Inter- and intra-observer variability of qualitative visual breast-composition assessment in mammography among Japanese physicians: a first multi-institutional observer performance study in Japan.

BACKGROUND: Visual assessment of mammographic breast composition remains the most common worldwide, although subjective variability limits its reproducibility. This study aimed to investigate the inter- and intra-observer variability in qualitative visual assessment of mammographic breast composition through a multi-institutional observer performance study for the first time in Japan. METHODS: This study enrolled 10 Japanese physicians from five different institutions. They used the new Japanese breast-composition classification system 4th edition to subjectively evaluate the breast composition in 200 pairs of right and left normal mediolateral oblique mammograms (number determined using precise sample size calculations) twice, with a 1-month interval (median patient age: 59 years [range 40-69 years]). The primary endpoint of this study was the inter-observer variability using kappa (κ) value. RESULTS: Inter-observer variability for the four and two classes of breast-composition assessment revealed moderate agreement (Fleiss' κ: first and second reading = 0.553 and 0.587, respectively) and substantial agreement (Fleiss' κ: first and second reading = 0.689 and 0.70, respectively). Intra-observer variability for the four and two classes of breast-composition assessment demonstrated substantial agreement (Cohen's κ, median = 0.758) and almost perfect agreement (Cohen's κ, median = 0.813). Assessments of consensus between the 10 physicians and the automated software Volpara® revealed slight agreement (Cohen's κ; first and second reading: 0.104 and 0.075, respectively). CONCLUSIONS: Qualitative visual assessment of mammographic breast composition using the new Japanese classification revealed excellent intra-observer reproducibility. However, persistent inter-observer variability, presenting a challenge in establishing it as the gold standard in Japan.

Scoring system for diagnosis and pretreatment risk assessment of neuroblastoma using urinary biomarker combinations.

The urinary catecholamine metabolites, homovanillic acid (HVA) and vanillylmandelic acid (VMA), are used for the adjunctive diagnosis of neuroblastomas. We aimed to develop a scoring system for the diagnosis and pretreatment risk assessment of neuroblastoma, incorporating age and other urinary catecholamine metabolite combinations. Urine samples from 227 controls (227 samples) and 68 patients with neuroblastoma (228 samples) were evaluated. First, the catecholamine metabolites vanillactic acid (VLA) and 3-methoxytyramine sulfate (MTS) were identified as urinary marker candidates through comprehensive analysis using liquid chromatography-mass spectrometry. The concentrations of these marker candidates and conventional markers were then compared among controls, patients, and numerous risk groups to develop a scoring system. Participants were classified into four groups: control, low risk, intermediate risk, and high risk, and the proportional odds model was fitted using the L2-penalized maximum likelihood method, incorporating age on a monthly scale for adjustment. This scoring model using the novel urine catecholamine metabolite combinations, VLA and MTS, had greater area under the curve values than the model using HVA and VMA for diagnosis (0.978 vs. 0.964), pretreatment risk assessment (low and intermediate risk vs. high risk: 0.866 vs. 0.724; low risk vs. intermediate and high risk: 0.871 vs. 0.680), and prognostic factors (MYCN status: 0.741 vs. 0.369, histology: 0.932 vs. 0.747). The new system also had greater accuracy in detecting missing high-risk neuroblastomas, and in predicting the pretreatment risk at the time of screening. The new scoring system employing VLA and MTS has the potential to replace the conventional adjunctive diagnostic method using HVA and VMA.

Effect of Nudge-Based Intervention on Adherence to Physician Visit Recommendations and Early Health Outcomes among Individuals Identified with Chronic Kidney Disease in Screens.

BACKGROUND: Although CKD screening programs have been provided in many settings, little is known as to how we can effectively translate those screening programs into improved health. METHODS: We conducted a randomized clinical trial on national health screening for CKD in Japan between April 2018 and March 2019. A total of 4011 participants in CKD screening programs aged 40-63 years were randomly assigned to two interventions or the control, with a ratio of 2:2:1, respectively: (1) the nudge-based letter that contained a message on the basis of behavioral economics, (2) the clinical letter including general information about CKD risks, and (3) the control (informed only of the screening results). The main outcome was adherence to a recommended physician visit within 6 months of the intervention. The secondary outcomes were eGFR, proteinuria, and BP 1 year after the intervention. RESULTS: Compared with the control group, the probability of undergoing a recommended physician visit was higher among participants who received the nudge-based letter (19.7% for the intervention group versus 15.8% for the control; difference, +3.9 percentage points [pp]; 95% CI, +0.8 to +7.0; P=0.02) and the clinical letter (19.7% versus 15.8%; difference, +3.9 pp; 95% CI, +0.8 to +7.0; P=0.02). We found no evidence that interventions were associated with improved early health outcomes. CONCLUSIONS: The behavioral economics intervention tested in this large RCT had limited effect on changing behavior or improving health outcomes. Although the approach has promise, this study demonstrates the challenge of developing behavioral interventions that improve the effectiveness of CKD screening programs.Clinical Trial registry name and registration number: University Hospital Medical Information Network Clinical Trial Registry, UMIN000035230.

Real impact of tumor marker AFP and PIVKA-II in detecting very small hepatocellular carcinoma (≤ 2 cm, Barcelona stage 0) - assessment with large number of cases.

BACKGROUND: In hepatocellular carcinoma (HCC), detection and treatment prior to growth beyond 2 cm are relevant as a larger tumor size is more frequently associated with microvascular invasion and/or satellites. AIM: To examine the impact of the tumor marker alpha-fetoprotein (AFP) or PIVKA-II in detecting very small HCC nodules (≤ 2 cm in maximum diameter, Barcelona stage 0) in the large number of very small HCC. The difference in the behavior of these tumor markers in HCC development was also examined. METHODS: A total of 933 patients with single-nodule HCC were examined. They were subdivided into 394 patients with HCC nodules ≤ 2 cm in maximum diameter and 539 patients whose nodules were > 2 cm. The rates of patients whose AFP and PIVKA-II showed normal values were examined. RESULTS: The positive ratio of the marker PIVKA-II was significantly different (P < 0.0001) between patients with nodules ≤ 2 cm in diameter and those with nodules > 2 cm, but there was no significant difference in AFP (P = 0.4254). In the patients whose tumor was ≤ 2 cm, 50.5% showed normal levels in AFP and 68.8% showed normal levels in PIVKA-II. In 36.4% of those patients, both AFP and PIVKA-II showed normal levels. The PIVKA-II-positive ratio was markedly increased with an increase in the tumor size. In contrast, the positivity in AFP was increased gradually and slowly. CONCLUSION: In the surveillance of very small HCC nodules (≤ 2 cm in diameter, Barcelona clinical stage 0) the tumor markers AFP and PIVKA-II are not so useful.

Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases-meta-analytic assessment.

BACKGROUND: It is well known that the incidence of developing hepatocelluler carcinoma (HCC) is increased in liver cirrhosis of different etiologies. However, comparison of HCC incidence in various liver diseases has not yet been estimated. We surveyed this comparison. METHODS: The PubMed database was examined (1989-2017) for studies published in English language regarding the prospective follow-up results for the development of HCC in various liver diseases. A meta-analysis was performed for each liver disease. RESULTS: The annual incidence (%) of HCC in the non-cirrhotic stage and cirrhotic stage, and the ratio of HCC incidence in the cirrhotic stage/non-cirrhotic stage were as follows. (a) hepatitis B virus liver disease: 0.37%→3.23% (8.73-fold), (b) hepatitis C virus liver diseases: 0.68%→4.81% (7.07-fold), (c) primary biliary cholangitis (0.26%→1.79%, 6.88-fold), (d) autoimmune hepatitis (0.19%→0.53%, 2.79-fold), and (e) NASH (0.03%→1.35%, 45.00-fold). Regarding primary hemochromatosis and alcoholic liver diseases, only follow-up studies in the cirrhotic stage were presented, 1.20% and 2.06%, respectively. CONCLUSIONS: When the liver diseases advance to cirrhosis, the incidence of HCC is markedly increased. The development of HCC must be closely monitored by ultrasonography, magnetic resonance imaging, and computed tomography, irrespective of the different kinds of liver diseases.

Community-wide intervention and population-level physical activity: a 5-year cluster randomized trial.

Background: Evidence from a limited number of short-term trials indicates the difficulty in achieving population-level improvements in physical activity (PA) through community-wide interventions (CWIs). We sought to evaluate the effectiveness of a 5-year CWI for promoting PA in middle-aged and older adults using a cluster randomized design. Methods: We randomized 12 communities in Unnan, Japan, to either intervention (9) or control (3). Additionally, intervention communities were randomly allocated to three subgroups by different PA types promoted. Randomly sampled residents aged 40-79 years responded to the baseline survey (n = 4414; 74%) and were followed at 1, 3 and 5 years (78-83% response rate). The intervention was a 5-year CWI using social marketing to promote PA. The primary outcome was a change in recommended levels of PA. Results: Compared with control communities, adults achieving recommended levels of PA increased in intervention communities [adjusted change difference = 4.6 percentage points (95% confidence interval: 0.4, 8.8)]. The intervention was effective for promoting all types of recommended PAs, i.e. aerobic (walking, 6.4%), flexibility (6.1%) and muscle-strengthening activities (5.7%). However, a bundled approach, which attempted to promote all forms of PAs above simultaneously, was not effective (1.3-3.4%, P ≥ 0.138). Linear dose-response relationships between the CWI awareness and changes in PA were observed (P ≤ 0.02). Pain intensity decreased in shoulder (intervention and control) and lower back (intervention only) but there was little change difference in all musculoskeletal pain outcomes between the groups. Conclusions: The 5-year CWI using the focused social marketing strategy increased the population-level of PA.

Successful prediction of cardiovascular risk by new non-invasive vascular indexes using suprasystolic cuff oscillometric waveform analysis.

BACKGROUND: Recently, new non-invasive vascular indexes named arterial velocity pulse index (AVI) and arterial pressure volume index (API), which is evaluated by a multifunctional blood pressure monitoring device, were developed using cuff oscillometric technologies and suprasystolic cuff oscillometric wave measurement. However, although a few studies including a computational model have been performed, data on subjects with cardiovascular diseases in actual outpatient clinics remain scant. METHODS: We examined a total 252 consecutive outpatients and analyzed two vascular indexes with various clinical parameters to explore potential utilities of these two indexes in actual clinical settings. RESULTS: Although we found that two indexes were correlated with each other, the clinical implications of these indexes seemed to differ. Our analyses showed that AVI significantly correlated with augmentation index, but not with flow-mediated dilatation, and multivariate analyses suggested that enhanced AVI represents increased workload on the heart with elevated central blood pressure. In contrast, although the results of analyses performed to identify clinical parameters independently related to API were obscure and non-specific, after adjustment for multiple clinical variables, API was found to be significantly and independently associated with both Framingham Cardiovascular Risk Score and the Suita Score, suggesting that API is a useful predictor of future cardiovascular events. CONCLUSIONS: These two new vascular indexes might be useful in actual clinical settings to evaluate cardiovascular risks with various clinical backgrounds.

Prognostic significance of quantitative assessment of focal myocardial fibrosis in patients with heart failure with preserved ejection fraction.

BACKGROUND: The aim of this study was to investigate the prognostic value of myocardial focal fibrosis quantified by late gadolinium enhanced (LGE) magnetic resonance imaging (MRI) in patients with heart failure with preserved ejection fraction (HFpEF). METHODS: One-hundred eleven HFpEF patients (mean age: 70 ± 14 years, 55 (50%) female) were enrolled. We excluded patients with previous history of coronary artery disease and/or ischemic pattern of hyper enhancement on LGE MRI. Myocardial enhancement was defined using signal intensity >2SD above the mean signal intensity of a remote myocardium. Major adverse cardiovascular events were defined as cardiovascular death and heart failure requiring hospitalization. RESULTS: During a mean follow up period of 851 ± 609 days, 10 events (2 cardiovascular death, 8 hospitalization for heart failure decompensation) were observed. Area under the receiver operating characteristics curve of LGE% for the detection of future events was 0.721 (95% CI: 0.628-0.802). Multivariate Cox proportional hazard analysis showed that LGE% is an independent predictor of future events after the adjustment with prognostic 5 factors - age, diabetes mellitus, New York Heart Association classification, history of heart failure hospitalization and left ventricular ejection fraction - which were identified in the I-PRESERVE study (Irbesartan in Heart Failure with Preserved Ejection Fraction Study) (hazard ratio=7.913, 95% CI: 1.603-39.05, P=0.012). CONCLUSIONS: Larger size of LGE was significantly associated with high rate of future cardiovascular death and heart failure hospitalization, suggesting that the quantification of myocardial focal fibrosis by LGE MRI could be useful for the risk stratification in HFpEF patients.

Doubly robust estimation of the generalized impact fraction.

The attributable fraction (AF) is commonly used in epidemiology to quantify the impact of an exposure to a disease. Recently, Sjölander and Vansteelandt (2011. Doubly robust estimation of attributable fractions. Biostatistics 12, 112-121) introduced the doubly robust (DR) estimator of the AF, which involves positing models for both the exposure and the outcome and is consistent if at least one of these models is correct. In this article, we derived a DR estimator of the generalized impact fraction (IF) with a polytomous exposure. The IF is a measure that generalizes the AF by allowing the possibility of incomplete removal of the exposure. We demonstrated the performance of the proposed estimator via a simulation study and by application to data from a large prospective cohort study conducted in Japan.

Single-incision laparoscopic surgery using colon-lifting technique for colorectal cancer: a matched case-control comparison with standard multiport laparoscopic surgery in terms of short-term results and access instrument cost.

BACKGROUND: Single-incision laparoscopic surgery (SILS) has been used for colorectal cancer as a minimally invasive procedure. However, there are still difficulties concerning effective triangulation and countertraction. The study's purpose was to clarify the usefulness of the colon-lifting technique (CLT) in SILS for colorectal cancer. METHODS: SILS was performed for cancer (cT2N0 or less) of the right-sided colon (near the ileocecum), sigmoid, or rectosigmoid. The SILS™ Port was used for transumbilical access. A suture string was inserted through the abdominal wall and passed through the mesocolon. The colon was retracted anteriorly and fixed to the abdominal wall. The main mesenteric vessels were placed under tension. Lymph node dissection was performed by medial approach. Short-term surgical outcomes and access port costs were compared between SILS (using CLT) and the standard multiport technique (MPT). The two groups were case-matched by propensity scoring. Analyzed variables included preoperative Dukes stage and tumor location. RESULTS: From June 2009 to April 2011, 27 patients underwent SILS, and from April 2005 to April 2011, 85 patients underwent MPT. Propensity scoring generated 23 matched patients per group for SILS versus MPT comparisons. There were no significant differences in operating time, blood loss, early complications, postoperative analgesic frequency, or length of hospital stay. One MPT patient was converted to open surgery (4.5%); no SILS patients were converted. There were no significant differences in the length of distal cut margin and the number of harvested lymph nodes, except incision length (SILS vs. MPT: 33 vs. 55 mm, P < 0.001). Significant differences favored SILS in access instrument cost (SILS vs. MPT: 62,761 vs. 77,130 Japanese yen, P < 0.001). CONCLUSIONS: SILS performed using CLT was safe and effective in providing radical treatment of cT2N0 cancer in the right-sided colon, sigmoid, or rectosigmoid. SILS was advantageous with respect to cosmesis and lower cost of access instruments.

Risk assessment chart for curability of early gastric cancer with endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) was introduced worldwide as a new treatment option for early gastric cancer, but curability prediction has not been evaluated on an individual basis. OBJECTIVE: To analyze factors contributing to the curability of early gastric cancer after ESD and to construct a risk assessment chart for the probability of curability. DESIGN: Single-institution retrospective review. SETTING: University hospital. PATIENTS: From June 2000 to April 2010, we treated 961 early gastric cancers in 784 patients (mean age 70.2 years). INTERVENTION: ESD procedures were performed using typical sequences. MAIN OUTCOME MEASUREMENTS: Risk factors related to resectability (en bloc or piecemeal resection) and curability (curative or noncurative resection) after ESD were analyzed using logistic regression analysis. Using this model, we constructed a risk assessment chart to predict the probability of noncurability from patient characteristics. RESULTS: The en bloc and curative resection rates were 98.9% and 88.1%, respectively, after ESD. Significant contributors to noncurative ESD were large lesions, upper location, and ulcer findings. Predicted noncurability probabilities were displayed in 4 colors for each risk level (light blue, blue, yellow, and red) by combining tumor size, tumor location, and ulcer findings. Probability of noncurability was highest (≥ 40%) in ulcerative large tumors (>30 mm in diameter) in the upper location (red) and lowest in nonulcerative small tumors (≤ 20 mm in diameter) in the lower location (light blue). LIMITATIONS: Retrospective design and single-site data collection. CONCLUSIONS: This risk assessment chart shows individuals their pretreatment curability assessment with successful ESD and may be an educational tool for trainees or a decision-making tool.

A meta-analysis of (18)F-Fluoride positron emission tomography for assessment of metastatic bone tumor.

PURPOSE: The aim of this study was to assess the diagnostic performance of (18)F-Fluoride positron emission tomography (PET) or positron emission tomography/computed tomography (PET/CT) compared with bone scintigraphy (BS) planar or BS planar and single photon emission computed tomography (SPECT) in evaluating patients with metastatic bone tumor. MATERIALS AND METHODS: We performed a meta-analysis of all available studies addressing the diagnostic accuracy of (18)F-Fluoride PET, (18)F-Fluoride PET/CT, BS planar, and BS planar and SPECT for detecting the metastatic bone tumor. We determined sensitivities and specificities across studies, calculated positive and negative likelihood ratios, and drew summary receiver operating characteristic curves using hierarchical regression models. We also compared the effective dose and cost-effectiveness estimated by data from the enrolled studies between (18)F-Fluoride PET or PET/CT and BS planar or BS planar and SPECT. RESULTS: When comparing all studies with data on (18)F-Fluoride PET or PET/CT, sensitivity and specificity were 96.2% [95% confidence interval (CI) 93.5-98.9%] and 98.5% (95% CI 97.0-100%), respectively, on a patient basis and 96.9% (95% CI 95.9-98.0%) and 98.0% (95% CI 97.1-98.9%), respectively, on a lesion basis. The Az values of (18)F-Fluoride PET or PET/CT were 0.986 for the patient basis and 0.905 for the lesion basis, whereas those of BS or BS and SPECT were 0.866 for the patient basis and 0.854 for the lesion basis. However, the estimated effective dose and average cost-effective ratio were poorer for (18)F-Fluoride PET or PET/CT than those of BS planar or BS planar and SPECT. CONCLUSION: (18)F-Fluoride PET or PET/CT has excellent diagnostic performance for the detection of metastatic bone tumor, but the estimated effective dose and average cost-effective ratio are at a disadvantage compared with BS planar or BS planar and SPECT.