Masahide Kondo

A Nonfucosylated Anti-HER2 Antibody Augments Antibody-Dependent Cellular Cytotoxicity in Breast Cancer Patients

Purpose: Removal of fucose residues from the oligosaccharides of human antibody is a powerful approach to enhance antibody-dependent cellular cytotoxicity (ADCC), a potential important antitumor mechanism of therapeutic antibodies. To provide clinically relevant evidence of this mechanism, we investigated ADCC of a fucose-negative version of trastuzumab [anti–human epidermal growth factor receptor 2 (HER2) humanized antibody] using peripheral blood mononuclear cells (PBMC) from breast cancer patients as effector cells. Experimental Design: Thirty volunteers, including 20 breast cancer patients and 10 normal healthy control donors, were recruited randomly, and aliquots of peripheral blood were collected. ADCC of commercial trastuzumab (fucosylated) and its fucose-negative version were measured using PBMCs drawn from the volunteers as effector cells and two breast cancer cell lines with different HER2 expression levels as target cells. Relationships between cytotoxicity and characteristics of the patients, such as content of natural killer cells in PBMCs, type of therapy, FCGR3A genotypes, etc. were also analyzed. Results: ADCC was significantly enhanced with the fucose-negative antibody compared with the fucose-positive antibody using PBMCs from either normal donors or breast cancer patients. Enhancement of ADCC was observed irrespective of the various clinical backgrounds of the patients, even in the chemotherapy cohort that presented with a reduced number of natural killer cells and weaker ADCC. Conclusions: This preliminary study suggests that the use of fucose-negative antibodies may improve the therapeutic effects of anti-HER2 therapy for patients independent of clinical backgrounds.

Economic evaluation of the 21-gene signature (Oncotype DX®) in lymph node-negative/positive, hormone receptor-positive early-stage breast cancer based on Japanese validation study (JBCRG-TR03)

The 21-gene signature is validated as a good predictor of recurrence for lymph node-negative/positive, hormone receptor-positive, early-stage breast cancer in Japanese patient population. This study evaluates the cost-effectiveness of two scenarios designed to include the assay into Japan’s social health insurance benefit package: one for LN−, ER+, ESBC and another for LN−/+, ER+, ESBC. An economic decision tree and Markov model under Japan’s health system from the societal perspective is constructed with new evidence from the Japanese validation study. Incremental cost-effectiveness ratios are estimated as ¥384,828 (US

Long-Term Blood Pressure Variability, New-Onset Diabetes Mellitus, and New-Onset Chronic Kidney Disease in the Japanese General Population

3,848) per QALY for the indication for LN− scenario and ¥568,533 (US

Prediction of axillary lymph node metastasis in primary breast cancer patients using a decision tree-based model

5,685) per QALY for the indication for LN−/+ scenario. Both are not more than the suggested social willingness-to-pay for one QALY gain from an innovative medical intervention in Japan, ¥5,000,000/QALY (US

Association between Combined Lifestyle Factors and Non-Restorative Sleep in Japan: A Cross-Sectional Study Based on a Japanese Health Database

50,000/QALY). Sensitivity analyses show that this result is plausibly robust, since ICERs do not exceed the threshold by various changes of assumptions made and values employed. In conclusion, the inclusion of the assay in Japan’s social health insurance benefit package for not only LN− diseases but also LN+ diseases is cost-effective. Such a decision can be justifiable as an efficient use of finite resources for health care.

Economic evaluation of the 70-gene prognosis-signature (MammaPrint®) in hormone receptor-positive, lymph node-negative, human epidermal growth factor receptor type 2-negative early stage breast cancer in Japan

Whether long-term blood pressure (BP) variability among individuals without diabetes mellitus is associated with new-onset chronic kidney disease (CKD) risk, independently of other BP parameters (eg, mean BP, cumulative exposure to BP) and metabolic profile changes during follow-up, remains uncertain. We used data from a nationwide study of 48 587 Japanese adults aged 40 to 74 years (mean age, 61.7 years; 39% men) without diabetes mellitus or CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m2 or proteinuria by dipstick). BP was measured at baseline and during 3 annual follow-up visits (4 visits). BP variability was defined as standard deviation (SD) and average real variability during the 4 visits. At the year 3 follow-up visit, 6.3% of the population had developed CKD. In multivariable-adjusted logistic regression models, 1 SD increases in SDSBP (per 5 mmHg), SDDBP (per 3 mmHg), average real variabilitySBP (per 6 mmHg), and average real variabilityDBP (per 4 mmHg) were associated with new-onset CKD (odds ratios [ORs] and 95% confidence intervals, 1.15 [1.11–1.20], 1.08 [1.04–1.12], 1.13 [1.09–1.17], 1.06 [1.02–1.10], respectively; all P<0.01) after adjustment for clinical characteristics, and with mean BP from year 0 to year 3. The associations of SDBP and average real variabilityBP with CKD remained significant after additional adjustments for metabolic parameter changes during follow-up (ORs, 1.06–1.15; all P<0.01). Sensitivity analyses by sex, antihypertensive medication use, and the presence of hypertension showed similar conclusions. Among those in the middle-aged and elderly general population without diabetes mellitus, long-term BP variability during 3 years was associated with new-onset CKD risk, independently of mean or cumulative exposure to BP and metabolic profile changes during follow-up.

Economic Evaluation of Immunisation Programme of 23-Valent Pneumococcal Polysaccharide Vaccine and the Inclusion of 13-Valent Pneumococcal Conjugate Vaccine in the List for Single-Dose Subsidy to the Elderly in Japan

BackgroundThe aim of this study was to develop a new data-mining model to predict axillary lymph node (AxLN) metastasis in primary breast cancer. To achieve this, we used a decision tree-based prediction method—the alternating decision tree (ADTree).MethodsClinical datasets for primary breast cancer patients who underwent sentinel lymph node biopsy or AxLN dissection without prior treatment were collected from three institutes (institute A, n = 148; institute B, n = 143; institute C, n = 174) and were used for variable selection, model training and external validation, respectively. The models were evaluated using area under the receiver operating characteristics (ROC) curve analysis to discriminate node-positive patients from node-negative patients.ResultsThe ADTree model selected 15 of 24 clinicopathological variables in the variable selection dataset. The resulting area under the ROC curve values were 0.770 [95% confidence interval (CI), 0.689–0.850] for the model training dataset and 0.772 (95% CI: 0.689–0.856) for the validation dataset, demonstrating high accuracy and generalization ability of the model. The bootstrap value of the validation dataset was 0.768 (95% CI: 0.763–0.774).ConclusionsOur prediction model showed high accuracy for predicting nodal metastasis in patients with breast cancer using commonly recorded clinical variables. Therefore, our model might help oncologists in the decision-making process for primary breast cancer patients before starting treatment.

Economic evaluation of intensive chemotherapy with prophylactic granulocyte colony-stimulating factor for patients with high-risk early breast cancer in Japan

Background Although lifestyle factors such as cigarette smoking, excessive drinking, obesity, low or no exercise, and unhealthy dietary habits have each been associated with inadequate sleep, little is known about their combined effect. The aim of this study was to quantify the overall impact of lifestyle-related factors on non-restorative sleep in the general Japanese population. Methods and Findings A cross-sectional study of 243,767 participants (men, 39.8%) was performed using the Specific Health Check and Guidance System in Japan. A healthy lifestyle score was calculated by adding up the number of low-risk lifestyle factors for each participant. Low risk was defined as (1) not smoking, (2) body mass index<25 kg/m2, (3) moderate or less alcohol consumption, (4) regular exercise, and (5) better eating patterns. Logistic regression analysis was used to examine the relationship between the score and the prevalence of non-restorative sleep, which was determined from questionnaire responses. Among 97,062 men (mean age, 63.9 years) and 146,705 women (mean age, 63.7 years), 18,678 (19.2%) and 38,539 (26.3%) reported non-restorative sleep, respectively. The prevalence of non-restorative sleep decreased with age for both sexes. Compared to participants with a healthy lifestyle score of 5 (most healthy), those with a score of 0 (least healthy) had a higher prevalence of non-restorative sleep (odds ratio, 1.59 [95% confidence interval, 1.29–1.97] for men and 2.88 [1.74–4.76] for women), independently of hypertension, hypercholesterolemia, diabetes, and chronic kidney disease. The main limitation of the study was the cross-sectional design, which limited causal inferences for the identified associations. Conclusions A combination of several unhealthy lifestyle factors was associated with non-restorative sleep among the general Japanese population. Further studies are needed to establish whether general lifestyle modification improves restorative sleep.

New-onset hypertension and risk for chronic kidney disease in the Japanese general population.

The 70-gene prognosis-signature is validated as a good predictor of recurrence for hormone receptor-positive (ER+), lymph node-negative (LN−), human epidermal growth factor receptor type 2-negative (HER2−) early stage breast cancer (ESBC) in Japanese patient population. Its high cost and potential in avoiding unnecessary adjuvant chemotherapy arouse interest in its economic impact. This study evaluates the cost-effectiveness of including the assay into Japan’s social health insurance benefit package. An economic decision tree and Markov model under Japan’s health system from the societal perspective is constructed with clinical evidence from the pool analysis of validation studies. One-way sensitivity analyses are also performed. Incremental cost-effectiveness ratio is estimated as ¥3,873,922/quality adjusted life year (QALY) (US

Growing concern about heatstroke this summer in Japan after Fukushima nuclear disaster

43,044/QALY), which is not more than the suggested social willingness-to-pay for one QALY gain from an innovative medical intervention in Japan, ¥5,000,000/QALY (US