Comparison of the specimen quality of endobronchial ultrasound-guided intranodal forceps biopsy using standard-sized forceps versus mini forceps for lung cancer: A prospective study.

BACKGROUND AND OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a diagnostic procedure with adequate performance; however, its ability to provide specimens of sufficient quality and quantity for treatment decision-making in advanced-stage lung cancer may be limited, primarily due to blood contamination. The use of a 0.96-mm miniforceps biopsy (MFB) permits true histological sampling, but the resulting small specimens are unsuitable for the intended applications. Therefore, we introduced a 1.9-mm standard-sized forceps biopsy (SFB) and compared its utility to that of MFB. METHODS: We prospectively enrolled patients from three institutions who presented with hilar/mediastinal lymphadenopathy and suspected advanced-stage lung cancer, or those who were already diagnosed but required additional tissue specimens for biomarker analysis. Each patient underwent MFB followed by SFB three or four times through the tract created by TBNA using a 22-gauge needle on the same lymph node (LN). Two pathologists assessed the quality and size of each specimen using a virtual slide system, and diagnostic performance was compared between the MFB and SFB groups. RESULTS: Among the 60 enrolled patients, 70.0% were diagnosed with adenocarcinoma. The most frequently targeted sites were the lower paratracheal LNs, followed by the interlobar LNs. The diagnostic yields of TBNA, MFB and SFB were 91.7%, 93.3% and 96.7%, respectively. The sampling rate of high-quality specimens was significantly higher in the SFB group. Moreover, the mean specimen size for SFB was three times larger than for MFB. CONCLUSION: SFB is useful for obtaining sufficient qualitative and quantitative specimens.

Clinical significance of KL-6 in immune-checkpoint inhibitor treatment for non-small cell lung cancer.

PURPOSE: Krebs von den Lungen-6 (KL-6) functions as a tumor marker, as well as a diagnostic tool for interstitial pneumonia (IP). However, the significance of KL-6 in the immune-checkpoint inhibitor (ICI) treatment of non-small cell lung cancer (NSCLC), especially in patients without IP, is unknown. METHODS: This multicenter, retrospective study, which included patients with advanced NSCLC who received ICI therapy, analyzed the association between serum KL-6 values and ICI efficacy and the association between serum KL-6 values and ICI-induced interstitial lung disease (ILD) occurrence, focusing primarily on patients without IP. RESULTS: In total, 322 patients had available KL-6 values before ICI therapy. Among 202 patients without IP who received ICI monotherapy, the high-KL-6 group (≥ 500 U/mL) showed significantly shorter progression-free survival (PFS) and overall survival (OS) than the low-KL-6 group (< 500 U/mL) (median: 2.1 vs. 3.6 months, p = 0.048; median: 9.2 vs. 14.5 months, p = 0.035). There was no significant difference in response rate between the KL-6 high and low groups (19% vs. 29%, p = 0.14). In the multivariate analysis, high KL-6 was a significant predictor of poor PFS (hazard ratio [HR], 1.52; 95% confidence interval [CI] 1.10-2.11, p = 0.012) and OS (HR, 1.51; 95% CI 1.07 - 2.13, p = 0.019) for patients treated with ICI monotherapy. There was no significant difference in the occurrence rate of ILD between the high KL-6 and low KL-6 groups in patients with (20% vs. 15%, p = 1.00) or without IP (12% vs. 12%, p = 1.00). CONCLUSION: In ICI monotherapy for NSCLC without IP, elevated serum KL-6 levels were associated with poorer outcomes.

Influence of Smoking History on the Effectiveness of Immune-checkpoint Inhibitor Therapy for Non-small Cell Lung Cancer: Analysis of Real-world Data.

BACKGROUND/AIM: There is no real-world data in an Asian population to investigate the difference between the outcome of immune-checkpoint inhibitor (ICI) monotherapy and combination therapy for non-small cell lung cancer (NSCLC) based on smoking status. In this study, we investigated the correlation between smoking status and the efficacy of ICI therapy for NSCLC patients. PATIENTS AND METHODS: This multicentre retrospective study enrolled patients with recurrent or metastatic NSCLC who were treated using ICI therapy between December 2015 and July 2020. We analysed the objective response rate (ORR) of patients who received ICI monotherapy or combination therapy, based on smoking status using Fisher's exact test, and progression-free survival (PFS) and overall survival (OS) based on smoking status using the Kaplan-Meier method, the log-rank test, and Cox proportional hazards model. RESULTS: A total of 487 patients were included in the study. In the ICI monotherapy group, non-smokers showed significantly lower ORR and shorter PFS and OS than smokers (10% vs. 26%, p=0.002; median: 1.8 vs. 3.8 months, p<0.001; median: 8.0 vs. 15.4 months, p=0.026). In the ICI combination therapy group, non-smokers showed significantly longer OS than smokers (median: not reached vs. 26.3 months, p=0.045), and there was no significant difference in ORR and PFS between non-smokers and smokers (63% vs. 51%, p=0.43; median: 10.2 vs. 9.2 months, p=0.81). In the multivariate analysis of patients who received ICI combination therapy, the "non-smoker" status was not significantly associated with PFS [hazard ratio (HR)=1.31; 95% confidence interval (CI)=0.70-2.45, p=0.40] and OS (HR=0.40; 95% CI=0.14-1.13, p=0.083). CONCLUSION: Non-smokers showed worse outcomes than smokers with ICI monotherapy, but not with ICI combination therapy.

Vimentin expression correlates with immune checkpoint inhibitor efficacy in non-small cell lung cancer.

BACKGROUND: Although vimentin is often expressed in non-small cell lung cancer (NSCLC), the association between vimentin expression and immune-checkpoint inhibitor (ICI) efficacy remains unclear. METHODS: This retrospective multicenter study enrolled patients with NSCLC who received ICI treatment between December 2015 and July 2020. The authors constructed tissue microarrays and performed immunohistochemical staining with vimentin. They analyzed the relationship between vimentin expression rate and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Immunohistochemically evaluable specimens on microarray blocks were available for 397 patients, of whom 343 (86%) were negative (<10%), 30 (8%) were positive (10%-49%), and 24 (6%) were highly positive (≥50%) for vimentin expression. Both rates of programmed death-ligand 1 (PD-L1) tumor proportion score ≥1% and ≥50% were significantly higher in the vimentin-positive group (≥10%) than the vimentin-negative group (<10%) (96% vs. 78%, p = .004; 64% vs. 42%, p = .006, respectively). In patients treated with ICI monotherapy, ORR, PFS, and OS were significantly better in the vimentin-positive group (10%-49%) than in the vimentin-negative group (<10%) (54% vs. 25%, p = .003, median = 7.9 vs. 3.2 months, p = .011; median = 27.0 vs. 13.6 months, p = .015, respectively), whereas there was no significant difference in PFS and OS between the vimentin highly positive group (≥50%) and the vimentin-negative group (<10%) (median = 3.4 vs. 3.2 months, p = .57; median = 7.2 vs. 13.6 months, p = .086, respectively). CONCLUSIONS: Vimentin expression correlated with PD-L1 expression and ICI efficacy. PLAIN LANGUAGE SUMMARY: We constructed tissue microarrays and performed immunohistochemical staining with vimentin on 397 patients with advanced non-small cell lung cancer who were treated with immune-checkpoint inhibitor (ICI). The vimentin-positive group who were treated with ICI monotherapy showed significantly better objective response rate, progression-free survival, and overall survival than the vimentin negative group. The measurement of vimentin expression will aid in determining appropriate immunotherapy strategies.

Vascular endothelial growth factor receptor 2 expression and immunotherapy efficacy in non-small cell lung cancer.

It is unclear whether tumor vascular endothelial growth factor receptor 2 expression affects the therapeutic efficacy of immune-checkpoint inhibitors and antiangiogenic agents. This retrospective, multicenter study included patients with advanced non-small cell lung cancer who were treated with immune-checkpoint inhibitors. We constructed tissue microarrays and performed immunohistochemistry with an anti-vascular endothelial growth factor receptor 2 antibody. We analyzed immune and tumor cell staining separately in order to determine their correlation with the objective response rate, progression-free survival, and overall survival in patients receiving immune-checkpoint inhibitors. Of 364 patients, 37 (10%) expressed vascular endothelial growth factor receptor 2 in immune cells and 165 (45%) in tumor cells. The objective response rate, progression-free survival, and overall survival were significantly worse in patients treated with immune checkpoint inhibitor monotherapy who expressed vascular endothelial growth factor receptor 2 in immune cells than those who did not (10% vs 30%, p = 0.028; median = 2.2 vs 3.6 months, p = 0.012; median = 7.9 vs 17.0 months, p = 0.049, respectively), while there was no significant difference based on tumor cell expression (24% vs 30%, p = 0.33; median = 3.1 vs 3.5 months, p = 0.55; median = 13.6 vs 16.8 months, p = 0.31). There was no significant difference in overall survival between patients treated with and without antiangiogenic agents in any treatment period based on vascular endothelial growth factor receptor 2 expression. Immune checkpoint inhibitor efficacy was limited in patients expressing vascular endothelial growth factor receptor 2 in immune cells.

Tumor microenvironment disparity in multiple primary lung cancers: Impact of non-intrinsic factors, histological subtypes, and genetic aberrations.

INTRODUCTION: Multiple primary lung cancers (MPLCs) occur in common carcinogenetic risks such as lifestyle, biological aging, immune responses, hormones, and metabolism. Although MPLCs harbor various genetic profiles within the same individuals, differences in the tumor microenvironment (TME) are unclear. We investigated the impact of genetic aberrations, non-intrinsic factors, and pathological subtypes on tumor immunity. MATERIALS AND METHODS: In total, 73 surgically resected specimens from 32 patients with MPLC were analyzed. PD-L1 expression in tumor cells (TCs) and immune cells (ICs), CD3-positive tumor-infiltrating lymphocytes (TILs), CD8/CD3 ratios, and FOXP3-positive TILs that compose TMEs were evaluated by immunohistochemistry and classified on a score of 0-2. 38 tumors were sequenced for somatic mutations in 409 cancer-associated genes. RESULTS: Females and never or light smokers had a higher incidence of PD-L1-negative tumors and a higher concordance rate. PD-L1 positivity in TCs and ICs was significantly less frequent in EGFR-mutated than in wild-type tumors. Differences in the score of TMEs were observed between the KRAS-mutated-only tumor and the KRAS and TP53-co-mutated tumors, and between the KRAS-mutated-only tumor and the KRAS and STK11-co-mutated tumors. Significantly more FOXP3-high TILs were observed in invasive pathological subtypes than in non-invasive ones. CONCLUSION: Comparing TMEs among MPLCs revealed that non-smokers or light smokers and females were unlikely to express PD-L1 regardless of tumor site and confirmed that the EGFR mutations and co-occurring KRAS and STK11 or TP53 mutations were associated with TME. Pathological subtypes may impact the efficacy of immune therapy due to their potential correlations with regulatory T cells.

Mutational landscape of multiple primary lung cancers and its correlation with non-intrinsic risk factors.

Multiple primary lung cancers (MPLCs) harbour various genetic profiles among the tumours, even from individuals with same non-intrinsic risk factors. Paired mutational analyses were performed to obtain a census of mutational events in MPLC and assess their relationship with non-intrinsic risk factors. Thirty-eight surgical specimens from 17 patients diagnosed as MPLC were used. Extracted DNAs were sequenced for somatic mutations in 409 cancer-associated genes from a comprehensive cancer panel. We statistically analysed the correlation between each driver mutation frequency and non-intrinsic risk factors using Fisher's exact test, and whether genetic mutations occurred concomitantly or randomly in MPLC using an exact test. Comprehensive genetic analyses suggested different mutation profiles in tumours within the same individuals, with some exceptions. EGFR, KRAS, TP53, or PARP1 mutations were concomitantly detected in some MPLC cases. EGFR mutations were significantly more frequent in never or light smokers and females. Concomitant EGFR or KRAS mutations in MPLCs were significantly more frequent than expected by chance (P = .0023 and .0049, respectively) suggesting a more prominent role of non-intrinsic risk factors in EGFR and KRAS mutations than other mutations, which occurred more randomly. Concomitant EGFR or KRAS mutations were particularly prominent in never or light smokers and males.

Can smoking duration alone replace pack-years to predict the risk of smoking-related oncogenic mutations in non-small cell lung cancer? A cross-sectional study in Japan.

OBJECTIVE: To investigate whether smoking duration alone can replace pack-years to predict the risk of oncogenic mutations in non-small cell lung cancer (NSCLC). DESIGN: A cross-sectional study using the baseline dataset from the Japan Molecular Epidemiology for Lung Cancer Study. SETTING: Forty-three medical institutions nationwide in Japan. PARTICIPANTS: From July 2012 to December 2013, 957 patients with newly diagnosed stage I-IIIB NSCLC who underwent surgery were enrolled, and molecular analyses were performed on 876 samples (from 441 ever-smokers and 435 never-smokers). MAIN OUTCOMES MEASURED: We calculated the area under the receiver operating characteristic curve (AUC) values using logistic regression to compare between the predictive values of smoking duration and pack-years for mutational frequencies in the v-Ki-ras2 Kirsten rat sarcoma (KRAS), tumour suppressor p53 (TP53), and epidermal growth factor receptor (EGFR) genes and for cytosine-to-adenine base substitution (C>A). RESULTS: For predicting KRAS mutations, the AUC values for smoking duration and pack-years were 0.746 (95% CI 0.682 to 0.800) and 0.759 (95% CI 0.700 to 0.810), respectively (p=0.058). For predicting KRAS mutations in smokers, the AUC values for smoking duration and pack-years were 0.772 (95% CI 0.697 to 0.833) and 0.787 (95% CI 0.714 to 0.845), respectively (p=0.036). There were no significant differences between the AUC values for smoking duration and pack-years in terms of predicting TP53 and EGFR mutations and C>A. Pack-years was a significantly better predictor of KRAS mutations than smoking duration. CONCLUSION: Smoking duration was not significantly different from pack-years in predicting the likelihood of smoking-related gene mutations. Given the recall bias in obtaining smoking information, smoking duration alone should be considered for further investigation as a simpler alternative to pack-years.

Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors.

OBJECTIVES: Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancer (NSCLC). However, the impact of pretreatment T790M (preT790M) on the efficacy of EGFR-TKIs and on resistance remains unclear. MATERIALS AND METHODS: Two independent cohorts consisting of advanced EGFR-mutated NSCLC patients treated with first-line EGFR-TKIs, a derivation cohort that started treatment between August 2013 and July 2016 (cohort A, n = 44) and a validation cohort between August 2016 and December 2017 (cohort B, n = 22), were examined in this study. Among these, 28 patients underwent re-biopsy at disease progression. DNAs from pretreatment tumor biopsy samples and re-biopsy samples were assessed to detect T790M by the Cobas EGFR Mutation Test v2 (Cobas) and for quantitating T790M by droplet digital polymerase chain reaction (ddPCR). RESULTS: Detection rates of preT790M were 40.9% (18/44) in cohort A and 45.5% (10/22) in cohort B by ddPCR, and none by Cobas. A cutoff value of 0.3% for dividing into high- vs. low-preT790M allele frequency was determined by receiver operating characteristic curve analysis in cohort A. Progression-free survival (PFS) was significantly shorter in the high- preT790M group (n = 12) than in the low-preT790M (n = 6) and negative (n = 26) groups (combined low-preT790M) (median: 6.9 vs. 13.8 months, P =  0.00073). These observations were validated in cohort B [median: 6.2 (n = 5) vs. 15.3 months (n = 17), P =  0.0029]. In 28 paired biopsies, Cobas detected post-progression T790M in 60% (3/5) of the high-preT790M, in 57% (4/7) of the low-preT790M, and in 56% (9/16) of the negative-preT790M groups. CONCLUSION: EGFR-mutated NSCLC with high preT790M had significantly shorter PFS on EGFR-TKIs. However, preT790M abundance may not necessarily confer post-TKI T790M resistance.

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with EGFR-mutant non-small cell lung cancer.

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) as first-line treatment in 70 patients with advanced EGFR-mutant non-small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28-8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death-1 ligand-1 (PD-L1), as high (50% or more) or low (less than 50%), and ligand-2 (PD-L2) expression, respectively. The extent of CD8+ tumor-infiltrating lymphocytes was evaluated on a scale of 0-3, with 0-1 as low and 2-3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD-L1 tumor proportion and CD8+ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD-L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression-free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR-TKIs differed according to the TME, and the phenotype with high PD-L1 and CD8+ expression might be the subset that would poorly benefit from such treatment.

Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial.

Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels. Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis. Design, Setting, and Participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015. Interventions: Treatment with 0.5 µg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481). Main Outcomes and Measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death. Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events. Conclusions and Relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these. Trial Registration: UMIN-CTR Identifier: UMIN000001194.

Verification of the sensitivity of functional scores for treatment results - Substantial clinical benefit thresholds for the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ).

BACKGROUND: Validity and reliability of the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) had already been verified as the patients' self-rating assessment of low back pain and lumbar spinal disease and, the present study demonstrated the responsiveness of this measure. METHODS: 192 subjects who were determined by medical instructors of the Japanese Society for Spine Surgery and Related Research were analyzed. They had completed a series of treatment and both surveys before and after the treatment. Authors investigated rates of concordance between assessment by physicians and subjective assessment by patients. The mean, standard deviation, minimum, 25th percentile, median, 75th percentile and maximum values for pre-treatment, post-treatment, and acquired points were calculated, and then, we also investigated the trend between subjective assessment by patients and mean acquired points for each JOABPEQ domain and substantial clinical benefit thresholds for the JOABPEQ. RESULTS: Symptom changes as assessed by physicians did not coincide with those by patients, and acquired points in each JOABPEQ domain were significantly increased with improved self-rating by patients. In addition, patients who rated symptom changes as "slightly improved" showed a mean acquired points of ≥20, and those reporting "improved" showed a 25th percentile points of the acquired points of ≥20 approximately. CONCLUSION: A significant correlation was noted between the self-rating of patients and acquired points JOABPEQ, suggesting that ≥20 acquired points can be interpreted as substantial clinical benefit thresholds for the JOABPEQ.

Rab6a releases LIS1 from a dynein idling complex and activates dynein for retrograde movement.

Cytoplasmic dynein drives the movement of a wide range of cargoes towards the minus ends of microtubules. We previously demonstrated that LIS1 forms an idling complex with dynein, which is transported to the plus ends of microtubules by kinesin motors. Here we report that the small GTPase Rab6a is essential for activation of idling dynein. Immunoprecipitation and microtubule pull-down assays reveal that the GTP bound mutant, Rab6a(Q72L), dissociates LIS1 from a LIS1-dynein complex, activating dynein movement in in vitro microtubule gliding assays. We monitor transient interaction between Rab6a(Q72L) and dynein in vivo using dual-colour fluorescence cross-correlation spectroscopy in dorsal root ganglion (DRG) neurons. Finally, we demonstrate that Rab6a(Q72L) mediates LIS1 release from a LIS1-dynein complex followed by dynein activation through an in vitro single-molecule assay using triple-colour quantum dots. Our findings reveal a surprising function for GTP bound Rab6a as an activator of idling dynein.

Theoretical risk of anterior femoral cortex notching in total knee arthroplasty using a navigation system.

Two important requirements for navigation systems in total knee arthroplasty (TKA), perpendicular cut from the distal femoral condyle to the femoral mechanical axis and prevention of notching of the anterior femoral cortex, might be difficult to meet simultaneously. The potential risk of notching was investigated using three-dimensional (3D) computed tomography data of 50 entire lower extremities of 50 female Japanese candidates for TKA and a 3D template system. Navigation systems for TKA carry the potentially higher risk of notching of the anterior femoral cortex (34% to 51%) than conventional technique (11%) (P<0.001). More anterior setting of the reference point for navigation systems on the distal femur and more external setting of the femoral component were risk factors for notching (P<0.001).

[The impact of sedentary lifestyle on risk factors for cardiovascular disease among Japanese young women].

OBJECTIVE: The purpose of this study was to examine body composition, blood biochemical markers, and dietary intake in 2 groups of young women engaged in different physical activities and to assess the impact of sedentary lifestyle on risk factors for diabetes and cardiovascular disease. METHODS: The subjects were 208 students of a women's university. Of these, 108 majored in nutrition (physically sedentary group, SG) and 100 majored in sports (physically active group, AG). We conducted a survey from mid-June to mid-July in 2004, during which physical examinations, including measurements of body weight and height, evaluation of body composition using dual energy X-ray absorptiometry (DXA), determination of the ankle brachial index (ABI) by measuring the brachial and ankle systolic and assessment of diastolic blood pressure, blood biochemical tests, and examination of 7-day weighted diet records (DRs) were all conducted. The physical and blood biochemical values and the food and nutrient intakes calculated from the DRs were then compared between the groups. RESULTS: We analyzed a total 133 subjects who had completed all the DRs (78 SG subjects and 55 AG subjects). A comparison between the 2 groups revealed mean body mass indices (BMIs) of 20.5 and 21.4 kg/m2 and mean body fat percentages of 29.4% and 22.6% in the SG and AG subjects, respectively. Even though the SG subjects had lower BMIs, they had significantly higher body fat percentages. The ankle systolic blood pressure and ABI were significantly higher in the AG subjects. With regard to blood biochemistry, the HOMA-beta, leptin, and apoprotein-B levels were significantly higher in the SG subjects. The mean energy intakes (kcal/day) of the SG and AG subjects was 1550 and 1853, respectively. The intakes of most nutrients were significantly higher in the AG subjects, and the amount of food consumed by the SG subjects was low. CONCLUSION: The levels of blood biochemical markers such as leptin and apoprotein-B were higher and the ABI was lower in the SG subjects than in the AG subjects. We think that these results are attributable to the accumulation of body fat, including visceral fat. Therefore, it is important for SG subjects to increase their energy expenditure by regular exercise and consume a diet that corresponds to their dietary requirements.

Fish, omega-3 polyunsaturated fatty acids, and mortality from cardiovascular diseases in a nationwide community-based cohort of Japanese men and women the JACC (Japan Collaborative Cohort Study for Evaluation of Cancer Risk) Study.

OBJECTIVES: The objective of our study was to test the hypothesis that fish or omega-3 polyunsaturated fatty acids (PUFA) intakes would be inversely associated with risks of mortality from ischemic heart disease, cardiac arrest, heart failure, stroke, and total cardiovascular disease. BACKGROUND: Data on associations of dietary intake of fish and of omega-3 PUFA with risk of cardiovascular disease among Asian societies have been limited. METHODS: We conducted a prospective study consisting of 57,972 Japanese men and women. Dietary intakes of fish and omega-3 PUFA were determined by food frequency questionnaire, and participants were followed up for 12.7 years. Hazard ratios and 95% confidence intervals were calculated according to quintiles of fish or omega-3 PUFA intake. RESULTS: We observed generally inverse associations of fish and omega-3 PUFA intakes with risks of mortality from heart failure (multivariable hazard ratio [95% confidence interval] for highest versus lowest quintiles = 0.76 [0.53 to 1.09] for fish and 0.58 [0.36 to 0.93] for omega-3 PUFA). Associations with ischemic heart disease or myocardial infarction were relatively weak and not statistically significant after adjustment for potential risk factors. Neither fish nor omega-3 PUFA dietary intake was associated with mortality from total stroke, its subtypes, or cardiac arrest. For mortality from total cardiovascular disease, intakes of fish and omega-3 PUFA were associated with 18% to 19% lower risk. CONCLUSIONS: We found an inverse association between fish and omega-3 PUFA dietary intakes and cardiovascular mortality, especially for heart failure, suggesting a protective effect of fish intake on cardiovascular diseases.

Dietary fiber and risk of colorectal cancer in the Japan collaborative cohort study.

To examine the association of dietary fiber with the risk of colorectal cancer in a population with a high incidence of cancer and a low fiber intake, we analyzed the data from the Japan Collaborative Cohort Study. From 1988 to 1990, 43,115 men and women aged 40 to 79 years completed a questionnaire on dietary and other factors. Intake of dietary fiber was estimated using a food frequency questionnaire. Rate ratios (RR) were computed by fitting proportional hazards models. During the mean follow-up of 7.6 years, 443 colorectal cancer cases were recorded. In all participants, we found a decreasing trend in risk of colorectal cancer with increasing intake of total dietary fiber; the multivariate-adjusted RRs across quartiles were 1.00, 0.96 [95% confidence interval (95% CI), 0.72-1.27], 0.72 (0.53-0.99), and 0.73 (0.51-1.03; P(trend) = 0.028). This trend was exclusively detected for colon cancer: the corresponding RRs were 1.00, 0.90 (95% CI, 0.64-1.26), 0.56 (0.38-0.83), and 0.58 (0.38-0.88; P(trend) = 0.002). The decrease in RRs with increasing intake of dietary fiber was larger in men than in women. No material differences appeared in the strength of associations with the risk between water-soluble and insoluble dietary fiber. For food sources of fiber, bean fiber intake was somewhat inversely correlated with colorectal cancer risk. This prospective study supported potential protective effects of dietary fiber against colorectal cancer, mainly against colon cancer. The role of dietary fiber in the prevention of colorectal cancer seems to remain inconsistent, and further investigations in various populations are warranted. (

The relationship between green tea and total caffeine intake and risk for self-reported type 2 diabetes among Japanese adults.

BACKGROUND: In western populations, coffee consumption is associated with a reduced risk for type 2 diabetes; however, the effect of green, black, and oolong teas is unclear. OBJECTIVE: To examine the relationship between consumption of these beverages and risk for diabetes. DESIGN: Retrospective cohort study. SETTING: 25 communities across Japan. PARTICIPANTS: A total of 17,413 persons (6727 men and 10,686 women; 49% of the original study population) who were 40 to 65 years of age; had no history of type 2 diabetes, cardiovascular disease, or cancer at the baseline lifestyle survey; and completed the 5-year follow-up questionnaire. There was no difference in body mass index levels at baseline between respondents and nonrespondents. MEASUREMENTS: Questionnaire on consumption of coffee; black, green, and oolong teas; and physician-diagnosed diabetes. RESULTS: During the 5-year follow-up, there were 444 self-reported new cases of diabetes in 231 men and 213 women (5-year event rates, 3.4% and 2.0%, respectively). Consumption of green tea and coffee was inversely associated with risk for diabetes after adjustment for age, sex, body mass index, and other risk factors. Multivariable odds ratios for diabetes among participants who frequently drank green tea and coffee (> or =6 cups of green tea per day and > or =3 cups of coffee per day) were 0.67 (95% CI, 0.47 to 0.94) and 0.58 (CI, 0.37 to 0.90), respectively, compared with those who drank less than 1 cup per week. No association was found between consumption of black or oolong teas and the risk for diabetes. Total caffeine intake from these beverages was associated with a 33% reduced risk for diabetes. These inverse associations were more pronounced in women and in overweight men. LIMITATIONS: Diabetes was self-reported, no data were available on consumption of soda, and the follow-up rate was low. CONCLUSIONS: Consumption of green tea, coffee, and total caffeine was associated with a reduced risk for type 2 diabetes.

Dietary intakes of fat and fatty acids and risk of breast cancer: a prospective study in Japan.

To examine the possible association of dietary fat and fatty acids with breast cancer risk in a population with a low total fat intake and a high consumption of fish, we analyzed data from the Japan Collaborative Cohort (JACC) Study. From 1988 to 1990, 26 291 women aged 40-79 years completed a questionnaire on dietary and other factors. Intakes of fat or fatty acids were estimated by using a food frequency questionnaire. Rate ratios (RR) were computed by fitting proportional hazards models. During the mean follow-up of 7.6 years, 129 breast cancer cases were documented. We found no clear association of total fat intake with breast cancer risk; the multivariate-adjusted RR across quartiles were 1.00, 1.29, 0.95, and 0.80 (95% confidence interval [CI] 0.46-1.38). A significant decrease in the risk was detected for the highest quartile of intake compared with the lowest for fish fat and long-chain n-3 fatty acids; the RR were 0.56 (95% CI 0.33-0.94) and 0.50 (0.30-0.85), respectively. A decreasing trend in risk was also suggested with an increasing intake of saturated fatty acids (trend P = 0.066). Among postmenopausal women at baseline, the highest quartile of vegetable fat intake was associated with a 2.08-fold increase in risk (95% CI 1.05-4.13). This prospective study did not support any increase in the risk of breast cancer associated with total or saturated fat intake, but it suggested the protective effects of the long-chain n-3 fatty acids that are abundant in fish.

Reproducibility and validity of a self-administered food frequency questionnaire used in the JACC study.

BACKGROUND: A self-administered questionnaire on dietary habits used in the JACC Study contained a 40-item food frequency questionnaire (FFQ). Although more than 110 thousand subjects enrolled in JACC Study and responded to the FFQ, no validation study has been conducted to date. METHODS: Eighty-five volunteers among the cohort members completed 2 FFQs (FFQs 1&2) and 12-day weighed dietary records (WDR). The interval between the two FFQs was one year. During the one year, the subjects carried out a 3-consecutive-day WDR in each season. We tested the reproducibility by using two FFQs. Also, we tested the validity of the FFQ by using the 12-day WDR as a gold standard. RESULTS: The intake frequencies of the 2 FFQs often agreed, showing the Spearman correlation coefficients ranging from 0.42 (edible wild plants) to 0.86 (coffee). The Spearman correlation coefficients of the energy and nutrient intakes from FFQ2, and that of the 12-day WDR were 0.20(energy) to 0.46 (animal protein, potassium). After adjusting the energy intake, the correlation coefficients showed 0.21(fish fat) to 0.51(animal fat). When classifying the FFQ2 and WDR by quartiles and examining the degree of agreement between the two methods, we obtained its median 30%. CONCLUSIONS: The FFQ is suitable to deal with a large group of subjects. However, since the energy and the amount of nutrient intake from this FFQ can not show the overall dietary intake situation, the subjects' dietary intake should be assessed by categories.