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Introduction: Despite the serious risks of diabetes with hepatitis C virus (HCV) infection, this preventable comorbidity is rarely a priority for HCV elimination. We aim to examine how a shared care model could eliminate HCV in patients with diabetes (PwD) in primary care., Methods: There were 27 community-based Diabetes Health Promotion Institutes in each township/city of Changhua, Taiwan. PwD from these institutes from January 2018 to December 2020 were enrolled. HCV screening and treatment were integrated into diabetes structured care through collaboration between diabetes care and HCV care teams. Outcome measures included HCV care continuum indicators. Township/city variation in HCV infection prevalence and care cascades were also examined., Results: Of the 10,684 eligible PwD, 9,984 (93.4%) underwent HCV screening, revealing a 6.18% (n = 617) anti-HCV seroprevalence. Among the 597 eligible seropositive individuals, 507 (84.9%) completed the RNA test, obtaining 71.8% positives. Treatment was initiated by 327 (89.8%) of 364 viremic patients, and 315 (86.5%) completed it, resulting in a final cure rate of 79.4% (n = 289). Overall, with the introduction of antivirals in this cohort, the prevalence of viremic HCV infection dropped from 4.44% to 1.34%, yielding a 69.70% (95% credible interval 63.64%-77.03%) absolute reduction., Discussion: Although HCV prevalence varied, the care cascades achieved consistent results across townships/cities. We have further successfully implemented the model in county-wide hospital-based diabetes clinics, eventually treating 89.6% of the total PwD. A collaborative effort between diabetes care and HCV elimination enhanced the testing and treatment in PwD through an innovative shared care model., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Purpose: To describe in detail the special features of a previously unappreciated "classic invasive lobular carcinoma" which is confined to the terminal ductal lobular units (TDLUs) and differs considerably from the extensive classic invasive lobular carcinoma, and to suggest specific terminology., Method: All invasive breast cancer cases without associated microcalcifications diagnosed in our Institution with the histopathologic diagnosis of classic invasive lobular carcinoma during the years 1996-2019 (n = 560) formed the basis of this study. The cases were prospectively classified according to their imaging biomarkers (mammographic features) and followed up to Dec 31, 2021, to determine long-term patient outcome. An additional 2600 invasive breast cancer cases (diagnosed other than invasive lobular carcinoma) without associated microcalcifications served as a reference group. Detailed histopathologic analysis used large format (10x8 cm) thin section technique and staining methods including hematoxylin-eosin (H&E), E-cadherin, cytokeratin CK 5/6, a transmembrane glycoprotein (CD44) and anti-actin or anti-smooth muscle myosin heavy chain., Results: The imaging biomarkers differentiated two separate disease subgroups, having the same histopathologic diagnosis, classic invasive lobular carcinoma. One of these has the imaging biomarker of extensive architectural distortion with no central tumour mass, occupies the extralobular mesenchyme and has a long-term survival of 56%. The other subgroup forms stellate or circular non-calcified tumour masses usually smaller than 20 mm, which appear to arise in the intralobular mesenchyme, and has a significantly better long-term survival of 84%., Conclusions: There is a striking difference between the subgross histopathology and the mammographic appearance (imaging biomarkers) of two breast malignancies having the same histopathologic diagnosis, "classic invasive lobular carcinoma". The large difference in the long-term outcome of these two tumour types is even more striking. Using the same specific term, "classic invasive lobular carcinoma", to describe these two separate entities can adversely affect management decisions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Clinical, imaging and outcome observations indicate that diffusely infiltrating breast cancer, presenting as a large region of architectural distortion on the mammogram and conventionally termed classic infiltrating lobular carcinoma of diffuse type, represents a very unusual breast malignancy. This article aims to draw attention to the complex clinical, imaging, and large format thin and thick section histopathologic features of this malignancy, which challenges our current diagnostic and therapeutic management practices., Methods: Prospectively collected data from the randomized controlled trial (1977-85) and from the subsequent, ongoing population-based mammography service screening (1985-2019) with more than four decades of follow up in Dalarna County, Sweden provided the database for investigating this breast cancer subtype. Large format thick (subgross) and thin section histopathologic images of breast cancers diagnosed as "diffusely infiltrating lobular carcinoma of the breast" were correlated with their mammographic tumour features (imaging biomarkers) and the long-term patient outcome., Results: This malignancy does not have a distinct tumour mass or focal skin retraction at clinical breast examination; instead, it causes an indistinct "thickening" and eventually shrinks the entire breast. A dominant feature is extensive architectural distortion on the mammograms caused by an excessive amount of cancer-associated connective tissue. Unlike other invasive breast malignancies, this subtype forms concave contours with the surrounding adipose connective tissue, a feature that makes it difficult to detect on mammograms. Women with this diffusely infiltrating breast malignancy have a 60% long-term survival. Its long-term patient outcome is surprisingly poor compared to that expected from its relatively favourable immunohistochemical biomarkers, including a low proliferation index and remains unaffected by adjuvant therapy., Conclusions: The unusual clinical, histopathologic and imaging features of this diffusely infiltrating breast cancer subtype are consistent with a site of origin quite different from that of other breast cancers. Additionally, the immunohistochemical biomarkers are deceptive and unreliable because they indicate a cancer with favourable prognostic features predictive of a good long-term outcome. The low proliferation index is usually indicative of a breast cancer with a good prognosis, but in this subtype the prognosis is poor. If we are to improve the dismal outcome of this malignancy, it will be necessary to clarify its true site of origin, which will be a prerequisite for gaining a better understanding why current management efforts often fail and why the fatality rate is so unfortunately high. Breast radiologists should be watchful for the development of subtle signs of architectural distortion at mammography. Large format histopathologic technique enables adequate correlation of the imaging and histopathologic findings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study was undertaken to assess the role of sex differences in the effects of exercise behavior change on incident metabolic syndrome (MetS) in Changhua County, Taiwan. Using data derived from the Changhua Community-based Integrated Screening (CHCIS), 22,594 eligible residents aged 40 years or older had the screening at least twice from 2005 to 2018. A prospective cohort study was designed to follow up the normal cohort without MetS at baseline to ascertain incident MetS in the light of the criteria of the Epidemiology Task Force Consensus Group. We then evaluated whether there was a sex difference in the outcome of incident MetS attributed to the change in exercise behavior from three (no, irregular, and regular exercise) maintained patterns already defined at baseline to either the enhanced pattern or the reduced pattern by the end of follow-up. We applied Cox proportional hazards regression model stratified by sex for estimating the hazard ratio of any two-group comparison. After adjustment for sociodemographic factors, the number of screenings attended, personal disease history, and other health behaviors, the influence of change in exercise behavior on incident MetS was statistically significant only in men. Specifically, maintaining no exercise showed a lower risk of MetS than maintaining regular exercise 21 % in men. Regarding the change in exercise behavior, men with the enhanced pattern reduced the risk of MetS by 15 % compared with those maintaining regular exercise. The findings suggest that positive changes in exercise behavior reduce the incidence of MetS in men but not in women., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Inc.)

Background: In the face of rapid emerging variants of concern (VOCs) with potential of evading immunity from Beta to Omicron and uneven distribution of different vaccine brands, a mix-match strategy has been considered to enhance immunity. However, whether increasing immunogenicity using such a mix-match can lead to high clinical efficacy, particularly when facing Omicron pandemic, still remains elusive without using the traditional phase 3 trial. The aim of this study is to demonstrate how to evaluate correlates of protection (CoP) of the mix-match vaccination., Methods: Data on neutralizing antibody (NtAb) titers and clinical efficacy against Wuhan or D614G strains of homologous ChAdOx1 nCov-19 or mRNA-1273 and heterologous vaccination were extracted from previous studies for demonstration. The reductions in NtAb titers of homologous vaccination against Beta, Delta, and Omicron variants were obtained from literatures. A Bayesian inversion method was used to derive CoP from homologous to mix-match vaccine. Findings The predicted efficacy of ChAdOx1 nCov-19 and mRNA-1273 for Wuhan or D614G strains was 93 % (89 %-97 %). Given 8 ∼ 11-fold, 2 ∼ 5.5-fold, and 32.5 ∼ 36-fold reduction of NtAb for Beta, Delta, and Omicron variants compared with D614G, the corresponding predictive efficacy of the mix-match ranged from 75.63 % to 73.87 %, 84.87 % to 81.25 %, and 0.067 % to 0.059 %, respectively. Interpretations While ChAdOx1 nCov-19 and mRNA-1273 used for demonstrating how to timely evaluate CoP for the mix-match vaccine still provides clinical efficacy against Beta and Delta VOCs but it appears ineffective for Omicron variants, which highlights the urgent need for next generation vaccine against Omicron variant., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Early detection of esophageal cancer in patients with head and neck cancers may alter treatment planning and improve survival. However, standard endoscopic screening is not feasible for some patients with tumor-related airway compromise or postirradiation trismus., Objective: To evaluate a novel, sequential approach by integrating ultrathin endoscopy with narrow-band imaging and Lugol chromoendoscopy., Design: Cross-sectional study., Setting: Single center in Taiwan., Patients: Forty-four consecutive patients with transoral difficulty screened for synchronous or metachronous esophageal cancer., Main Outcome Measurements: Sensitivity, specificity, and accuracy in the detection of mucosal high-grade neoplasia or invasive cancer., Results: Fifty-four endoscopic interpretations were obtained, and 11 mucosal high-grade neoplasia and 7 invasive cancers were confirmed by histology. The mean examination time was 19.4 minutes (range 7.9-35.2 minutes), and all patients tolerated the procedure well. Sensitivity, specificity, and accuracy (with 95% CI) were 55.6% (95% CI, 33.5%-75.6%), 97.2% (95% CI, 85.8%-99.3%), and 83.3% (95% CI, 71.2%-90.9%), respectively, for standard endoscopy; 88.9% (95% CI, 66.9%-96.6%), 97.2% (95% CI, 85.8%-99.3%), and 94.4% (95% CI, 84.9%-97.9%), respectively, with the adjunct of narrow-band imaging; and 88.9% (95% CI, 66.9%-96.6%), 72.2% (95% CI, 55.9%-84.1%), and 77.8% (95% CI, 64.9%-86.8%), respectively, with the adjunct of Lugol chromoendoscopy. When we integrated all interpretations on the basis of the sequential approach, the estimated probability of false-negative findings was 1.2% (95% CI, 0.1%-4.6%)., Limitations: Inherent shortcomings of ultrathin endoscopy, such as its resolution, light source, and lack of magnification., Conclusions: The use of ultrathin endoscopy in a sequential approach for multimodal detection is feasible in patients with transoral difficulty and substantially increases the detection rate of synchronous or metachronous neoplasms.

Summary: It makes intuitive sense to model the natural history of breast cancer, tumor progression from preclinical screen-detectable phase (PCDP) to clinical disease, as a multistate process, but the multilevel structure of the available data, which generally comes from cluster (family)-based service screening programs, makes the required parameter estimation intractable because there is a correlation between screening rounds in the same individual, and between subjects within clusters (families). There is also residual heterogeneity after adjusting for covariates. We therefore proposed a Bayesian hierarchical multistate Markov model with fixed and random effects and applied it to data from a high-risk group (women with a family history of breast cancer) participating in a family-based screening program for breast cancer. A total of 4867 women attended (representing 4464 families) and by the end of 2002, a total of 130 breast cancer cases were identified. Parameter estimation was carried out using Markov chain Monte Carlo (MCMC) simulation and the Bayesian software package WinBUGS. Models with and without random effects were considered. Our preferred model included a random-effect term for the transition rate from preclinical to clinical disease (sigma(2)(2f)), which was estimated to be 0.50 (95% credible interval = 0.22-1.49). Failure to account for this random effect was shown to lead to bias. The incorporation of covariates into multistate models with random effect not only reduced residual heterogeneity but also improved the convergence of stationary distribution. Our proposed Bayesian hierarchical multistate model is a valuable tool for estimating the rate of transitions between disease states in the natural history of breast cancer (and possibly other conditions). Unlike existing models, it can cope with the correlation structure of multilevel screening data, covariates, and residual (unexplained) variation.

Objective: The present study is done to assess the relative cost-effectiveness, optimal initial age, and interscreening interval between primary and secondary prevention strategies for gastric cancer., Methods: Base-case estimates, including variables of natural history, efficacy of intervention, and relevant cost, were derived from two preventive programs targeting a high-risk population. Cost-effectiveness was compared between chemoprevention with (13)C urea breath testing followed by Helicobacter pylori (H. pylori) eradication and high-risk surveillance based on serum pepsinogen measurement and confirmed by endoscopy. The main outcome measure was cost per life-year gained with a 3% annual discount rate., Results: The incremental cost-effectiveness ratio (ICER) for once-only chemoprevention at age 30 years versus no screening was U.S. $17,044 per life-year gained. Eradication of H. pylori at later age or with a periodic scheme yielded a less favorable result. Annual high-risk screening at age of 50 years versus no screening resulted in an ICER of U.S. $29,741 per life-year gained. The ICERs of surveillance did not substantially vary with different initial ages or interscreening intervals. Chemoprevention could be dominated by high-risk surveillance when the initial age was older than 44 years. Otherwise, chemoprevention was more cost-effective than high-risk surveillance, either at ceiling ratios of U.S. $15,762 or up to U.S. $50,000. The relative cost-effectiveness was most sensitive to the infection rate of H. pylori and proportion of early gastric cancer in all detectable cases., Conclusions: Early H. pylori eradication once in lifetime seems more cost-effective than surveillance strategy. However, the choice is still subject to the risk of infection, detectability of early gastric cancer, and timing of intervention.

Purpose: Prognosis of small hepatocellular carcinoma depends on a constellation of time-varying predictors in association with liver function. We aimed to elucidate the impact of these time-dependent predictors on survival., Patients and Methods: A total of 108 patients with hepatocellular carcinoma smaller than 5 cm in diameter were recruited. Series of laboratory data and clinical assessments were retrieved from medical records. The time-dependent scoring system for the prediction of death was developed in accordance with a time-dependent Cox regression model., Results: Time trends for biologic predictors parallel cumulative survival of small hepatocellular carcinoma cases. Higher serum alpha-fetoprotein level was identified as the most significant time-dependent predictor. Other significant predictors included aspartate transaminase, bilirubin, alkaline phosphatase, and albumin levels and prothrombin time. Time-dependent surveillance scoring system shows the cutoff points of scores at 6 months, 1 year, 2 years, and 3 years were 42, 21, 19, and 31, respectively; the estimates of sensitivity, 100%, 100%, 100%, and 87.5%, respectively; and the estimates of specificity, 91.26%, 67.02%, 60.27%, and 78.26%, respectively. Predictive validity for this time-dependent Cox regression model, particularly within 1-year of follow-up, is good., Discussion: The dynamic relationships between time-dependent predictors and risk of death were illustrated. A time-dependent predictive scoring system using these dynamic relationships was developed for real-time surveillance.

Application of case-cohort design to multi-state disease progression in epidemiological studies has been barely addressed. To estimate multi-state disease natural history, we proposed non-homogeneous exponential regression stochastic model to accommodate the data requiring a non-standard case-cohort design. We allowed transition rates to vary with time by modelling the time of transitions between two states with Weibull distribution. The exponential regression model was used to assess the effect of patient-specific covariates on multi-state disease progressions. This method was successfully applied to two epidemiological applications. The first application was to elucidate the effect of betel quids, smoking and alcohol on three-state disease progression, from normal, through leukoplakia and finally to oral cancer. The second application was to extend the three-state to a five-state model to estimate transition rates from normal to diminutive adenoma to small adenoma to large adenoma and finally to invasive carcinoma of the colon and rectum. Finally, an index for assessing the treatment efficacy for pre-cancerous lesion was developed by comparing transition probabilities derived from the proposed model with the probabilities of malignant transformation after a medical regime., (Copyright 2004 John Wiley & Sons, Ltd.)