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Reducing sodium (Na) intake is an urgent global challenge, especially in East Asia and high-income Asia-Pacific regions. However, the sources of Na and their effects on urinary Na excretion have not been fully studied. We sought to clarify these sources and their association with urinary Na excretion. We examined four 3-day weighed food records and five 24-h urinary collections from each of 253 participants in Japan, aged 35-80 years, between 2012 and 2013. We compared the levels of Na according to four categories: foods contributing to discretionary or nondiscretionary Na intake, the situation in which dishes were cooked and consumed, food groups and types of cuisine. We also conducted regression analysis in which 24-h urinary Na excretion was a dependent variable and the amounts of food intake in the four categories were independent variables. Levels of Na were the highest in discretionary intake (60.6%) and in home-prepared dishes (84.0%). Of the food groups

Several studies have reported an association between sarcopenia and depression. Their results, however, are inconsistent, partly due to small sample sizes and lack of consideration of important confounders. The present study aimed to cross-sectionally examine this association in community-dwelling people in Japan. This study used baseline data from the Yuzawa cohort study (age ≥ 40 years), with the final analysis population comprising 2,466 participants. A self-administered questionnaire was used to elicit information related to sarcopenia, depressive symptoms, demographic characteristics, anthropometrics, disease history, and lifestyles. Sarcopenia was diagnosed using SARC-F, a validated questionnaire including components of Strength, Assistance in walking, Rising from a chair, Climbing stairs, and Falls. Depressive symptoms were assessed using the 11-item version of the Center for Epidemiologic Studies Depression Scale (CES-D). For depressive symptoms, prevalence ratios (PRs) were calculated, and odds ratio (ORs) were obtained using simple and multiple logistic regression analyses. Mean age of participants was 61.7 years (standard deviation = 11.8), and 10.5% and 34.7% had sarcopenia and depressive symptoms, respectively. Sarcopenic individuals had a significantly higher PR (2.00), unadjusted OR (3.67), and adjusted OR (4.96) compared to non-sarcopenic individuals, with an estimated adjusted PR of 2.7. There was a significant dose-dependent association between SARC-F scores and depressive symptoms in sarcopenic individuals (adjusted P for trend = 0.0028). In conclusion, sarcopenia and depressive symptoms were robustly associated in community-dwelling, middle-aged and older people in Japan. However, the direction of this association is unclear, and a future cohort study will be needed to determine causality.

Recent innovations in information and communication technology have made it possible to assess diet using web-based methods; however, their applicability in the general population remains unclear. Hence, we aimed to examine the applicability of a web-based 24-hour dietary recall (24HR) tool to large-scale epidemiological studies by determining the sampling rate and characteristics of randomly selected participants (partially entire population) from a Japanese cohort study.In total, 5,013 individuals were recruited from a cohort of 21,537 individuals, and 975 agreed to participate in this study. The participants selected either self-administered web-based dietary 24HR (self-administered 24HR) or interviewer-administered telephone-based 24HR (interviewer-administered 24HR) as the method for the dietary assessment and answered questions regarding the acceptability of the system.The response rate of the 975 participants was 19.4%, and approximately 4.5% of the total study population. About half of them chose the self-administered 24HR (46.9%). The median time required for the self-administered and interviewer-administered 24HR was 25 and 27 minutes, respectively. In the self-administered 24HR, older people, regardless of sex, tended to require a longer time, and approximately 60% of the participants rated the ease of use of the system as "somewhat difficult" or "difficult."Characteristics of the participants in this study were not systemically different from those of the entire study population. Improvements in approach for the entering cooking details and the dish name selection may be necessary for better acceptability in order to be accepted as a self-administered 24HR.

Background Due to concerns of carcinogenicity, it is necessary to assess long-term acrylamide exposure in individuals. Whether the available methods of estimating acrylamide intake can indicate long-term exposure remains unknown. We examined variations in the estimated dietary acrylamide intake of the Japanese population. Methods The study included 240 participants aged 40–74 years who were a part of the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT). Twelve-day dietary records (DRs) were collected over a one-year period, and food frequency questionnaires (FFQs) were collected twice during the year. Dietary acrylamide intake was estimated from an acrylamide content database. Within-individual variations and between-individual variations were calculated using the random effects model. A linear regression analysis was performed to identify foods with large between-individual variations. Results The ratios of within-individual variance to between-individual variation were 3.2 for men and 4.3 for women. Days of DRs required to estimate the usual individual intake within 20% of the true mean intake with 95% confidence were 60 days for men and 66 days for women. Coffee/cocoa, potato, and green tea contributed to between-individual variations, in that order, and seven foods contributed to 93% of the between-individual variation. Conclusions Estimating the acrylamide intake using DRs requires an extended data collection period to estimate the intragroup ranking and habitual intake of individuals. Long-term exposure assessments should be based on methods with less potential for measurement errors, such as the use of biomarkers.

Background Income inequality has dramatically increased worldwide, and there is a need to re-evaluate the association between socio-economic status (SES) and depression. Relative contributions of household income and education to depression, as well as their interactions, have not been fully evaluated. This study aimed to examine the association between SES and depressive symptoms in Japanese adults, focusing on interactions between education and household income levels. Methods This cross-sectional study used data from baseline surveys of two cohort studies. Participants were 38,499 community-dwelling people aged 40–74 years who participated in baseline surveys of the Murakami cohort study (2011–2012) and Uonuma cohort study (2012–2015) conducted in Niigata Prefecture, Japan. Information regarding marital status, education level, household income, occupation, activities of daily living (ADL), and history of cancer, myocardial infarction, stroke, and diabetes was obtained using a self-administered questionnaire. Depressive symptoms were examined using the Center for Epidemiologic Studies Depression Scale (CES-D). Logistic regression analysis was used to obtain odds ratios (ORs). Covariates included age, sex, marital status, education, household income, occupation, ADL, and disease history. Results Individuals with higher education levels had lower ORs (adjusted P for trend = 0.0007) for depressive symptoms, independently of household income level. The OR of the university-or-higher group was significantly lower than that of the junior high school group (adjusted OR = 0.79). Individuals with lower household income levels had higher ORs (adjusted P for trend Conclusions Both education and household income levels are independently associated with the prevalence of depressive symptoms, with household income levels showing a more robust association with depressive symptoms than education levels. This suggests that a high household income level may offset the risk of depressive symptoms from having a low education level.

Background Although metabolic syndrome traits are risk factors for chronic kidney disease, few studies have examined their association with urinary biomarkers. Methods Urinary biomarkers, including A-megalin, C-megalin, podocalyxin, albumin, α1-microglobulin, β2-microglobulin, and N-acetyl-β-D-glucosaminidase, were cross-sectionally assessed in 347 individuals (52.7% men) with a urine albumin-to-creatinine ratio (ACR) Results Participants had a mean body mass index, estimated glomerular filtration rate (eGFR), and median ACR of 23.0 kg/m2, 74.8 mL/min/1.73 m2, and 7.5 mg/g, respectively. In age- and sex-adjusted logistic regression analysis, A-megalin and albumin were significantly associated with the clustering number of metabolic syndrome traits (3 or more). After further adjustment with eGFR, higher quartiles of A-megalin and albumin were each independently associated with the clustering number of metabolic syndrome traits (adjusted odds ratio for A-megalin: 1.30 per quartile, 95% CI 1.03–1.64; albumin: 1.42 per quartile, 95% CI 1.12–1.79). Conclusions Both urinary A-megalin and albumin are associated with the clustering number of metabolic syndrome traits. Further research on urinary A-megalin is warranted to examine its role as a potential marker of kidney damage from metabolic risk factors.

Positive associations between vitamin D levels and hand grip strength have been reported worldwide, but the results are not consistent and few studies on East Asian populations have been published. The aim of this study was to determine whether such an association is present in a community-dwelling Japanese population, including elderly and middle-aged individuals. This study used a cross-sectional design. Participants were 492 community-dwelling individuals aged ≥ 40 years living in Yuzawa Town, Japan. The health check examination was conducted in 2015, and serum 25-hydroxyvitamin D [25(OH)D, an index of vitamin D levels], and hand grip strength were measured. Covariates were serum albumin concentration, body mass index, and physical activity level. The associations of serum 25(OH)D concentrations with hand grip strength and low grip strength (

Physical activity is associated with subjective well-being. In rural communities, however, physical activity may be affected by environmental factors (e.g., nature and socioecological factors). We examined the association of two physical activities in rural life (farming activity and snow removal) with subjective well-being in terms of happiness and ikigai (a Japanese word meaning purpose in life). In this cross-sectional study, we analysed data collected from community-dwelling adults aged ≥ 40 years in the 2012–2014 survey of the Uonuma cohort study, Niigata, Japan. Happiness (n = 31,848) and ikigai (n = 31,785) were evaluated with respect to farming activity from May through November and snow removal from December through April by using an ordinal logistic regression model with adjustments for potential confounders. The analyses were conducted in 2019. Among the participants who reported some farming or snow-removal time, median farming and snow-removal time (minutes per day) was 90.0 and 64.3 for men and 85.7 and 51.4 for women, respectively. Ordinal logistic regression analysis showed that longer time farming was associated with greater happiness and ikigai in men (adjusted odds ratio for first vs. fourth quartile: happiness = 1.17, 95% confidence interval [CI] = 1.01, 1.35; ikigai = 1.29, 95% CI = 1.10, 1.50), and also in women (adjusted odds ratio for first vs. fourth quartile: happiness = 1.17, 95% CI = 1.001, 1.36; ikigai = 1.42, 95% CI = 1.20, 1.67). More snow-removal time was inversely associated with happiness and with ikigai in women only (adjusted odds ratio for first vs. fourth quartile: happiness = 0.75, 95% CI = 0.67, 0.85; ikigai = 0.78, 95% CI = 0.69, 0.88). Our findings showed that physical activity in rural life was associated with happiness and with ikigai, and gender differences were observed in their associations with more snow-removal time. These results may be useful in helping to identify people in rural communities who are vulnerable in terms of psychological well-being.

Background/objectives Isothiocyanate (ITC) is formed via the hydrolysis of glucosinolates by myrosinase, found in cruciferous vegetables. Although myrosinase is inactivated by the cooking process, no studies have incorporated the effect of cooking into the estimation of dietary ITC intake or evaluated the validity. We evaluated the validity of dietary ITC intake estimated from a food frequency questionnaire (FFQ), and urinary ITC levels using 24 h urine samples or a WFR (weighed food record), and evaluated the reproducibility of dietary ITC in two FFQs administered at an interval of 1-year. Subjects/methods The JPHC-NEXT Protocol Area included a total of 255 middle-aged participants across Japan. We calculated dietary ITC intake from WFR and two FFQs by assuming that cooked cruciferous vegetables contain zero ITC. Urinary ITC excretion was measured at two points during summer and winter. The validity and reproducibility of dietary ITC intake estimated by FFQ were assessed using Spearman's correlation coefficients. Results Although we observed a moderate correlation between dietary ITC intake derived from a 12-day WFR and urinary ITC excretion, notwithstanding the cooking process, the correlation between dietary ITC intake estimated by FFQ and mean urinary ITC excretion was low. However, the correlation was improved when we compared urinary ITC excretion and a 3-day WFR or FFQ collected during winter. Our FFQ showed good reproducibility. Conclusion Although seasonality is a critical factor, dietary ITC intake estimated using an FFQ showed moderate validity and reproducibility and can be used in future epidemiological studies.

Background Kidney dysfunction is associated with sarcopenia. Estimated glomerular filtration rate based on cystatin C (eGFRcys), an alternative to creatinine-based measures of kidney function eGFR, is not affected by muscle mass. Given that the association of eGFRcys with muscle weakness would be limited, we examined the association in older adults with normal or compromised kidney function. Methods This cross-sectional study involved 594 community-dwelling Japanese adults aged ≥40 years living in Yuzawa, Japan. Serum creatinine, cystatin C, and handgrip strength were concurrently measured at a health-check examination in 2015. eGFR was calculated according to the equation developed for the Japanese population using creatinine and cystatin C. Associations of eGFRcys and eGFRcreat with low grip strength (men, Results Participants (mean age, 74.9 years) included 319 women and 109 individuals with low grip strength. Mean eGFRcys was 75.2 (SD 18.6) mL/min/1.73 m2. Pearson’s correlation coefficients of handgrip strength for eGFRcys and eGFRcreat were 0.19 (p < .001) and −0.04 (p = .281), respectively. Multivariate logistic regression analysis showed the adjusted odds ratio (OR) of low grip strength for the highest versus lowest quartile of eGFRcys value was 2.46 (95% confidence interval, 1.03–5.86; p-trend = .026); whereas the comparative adjusted OR for eGFRcreat was 0.67 (95% confidence interval, 0.34–1.32). Conclusions Low kidney function as assessed by eGFRcys was associated with muscle weakness in community-dwelling Japanese older adults.

Additional file 2 : Table S2. Contribution of food groups to total acrylamide intake estimated using dietary records.

Additional file 1 : Table S1. Evaluation of the relationships between dietary records, food frequency questionnaires used for the validation analysis, and food frequency questionnaires.

The COVID-19 pandemic might affect many aspects of the community and a range of psychiatric risk factors due to life changes, including people’s behaviors and perceptions. In this study, we aim to identify specific life changes that correlate with psychological distress within the social context of the COVID-19 pandemic in Japan. In July 2020, workers (company employees and civil servants) in Japan were recruited from local institutions that had not had any confirmed COVID-19 cases as well as neighborhoods that had only a few cases. Participants completed a COVID-19 mental health survey (N = 609; 66.9% male). Psychological distress was identified based on Kessler-6 scores (≥13). Life changes were assessed by an open-ended question about life changes in participants and their family, workplace, and community due to the COVID-19 pandemic. A convergent mixed-method approach was used to compare the context of perceived life changes in participants with psychological distress and those without. As a result, 8.9% of participants had psychological distress, and sex and age categories were different between those with psychological distress and those without. Among the participants who responded to the open-ended question, the biggest life change was “staying at home,” and the next biggest life changes were “event cancellations” and “increased workload” in participants with psychological distress, and “no changes” and “mask-wearing” in those without psychological distress, respectively. Regarding emotional/perceptual changes, “stress,” “fear,” and “anger” were more frequently reported by participants with psychological distress than those without (P

Background Online dietary assessment tools offer advantages over printed questionnaires, such as the automatic and direct data storage of answers, and have the potential to become valuable research methods. We developed an online survey system (web-FFQ) for the existing printed FFQ used in the JPHC-NEXT protocol, the platform of a large-scale genetic cohort study. Here, we examined the validity of ranking individuals according to dietary intake using this web-FFQ and its usability compared with the printed questionnaire (print-FFQ) for combined usage. Methods We included 237 men and women aged 40–74 years from five areas specified in the JPHC-NEXT protocol. From 2012 to 2013, participants were asked to provide 12-day weighed food records (12d-WFR) as the reference intake and to respond to the print- and web-FFQs. Spearman's correlation coefficients (CCs) between estimates using the web-FFQ and 12d-WFR were calculated. Cross-classification of intakes was compared with those using the print-FFQ. Results Most participants (83%) answered that completing the web-FFQ was comparable to or easier than completing the printed questionnaire. The median value of CCs across energy and 53 nutrients for men and women was 0.47 (range, 0.10–0.86) and 0.46 (range, 0.16–0.69), respectively. CCs for individual nutrient intakes were closely similar to those based on the print-FFQ, irrespective of response location. Cross-classification by quintile of intake based on two FFQs was reasonably accurate for many nutrients and food groups. Conclusion This online survey system is a reasonably valid measure for ranking individuals by intake for many nutrients, like the printed FFQ. Mixing of two FFQs for exposure assessments in epidemiological studies appears acceptable., Highlights • We examined validity of intakes using web-FFQ compared with those for the print-FFQ. • Moderate validities were shown for many estimates based on the web-FFQ. • These CCs (with 12-day food record) were closely similar to those of the print-FFQ. • Good concordance between individual rankings were obtained with the two FFQs. • Mixing of these FFQs for diet survey in epidemiological studies appears acceptable.

The aim of this study was to examine the reproducibility of a self-administered food frequency questionnaire (FFQ) originally developed for the Japan Public Health Center-Based Prospective Study (JPHC study) and modified for use in the Next Generation (JPHC-NEXT) study.Participants included 98 men and 142 women aged 40-74 years from the five areas included in the JPHCNEXT protocol. In November 2012, participants were recruited and asked to complete the first nutrition survey. The second nutrition survey was completed after 1 year.We estimated daily energy as well as 53 nutrient and 29 food group intakes using the FFQ. To assess reproducibility, we calculated Spearman correlation coefficients between both FFQs, which showed mostly intermediate-to-high values. Median (range) correlation coefficients and quartile distribution in the same and adjacent categories for energy-adjusted nutrient intakes were 0.55 (0.42-0.84) and 84.7% (76.5%-98.0%) in men and 0.54 (0.35-0.80) and 84.5% (76.1%-94.4%) in women. The respective values for energy-adjusted food group intakes in men and women were also mostly intermediate to high: 0.54 (0.39-0.79) and 83.7% (75.5%-90.8%) in men and 0.57 (0.40-0.83) and 84.5% (77.5%-93.7%) in women.The FFQ developed for the JPHC-NEXT study has reasonable reproducibility. Because this FFQ has also been validated in a previous study, it can be considered a useful dietary assessment tool to examine associations between dietary consumption and lifestyle-related diseases.

Background Longitudinal epidemiological studies require both the periodic update of intake information via repeated dietary survey and the minimization of subject burden in responding to questionnaires. We developed a 66-item Food Frequency Questionnaire (short-FFQ) for the Japan Public Health Center-based prospective Study for the Next Generation (JPHC-NEXT) follow-up survey using major foods from the FFQ developed for the original JPHC Study. For the JPHC-NEXT baseline survey, we used a larger 172-item FFQ (long-FFQ), which was also derived from the JPHC-FFQ. We compared the validity of ranking individuals by levels of dietary consumption by these FFQs among residents of selected JPHC-NEXT study areas. Methods From 2012 to 2013, 240 men and women aged 40-74 years from five areas in the JPHC-NEXT protocol were asked to respond to the long-FFQ and provide 12-day weighed food records (WFR) as reference; 228 also completed the short-FFQ. Spearman's correlation coefficients (CCs) between estimates from the FFQs and WFR were calculated and corrected for intra-individual variation of the WFR. Results Median CC values for energy and 53 nutrients for the short-FFQ for men and women were 0.46 and 0.44, respectively. Respective values for the long-FFQ were 0.50 and 0.43. Compared with the long-FFQ, cross-classification into exact plus adjacent quintiles with the short-FFQ ranged from 68% to 91% in men and 58% to 85% in women. Conclusions Similar to the long-FFQ, the short-FFQ provided reasonably valid measures for ranking middle-aged and elderly Japanese for many nutrients and food groups. The short-FFQ can be used in follow-up surveys in prospective cohort studies aimed at updating diet rank information.

Antitumor immunity is augmented by cytotoxic lymphodepletion therapies. Adoptively transferred naive and effector T cells proliferate extensively and show enhanced antitumor effects in lymphopenic recipients. Although the impact of lymphodepletion on transferred donor T cells has been well evaluated, its influence on recipient T cells is largely unknown. The current study demonstrates that both regulatory T cells (Tregs) and effector CD8+ T cells from lymphopenic recipients play critical roles in the development of antitumor immunity after lymphodepletion. Cyclophosphamide (CPA) treatment depleted lymphocytes more efficiently than other cytotoxic agents; however, the percentage of CD4+CD25+ Foxp3+ Tregs was significantly increased in CPA-treated lymphopenic mice. Depletion of these chemoresistant Tregs following CPA treatment and transfer of naive CD4+ T cells augmented the antitumor immunity and significantly suppressed tumor progression. Further analyses revealed that recipient CD8+ T cells were responsible for this augmentation. Using Rag2−/− mice or depletion of recipient CD8+ T cells after CPA treatment abrogated the augmentation of antitumor effects in CPA-treated reconstituted mice. The transfer of donor CD4+ T cells enhanced the proliferation of CD8+ T cells and the priming of tumor-specific CD8+ T cells originating from the lymphopenic recipients. These results highlight the importance of the recipient cells surviving cytotoxic regimens in cancer immunotherapies.

Objective methods such as the monitoring of salt concentrations in home-prepared dishes may be effective in reducing salt intake. We investigated the effect of monitoring the salt concentration of home-prepared dishes (Monitoring) on salt reduction and change in taste threshold, and the effect of the simultaneous use of low-sodium seasonings (Seasoning) to compare the effect of Monitoring with the conventional method. We conducted a double-blind randomized controlled study using a 2 × 2 factorial design with two interventions. A total of 50 participants (40–75 years-old) were recruited among residents of Niigata Prefecture, a high sodium-consuming population in Japan, then randomly allocated to four groups. After excluding participants with incomplete urine collection, change in salt intake was evaluated using 24-hour urinary excretion as a surrogate of intake for 43 participants. Change in taste threshold was evaluated in 48 participants after excluding those with incomplete threshold measurement. The Monitoring intervention group showed a significant decrease in sodium intake (−777 mg/24 h), whereas the decrease in the Seasoning intervention group was not significant (−413 mg/24 h). Sodium intake did not statistically differ between the intervention and control groups (−1011 mg/24 h and −283 mg/24 h for Monitoring and Seasoning, respectively). The changes in taste threshold measurement were very small and did not markedly differ between groups. Monitoring the salt concentration of dishes had a potentially stronger salt-reducing effect than the use of low-sodium seasonings, a conventional method. Confirmation requires additional study with a larger sample size.

Objective: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or refractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of irinotecan as a single agent. This study was designed to determine the antitumor activity, toxicity, and survival in previously treated SCLC patients. Methods: Previously treated SCLC patients with at least one platinum-based regimen received irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression. The assessment of the response rate was the primary endpoint. Results: Thirty patients were enrolled, with an objective response rate of 41.3% (95% confidence interval [CI] 25.5–59.3), and a disease control rate of 69%. Median progression-free and overall survival was 4.1 months (95% CI, 2.2–5.4) and 10.4 months (95% CI, 8.1–14), respectively. The grade 3/4 hematological toxicities were neutropenia (36.7%), thrombocytopenia (3.3%), anemia (13.3%), and febrile neutropenia (6.6%). There were no grade 4 nonhematological toxicities. Frequent grade 3 nonhematological toxicities included diarrhea (10%), anorexia (6.6%), and hyponatremia (6.6%). Conclusions: This phase II study showed a high objective response rate and long survival. Irinotecan monotherapy schedule used was well tolerated, and could be an active treatment option for these patients.

Background Although open-ended dietary assessment methods, such as weighed food records (WFRs), are generally considered to be comparable, differences between procedures may influence outcome when WFRs are conducted independently. In this paper, we assess the procedures of WFRs in two studies to describe their dietary assessment procedures and compare the subsequent outcomes. Methods WFRs of 12 days (3 days for four seasons) were conducted as reference methods for intake data, in accordance with the study protocol, among a subsample of participants of two large cohort studies. We compared the WFR procedures descriptively. We also compared some dietary intake variables, such as the frequency of foods and dishes and contributing foods, to determine whether there were differences in the portion size distribution and intra- and inter-individual variation in nutrient intakes caused by the difference in procedures. Results General procedures of the dietary records were conducted in accordance with the National Health and Nutrition Survey and were the same for both studies. Differences were seen in 1) selection of multiple days (non-consecutive days versus consecutive days); and 2) survey sheet recording method (individual versus family participation). However, the foods contributing to intake of energy and selected nutrients, the portion size distribution, and intra- and inter-individual variation in nutrient intakes were similar between the two studies. Conclusion Our comparison of WFR procedures in two independent studies revealed several differences. Notwithstanding these procedural differences, however, the subsequent outcomes were similar., Highlights • The procedures of weighed food records in two independent studies were compared. • General procedures of the dietary records were the mostly same for both studies. • Differences were found in the setting of survey days and the survey sheet. • Setting of survey days did not influence the intra- and inter-individual variation. • Differences in survey sheets did not influence the portion sizes.

Cisplatin is an anticancer drug widely used in the treatment of many cancers, including lung cancers. Although cisplatin causes various types of adverse events, the main dose-limiting toxicity of cisplatin is nephrotoxicity. Megalin is an endocytic receptor expressed at the apical membranes of proximal tubules. We previously demonstrated that cisplatin was reabsorbed through megalin and caused kidney injury. Cilastatin, an inhibitor of renal dehydropeptidase-I and used with imipenem, blocked the binding of cisplatin to megalin and reduced the nephrotoxicity induced by cisplatin. In the current study, we precisely evaluated the effect of cilastatin-mediated suppression of cisplatin nephrotoxicity to safely enhance the antitumor activity of cisplatin. BALB/c mice were administrated cisplatin with or without cilastatin. Tubular dilation or atrophy, brush border loss, tubular cell lysis and cast formation were observed in mice treated with cisplatin alone. However, these kidney injuries were decreased or disappeared in mice treated with cisplatin and cilastatin. Cilastatin also decreased the urinary levels of N-acetyl-β-D-glucosaminidase and neutrophil gelatinase-associated lipocalin, proximal tubular injury markers. Next, SCID mice were injected s.c. with A549, a human lung cancer cell line, and treated with cisplatin with or without cilastatin. Cilastatin did not affect the antitumor activity of cilastatin. Notably, A549 did not express megalin. Combined with cilastatin, the mice were successfully treated with 1.5 times dose of cisplatin with enhanced antitumor effects of cisplatin but without nephrotoxicity. In conclusion, cilastatin effectively suppressed nephrotoxicity of cisplatin by blocking the binding of cisplatin to megalin. These findings indicated that we could administer cisplatin into cancer patients without nephrotoxicity if we used cilastatin. Moreover, we might increase the dose of cisplatin and improve the outcome of cancer patients. Citation Format: Masashi Arita, Satoshi Watanabe, Nobumasa Aoki, Miho Takahashi, Satoshi Shoji, Koichiro Nozaki, Kosuke Ichikawa, Rie Kondo, Shoji Kuwahara, Junta Tanaka, Toshiyuki Koya, Akihiko Saito, Toshiaki Kikuchi. Combination therapy of cisplatin with cilastatin enables to increase the dose of cisplatin for enhancing its antitumor effect by suppressing nephrotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 304.

Chemotherapy-induced nausea and vomiting (CINV) are some of the most problematic symptoms for cancer patients. Triplet therapy consisting of a 5HT3 receptor antagonist, aprepitant, and dexamethasone is a guideline-recommended antiemetic prophylaxis for highly emetogenic chemotherapy (HEC). The efficacy and safety of triplet therapy using a 0.75-mg dose of palonosetron have not yet been investigated. We performed a prospective phase II study using triplet antiemetic therapy with 0.75 mg of palonosetron. Chemotherapy-naive lung cancer patients scheduled to receive HEC were enrolled. The eligible patients were pretreated with antiemetic therapy consisting of the intravenous administration of 0.75 mg of palonosetron, and 9.9 mg of dexamethasone and the oral administration of 125 mg of aprepitant on day 1, followed by the oral administration of 80 mg of aprepitant on days 2–3 and the oral administration of 8 mg of dexamethasone on days 2–4. The primary endpoint was the complete response rate (the CR rate; no vomiting and no rescue medication) during the overall phase (0–120 h). The efficacy analysis was performed in 63 patients. The CR rates during the overall, acute and delayed phases were 81.0, 96.8, and 81.0 %, respectively. The no nausea and no significant nausea rate during the overall phase were 54.0 and 66.7 %, respectively. The most common adverse event was grade 1 or 2 constipation. Triplet antiemetic therapy using a 0.75-mg dose of palonosetron shows a promising antiemetic effect in preventing CINV in lung cancer patients receiving HEC.

Chemotherapy hydration protocol used in this study. Cisplatin and other anticancer drugs were administrated with 3850Â ml of hydration, magnesium sulfate (40Â mEq) and mannitol (300Â ml). (PPTX 79Â kb)

In recent years, cancer immunotherapy has been emerged as a major therapeutic modality in several malignancies. Immune-checkpoint inhibitors (ICI), such as anti-programmed death 1 (PD-1) / programmed death -ligand 1 (PD-L1) antibodies and anti-cytotoxic-T-lymphocyte associated protein-4 (CTLA-4) antibodies have demonstrated durable antitumor effects. In phase III trials, PD-1 / PD-L1 blockade therapies have shown better survival benefits compared to standard chemotherapies in patients with non-small lung cancer. However, the mechanisms of anti-PD-1 treatments have not been fully understood. Immune-checkpoint molecules play an important role to regulate autoimmune reactions by T cells. Thus, PD-1 / PD-L1 blockade therapy and anti-CTLA-4 treatment can cause immune-related adverse events including interstitial-lung disease (ILD). ILD is a serious and life threatening adverse event. On the other hand, better outcomes have been reported in lung cancer patients who developed ILD during anti-PD-1 treatment. These findings suggest that effector T cells attack similar antigens presented on both tumor cells and normal lung tissues. In order to elucidate the mechanisms of development of ILD and augmentation of anti-tumor effect by ICI, we established mouse model of ILD. In this study, C57BL/6J mice were injected intravenously with MCA 205 fibrosarcoma or B16 melanoma to make lung metastases. These mice were administered intraperitoneally with anti-PD-1 antibodies and/or anti-CTLA-4 antibodies. EGFR-TKI-ILD mice, which have been previously reported elsewhere, were also established to compare the pathological findings with those of ICI-induced ILD. Also, we administered lipopolysaccharide (LPS) intratracheally before injection of ICIs to test whether lung inflammation exacerbate ILD caused by ICIs. The infiltration of inflammatory cells and thickening of interstitial wall in the lung tissue were observed in mice treated with the combination of anti-CTLA-4 antibodies and anti-PD-1 antibodies. The antitumor effects of anti-PD-1 treatment against lung metastases were enhanced in mice which had ILD caused by anti-PD-1 antibodies and injury of bronchial epithelium. High density of infiltration of lymphocytes in tumor tissues was observed in ILD mice. Further study is warranted to determine effector cells which are responsible for establishment of ILD and augmentation of antitumor effects. Citation Format: Masashi Arita, Satoshi Watanabe, Naohiro Yanagimura, Yuko Mishina, Miyuki Sato, Satoshi Shoji, Kosuke Ichikawa, Rie Kondo, Junta Tanaka, Takuro Sakagami, Toshiyuki Koya, Toshiaki Kikuchi. Antitumor effects are augmented in mouse models of interstitial-lung disease caused by immune-checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2717.