Association of longitudinal pet ownership with wheezing in 3-year-old children using the distributed lag model: the Japan Environment and Children's Study.

BACKGROUND: Time-varying exposures like pet ownership pose challenges for identifying critical windows due to multicollinearity when modeled simultaneously. The Distributed Lag Model (DLM) estimates critical windows for time-varying exposures, which are mainly continuous variables. However, applying complex functions such as high-order splines and nonlinear functions within DLMs may not be suitable for situations with limited time points or binary exposure, such as in questionnaire surveys. OBJECTIVES: (1) We examined the estimation performance of a simple DLM with fractional polynomial function for time-varying binary exposures through simulation experiments. (2) We evaluated the impact of pet ownership on childhood wheezing onset and estimate critical windows. METHODS: (1) We compared logistic regression including time-varying exposure in separate models, in one model simultaneously, and using DLM. For evaluation, we employed bias, empirical standard error (EmpSE), and mean squared error (MSE). (2) The Japan Environment and Children's Study (JECS) is a prospective birth cohort study of approximately 100,000 parent-child pairs, registered across Japan from 2011 to 2014. We applied DLM to the JECS data up to age 3. The estimated odds ratios (OR) were considered to be within critical windows when they were significant at the 5% level. RESULTS: (1) DLM and the separate model exhibited lower bias compared to the simultaneously model. Additionally, both DLM and the simultaneously model demonstrated lower EmpSEs than the separate model. In all scenarios, DLM had lower MSEs than the other methods. Specifically, where critical windows is clearly present and exposure correlation is high, DLM showed MSEs about 1/2 to 1/200 of those of other models. (2) Application of DLM to the JECS data showed that, unlike other models, a significant exposure effect was observed only between the ages of 0 and 6 months. During that periods, the highest ORs were 1.07 (95% confidence interval, 1.01 to 1.14) , observed between the ages of 2 and 5 months. CONCLUSIONS: (1) A simple DLM improves the accuracy of exposure effect and critical windows estimation. (2) 0-6 months may be the critical windows for the effect of pet ownership on the wheezing onset at 3 years.

Goodness-of-fit tests for modified Poisson regression possibly producing fitted values exceeding one in binary outcome analysis.

Modified Poisson regression, which estimates the regression parameters in the log-binomial regression model using the Poisson quasi-likelihood estimating equation and robust variance, is a useful tool for estimating the adjusted risk and prevalence ratio in binary outcome analysis. Although several goodness-of-fit tests have been developed for other binary regressions, few goodness-of-fit tests are available for modified Poisson regression. In this study, we proposed several goodness-of-fit tests for modified Poisson regression, including the modified Hosmer-Lemeshow test with empirical variance, Tsiatis test, normalized Pearson chi-square tests with binomial variance and Poisson variance, and normalized residual sum of squares test. The original Hosmer-Lemeshow test and normalized Pearson chi-square test with binomial variance are inappropriate for the modified Poisson regression, which can produce a fitted value exceeding 1 owing to the unconstrained parameter space. A simulation study revealed that the normalized residual sum of squares test performed well regarding the type I error probability and the power for a wrong link function. We applied the proposed goodness-of-fit tests to the analysis of cross-sectional data of patients with cancer. We recommend the normalized residual sum of squares test as a goodness-of-fit test in the modified Poisson regression.

Estimation of the causal effects of time-varying treatments in nested case-control studies using marginal structural Cox models.

When estimating the causal effects of time-varying treatments on survival in nested case-control (NCC) studies, marginal structural Cox models (Cox-MSMs) with inverse probability weights (IPWs) are a natural approach. However, calculating IPWs from the cases and controls is difficult because they are not random samples from the full cohort, and the number of subjects may be insufficient for calculation. To overcome these difficulties, we propose a method for calculating IPWs to fit Cox-MSMs to NCC sampling data. We estimate the IPWs using a pseudo-likelihood estimation method with an inverse probability of sampling weight using NCC samples, and additional samples of subjects who experience treatment changes and subjects whose follow-up is censored are required to calculate the weights. Our method only requires covariate histories for the samples. The confidence intervals are calculated from the robust variance estimator for the NCC sampling data. We also derive the asymptotic properties of the estimator of Cox-MSM under NCC sampling. The proposed methods will allow researchers to apply several case-control matching methods to improve statistical efficiency. A simulation study was conducted to evaluate the finite sample performance of the proposed method. We also applied our method to a motivating pharmacoepidemiological study examining the effect of statins on the incidence of coronary heart disease. The proposed method may be useful for estimating the causal effects of time-varying treatments in NCC studies.

Comparison of the Effectiveness of Vedolizumab and Ustekinumab in Crohn's Disease Patients Who Failed Anti-tumor Necrosis Factor-α Treatment in Japan: An Observational Study Utilizing Claims Database.

This study aimed to investigate whether the approved sequence of vedolizumab and ustekinumab impacts the results of previous observational studies conducted in the European Union (EU), comparing the effectiveness of these drugs in Crohn's disease (CD) patients who failed anti-tumor necrosis factor-α (TNFα) treatment. We conducted this study in Japan, where the approved sequence of drugs is different from that of the EU. We extracted 256 patients diagnosed with CD, who had a history of anti-TNFα treatment and were prescribed either vedolizumab or ustekinumab, from JMDC claims database. The patients' backgrounds were adjusted by inverse probability of treatment weighting using propensity score. The primary outcome was treatment persistence. Secondary outcomes were a steroid-free period, time to hospitalization, and time to CD-related surgery. The hazard ratios (HR) for survival times were estimated using the Cox proportional hazard model. The treatment persistence (primary endpoint) was significantly longer for ustekinumab than vedolizumab (HR, 0.32; 95% confidence interval (CI), 0.15-0.72). The results of the secondary endpoints were as follows: steroid-free period (HR, 0.38; 95% CI, 0.10-1.48), time to hospitalization (HR, 1.07; 95% CI, 0.60-1.91), or time to CD-related surgery (HR, 0.33; 95% CI, 0.11-0.97). There were no outcomes indicating the superiority of vedolizumab. Our findings suggest that ustekinumab is a more effective treatment option than vedolizumab for CD patients who failed to anti-TNFα treatment, and this finding remains consistent across both Japan and the EU.

Gastric cancer detection rates using GI endoscopy with serologic risk stratification: A randomized controlled trial.

BACKGROUND AND AIMS: Efforts have been made to develop an endoscopic screening system incorporating serologic gastric cancer (GC) risk stratification (ABC classification) alongside annual population-based GC screening using barium. We conducted a randomized controlled trial (RCT) to compare GC detection rates between the Ba-Endo group, which underwent annual barium tests for primary screening followed by detailed endoscopic examinations, and the ABC-Endo group, where endoscopy intervals were determined based on individual gastric cancer risk in the ABC classification. METHODS: In total, 1206 individuals from Yurihonjo and Nikaho City, Akita Prefecture, were randomized through the minimization method using sex and age as allocation factors. The intervention study was conducted for both groups over 5 years. The Ba-Endo group received annual barium tests, and the ABC-Endo group underwent EGD at different intervals: group A, EGD only at entry; group B, EGD once every 3 years; group C, EGD once every 2 years; and group D, EGD every year. RESULTS: There were 24 detected GC lesions, with a GC detection rate of 1.9%. GC detection rates in the Ba-Endo and ABC-Endo groups were 2.0% and 1.8%, respectively, with no significant differences between groups (P = 1.0). However, the rate of GC cured by endoscopic resection alone was 41.6% in the Ba-Endo group and was significantly higher at 90.9% in the ABC-Endo group (P = .02). CONCLUSIONS: There were no differences between the Ba-Endo and ABC-Endo groups in GC detection rates. However, the rate of detected GCs that could be cured by endoscopic resection alone was significantly higher in the ABC-Endo group. (Clinical trial registration number: UMIN000005962.).

Randomized controlled trial comparing the costs of gastric cancer screening systems between serological risk-based upper gastrointestinal endoscopy and the existing barium photofluorography: gastric cancer screening labeled by serum examination in place of aged gastric cancer organized screening systems (GALAPAGOS study).

BACKGROUND: Although the risk of gastric cancer can be stratified according to Helicobacter pylori (H. pylori) IgG antibody titer and pepsinogen levels (ABC classification), a population-based gastric cancer screening system combining serological tests and endoscopy has not been introduced. This study aimed to compare the total testing cost per participant between the ABC classification method and the existing protocol. METHODS: Using the minimization method with sex and age as allocation factors, 1206 participants were randomly assigned to the following two methods for a 5-year intervention: barium photofluorography as primary examination followed by detailed examination with upper gastrointestinal endoscopy (Ba-Endo) and risk-based upper gastrointestinal endoscopy by ABC classification (ABC-Endo). The primary endpoint was the total testing cost per participant over a 5-year period. The secondary endpoint was the expense required to detect one gastric cancer. RESULTS: The total testing cost per participant was 39,711 yen in Ba-Endo (604 participants) and 45,227 yen in ABC-Endo (602 participants), with the latter being significantly higher (p < 0.001). During the intervention period, gastric cancer was found in 11 and eight participants in Ba-Endo and ABC-Endo, respectively. The expenses required to detect one gastric cancer were 2,240,931 yen in Ba-Endo and 3,486,662 yen in ABC-Endo. CONCLUSIONS: The testing cost per participant turned out to be higher in the ABC-Endo group than in the Ba-Endo group. This superiority trial, based on the hypothesis that the cost of testing is lower for ABC-Endo than for Ba-Endo, was rejected.

Angiotensin II Receptor Blockers Cause Changes in Prostate-specific Antigen Levels: A Retrospective Cohort Study.

BACKGROUND/AIM: We previously reported a decrease in prostate-specific antigen (PSA) levels in patients with castration-resistant prostate cancer treated with angiotensin II receptor blockers (ARBs). However, no studies have reported the effect of ARBs on PSA variability in patients without a history of prostate cancer. Therefore, we conducted a population-based, retrospective study to determine whether ARBs have an inhibitory effect on elevated PSA levels in Japanese patients without a history of prostate cancer. PATIENTS AND METHODS: This study was conducted using a large-scale Japanese claim database, including male patients aged ≥60 years who had two or more PSA measurements with an interval between measurements of 3 months to 2 years between April 2008 and June 2019. Patients who had been prescribed ARBs were grouped into the ARB group, and those who were prescribed antihypertensive drugs other than ARBs were grouped into the non-ARB group. We compared the proportions of patients with second PSA levels greater than the first. The numbers of eligible patients in the ARB and non-ARB groups were 777 and 527, respectively. RESULTS: Multivariate logistic regression analysis revealed that the proportion of patients with elevated PSA levels was significantly lower in the ARB group than in the non-ARB group (adjusted odds ratio=0.80, 95% confidence interval=0.64-0.99, p=0.047). CONCLUSION: ARBs may suppress elevated PSA levels in patients without a history of prostate cancer. This contributes to the prevention of prostate cancer.

Association of PSA variability with prostate cancer development using large-scale medical information data: a retrospective cohort study.

BACKGROUND: Prostate cancer is one of the most common cancers among men worldwide and the fourth most common cause of death. The number of prostate cancer cases and deaths is increasing every year because of population aging. This study aimed to clarify the risk of developing prostate cancer due to fluctuations in Prostate Specific Antigen (PSA) levels in patients without a history of prostate cancer using large medical information data. RESULTS: This retrospective cohort included 1707 male patients aged 60 years or older who had a PSA level measurement date (2-PSA) within 3 months or more and 2 years from the first PSA level measurement date (1-PSA) in the database between 2008 and 2019. We subtracted 1-PSA from 2-PSA and designated patients with a higher 2-PSA than 1-PSA to the "up" group (n = 967) and patients with a lower 2-PSA than 1-PSA to the "down" group (n = 740). By using Cox proportional hazards model, a significant increase in prostate cancer risk was observed in the up group compared with the down group (adjusted hazard ratio [HR] = 1.82, 95% confidence interval [CI] = 1.21-2.72; adjusted for patient background factors). Subgroup analysis showed that patients with PSA levels < 4 ng/mL had a significantly increased risk of developing prostate cancer if the next PSA level increases by approximately 20% (adjusted HR = 2.94, 95% CI = 1.14-7.58), and patients with PSA levels of 4 ng/mL or higher if the next PSA level is decreased by approximately 20% had a significantly reduced risk of developing prostate cancer (adjusted HR = 0.36, 95% CI = 0.18-0.74), compared to that with no change. CONCLUSIONS: This is the first study to clarify the association between PSA variability and risk of developing prostate cancer in patients without a history of prostate cancer. These results suggest that the suppression of elevated PSA levels may lead to the prevention of prostate cancer and that it would be better to perform a biopsy because the risk of developing prostate cancer may increase in the future if the PSA value increases above a certain level.

Report of the 23rd nationwide follow-up survey of primary liver cancer in Japan (2014-2015).

For the 23rd Nationwide Follow-up Survey of Primary Liver Cancer in Japan, data from 20 889 newly registered patients and 42 274 previously registered follow-up patients were compiled from 516 institutions over a 2-year period from January 1, 2014 to December 31, 2015. Basic statistics compiled for patients newly registered in the 23rd survey were cause of death, past medical history, clinical diagnosis, imaging diagnosis, treatment-related factors, pathological diagnosis, recurrence status, and autopsy findings. Compared with the previous 22nd survey, the population of patients with hepatocellular carcinoma (HCC) was older at the time of clinical diagnosis, had more female patients, had more patients with non-B non-C HCC, had smaller tumor diameter, and was more frequently treated with hepatectomy. Cumulative survival rates were calculated for HCC, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma (combined HCC and intrahepatic cholangiocarcinoma) by treatment type and background characteristics for patients newly registered between 2004 and 2015 whose final outcome was survival or death. The median overall survival and cumulative survival rates for HCC were calculated by dividing patients by combinations of background factors (number of tumors, tumor diameter, Child-Pugh grade, or albumin-bilirubin grade) and by treatment type (hepatectomy, radiofrequency ablation therapy, transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, and systemic therapy). The same values were also calculated according to registration date by dividing patients newly registered between 1978 and 2015 into five time period groups. The data obtained from this nationwide follow-up survey are expected to contribute to advancing clinical research and treatment of primary liver cancer in the world.

Plasma ANGPTL8 Levels and Risk for Secondary Cardiovascular Events in Japanese Patients With Stable Coronary Artery Disease Receiving Statin Therapy.

BACKGROUND: The ability to predict secondary cardiovascular events could improve health of patients undergoing statin treatment. Circulating ANGPTL8 (angiopoietin-like protein 8) levels, which positively correlate with proatherosclerotic lipid profiles, activate the pivotal proatherosclerotic factor ANGPTL3. Here, we assessed potential association between circulating ANGPTL8 levels and risk of secondary cardiovascular events in statin-treated patients. METHODS: We conducted a biomarker study with a case-cohort design, using samples from a 2018 randomized control trial known as randomized evaluation of high-dose (4 mg/day) or low-dose (1 mg/day) lipid-lowering therapy with pitavastatin in coronary artery disease (REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease])." From that study's full analysis set (n=12 413), we selected 2250 patients with stable coronary artery disease (582 with the primary outcome, 1745 randomly chosen, and 77 overlapping subjects). A composite end point including cardiovascular-related death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergent admission was set as a primary end point. Circulating ANGPTL8 levels were measured at baseline and 6 months after randomization. RESULTS: Over a 6-month period, ANGPTL8 level changes significantly decreased in the high-dose pitavastatin group, which showed 19% risk reduction of secondary cardiovascular events compared with the low-dose group in the REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease] study. In the highest quartiles, relative increases in ANGPTL8 levels were significantly associated with increased risk for secondary cardiovascular events, after adjustment for several cardiovascular disease risk factors and pitavastatin treatment (hazard ratio in Q4, 1.67 [95% CI, 1.17-2.39). Subgroup analyses showed relatively strong relationships between relative ANGPTL8 increases and secondary cardiovascular events in the high-dose pitavastatin group (hazard ratio in Q4, 2.07 [95% CI, 1.21-3.55]) and in the low ANGPTL8 group at baseline (166

Differential prediction of high-sensitivity cardiac troponin-I, but not N-terminal pro-brain natriuretic peptide, in different pitavastatin doses on cardiovascular events in stable coronary artery disease.

BACKGROUND: This study aimed to examine whether high-sensitivity cardiac troponin-I (hsTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) could predict future major adverse cardiovascular events (MACE) in stable coronary artery disease (CAD) patients with high- or low-dose of pitavastatin. METHODS: This was a case-cohort analysis of the REAL-CAD study, a randomized trial of high- or low-dose (4 or 1 mg/day) pitavastatin therapy in patients with stable CAD. We examined the MACE risk according to the quartile of hsTnI and NT-proBNP at baseline. RESULTS: A total of 1336 and 1396 patients including 582 MACE cases were randomly examined into the hsTnI and NT-proBNP cohort, respectively. Both higher levels of hsTnI and NT-proBNP at baseline were significantly associated with increased risk of MACE (p < 0.001, respectively). When separately analyzed in statin dose, the higher marker levels were significantly associated with higher MACE risk in all cohorts (p < 0.001 in all cohorts). After multivariable adjustment, hsTnI levels were significantly associated with MACE risk in low-dose statin group (HR 2.54, p = 0.0001); however, in high-dose pitavastatin therapy, a significant association was diminished in MACE risk among the quartiles of baseline hsTnI levels (p = 0.154). Conversely in the NT-proBNP cohort, the association between NT-proBNP levels and MACE risk was constantly observed regardless of pitavastatin dose even after multivariable adjustment (both p < 0.0001). CONCLUSIONS: Patients with high hsTnI levels had high risk of MACE in low-dose statin group, but not in high-dose, suggesting that high-dose statin treatment might decrease MACE risk in stable CAD patients with high hsTnI levels.

A multi-center, randomized, parallel-group study to compare the efficacy of enhanced cognitive behavior therapy (CBT-E) with treatment as usual (TAU) for anorexia nervosa: study protocol.

BACKGROUND: The superiority of Enhanced Cognitive Behavior Therapy (CBT-E) with regard to weight gain and improvement of psychopathology of eating disorders for patients with anorexia nervosa (AN) over other psychotherapies and treatment as usual (TAU) has not been demonstrated in randomized controlled trials (RCTs). However, a previous RCT showed that patients with AN whose baseline body mass index (BMI) was less than 17.5 kg/m2 gained more weight when treated with CBT-E than with other psychotherapies. The aim of the study is to compare the efficacy of CBT-E and TAU for patients with AN. It was hypothesized that CBT-E would be superior to TAU, at least in terms of weight gain, as most patients with AN are likely to have a BMI lower than 17.5 kg/m2. METHODS/DESIGN: A randomized parallel-group multicenter trial will be conducted in three teaching hospitals in Japan between January 2023 and March 2026. Patients with DSM-5 AN, aged 16 years and older, with a BMI equal to or above 14.0 and below 18.5 will be eligible to participate. 56 patients will be randomly and evenly assigned to two intervention groups (CBT-E and TAU). Those assigned to CBT-E will be offered 25-40 sessions in accordance with their initial BMI. Patients assigned to TAU will have at least one session every 2 weeks, with the number of sessions and treatment period not fixed in advance. The primary outcome is BMI at 40 weeks after treatment initiation. The secondary outcomes are the results from the Japanese version of the Eating Disorder Examination Questionnaire and Clinical Impairment Assessment questionnaire to measure eating disorder psychopathology and psychological impairment. The follow-up assessment will be performed 6 months after the 40-week assessment. DISCUSSION: This multi-center randomized controlled study will probably evaluate the efficacy of CBT-E compared with TAU for patients with more severe AN than in previous studies since Japanese patients are likely to have a lower BMI than those in Western countries. While it may be difficult to generalize the results of a study conducted in Japan, it would be valuable to clarify the efficacy of CBT-E as a treatment package. TRIAL REGISTRATION: UMIN, UMIN000048847. Registered 12 Sep 2022.

Distribution of the follicular and luteal phase lengths and their age-dependent changes in Japanese women: A large population study.

Purpose: The current definition of menstrual cycle length in a Japanese woman is different from those of WHO definition, and the original data are outdated. We aimed to calculate the distribution of follicular and luteal phases length in modern Japanese women with various menstrual cycles. Methods: This study determined the lengths of the follicular and luteal phases of Japanese women using basal body temperature data collected via a smartphone application from 2015 to 2019, and the data were analyzed using the Sensiplan method. Over 9 million temperature readings from more than 80 000 participants were analyzed. Results: The mean duration of the low-temperature (follicular) phase averaged 17.1 days and was shorter among participants aged 40-49 years. The mean duration of the high-temperature (luteal) phase was 11.8 days. The variance and maximum-minimum difference of the length of the low temperature period were significant in women under 35 years old than women aged more than 35 years. Conclusions: The shortening of the follicular phase in women aged 40-49 years implied a relationship with the rapid decline of ovarian reserve in these women, and the age 35 years old was turning point of ovulatory function.

Effects of work-family life support program on the work-family interface and mental health among Japanese dual-earner couples with a preschool child: A randomized controlled trial.

OBJECTIVES: This study examined the effectiveness of a newly developed work-family life support program on the work-family interface and mental health indicators among Japanese dual-earner couples with a preschool child(/ren) using a randomized controlled trial with a waitlist. METHODS: Participants who met the inclusion criteria were randomly allocated to the intervention or the control groups (n = 79 and n = 85, respectively). The program comprised two 3-h sessions with a 1-month interval between them and provided comprehensive skills by including self-management, couple management, and parenting management components. The program sessions were conducted on weekends in a community center room with 3-10 participants. Outcomes were assessed at baseline, 1-month, and 3-month follow-ups. Primary outcomes were work-family balance self-efficacy (WFBSE), four types of work-family spillovers (i.e., work-to-family conflict, family-to-work conflict, work-to-family facilitation, and family-to-work facilitation), psychological distress, and work engagement reported by the participants. RESULTS: The program had significantly pooled intervention effects on WFBSE (P = .031) and psychological distress (P = .014). The effect sizes (Cohen's d) were small, with values of 0.22 at the 1-month follow-up and 0.24 at the 3-month follow-up for WFBSE, and -0.36 at the 3-month follow-up for psychological distress. However, the program had nonsignificant pooled effects on four types of work-family spillovers and work engagement. CONCLUSIONS: The program effectively increased WFBSE and decreased psychological distress among Japanese dual-earner couples with a preschool child(/ren).

The utility of the self-controlled study design for pharmacoepidemiological studies without an active comparator medication using a medical information database: An application to assess the risk of varenicline on cardiovascular outcomes.

PURPOSE: To illustrate the utility of the self-controlled study design for studies without an active comparator, we compared the results of a cohort design study with a non-user comparator with those of a self-controlled design study in evaluating the risk of varenicline on cardiovascular outcomes, using a Japanese medical claims database. METHODS: The participating smokers were identified from health-screening results collected between May 2008 and April 2017. Using a non-user-comparator cohort study design, we estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) of varenicline on initial hospitalization with cardiovascular outcomes using Cox's model adjusted for patients' sex, age, medical history, medication history, and health-screening results. Using a self-controlled study design, the within-subject HR was estimated using a stratified Cox's model adjusted for medical history, medication history, and health-screening results. The estimate from a recent meta-analysis was considered the gold standard (risk ratio: 1.03). RESULTS: We identified 460 464 smokers (398 694 males [86.6%]; mean (standard deviation) age: 42.9 [10.8] years) in the database. Of these, 11 561 had been dispensed varenicline at least once, and 4511 had experienced cardiovascular outcomes. The estimate of the non-user-comparator cohort study design exceeded the gold standard (HR [95% CI]: 2.04 [1.22-3.42]), whereas that of the self-controlled study design was close to the gold standard (within-subject HR [95% CI]: 1.12 [0.27-4.70]). CONCLUSIONS: The self-controlled study design is useful alternative to a non-user-comparator cohort design when evaluating the risk of medications relative to their non-use, based on a medical information database.

Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2021 version (5th JSH-HCC Guidelines).

The fifth version of the Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine and partly to the Grading of Recommendations Assessment, Development and Evaluation system, which was published in October 2021 in Japanese. In addition to surveillance-diagnostic and treatment algorithms, a new algorithm for systemic therapy has been created, as multiple drugs for hepatocellular carcinoma can be currently selected. Here, new or revised algorithms and evidence on which the recommendations are based are described.

Impacts of the preceding cancer-specific health-related quality of life instruments on the responses to the subsequent EQ-5D-5L.

BACKGROUND: In clinical studies, the EQ-5D-5L is often employed with disease-specific health-related quality of life instruments. The questions in the former are more general than the latter; however, it is known that responses to general questions can be influenced by preceding specific questions. Thus, the responses to the EQ-5D-5L have the possibility of being influenced by the preceding disease-specific health-related quality of life instruments. This may lead to bias in the cost-effectiveness analysis results. Therefore, this study aimed to evaluate the impact of the preceding cancer-specific health-related quality of life instruments on the EQ-5D-5L responses. METHODS: We prepared questionnaire booklets containing the EQ-5D-5L, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, and the Functional Assessment of Cancer Therapy General with different orders. Using a quasi-randomized design, they were distributed to the patients undergoing drug therapy for advanced cancer, who were classified into three groups: Groups 1, 2, and 3 (the EQ-5D-5L placed first, second, and last, respectively). We compared the EQ-5D-5L index and the missingness of EQ-5D-5L among the groups. RESULTS: The mean EQ-5D-5L index was 0.796, 0.760, and 0.789 for groups 1 (n = 300), 2 (n = 306), and 3 (n = 331), respectively. The difference between Groups 2 and 1 was - 0.036 (95% CI - 0.065 to - 0.007; p = 0.015). The proportion of patients with an incomplete EQ-5D-5L was 0.11, 0.11, and 0.05 for Groups 1, 2, and 3, respectively. The difference of the proportions between group 3 and 1 and between 3 and 2 was - 0.06 (95% CI - 0.10 to - 0.02; p = 0.003) and - 0.06 (95% CI - 0.10 to - 0.02; p = 0.003), respectively. CONCLUSIONS: Although the EQ-5D-5L index differed according to the instrument orders, the difference size would not be considerably larger than the minimally important difference. The patients tended to complete the EQ-5D-5L when they were placed at the end of the questionnaire.

Liver Resection for Hepatocellular Carcinoma With Tumor Thrombus in the Inferior Vena Cava or Right Atrium: A Large-scale Multicenter Survey Conducted in Japan.

OBJECTIVE: To clarify the short and long-term postoperative outcomes and surgical indications for patients accompanied by hepatocellular carcinoma with tumor thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA). BACKGROUND: These patients are known to have an extremely poor prognosis; however, the postoperative outcomes have not been fully verified because of the rarity of this disease. METHODS: We contacted 211 specialized centers in Japan and collected data on liver resection for hepatocellular carcinoma with TT in the IVC or RA from centers with experience performing surgery for such patients. The patient characteristics, operative procedures, and surgical outcomes were then analyzed. RESULTS: A total of 119 patients from 23 institutions were enrolled; 49 patients had TT in the IVC below the diaphragm (type I), 42 had TT in the IVC above the diaphragm (type II), and 28 had TT entering the RA (type III). The severity and frequency of postoperative complications did not differ among the 3 groups. There was one surgery-related death in the type III group. The median survival times were 2.47 years in the type I group, 1.77 years in the type II group, and 1.02 years in the type III group. Multivariate analysis identified an indocyanine green retention rate at 15 minutes >15% and ≥3 tumors as prognostic factors affecting survival, whereas the use of cardiopulmonary bypass and ≥3 tumors were risk factors for recurrence. CONCLUSIONS: As the postoperative prognosis of patients with type I or type II disease and of patients with no risk factors is relatively good, surgery should be considered for these patient populations.

Predictors of liver cirrhosis and hepatocellular carcinoma among perioperative survivors of the Fontan operation.

OBJECTIVE: Fontan-associated liver disease (FALD) is widely recognised as a common complication in patients long after the Fontan operation. However, data on the predictors of FALD that can guide its screening and management are lacking. The present study aimed to identify the predictors of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) in post-Fontan patients. METHODS: This was a multi-institutional retrospective cohort study. Clinical data of all perioperative survivors of Fontan operation before 2011 who underwent postoperative catheterisation were collected through a retrospective chart review. RESULTS: A total of 1117 patients (538 women, 48.2%) underwent their first Fontan operation at a median age of 3.4 years. Postoperative cardiac catheterisation was conducted at a median of 1.0 year. During a median follow-up period of 10.3 years, 67 patients (6.0%) died; 181 (16.2%) were diagnosed with liver fibrosis, 67 (6.0%) with LC, 54 (4.8%) with focal nodular hyperplasia and 7 (0.6%) with HCC. On multivariable analysis, high central venous pressure (CVP) (HR, 1.28 (95% CI 1.01 to 1.63) per 3 mm Hg; p=0.042) and severe atrioventricular valve regurgitation (HR, 6.02 (95% CI 1.53 to 23.77); p=0.010) at the postoperative catheterisation were identified as independent predictors of LC/HCC. CONCLUSIONS: Patients with high CVP and/or severe atrioventricular valve regurgitation approximately 1 year after the Fontan operation are at increased risk of developing advanced liver disease in the long term. Whether therapeutic interventions to reduce CVP and atrioventricular valve regurgitation decrease the incidence of advanced liver disease requires further elucidation.

Association between Statins and Incidence of Cancer in Patients with Dyslipidemia Using Large-Scale Health Insurance Claims Data.

Recent experimental studies have examined the efficacy of statins in preventing cancer, but the findings of clinical studies are inconsistent, and studies on Japanese patients are limited. This study aimed to clarify the association between statins and cancer risk among Japanese patients. We conducted a large population-based retrospective cohort study using the Japanese health insurance claims database, including patients newly diagnosed with dyslipidemia between 2005 and 2015. Patients who were on newly prescribed statins during the study period were designated as statin users. They were matched 1:1 with randomly selected drug nonusers who were not prescribed drugs for dyslipidemia according to age, sex, and year of first diagnosis of dyslipidemia. There were 23,746 patients in each group. The mean duration of follow-up for statin users and drug nonusers was approximately 2 years. Using a Cox proportional hazards model, significant reduction in cancer risk was observed in statin users compared with that in drug nonusers [adjusted HR = 0.84; 95% confidence interval (CI), 0.72-0.97; adjusted for patient background factors]. The results of subgroup analyses suggested that prescribed statins reduced the incidence of cancer of the digestive organs (adjusted HR = 0.79; 95% CI, 0.63-0.99) as well as reduced cancer risk in patients with nonsmokers (adjusted HR = 0.78, 95% CI = 0.65-0.92). Our results suggest that statin use may reduce cancer risk in patients with dyslipidemia. PREVENTION RELEVANCE: This study clarified the relationship between statin use and cancer risk in patients with dyslipidemia. Our study will contribute to medicine selection in patients with hypercholesterolemia level. See related Spotlight, p. 1.