Racial Differences in Age-Related Changes in Left Ventricular Structural and Functional Echocardiographic Measurements Among Healthy Japanese and American Participants　- A Subanalysis of the World Alliance Society of Echocardiography Normal Values Study.

BACKGROUND: Age-related changes in left ventricular (LV) structure and function lower the threshold for the onset of heart failure with preserved ejection fraction (HFpEF). LV parameters change also with race; however, the racial differences in age-related changes in LV parameters with and without adjustment for body mass index (BMI), heart rate (HR), and blood pressure (BP) remain unclear.Methods and Results: We performed a subanalysis of the World Alliance Society of Echocardiography Normal Values Study, an international cross-sectional study that examined normal echocardiographic values in 15 countries. The age-related changes in 2-dimensional echocardiographic derived parameters including LV size, systolic function, and mass, were compared between healthy Japanese (n=227) and healthy White (n=98) and Black (n=69) American participants. In men, age-related changes in all parameters did not differ significantly among races. However, compared with Japanese women, White American women had a smaller body surface area (BSA)-indexed LV volume, BSA-indexed LV internal dimension at end-systole, BSA-indexed LV stroke volume, and LV mass index to BSA, and a larger LV ejection fraction with age, even after adjusting for BMI, HR, and BP. CONCLUSIONS: Age-related changes in LV structure and function, which are important for the pathophysiology of HFpEF, may differ by race. Therefore, future studies examining echocardiographic reference values for each age group in each race are needed.

Motion capture device reveals a quick learning curve in vascular anastomosis training.

PURPOSE: Surgical procedures are often evaluated subjectively, and an objective evaluation has been considered difficult to make and rarely reported, especially in open surgery, where the range of motion is wide. This study evaluated the effectiveness of surgical suturing training as an educational tool using the Leap Motion Controller (LMC), which can capture hand movements and reproduce them as data comprising parametric elements. METHODS: We developed an off-the-job training system (Off-JT) in our department, mainly using prosthetic grafts and various anastomotic methodologies with graded difficulty levels. We recruited 50 medical students (novice group) and 6 vascular surgeons (expert group) for the study. We evaluated four parameters for intraoperative skills: suturing time, slope of the roll, smoothness, and rate of excess motion. RESULTS: All 4 parameters distinguished the skill of the novice group at 1 and 10 h off-JT. After 10 h of off-JT, all 4 parameters of the novices were comparable to those of the expert group. CONCLUSION: Our education system using the LMC is relatively inexpensive and easy to set up, with a free application for analyses, serving as an effective and ubiquitous educational tool for young surgeons.

Impact of correlations between prioritized outcomes on the net benefit and its estimate by generalized pairwise comparisons.

Benefit-risk balance is gaining interest in clinical trials. For the comprehensive assessment of benefits and risks, generalized pairwise comparisons are increasingly used to estimate the net benefit based on multiple prioritized outcomes. Although previous research has demonstrated that the correlations between the outcomes impact the net benefit and its estimate, the direction and magnitude of this impact remain unclear. In this study, we investigated the impact of correlations between two binary or Gaussian variables on the true net benefit values via theoretical and numerical analyses. We also explored the impact of correlations between survival and categorical variables on the net benefit estimates based on four existing methods (Gehan, Péron, Gehan with correction, and Péron with correction) in the presence of right censoring via simulation and application to actual oncology clinical trial data. Our theoretical and numerical analyses revealed that the true net benefit values were impacted by the correlations in various directions depending on the outcome distributions. With binary endpoints, this direction was governed by a simple rule with a threshold of 50% for a favorable outcome. Our simulation showed that the net benefit estimates based on Gehan's or Péron's scoring rule could be substantially biased in the presence of right censoring, and that the direction and magnitude of this bias were associated with the outcome correlations. The recently proposed correction method greatly reduced this bias, even in the presence of strong outcome correlations. The impact of correlations should be carefully considered when interpreting the net benefit and its estimate.

Gradient Boosted Tree Approaches for Mapping European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Onto 5-Level Version of EQ-5D Index for Patients With Cancer.

OBJECTIVES: This study aimed to develop direct and response mapping algorithms from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 onto the 5-level version of EQ-5D index based on the gradient boosted tree (GBT), a promising modern machine learning method. METHODS: We used the Quality of Life Mapping Algorithm for Cancer study data (903 observations from 903 patients) for training GBTs and testing their predictive performance. In the Quality of Life Mapping Algorithm for Cancer study, patients with advanced solid tumor were enrolled, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and 5-level version of EQ-5D were simultaneously evaluated. The Japanese value set was used for direct mapping, whereas the Japanese and US value sets were used for response mapping. We trained the GBTs in the training data set (80%) with cross-validation and tested the predictive performance measured by the root mean squared error (RMSE), mean absolute error (MAE), and mean error in the test data set (20%). RESULTS: The RMSE and MAE in the test data set were larger in the GBT approaches than in the previously developed regression-based approaches. The mean error in the test data set tended to be smaller in the GBT approaches than in the previously developed regression-based approaches. CONCLUSIONS: The predictive performances in the RMSE and MAE did not improve by the GBT approaches compared with regression approaches. The flexibility of the GBT approaches had the potential to reduce overprediction and underprediction in poor and good health, respectively. Further research is needed to establish the role of machine learning methods in mapping a nonpreference-based measure onto health utility.

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.

Effectiveness of mock scanners and preparation programs for successful magnetic resonance imaging: a systematic review and meta-analysis.

This review aimed to summarise the effectiveness of preparation programs for magnetic resonance imaging (MRI) in children using mock scanners and the success rates by systematically reviewing the current literature. We initially identified 67 articles using the search terms "MRI," "mock" and "child" on online databases. All studies involving a preparation programme for MRI on children ages 18 years or younger, healthy children and those with medical diagnoses were included. The authors extracted data on study design, participant data, details of the MRI protocol and the total numbers of patients who underwent preparation programs and were scanned while awake, without sedation or general anesthesia. Twenty-three studies were included in this review. Preparation programs included in-home and hospital/research facility components; these consisted of a mock scanner, explanatory booklets, recorded MRI scan sounds and other educational materials. The success rate of MRI after the preparation programme reported in each study ranged from 40% to 100%. When all participants from studies that specifically assessed the efficacy of preparation programs were combined, participants who underwent a preparation programme (n = 196) were more likely to complete a successful MRI than those who did not undergo a preparation programme (n = 263) (odds ratio [OR] = 1.98). Our results suggest that preparation programs may help reduce the risk of children failing MRI scans.

Alterations in Intratumoral Immune Response before and during Early-On Nivolumab Treatment for Unresectable Advanced or Recurrent Gastric Cancer.

We investigated the tumor immune response in gastric cancer patients receiving third-line nivolumab monotherapy to identify immune-related biomarkers for better patient selection. Nineteen patients (10 males, median age 67 years) who received nivolumab as a third- or later-line therapy were enrolled. We analyzed the tumor immune response in durable clinical benefit (DCB) and non-DCB patients. Pre-treatment and early-on-treatment tumor transcriptomes were examined, and gene expression profiles, immunograms, and T cell receptor (TCR) repertoire were analyzed. DCB was observed in 15.8% of patients, with comparable secondary endpoints (ORR; objective response rate, OS; overall survival, PFS; progression-free survival) to previous trials. The immunograms of individual subjects displayed no significant changes before or early in the treatment, except for the regulatory T cell (Treg) score. Moreover, there were no consistent alterations observed among cases experiencing DCB. The intratumoral immune response was suppressed by previous treatments in most third- or later-line nivolumab recipients. TCR repertoire analysis revealed newly emerged clonotypes in early-on-treatment tumors, but clonal replacement did not impact efficacy. High T cell/Treg ratios and a low UV-radiation-response gene signature were linked to DCB and treatment response. This study emphasizes the tumor immune response's importance in nivolumab efficacy for gastric cancer. High T cell/Treg ratios and specific gene expression signatures show promise as potential biomarkers for treatment response. The tumor-infiltrating immune response was compromised by prior treatments in third-line therapy, implying that, to enhance immunotherapeutic outcomes, commencing treatment at an earlier stage might be preferable. Larger cohort validation is crucial to optimize immune-checkpoint inhibitors in gastric cancer treatment.

Branched chain amino acids in the treatment of polymyositis and dermatomyositis: a phase II/III, multi-centre, randomized controlled trial.

OBJECTIVES: To assess the efficacy and safety of branched chain amino acids (BCAAs) in the treatment of PM/DM prior to official approval of their use in Japan. METHODS: Treatment naïve adults with PM/DM were enrolled in a randomized, double-blind trial to receive either TK-98 (drug name of BCAAs) or placebo in addition to conventional treatment. After 12 weeks, patients with an average manual muscle test (MMT) score <9.5 were enrolled in an open label extension study for a further 12 weeks. The primary endpoint was the change of the MMT score at 12 weeks. The secondary endpoints were the clinical response and the change of functional index (FI). RESULTS: Forty-seven patients were randomized either to the TK-98 (n = 24) or placebo (n = 23) group. The changes of MMT scores at 12 weeks were 0.70 (0.19) [mean (s.e.m.)] and 0.69 (0.18), respectively (P = 0.98). Thirteen patients from the TK-98 group and 12 from the placebo group were enrolled in the extension study. The MMT scores in both groups improved similarly. The increase of the FI scores of the shoulder flexion at 12 weeks was significantly greater in the TK-98 group [27.9 (5.67) vs 12.8 (5.67) for the right shoulder flexion, and 27.0 (5.44) vs 13.4 (5.95) for the left shoulder; P < 0.05]. Frequencies of adverse events up to 12 weeks were similar. CONCLUSION: BCAAs showed no effect on the improvement of the muscle strength evaluated by MMT and the clinical response. However, they were partly effective for improving dynamic repetitive muscle functions. TRIAL REGISTRATION: UMIN-CTR Clinical Trial, https://center6.umin.ac.jp/, UMIN000016233.

Combination of Skeletal Muscle Mass and Density Predicts Postoperative Complications and Survival of Patients With Non-Small Cell Lung Cancer.

BACKGROUND: Few studies have assessed the comprehensive skeletal muscle depletion associated with loss of muscle quantity (sarcopenia) and reduced muscle quality in cancer patients. This study aimed to clarify the impact of skeletal muscle depletion on outcomes after non-small cell lung cancer surgery. METHODS: Data for 341 patients with pathologic stages 1 to 3A non-small cell lung cancer who underwent lobectomy and mediastinal lymph node dissection from 2009 to 2013 were retrospectively reviewed. The integrative pectoralis muscle index (IPMI) was assessed by multiplying the normalized pectoralis muscle area (area/body mass index) and mean radiodensity on chest images. Postoperative outcomes were compared among sex-specific quartiles of IPMI. The trend of continuous and categorical variables was analyzed using the Jonckheere-Terpstra test and the Cochrane-Armitage test, respectively. RESULTS: Respiratory strength declined with decreasing quartiles of IPMI (P < 0.001). The risk of major complications escalated with the decrease of IPMI among four quartiles (7.1 %, 16.7 %, 18.4 %, and 22.4 %; P = 0.008). The hospital stay was prolonged for patients with reduced IPMI (P = 0.001). Patients in the lowest and highest quartiles had the worst and best 5-year overall survival, respectively, compared with those in the two intermediate quartiles of IPMI (67.0 %, 87.9 %, and 81.2 %, respectively; P=0.001). Multivariate analysis identified the lowest quartile of IPMI as an independent poor prognostic factor (hazard ratio, 1.88; 95 % confidence interval, 1.11-3.19; P = 0.020). CONCLUSION: Comprehensive skeletal muscle profiling, including morphometric mass and componential density on chest imaging, has the potential to refine risk stratification and prognostication in non-small cell lung cancer.

Artificial intelligence versus expert endoscopists for diagnosis of gastric cancer in patients who have undergone upper gastrointestinal endoscopy.

AIMS: To compare endoscopy gastric cancer images diagnosis rate between artificial intelligence (AI) and expert endoscopists. PATIENTS AND METHODS: We used the retrospective data of 500 patients, including 100 with gastric cancer, matched 1:1 to diagnosis by AI or expert endoscopists. We retrospectively evaluated the noninferiority (prespecified margin 5 %) of the per-patient rate of gastric cancer diagnosis by AI and compared the per-image rate of gastric cancer diagnosis. RESULTS: Gastric cancer was diagnosed in 49 of 49 patients (100 %) in the AI group and 48 of 51 patients (94.12 %) in the expert endoscopist group (difference 5.88, 95 % confidence interval: -0.58 to 12.3). The per-image rate of gastric cancer diagnosis was higher in the AI group (99.87 %, 747 /748 images) than in the expert endoscopist group (88.17 %, 693 /786 images) (difference 11.7 %). CONCLUSIONS: Noninferiority of the rate of gastric cancer diagnosis by AI was demonstrated but superiority was not demonstrated.

Statistical methods and graphical displays of quality of life with survival outcomes in oncology clinical trials for supporting the estimand framework.

BACKGROUND: Although there are discussions regarding standards of the analysis of patient-reported outcomes and quality of life (QOL) in oncology clinical trials, that of QOL with death events is not within their scope. For example, ignoring death can lead to bias in the QOL analysis for patients with moderate or high mortality rates in the palliative care setting. This is discussed in the estimand framework but is controversial. Information loss by summary measures under the estimand framework may make it challenging for clinicians to interpret the QOL analysis results. This study illustrated the use of graphical displays in the framework. They can be helpful for discussions between clinicians and statisticians and decision-making by stakeholders. METHODS: We reviewed the time-to-deterioration analysis, prioritized composite outcome approach, semi-competing risk analysis, survivor analysis, linear mixed model for repeated measures, and principal stratification approach. We summarized attributes of estimands and graphs in the statistical analysis and evaluated them in various hypothetical randomized controlled trials. RESULTS: Graphs for each analysis method provide different information and impressions. In the time-to-deterioration analysis, it was not easy to interpret the difference in the curves as an effect on QOL. The prioritized composite outcome approach provided new insights for QOL considering death by defining better conditions based on the distinction of OS and QOL. The semi-competing risk analysis provided different insights compared with the time-to-deterioration analysis and prioritized composite outcome approach. Due to the missing assumption, graphs by the linear mixed model for repeated measures should be carefully interpreted, even for descriptive purposes. The principal stratification approach provided pure comparison, but the interpretation was difficult because the target population was unknown. CONCLUSIONS: Graphical displays can capture different aspects of treatment effects that should be described in the estimand framework.

Localization of the central sulcus using the distinctive high signal intensity of the paracentral lobule on T1-weighted images.

PURPOSE: The central sulcus is an important landmark in the brain. This study aimed to investigate the distinctive signal of the paracentral lobule (PL) on T1-weighted images (T1WIs; the white PL sign) and evaluate its usefulness as a new method of identifying the central sulcus. METHODS: T1WIs of the brain of 96 participants (age, 58.9 ± 17.9 years; range, 8-87 years) scanned at 3-T MR system were retrospectively reviewed. First, we qualitatively analyzed the signal of the cortex of the PL by comparing it with that of the ipsilateral superior frontal gyrus on a 4-point grading score. Second, we compared the cortical signal intensity and gray/white-matter contrast between the PL and superior frontal gyrus. Third, we evaluated the usefulness of the PL signal for identifying the central sulcus. RESULTS: The PL cortex was either mildly hyperintense (grade 2) or definitely hyperintense (grade 3) in comparison with that of superior frontal cortex in all participants. The signal intensity of the PL cortex was significantly higher than that of the superior frontal cortex (p < 0.001), whereas the gray/white-matter contrast of the PL was weaker than that of the superior frontal gyrus (p < 0.001). The central sulci were identified with 94.3% accuracy (181/192) using the new method. CONCLUSION: The white PL sign may be helpful in identifying the central sulcus, and this approach can be recognized as a new method for identification of the central sulcus.

Association of change in health-related quality of life and treatment discontinuation in metastatic breast cancer: a post hoc, exploratory analysis of two randomized clinical trials.

PURPOSE: Identifying factors associated with treatment alteration (treatment discontinuation and dose reduction) may help to attain the treatment goals for metastatic breast cancer. The value of changes in the quality of life (QOL) in predicting treatment alteration remained unclear. This study aimed to examine the relationship between changes in the QOL and treatment alteration of first-line chemotherapy for metastatic breast cancer. METHODS: We merged data from two randomized clinical trials in Japan, conducted from 2006 to 2017, that included patients who were diagnosed with human epidermal growth factor receptor 2-negative and endocrine treatment-resistant breast cancer, with metastatic disease at presentation or recurrence after surgery. The European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 was used to assess QOL. The association between change in time-dependent QOL (worsening by 10-point or not) and time to treatment alteration was assessed using the Cox regression models controlling for patient characteristics (age, liver metastasis, hormone status, and treatment regimen) and baseline QOL. RESULTS: Worsening physical functioning, global health status, and dyspnea were significantly associated with treatment discontinuation. Worsening role functioning, global health status, and fatigue were significantly associated with dose reduction. The threshold for defining worsening did not have a significant impact on the relationship. CONCLUSION: Changes in QOL are associated with the probability of treatment alteration among metastatic breast cancer patients. Physical functioning, role functioning, global health status, dyspnea, and fatigue should be prioritized for symptom management in patients with metastatic breast cancer.

Chemoprevention of Oesophageal Squamous-Cell Carcinoma and Adenocarcinoma: A Multicentre Retrospective Cohort Study.

BACKGROUND: Oesophageal cancer comprises 2 different histological variants: oesophageal squamous-cell carcinoma (ESCC) and adenocarcinoma (EAC). While there are multiple therapeutic options for both types, patients with advanced or metastatic oesophageal cancer still suffer from poor prognosis. AIMS: The study aimed to examine the association between the risk of oesophageal cancer and medications and to estimate the chemopreventive effects of commonly used drugs. METHODS: A multicentre retrospective cohort study was conducted using data from 9 hospital databases of hospitalized patients between 2014 and 2019. The primary outcomes were ESCC and EAC. The association of oesophageal cancer with drug use and clinical factors was evaluated. Odds ratios (ORs) were adjusted for age, sex, Charlson comorbidity index scores, and smoking with/without gastro-oesophageal reflux disease. RESULTS: The use of proton pump inhibitors (PPIs) (adjusted OR [aOR] 0.48, p < 0.0001), aspirin (aOR 0.32, p < 0.0001), cyclooxygenase-2 inhibitor (COX2I) (aOR 0.70, p = 0.0005), steroid (aOR 0.19, p < 0.0001), statin (aOR 0.43, p < 0.0001), and metformin (aOR 0.42, p < 0.0001) was associated with a lower risk of ESCC than that in non-use. The use of aspirin (aOR 0.33, p = 0.0006) and steroids (aOR 0.54, p = 0.022) was associated with a lower risk of EAC than that in non-use. CONCLUSION: COX2Is, statins, metformin, and PPIs could help in prevention of ESCC, and aspirin and steroids may be chemopreventive for both types of oesophageal cancer.

Chemoprevention for Colorectal Cancers: Are Chemopreventive Effects Different Between Left and Right Sided Colorectal Cancers?

BACKGROUND AND AIMS: Recent studies have suggested that right- and left-sided colorectal cancers (CRCs) are molecularly distinct. In this study, we examined the association between the risk of right- and left-sided CRC and drug use to estimate their chemopreventive effects METHODS: This multicenter retrospective cohort study was conducted using the data of hospitalized patients between 2014 and 2019 from nine hospital databases. The primary outcomes were right- and left-sided CRC. We evaluated the association of CRCs with drug use and clinical factors. Odds ratios adjusted for age, sex, Charlson Comorbidity Index scores, and smoking status were calculated. We also compared the transcriptional profiling in precancerous lesions, including sessile serrated lesions (SSLs) RESULTS: A total of 307,938 patients, including 2745 with right-sided CRC and 4819 with left-sided CRC, were analyzed. The use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, cyclooxygenase-2 inhibitors, and steroids was associated with a lower risk of both right- and left-sided CRCs. In contrast, statins, other lipid-lowering agents, and metformin were associated with a lower risk of left-sided CRC. Transcriptomic analysis showed that SSL, which predominantly develops in the right colon, was associated with a lower expression of lipid metabolism-related genes. CONCLUSIONS: Targeting lipid metabolism may be useful for chemoprevention of left-sided CRCs, while development of right-sided CRCs may be independent of this pathway.

Minimal important differences of EORTC QLQ-C30 for metastatic breast cancer patients: Results from a randomized clinical trial.

PURPOSE: To establish minimal important differences (MIDs) for the European Organisation for Research and Treatment for Cancer Quality of life Questionnaire core 30 (EORTC QLQ-C30) in patients with metastatic breast cancer. METHODS: The dataset was obtained from the SELECT BC-CONFIRM randomized clinical trial. Anchors obtained from patients (transition items) and clinicians (performance status) were used for anchor-based methods. Anchors obtained through 6 months after starting treatment were used for this analysis. Correlation coefficients of anchor and change in QLQ-C30 and effect size were used to qualify for estimating MIDs. Mean change method and generalized estimating equation were applied to estimate MIDs. Distribution-based methods were used for comparison. RESULTS: We analyzed a dataset of 154 metastatic breast cancer patients. MIDs were estimated in 8 of 15 scales of QLQ-C30. Estimated MIDs for within-group improvement varied from 7 to 15 and those for deterioration varied from - 7 to - 17. Estimated MIDs for between-group improvement varied from 5 to 11 and those for deterioration varied from - 5 to - 8 across QLQ-C30 scales. Patient-reported anchors were more susceptible to early changes in health status than clinician-reported anchors. CONCLUSION: We provided the MIDs of the QLQ-C30 using both patient- and clinicians-reported anchors measured in a randomized trial of Japanese patients with metastatic breast cancer. We recommend patient-reported anchors for anchor-based estimation of MID. Our results can aid patients and clinicians, as well as researchers, in the interpretation of QLQ-C30.

Diagnostic value of a new cryoprobe for peripheral pulmonary lesions: a prospective study.

BACKGROUND: Cryobiopsy is an established technique that yields larger and higher-quality samples than does a forceps biopsy. However, it remains underutilised in the diagnosis of peripheral pulmonary lesions (PPLs), mainly because of difficulties in handling conventional cryoprobes. A recently introduced single-use cryoprobe with a smaller diameter and more flexibility than conventional ones may improve its diagnostic ability for PPLs. We conducted this prospective study to evaluate the feasibility of transbronchial cryobiopsy in the diagnoses of PPLs, using a new 1.7-mm cryoprobe. METHODS: The study included patients with PPLs less than 30 mm in diameter scheduled to undergo bronchoscopy. All the procedures were performed using a combination of virtual bronchoscopic navigation, radial endobronchial ultrasound (R-EBUS) and X-ray fluoroscopy, and all the samples were collected using the cryoprobe alone. Thereafter, we assessed the diagnostic outcomes and safety profiles. RESULTS: A total of 50 patients were enrolled and underwent cryobiopsy. The median lesion size was 20.8 mm (range, 8.2-29.6 mm), and the negative bronchus sign was seen in 34% of lesions. The diagnostic yield was 94% (95% confidence interval, 83.5-98.8%). A positive bronchus sign had a significantly higher diagnostic yield than did a negative bronchus sign (100% vs. 82.4%; P = 0.035). The yield was achieved regardless of other variables, including lesion size, location, and R-EBUS findings. The major complications were mild and moderate bleeding in 28% and 62% of patients, respectively. Pneumothorax was identified in one patient. CONCLUSION: Transbronchial cryobiopsy using the new 1.7-mm cryoprobe is a feasible procedure that has the potential to increase the diagnostic accuracy for PPLs. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCT1032200065. Registered July 8 2020, https://jrct.niph.go.jp/en-latest-detail/jRCT1032200065.

The impact of the covalently closed circular DNA level on recurrence of hepatocellular carcinoma after initial hepatectomy: an analysis of patients with resolved hepatitis B virus infection.

BACKGROUND: We assessed whether or not covalently closed circular DNA (cccDNA) levels in the background liver influence the recurrence of hepatocellular carcinoma (HCC) in patients with resolved hepatitis B virus (HBV) infection. METHODS: Among 425 patients who underwent initial hepatectomy for HCC between 2010 and 2018, a retrospective review was performed in 44 with resolved HBV infection. The clinicopathologic characteristics were analyzed for correlation with tumor recurrence. The HBV cccDNA levels were tested via a droplet digital polymerase chain reaction assay. RESULTS: HBV cccDNA was detected in 27 of 44 patients (61%), and the median level was 1.0 copies/1000 ng (range, 0-931.3 copies/1000 ng). Anti-HBc ≥8.9 S/CO was associated with cccDNA detection (odds ratio, 11.08; 95% confidence interval [95% CI], 2.48-49.46; P = 0.002). Twenty-eight patients (64%) developed HCC recurrence after hepatectomy. The overall 3- and 5-year recurrence-free survival rates were 45.7% and 34.3%, respectively.19 HBV cccDNA levels was not significantly associated with HCC recurrence, while the presence of multiple tumors was an independent risk fact or (hazard ratio, 6.53; 95% CI, 2.48-17.19; P < 0.001. CONCLUSION: HBV cccDNA levels did not influence HCC recurrence after hepatectomy. Anti-HBc levels may be used as a surrogate marker for cccDNA.

Causal Inference in Studying the Long-Term Health Effects of Disasters: Challenges and Potential Solutions.

Two frequently encountered but underrecognized challenges for causal inference in studying the long-term health effects of disasters among survivors include 1) time-varying effects of disasters on a time-to-event outcome and 2) selection bias due to selective attrition. In this paper, we review approaches for overcoming these challenges and demonstrate application of the approaches to a real-world longitudinal data set of older adults who were directly affected by the 2011 Great East Japan Earthquake and Tsunami (n = 4,857). To illustrate the problem of time-varying effects of disasters, we examined the association between degree of damage due to the tsunami and all-cause mortality. We compared results from Cox regression analysis assuming proportional hazards with those derived using adjusted parametric survival curves allowing for time-varying hazard ratios. To illustrate the problem of selection bias, we examined the association between proximity to the coast (a proxy for housing damage from the tsunami) and depressive symptoms. We corrected for selection bias due to attrition in the 2 postdisaster follow-up surveys (conducted in 2013 and 2016) using multivariable adjustment, inverse probability of censoring weighting, and survivor average causal effect estimation. Our results demonstrate that analytical approaches which ignore time-varying effects on mortality and selection bias due to selective attrition may underestimate the long-term health effects of disasters.

Anthracycline-containing regimens or taxane versus S-1 as first-line chemotherapy for metastatic breast cancer.

BACKGROUND: We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. METHODS: We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. RESULTS: We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062). CONCLUSIONS: S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. CLINICAL TRIAL REGISTRATION: The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.