence of CV events.
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http://dx.doi.org/10.1007/s10157-020-02005-4DOI Listing
May 2021

Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 01;22(1):74-84

Cancer Institute Hospital, Tokyo, Japan.

Background: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer.

Methods: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969.

Findings: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis.

Interpretation: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer.

Funding: Public Health Research Foundation (Japan), Taiho Pharmaceutical.
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http://dx.doi.org/10.1016/S1470-2045(20)30534-9DOI Listing
January 2021

Relationships between pathological factors and long-term outcomes in patients enrolled in two prospective randomized controlled trials comparing the efficacy of oral tegafur-uracil with CMF (N·SAS-BC 01 trial and CUBC trial).

Breast Cancer Res Treat 2021 Feb 1;186(1):135-147. Epub 2020 Dec 1.

Chuo University, Tokyo, Japan.

Purpose: To evaluate the efficacies of cyclophosphamide, methotrexate, and fluorouracil (CMF) and tegafur-uracil (UFT) as adjuvant therapy in patients with resected stage I-IIIA breast cancer by immunohistochemistry (IHC)-based subtype and to determine the relationships between clinicopathological factors and long-term outcomes.

Methods: A pooled analysis of the randomized controlled N·SAS-BC 01 and CUBC studies was conducted. Expression of hormone receptors (HRs; estrogen and progesterone receptors), human epidermal growth factor receptor 2 (HER2), and Ki67were assessed by IHC. Tumor-infiltrating lymphocytes (TILs) and nuclear/histological grades were determined by hematoxylin and eosin staining. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and hazard ratios were determined by Cox model adjusted for baseline tumor size and nodal status.

Results: A total of 689 patients (342 CMF and 347 UFT) were included in the analyses with a median follow-up of 11.1 years. There was no significant difference in RFS or OS between the two cohorts (RFS: 0.96 [95% confidence interval: 0.71-1.30], log-rank test p = 0.80; OS: 0.93 [0.64-1.35], p = 0.70). There was no difference in RFS or OS between the two cohorts for HR+/HER2- and HR+/HER2+ subtypes. RFS was significantly longer in patients treated with UFT compared with CMF in patients with HR-/HER2+ subtype (0.30 [0.10-0.88], p = 0.03). A high TILs level was associated with a better OS compared with low TILs level (p = 0.02).

Conclusions: This long-term follow-up study showed that RFS and OS were similar in patients with luminal-type breast cancer treated with CMF and UFT.
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http://dx.doi.org/10.1007/s10549-020-06018-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940338PMC
February 2021

A phase II Japanese trial of fludarabine, cyclophosphamide and rituximab for previously untreated chronic lymphocytic leukemia.

Jpn J Clin Oncol 2021 Mar;51(3):408-415

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

Objective: Fludarabine, cyclophosphamide and rituximab (FCR) is the standard regimen for fit patients with untreated CD20-positive chronic lymphocytic leukemia (CLL). However, this combination is unavailable in Japan because rituximab is not approved for CLL. We investigated the efficacy and safety of FCR in this single-arm, multicenter study designed as a bridging study to the CLL8 study by the German CLL Study Group.

Methods: The study enrolled previously untreated patients with CLL of Binet stage B or C with active disease. Patients with a Cumulative Illness Rating Scale score of ≤6 and creatinine clearance of ≥70 ml/min were eligible. Patients received 6 cycles of FCR every 28 days and were followed for up to 1 year.

Results: Seven patients were enrolled. The best overall response rate according to the 1996 NCI-WG Guidelines, the primary endpoint of the study, was 71.4% (95% confidence interval, 29.0-96.3%), with one patient achieving complete response. No deaths or progression occurred during follow-up. The main adverse event was hematotoxicity. CD4-positive T-cell count decreased in all patients; most patients showed no reduction in serum immunoglobulin G.

Conclusion: Although the number of patients was limited, FCR appears to be effective with manageable toxicity for treatment-naïve fit Japanese patients with CD20-positive CLL.

Clinical Trial Number: JapicCTI-132285.
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http://dx.doi.org/10.1093/jjco/hyaa215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937417PMC
March 2021

Effectiveness of HPV vaccination against the development of high-grade cervical lesions in young Japanese women.

BMC Infect Dis 2020 Nov 5;20(1):808. Epub 2020 Nov 5.

Japan Cancer Society, Tokyo, Japan.

Background: Although more than 10 years have passed since HPV vaccination was implemented, first as an interim programme (Emergent vaccine promotion programme) in November 2010, followed by incorporating into the National Immunization Programme in April, 2013 and suspended in June 2013, limited studies have investigated the HPV vaccine effectiveness against high-grade cervical lesions in Japan.

Methods: We collected the matched data of the results of cervical biopsy and history of vaccination from the Japan Cancer Society database. The subjects were women aged 20 to 29 years screened for cervical cancer between April, 2015 and March, 2017, and with information on HPV vaccination status. We estimated the relative risk of developing high-grade cervical lesions in vaccinated subjects using Poisson regression as compared to unvaccinated subjects.

Results: Among the 34,281 women screened, 3770 (11.0%) were vaccinated. The prevalence of CIN2+ was statistically significantly lower in the vaccinated women as compared to the unvaccinated women (Vaccine Effectiveness (VE) =76%; RR = 0.24, 95% CI:0.10-0.60). High VE against CIN3+ was also observed (91%; RR = 0.09, 95% CI:0.00-0.42).

Conclusion: Women aged 20-29 years who received at least one dose of HPV vaccine had a significantly lower risk of high-grade cervical lesions than those not vaccinated. In Japan, HPV vaccination should be resumed in order to reduce the incidence of cervical cancer.
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http://dx.doi.org/10.1186/s12879-020-05513-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643434PMC
November 2020

Intrauterine administration of platelet-rich plasma improves embryo implantation by increasing the endometrial thickness in women with repeated implantation failure: A single-arm self-controlled trial.

Reprod Med Biol 2020 Oct 25;19(4):350-356. Epub 2020 Jun 25.

Director of Sanno Hospital Tokyo Japan.

Purpose: The purpose of this study was to investigate the effectiveness of intrauterine administration of platelet-rich plasma (PRP) in frozen embryo transfer (FET) cycle in Japanese patients with a thin endometrium.

Method: A prospective single-arm self-controlled trial was conducted in Japan. PRP administration was performed in 36 of the 39 eligible patients with a thin endometrium (≤7 mm). Hormone replacement therapy (HRT) with estrogen was performed for 2 menstrual cycles, and PRP was administrated on the 10th and 12th days of the second HRT cycle. The endometrial thickness was evaluated on transvaginal ultrasonography by two physicians at every visit, one an attending physician and the other a specialist physician blinded to the date and timing of the sonography. FET was performed during the second HRT cycle after PRP administration.

Results: After PRP administration, the mean (SD) endometrial thickness on the 14th day was significantly increased by 1.27 mm ( < .001) and 0.72 mm ( = .001) on the basis of the unblinded and blinded measurements, respectively. Of the 36 patients, 32 (88.9%) underwent FET. The clinical pregnancy rate was 15.6%. No adverse events occurred.

Conclusions: PRP therapy was safe and effective in increasing endometrial thickness improving possibly pregnancy rate.
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http://dx.doi.org/10.1002/rmb2.12334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542012PMC
October 2020

[Secular trends of breast cancer detection rate in Japan: Age, period, birth cohort, and region effects from 2004 to 2015].

Nihon Koshu Eisei Zasshi 2020 ;67(9):593-602

Department of Integrated Science and Engineering for Sustainable Society, Faculty of Science and Engineering, Chuo University.

Objective The purpose of this study was to investigate the influence of age, period, birth cohort, and regional differences in the detection of breast cancer using screening data.Method Data from the Japan Cancer Society's breast cancer screening program, collected from 21 prefectural branches between 2004 to 2015, were used to generate age-specific estimates of cancer detection for women aged between 40 to 79 years. We used Bayesian age-period-cohort (APC) analyses based on the cohort table to describe the simultaneous effects of age, period, and cohort on breast cancer detection rates to understand the population dynamics underlying the detection patterns. We also incorporated region as a random effect to examine regional characteristics.Results The age effect showed bimodality in the late 40s and late 50s. The period effect decreased from 2004 to 2007 and remained constant thereafter. The cohort effect showed that the detection rate for women born between 1943 and 1958 was high. Furthermore, we found regional differences in the breast cancer detection rate: Miyazaki, Fukui, Tochigi, and Hokkaido prefectures showed higher detection rates, while Kagoshima and Chiba prefecture had lower rates.Conclusion Age effect has the strongest influence on the secular trend of breast cancer detection, and there is a regional difference in the detection rate. The present study that used screening data presented similar results to those of previous studies. The National Cancer Registry, based on the Cancer Registry Act of 2016, reports accurate national data. Similar to the National Cancer Registry data, analysis using screening data has immediacy and could be used for disease prevention.
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http://dx.doi.org/10.11236/jph.19-111DOI Listing
October 2020

Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients.

J Clin Oncol 2020 11 16;38(32):3743-3752. Epub 2020 Sep 16.

Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Purpose: Adjuvant trastuzumab monotherapy has not been compared with trastuzumab + chemotherapy. We investigated the relative value of trastuzumab monotherapy for older patients with breast cancer.

Methods: This study was an open-label, randomized controlled study with a treatment selection design in which a noninferiority criterion was predefined. Patients aged 70-80 years with surgically treated human epidermal growth factor receptor 2-positive invasive breast cancer received trastuzumab monotherapy or trastuzumab + chemotherapy. The primary end point was disease-free survival (DFS) with assessment of prespecified hazard ratio (HR), relapse-free survival (RFS), adverse events (AEs), health-related quality of life (HRQoL), and restricted mean survival time (RMST).

Results: The study involved 275 patients (mean age, 73.5 years) who were followed up for a mean of 4.1 years (range, 0.3-8.0 years). The percentages of patients by cancer stage were as follows: I (pT > 0.5 cm), 43.6%; IIA, 41.7%; IIB, 13.5%; and IIIA, 1.1%. Three-year DFS was 89.5% with trastuzumab monotherapy versus 93.8% with trastuzumab + chemotherapy (HR, 1.36; 95% CI, 0.72 to 2.58; = .51). At 3 years, RMST differed by -0.39 months between arms (95% CI, -1.71 to 0.93; = .56). Three-year RFS was 92.4% with trastuzumab monotherapy versus 95.3% with trastuzumab + chemotherapy (HR, 1.33; 95% CI, 0.63 to 2.79; = .53). Common AEs were anorexia (7.4% 44.3%; < .0001) and alopecia (2.2% 71.7%; < .0001), and grade 3/4 nonhematologic AEs occurred in 11.9% versus 29.8% ( = .0003) for trastuzumab monotherapy versus trastuzumab + chemotherapy, respectively. Clinically meaningful HRQoL deterioration rate showed significant differences at 2 months (31% for trastuzumab monotherapy 48% for trastuzumab + chemotherapy; = .016) and at 1 year (19% 38%; = .009).

Conclusion: The primary objective of noninferiority for trastuzumab monotherapy was not met. However, the observed loss of survival without chemotherapy was < 1 month at 3 years. Therefore, and in light of the lower toxicity and more favorable HRQoL profile, trastuzumab monotherapy can be considered an adjuvant therapy option for selected older patients.
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http://dx.doi.org/10.1200/JCO.20.00184DOI Listing
November 2020

Multifactorial intervention has a significant effect on diabetic kidney disease in patients with type 2 diabetes.

Kidney Int 2021 01 4;99(1):256-266. Epub 2020 Sep 4.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Toranomon Hospital, Tokyo, Japan. Electronic address:

To evaluate the effect of multifactorial intervention on the onset and progression of diabetic kidney disease in the patients with type 2 diabetes, we analyzed the effects of intensified multifactorial intervention by step-wise intensification of medications and life-style modifications (intensive therapy treatment targets; HbA1c under 6.2%, blood pressure under 120/75 mmHg, low-density lipoprotein cholesterol under 80 mg/dL) comparing with the guideline-based standard care (conventional therapy treatment targets: HbA1c under 6.9%, blood pressure under 130/80 mmHg, low-density lipoprotein cholesterol under 120 mg/dL) on diabetic kidney disease. A total of 2540 eligible patients in the Japan Diabetes Optimal Integrated Treatment for three major risk factors of cardiovascular diseases (J-DOIT3) cohort were randomly assigned to intensive therapy (1269) and conventional therapy (1271) and treated for a median of 8.5 years. The prespecified kidney outcome measure was a composite of progression from normoalbuminuria to microalbuminuria or progression from normoalbuminuria to macroalbuminuria or progression from microalbuminuria to macroalbuminuria, serum creatinine levels elevated by two-fold or more compared to baseline, or kidney failure. Primary analysis was carried out on the intention-to-treat population. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. A total of 438 kidney events occurred (181 in the intensive therapy group and 257 in the conventional therapy group). Intensive therapy was associated with a significant 32% reduction in kidney events compared to conventional therapy and was associated with a change in HbA1c at one year from study initiation. Thus, prespecified analysis shows that intensified multifactorial intervention significantly reduced the onset and progression of diabetic kidney disease compared to currently recommended care.
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http://dx.doi.org/10.1016/j.kint.2020.08.012DOI Listing
January 2021

Venous thromboembolism in cancer patients: report of baseline data from the multicentre, prospective Cancer-VTE Registry.

Jpn J Clin Oncol 2020 Oct;50(11):1246-1253

Department of Gastrointestinal Surgery, Osaka International Cancer Institute, Osaka, Japan.

Background: The Cancer-VTE Registry evaluates the occurrence and management of venous thromboembolism in Japanese participants with major solid tumors. Using Registry data, we evaluated the frequency of concurrent venous thromboembolism in cancer patients prior to treatment initiation by cancer type.

Methods: The Cancer-VTE Registry is an ongoing (March 2017-September 2020) prospective cohort study using a nationwide, multicentre clinical registry. Participants aged ≥20 years with colorectal, lung, stomach, pancreatic, breast or gynecologic cancer, confirmed staging, ≥6 months life expectancy post-registration and who had undergone venous thromboembolism screening were managed with routine clinical care. Venous thromboembolism frequency at registration was evaluated.

Results: Of 9735 participants, 571 (5.9%) had venous thromboembolism at baseline, including asymptomatic [5.5% (n = 540)] and symptomatic venous thromboembolism [0.3% (n = 31)]. Most participants with venous thromboembolism (n = 506, 5.2%) had deep vein thrombosis only; 65 (0.7%) had pulmonary embolism with/without deep vein thrombosis. The prevalence of distal and proximal deep vein thrombosis was 4.8% (n = 466) and 0.9% (n = 83), respectively. The highest prevalence of venous thromboembolism was for pancreatic cancer (8.5%) and the lowest for breast cancer (2.0%). Venous thromboembolism prevalence increased as cancer stage advanced.

Conclusions: Although there was a marked difference in venous thromboembolism by cancer type, the data suggest that cancer stage is an important risk factor for venous thromboembolism. Thus, metastasis seems a critical risk factor for venous thromboembolism. This is the first demonstration of venous thromboembolism prevalence and risk factors in Japanese cancer patients prior to treatment.

Trial Registration: UMIN000024942.
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http://dx.doi.org/10.1093/jjco/hyaa112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579341PMC
October 2020

Oncological outcomes for patients with locally advanced prostate cancer treated with neoadjuvant endocrine and external-beam radiation therapy followed by adjuvant continuous/intermittent endocrine therapy in an open-label, randomized, phase 3 trial.

Cancer 2020 09 23;126(17):3961-3971. Epub 2020 Jun 23.

Kotake Clinic, Osaka, Japan.

Background: To date, research has not determined the optimal procedure for adjuvant androgen deprivation therapy (ADT) in patients with locally advanced prostate cancer (PCa) treated for 6 months with neoadjuvant ADT and external-beam radiation therapy (EBRT).

Methods: A multicenter, randomized, phase 3 trial enrolled 303 patients with locally advanced PCa between 2001 and 2006. Participants were treated with neoadjuvant ADT for 6 months. Then, 280 patients whose prostate-specific antigen levels were less than pretreatment levels and less than 10 ng/mL were randomized. All 280 participants were treated with 72 Gy of EBRT in combination with adjuvant ADT for 8 months. Thereafter, participants were assigned to long-term ADT (5 years in all; arm 1) or intermittent ADT (arm 2). The primary endpoint was modified biochemical relapse-free survival (bRFS) with respect to nonmetastatic castration-resistant prostate cancer (nmCRPC) progression, clinical relapse, or any cause of death.

Results: The median follow-up time after randomization was 8.2 years. Among the 136 and 144 men assigned to trial arms 1 and 2, respectively, 24 and 30 progressed to nmCRPC or clinical relapse, and 5 and 6 died of PCa. The 5-year modified bRFS rates were 84.8% and 82.8% in trial arms 1 and 2, respectively (hazard ratio, 1.132; 95% confidence interval, 0.744-1.722).

Conclusions: Although modified bRFS data did not demonstrate noninferiority for arm 2, intermittent adjuvant ADT after EBRT with 14 months of neoadjuvant and short-term adjuvant ADT is a promising treatment strategy, especially in a population of responders after 6 months of ADT for locally advanced PCa.
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http://dx.doi.org/10.1002/cncr.33034DOI Listing
September 2020

Response Shift-Adjusted Treatment Effect on Health-Related Quality of Life in a Randomized Controlled Trial of Taxane Versus S-1 for Metastatic Breast Cancer: Structural Equation Modeling.

Value Health 2020 06 17;23(6):768-774. Epub 2020 May 17.

Division of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Objective: We investigated the quantification of the response shift-adjusted treatment effect on quality-of-life (QOL) data in a randomized controlled trial of taxane versus S-1 for patients with metastatic breast cancer (SELECT-BC).

Methods: This study was a secondary data analysis of a previously published trial. The response shift-adjusted treatment effect on health-related QOL (HRQOL) data measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was estimated using structural equation modeling techniques in addition to quantifying the "true" treatment effect. Measurement invariances in the values of the common factor loadings, intercepts, and residual variances between before treatment and at the 3-, 6-, and 12-month visits were considered the response shift effects.

Results: In the taxane group, we observed positive recalibration effects for role functioning and positive reprioritization and negative recalibration effects for emotional functioning. The observed change of -4.56 for role functioning comprised +2.26 response shifts and -6.82 "true" change. The observed change of +9.41 for emotional functioning comprised +12.43 response shifts and -1.17 "true" change. In the S-1 group, we observed positive reprioritization and negative recalibration effects for emotional functioning and positive reprioritization effects for social functioning. The observed change of +10.54 for emotional functioning comprised +10.07 response shifts and +0.47 "true" change. The observed change of +2.43 for social functioning comprised +3.50 response shifts and -1.07 "true" change.

Conclusion: Detailed analysis of the response shift effects will improve the evaluation reliability of observed HRQOL data during clinical trials.
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http://dx.doi.org/10.1016/j.jval.2020.02.003DOI Listing
June 2020

Association between Low Protein Intake and Mortality in Patients with Type 2 Diabetes.

Nutrients 2020 Jun 1;12(6). Epub 2020 Jun 1.

Department of Hematology, Endocrinology, and Metabolism, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuoh-ku, Niigata 951-8510, Japan.

The aim of this study was to investigate the association between protein intake and mortality risk in patients with type 2 diabetes. We analyzed a pooled data of 2494 diabetic patients from two prospective longitudinal studies. Nutritional intake was assessed using a Food Frequency Questionnaire at baseline. Protein intake per body weight (kg) per day was categorized into quartile groups. Adjusted hazard ratios (HRs) and 95% confidence interval (CI) were calculated using Cox regression analysis. During the six-year follow-up, there were 152 incidents of all-cause mortality. The HR for mortality in the lowest quartile of protein intake per body weight compared with the highest quartile was 2.26 (95% CI: 1.34-3.82, = 0.002) after adjustment for covariates. Subgroup analyses revealed significant associations between low protein intake and mortality in patients aged over 75 years or under 65 years. After further adjustment of the total energy intake, a significant association between protein intake and mortality remained in patients aged ≥ 75 years, whereas the association was attenuated in those aged < 65 years. Our results suggest that adequate protein intake is necessary in older diabetic patients over 75 years, whereas with diabetes, whereas whole optimal total energy intake is required in younger patients with type 2 diabetes.
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http://dx.doi.org/10.3390/nu12061629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352318PMC
June 2020

Factors affecting enrollment in randomized controlled trials conducted for patients with metastatic breast cancer.

Jpn J Clin Oncol 2020 Aug;50(8):873-881

Faculty of Science and Engineering, Chuo University, Tokyo.

Background: It is critical to obtain informed consent from eligible patients to complete clinical trials. We investigated the factors that affect the participation rates of eligible patients.

Patients And Methods: Patients with metastatic breast cancer who were eligible for SELECT BC or SELECT BC-CONFIRM trials, randomized controlled trials conducted for patients with chemotherapy-naive metastatic breast cancer were recruited to prospective studies, SELECT BC-FEEL and SELECT BC-FEEL II, respectively. SELECT BC FEEL and SELECT BC-FEEL II were conducted to identify the factors affecting the rates at which informed consent was obtained, using a self-administered questionnaire we developed.

Results: In total, 232 patients participated in the studies. The patients who agreed to take part in the randomized trials were more likely than the refusers to answer that they decided to participate because: 'My doctor wanted me to participate in this trial' (P = 0.00000), ' My family or friends wanted me to participate in this trial' (P = 0.00000), 'Both treatment regimens used in the trial are suitable to me' (P = 0.00383), 'I know that the trial is conducted to determine which is a better treatment' (P = 0.01196), and ' I think that my participation in the trial will contribute to the benefit to future patients with the same disease' (P = 0.00756).

Conclusions: To enhance the consent rate in randomized trials of metastatic breast cancer patients, concepts of the trials must be considered important and acceptable not only by patients but also by doctors and their families.
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http://dx.doi.org/10.1093/jjco/hyaa065DOI Listing
August 2020

NSAS-BC02 substudy of chemotherapy-induced amenorrhea (CIA) in premenopausal patients who received either taxane alone or doxorubicin(A) cyclophosphamide(C) followed by taxane as postoperative chemotherapy.

Breast Cancer Res Treat 2020 Jul 28;182(2):325-332. Epub 2020 May 28.

Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan.

Background: Chemotherapy-induced amenorrhea (CIA) is one of the critical side effects from the chemotherapy in premenopausal patients with breast cancer. The goals of our study are the following: (1) to investigate the factors affecting the incidence of CIA; and (2) to evaluate the prognostic role of CIA in premenopausal patients with breast cancer.

Methods: We conducted a post hoc retrospective substudy to examine the incidence of the CIA and the relationship between CIA and prognosis in NSAS-BC02 that compared taxane alone to Doxorubicin(A) Cyclophosphamide(C) followed by taxane in postoperative patients with node-positive breast cancer RESULTS: Of 395 premenopausal women, 287 (72.7%) had CIA due to protocol treatment. Regarding type of protocol regimen, proportion of CIA was 76.9% in AC Paclitaxel(P), 75.2% in AC Docetaxel(D), 62.8% in PTX, and 75.2% in DTX. Predictive factors of CIA were age increase by 5 years (OR 1.50), ER positivity (OR 2.08), and HER2 3 + ( OR 0.40) according to logistic regression analysis. According to the log rank test and the Cox proportional hazards model, CIA group had significantly better disease-free survival than non-CIA group (P < .0001). However, according to time-dependent Cox model that was used to reduce guarantee-time bias, CIA was not a statistically significant prognostic factor in both ER-positive and ER-negative patients.

Conclusion: Treatment with taxane alone caused high frequency of CIA in premenopausal women with breast cancer. CIA did not turn out to be an independent prognostic factor, taking guarantee-time bias into consideration. Further clinical studies are needed to validate these findings.
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http://dx.doi.org/10.1007/s10549-020-05692-5DOI Listing
July 2020

Moving a neodymium magnet promotes the migration of a magnetic tracer and increases the monitoring counts on the skin surface of sentinel lymph nodes in breast cancer.

BMC Med Imaging 2020 05 27;20(1):58. Epub 2020 May 27.

Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan.

Background: We suspected that moving a small neodymium magnet would promote migration of the magnetic tracer to the sentinel lymph node (SLN). Higher monitoring counts on the skin surface before making an incision help us detect SLNs easily and successfully. The present study evaluated the enhancement of the monitoring count on the skin surface in SLN detection based on the magnet movement in a sentinel lymph node biopsy (SNB) using superparamagnetic iron oxide (SPIO) nanoparticles.

Methods: After induction of general anesthesia, superparamagnetic iron oxide nanoparticles were injected sub-dermally into the subareolar area or peritumorally. The neodymium magnet was moved over the skin from the injection site to the axilla to promote migration of the magnetic tracer without massage. A total of 62 patients were enrolled from February 2018 to November 2018: 13 cases were subjected to magnet movement 20 times (Group A), 8 were subjected to 1-min magnet movement (Group B), 26 were given a short (about 5 min) interval from injection to 1-min magnet movement (Group C), and 15 were given a long (about 25 min) interval before 1-min magnet movement using the magnetometer's head (Group D). In all cases, an SNB was conducted using both the radioisotope (RI) and SPIO methods. The monitoring counts on the skin surface were measured by a handheld magnetometer and compared among the four groups. Changes in the monitoring count by the interval and magnet movement were evaluated.

Results: The identification rates of the SPIO and RI methods were 100 and 95.2%, respectively. The mean monitoring counts of Group A, B, C, and D were 2.39 μT, 2.73 μT, 3.15 μT, and 3.92 μT, respectively (p < 0.0001; Kruskal-Wallis test). The monitoring counts were higher with longer magnet movement and with the insertion of an interval. Although there were no relationships between the monitoring count on the skin surface and clinicopathologic factors, magnet movement strongly influenced the monitoring count on the skin surface.

Conclusion: Moving a small neodymium magnet is effective for promoting migration of a magnetic tracer and increasing monitoring counts on the skin surface.

Trial Registration: UMIN, UMIN000029475. Registered 9 October 2017.
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http://dx.doi.org/10.1186/s12880-020-00459-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254765PMC
May 2020

Real-world, retrospective study evaluating thromboembolic events, associated risk factors, and health-care resource utilization in Japanese patients with polycythemia vera.

Int J Hematol 2020 Aug 11;112(2):176-184. Epub 2020 May 11.

Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan.

In this retrospective, real-world study, we used medical claims data to evaluate the incidence of thromboembolic events (TEs), time to TE, associated risk factors, and health-care resource utilization (HRU) in Japanese patients with polycythemia vera (PV; N = 606) from April 1, 2008, to August 31, 2015. Baseline characteristics of interest included median age, 67.0 years; previous TEs, 11.6%; cardiovascular conditions (CVCs), 45.7%; and ≥ 3 risk factors, 17.8%. Overall, 100 patients experienced TEs (118 events) at a rate of 8.15/100 person-years [TE-free survival rate, 69.3% (2008-2015)]. The annual total health-care costs [mean (per person)] were significantly impacted by the presence of TEs (yes vs. no: ¥993,000 vs ¥459,000; P < 0.001). These results confirm that the presence of CVCs increases the risk of TEs in Japanese patients with PV; occurrence of TEs was associated with a higher HRU in these patients.
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http://dx.doi.org/10.1007/s12185-020-02887-wDOI Listing
August 2020
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