Utility of polygenic scores across diverse diseases in a hospital cohort for predictive modeling.

Polygenic scores estimate genetic susceptibility to diseases. We systematically calculated polygenic scores across 457 phenotypes using genotyping array data from China Medical University Hospital. Logistic regression models assessed polygenic scores' ability to predict disease traits. The polygenic score model with the highest accuracy, based on maximal area under the receiver operating characteristic curve (AUC), is provided on the GeneAnaBase website of the hospital. Our findings indicate 49 phenotypes with AUC greater than 0.6, predominantly linked to endocrine and metabolic diseases. Notably, hyperplasia of the prostate exhibited the highest disease prediction ability (P value = 1.01 × 10-19, AUC = 0.874), highlighting the potential of these polygenic scores in preventive medicine and diagnosis. This study offers a comprehensive evaluation of polygenic scores performance across diverse human traits, identifying promising applications for precision medicine and personalized healthcare, thereby inspiring further research and development in this field.

Sequential multimodal treatments with chemotherapy and surgery for advanced soft tissue sarcoma may be associated with better survival than chemotherapy.

BACKGROUND: In patients with advanced soft tissue sarcoma (STS), surgery had been reported to be associated with superior overall survival (OS). Chemotherapy details for such patients were less reported, and whether multimodal treatment with surgery and chemotherapy provides extra survival benefit remains unclear. METHODS: We retrospectively reviewed patients with newly diagnosed advanced STS treated at National Taiwan University Hospital from January 1, 2011, to December 31, 2017. OS was calculated from the day of diagnosis of advanced STS to the day of death or last follow-up. Baseline patient characteristics and details regarding surgery and chemotherapy were recorded. RESULTS: A total of 545 patients were diagnosed with STS from 2011 to 2017, of which 226 patients had advanced STS. The median age was 54.7 years, and 54% of patients were women. Approximately 38% of patients with advanced STS underwent surgery and exhibited a trend of longer OS compared with who did not (median = 18.6 vs. 11.9 months, p = 0.083). In the chemotherapy subgroup, the benefit of surgery was more prominent (median = 21.9 vs. 16.5 months, p = 0.037). Patients who received chemotherapy prior to surgery exhibited numerically longer OS than those who underwent surgery first (median = 33.9 vs. 18.3 months, p = 0.155). After adjusting other clinical factors, chemotherapy remained an independent factor associated with favourable OS. CONCLUSION: Surgery may be more beneficial for the patients who receive chemotherapy. Our results support evaluation of sequential multimodal treatments strategy including surgery and chemotherapy in patients with advanced STS.

The Risk of Cancer-Associated and Radiotherapy-Associated Cardiovascular Diseases among Patients with Breast Cancer.

BACKGROUND: The cardio-related issues should be emphasized as the survival rates of breast cancer increased. We investigated the risk of coronary artery disease (CAD) and stroke due to breast cancer or radiotherapy. METHODS: In this retrospective cohort study, breast cancer patients diagnosed between 2007 and 2016 were recruited from Taiwan Cancer Registry Database and were followed until the end of 2018 by linking with the Taiwan National Health Insurance Database. The general population was randomly selected from the whole population in 2007. Standardized incidence ratios (SIR) were calculated to compare the risk of CAD and stroke between patients and the general population. Within the cohort, we included the patients diagnosed between 2011 and 2016. Cox proportional hazards model and subdistribution hazard function were used to investigate the associations of radiotherapy with the risk of CAD and stroke. RESULTS: Overall SIR of CAD was 0.82 (95% confidence interval [CI]: 0.78-0.86), while were 1.43 and 1.08 (95% CI: 1.30-1.55 and 1.00-1.16) 1 and 2 years after diagnosis, respectively. Overall SIR of stroke was 0.63 (95% CI: 0.60-0.67), the results were similar after considering the time since diagnosis. The adjusted hazard ratios (HR) for the associations of radiotherapy with CAD and stroke risk were 0.91 (95% [CI] = 0.76-1.09) and 0.84 (95% CI = 0.68-1.04), respectively. The results were similar by using subdistribution hazard function. CONCLUSIONS: The risk of CAD was higher within the first 2 years of breast cancer diagnosis. We found no association between radiotherapy and the risk of CAD and stroke.

Machine learning approaches for biomarker discovery to predict large-artery atherosclerosis.

Large-artery atherosclerosis (LAA) is a leading cause of cerebrovascular disease. However, LAA diagnosis is costly and needs professional identification. Many metabolites have been identified as biomarkers of specific traits. However, there are inconsistent findings regarding suitable biomarkers for the prediction of LAA. In this study, we propose a new method integrates multiple machine learning algorithms and feature selection method to handle multidimensional data. Among the six machine learning models, logistic regression (LR) model exhibited the best prediction performance. The value of area under the receiver operating characteristic curve (AUC) was 0.92 when 62 features were incorporated in the external validation set for the LR model. In this model, LAA could be well predicted by clinical risk factors including body mass index, smoking, and medications for controlling diabetes, hypertension, and hyperlipidemia as well as metabolites involved in aminoacyl-tRNA biosynthesis and lipid metabolism. In addition, we found that 27 features were present among the five adopted models that could provide good results. If these 27 features were used in the LR model, an AUC value of 0.93 could be achieved. Our study has demonstrated the effectiveness of combining machine learning algorithms with recursive feature elimination and cross-validation methods for biomarker identification. Moreover, we have shown that using shared features can yield more reliable correlations than either model, which can be valuable for future identification of LAA.

Efficient method for whole-breast irradiation therapy using Halcyon linear accelerators.

BACKGROUND: The Halcyon is a linear accelerator-based treatment machine designed for a high-throughput simplified workflow. The machine features a compact jawless design, dual-layer multileaf collimators, and a single 6-MV flattening filter-free (FFF) beam. However, the machine's 6-MV FFF beam may restrict its applicability to conventional techniques, such as field-in-field (FiF) radiotherapy, for breast cancer treatment. This study developed a practical and efficient hybrid method for imaging, planning, and irradiation procedures for whole-breast irradiation using Halcyon linear accelerators. MATERIALS AND METHODS: The proposed method involves five major steps: (1) field arrangement, (2) planning target volume (PTV) generation and evaluation, (3) basal plan generation, (4) inverse planning intensity-modulated radiation therapy plan generation, and (5) plan evaluation and irradiation. The PTV is generated using isodose curves plotted on the basis of tangential fields, which are applied to create a basal plan. Subsequently, a basal-dose-compensation approach is applied to further optimize the treatment plan. This efficient workflow necessitates executing only one onboard cone-beam computed tomography procedure. This study included 10 patients with early-stage breast cancer who were treated at our center. The performance of the proposed method was evaluated by comparing its corresponding irradiation time and dose statistics with those derived for a dynamically flattened beam-based FiF (DFB-FiF) method. RESULTS: All plans were normalized to ensure that 98% of the prescribed dose covered 95% of the PTV. On average, the global maximum doses in the proposed and DFB-FiF methods were lower than 106%. The homogeneity index for right-sided (left-sided) breast cancer was 0.053 (0.056) in the proposed method and 0.073 (0.076) in the DFB-FiF method. The dose statistics of normal tissues, including the contralateral breast, heart, and lungs, were comparable between the methods. However, the irradiation time per monitor unit in the proposed method was approximately five times faster than that in the DFB-FiF method, but the planning time and complexity were similar between the methods. CONCLUSIONS: This study developed and evaluated an efficient and practical hybrid method for whole-breast irradiation using the Halcyon. This method can significantly reduce the irradiation time, while providing comparable dose statistics to the DFB-FiF method.

Increased standardised incidence ratio of cardiovascular diseases among colorectal cancer patients.

PURPOSE: Evidence regarding the relationship between colorectal cancer and the risk of cardiovascular disease (CVD) is limited. Thus, in this study, we aimed to determine the standardised incidence ratio (SIR) of CVDs in colorectal cancer patients in Taiwan. METHODS: A population-based cohort study enrolling the incident colorectal cancer population based on the Cancer Registry Database from 2007 to 2016 was conducted (n = 94,233, mean age: 62.4 years, 43.0% women). New cases of CVD, including coronary heart disease and ischemic stroke, through 31 December 2018 were obtained from the National Health Insurance Research Database and National Death Registry. Compared with the general population (n = 1,977,659, mean age: 44.3 years, 49.6% women), age- and sex-specific SIRs for CVDs were calculated by the time since diagnosis. RESULTS: A total of 6852 cardiovascular events occurred in colorectal cancer patients during a median follow-up of 4.4 years. The SIR of CVD was highest in the first year after diagnosis (SIR: 1.45, 95% confidence interval: 1.39-1.50); however, this decreased to the same value as that of the general population in later years. Similar patterns were observed for the SIR of coronary heart disease. However, the SIR of ischemic stroke among colorectal cancer patients was low from the second year following cancer diagnosis. CONCLUSIONS: Colorectal cancer patients are at an increased risk of developing CVD, especially coronary heart disease, during the first 3 years following colorectal cancer diagnosis.

The Risk of Ischemic Stroke in Head and Neck Cancer Patients and Those Who Were Treated with Radiotherapy: A Population-Based Cohort Study.

BACKGROUND: To investigate the standardized incidence ratios (SIR) of stroke in patients with head and neck cancer and their relationship to radiotherapy. METHODS: Patients with head and neck cancer ages 20-85 years were enrolled from 2007 to 2016 using the Taiwan Cancer Registry. The study endpoint was fatal and non-fatal ischemic stroke, ascertained by the National Health Insurance Research Database. Age- and sex-adjusted SIRs, categorized by 10-year age standardization, were used to compare the patients with head and neck cancer with a randomly selected 2,000,000 general population. We compared the risk of stroke in patients with head and neck cancer who received radiotherapy or surgery alone. Multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox regression analysis with competing risk. RESULTS: Among 41,266 patients (mean age, 54.1 years; men, 90.6%) in the median follow-up period of 3.9 years, 1,407 strokes occurred. Compared with the general population, the overall SIR of stroke was 1.37 (95% CI, 1.30-1.44) in patients with head and neck cancer. In patients with head and neck cancer, the fully adjusted HR of stroke in those who received radiotherapy was 0.96 (95% CI, 0.83-1.10), compared with those who received surgery alone. CONCLUSIONS: Patients with head and neck cancer had a higher risk of fatal or non-fatal ischemic stroke. The risk of stroke was not higher in patients initially treated with radiotherapy. IMPACT: Oncologists should emphasize stroke prevention in all patients with head and neck cancer, not only in those who received radiotherapy.

The selection of photoinitiators for photopolymerization of biodegradable polymers and its application in digital light processing additive manufacturing.

Digital light processing additive manufacturing (DLP-AM) technology has received a lot of attention in the field of biomedical engineering due to its high precision and customizability. However, some photoinitiators, as one of the key components in DLP-AM, may present toxicity and limit the application of DLP-AM toward biomedical applications. In order to gain further insights into the correlation between biocompatibility and photoinitiators in photoresins, a study on the selection of photoinitiators used in DLP-AM is conducted. The light absorbance range and cytocompatibility of four photoinitiators, vitamin B2 combined with triethanolamine (B2/TEOA), diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO), 2-dimethoxy-2-phenylacetophenone (DMPA), and 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone (I2959), are characterized. Each photoinitiator is then combined with poly(glycerol sebacate) acrylate (PGSA) and poly(ε-caprolactone) diacrylate (PCLDA), to evaluate their miscibility and film formation ability through photopolymerization. The mechanical properties, in vitro and in vivo biocompatibility studies on bulk films are investigated. It is found that B2/TEOA and TPO exhibit a wider light absorbance range than I2959 and DMPA. PGSA films with B2/TEOA (PGSA-B2/TEOA) is capable of sustaining cell proliferation up to 10 days and showing low immune responses after 14 days post implantation, proving its biocompatibility. Although B2/TEOA requires longer photopolymerization time, the mechanical strength of PGSA-B2/TEOA is comparable to PGSA films with TPO and DMPA, and this combination is 3D-printable through DLP-AM at the rate of 100 s per layer. In summary, B2/TEOA is a promising photoinitiator for 3D printing.

GWAS Meta-Analysis Reveals Shared Genes and Biological Pathways between Major Depressive Disorder and Insomnia.

Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders worldwide. Among the symptoms of MDD, sleep disturbance such as insomnia is prominent, and the first reason patients may seek professional help. However, the underlying pathophysiology of this comorbidity is still elusive. Recently, genome-wide association studies (GWAS) have begun to unveil the genetic background of several psychiatric disorders, including MDD and insomnia. Identifying the shared genomic risk loci between comorbid psychiatric disorders could be a valuable strategy to understanding their comorbidity. This study seeks to identify the shared genes and biological pathways between MDD and insomnia based on their shared genetic variants. First, we performed a meta-analysis based on the GWAS summary statistics of MDD and insomnia obtained from Psychiatric Genomics Consortium and UK Biobank, respectively. Next, we associated shared genetic variants to genes using two gene mapping strategies: (a) positional mapping based on genomic proximity and (b) expression quantitative trait loci (eQTL) mapping based on gene expression linkage across multiple tissues. As a result, a total of 719 shared genes were identified. Over half (51%) of them are protein-coding genes. Functional enrichment analysis shows that the most enriched biological pathways are related to epigenetic modification, sensory perception, and immunologic signatures. We also identified druggable targets using a network approach. Together, these results may provide insights into understanding the genetic predisposition and underlying biological pathways of comorbid MDD and insomnia symptoms.

Peri-radiosurgical administration of bevacizumab improves radiographic response to single and fractionated stereotactic radiosurgery for large brain metastasis.

INTRODUCTION: Stereotactic radiosurgery (SRS) is a standard of care for brain metastases (BM) patients, yet large BM are at a greater risk for radionecrosis and local progression (LP). Concomitant bevacizumab and radiotherapy has been shown to improve outcomes in primary and metastatic brain tumors. This retrospective study investigated the efficacy and safety of concurrent bevacizumab and SRS for large BM. METHODS: From 2015 to 2019, patients with a BM diameter ≥ 2 cm who received either combination therapy (n = 49, SRS + BVZ group), or SRS alone (n = 73, SRS group) were enrolled. Bevacizumab was given peri-radiosurgically with a 2-week interval. Radiographic response was assessed using the RECIST version 1.1. Competing risk and logistic regression analysis were performed to evaluate prognostic factors. RESULTS: Radiographic response was achieved in 41 patients (84%) in the SRS + BVZ group and 37 patients (51%) in the SRS group (p = 0.001). In the multivariate regression analysis, concurrent bevacizumab was independently associated with a better radiographic response (p = 0.003). The cumulative incidences of LP and ≥ grade 2 radionecrosis at 12 months between the SRS + BVZ group and SRS group were 2% versus 6.8%, and 14.3% versus 14.6%, respectively. For patients with BM size ≥ 3 cm, the cumulative incidence of LP was significantly lower in the SRS + BVZ group (p = 0.03). No ≥ grade 4 toxicity was observed in either group. CONCLUSIONS: Concurrent bevacizumab and SRS for large BM is highly effective, with a better radiographic response and minimal excessive treatment-related toxicities. Peri-radiosurgical bevacizumab preferentially reduced the risk of LP, especially for BM size ≥ 3 cm.

The impact of variable relative biological effectiveness in proton therapy for left-sided breast cancer when estimating normal tissue complications in the heart and lung.

The aim of this study was to evaluate the clinical impact of relative biological effectiveness (RBE) variations in proton beam scanning treatment (PBS) for left-sided breast cancer versus the assumption of a fixed RBE of 1.1, particularly in the context of comparisons with photon-based three-dimensional conformal radiotherapy (3DCRT) and volumetric modulated arc therapy (VMAT). Ten patients receiving radiation treatment to the whole breast/chest wall and regional lymph nodes were selected for each modality. For PBS, the dose distributions were re-calculated with both a fixed RBE and a variable RBE using an empirical RBE model. Dosimetric indices based on dose-volume histogram analysis were calculated for the entire heart wall, left anterior descending artery (LAD) and left lung. Furthermore, normal tissue toxicity probabilities for different endpoints were evaluated. The results show that applying a variable RBE significantly increases the RBE-weighted dose and consequently the calculated dosimetric indices increases for all organs compared to a fixed RBE. The mean dose to the heart and the maximum dose to the LAD and the left lung are significantly lower for PBS assuming a fixed RBE compared to 3DCRT. However, no statistically significant difference is seen when a variable RBE is applied. For a fixed RBE, lung toxicities are significantly lower compared to 3DCRT but when applying a variable RBE, no statistically significant differences are noted. A disadvantage is seen for VMAT over both PBS and 3DCRT. One-to-one plan comparison on 8 patients between PBS and 3DCRT shows similar results. We conclude that dosimetric analysis for all organs and toxicity estimation for the left lung might be underestimated when applying a fixed RBE for protons. Potential RBE variations should therefore be considered as uncertainty bands in outcome analysis.

Simvastatin Inhibits CYR61 Expression in Orbital Fibroblasts in Graves' Ophthalmopathy through the Regulation of FoxO3a Signaling.

Graves' ophthalmopathy (GO), which is characterized by orbital tissue inflammation, expansion, and fibrosis, is the ocular manifestation in 25% to 50% of patients with Graves' disease. As the pathology of GO is driven by autoimmune inflammation, many proinflammatory cytokines/chemokines, including TNF-α, IL-1ß, IL-6, and CCL20, are crucial in the pathogenesis of GO to activate the orbital fibroblasts. Cysteine-rich protein 61 (CYR61), which is known to regulate cell proliferation, adhesion, and migration, plays a proinflammatory role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. CYR61 was considered a potential biomarker of GO in recent studies. Statins, which are cholesterol-lowering drugs, were found to reduce the risk of GO, probably through their anti-inflammatory and immunomodulatory effects. In this study, we established a link between CYR61 and statins in the pathogenesis and potential treatment for GO. Firstly, our data showed the overexpression of CYR61 in the orbital tissue (n = 4) and serum specimens (n = 6) obtained from the patients with inactive GO. CYR61 could induce the production of IL-6 and CCL20 in cultured GO orbital fibroblasts. The expression of CYR61 in cultured GO orbital fibroblasts was upregulated via TNF-α stimulation. Secondly, we pretreated cultured GO orbital fibroblasts using simvastatin, a statin, followed by TNF-α stimulation. The data revealed that simvastatin could inhibit TNF-α-induced CYR61 expression by modulating the activity of transcription factor FoxO3a. Our results provided insights into some cellular mechanisms that may explain the possible protective effects of simvastatin against the development of GO.

l-Arginine Grafted Poly(Glycerol Sebacate) Materials: An Antimicrobial Material for Wound Dressing.

This study focuses on the development and evaluation of a novel wound dressing material. l-arginine grafted poly(glycerol sebacate) materials (PGS-g-Arg) are developed by chemical conjugation of l-arginine on poly(glycerol sebacate) chains and the mechanical property, water vapor transmission rate, antimicrobial functions and biocompatibility are investigated. At various l-arginine grafting ratio, the mechanical properties are tunable. It was found that between 7-13% l-arginine grafting ratios, the tensile strengths of PGS-g-Arg were similar to that of natural skin. These materials are shown with a low water vapor transmission rate, 6.1 to 10.3 g/m2/h, which may form a barrier and assist in the closure of wounds. Inhibition in the growth of Pseudomonas aeruginosa and Staphylococcus aureus was observed on PGS-g-Arg, and a series of experiments were conducted to confirm its biocompatibility. In summary, l -arginine grafted poly(glycerol sebacate) may offer a novel option for wound dressing.

End-of-Range Radiobiological Effect on Rib Fractures in Patients Receiving Proton Therapy for Breast Cancer.

PURPOSE: A prospective trial of proton therapy for breast cancer revealed an increased rib fracture rate of 7%, which is higher than the expected rate based on the literature on photon therapies. We aim to evaluate the hypothesis that the increased relative biological effectiveness (RBE) at the distal edge of proton beams is the cause. METHODS AND MATERIALS: We combined the cohort from the prospective clinical trial and a retrospective cohort from a database. Monte Carlo simulations were performed to recalculate the physical dose and dose-averaged linear energy transfer (LETd). The first 10 ribs and fracture areas in patients with fractures were contoured and deformably registered. The LETd-weighted dose was used as a surrogate for biological effectiveness and compared with the conventional fixed RBE of 1.1. Dose to 0.5 cm3 of the ribs (D0.5) was selected to analyze the dose-response relationship using logistic regression. We chose an alpha/beta ratio of 3 to calculate the biological effective dose in Gy3(RBE). RESULTS: Thirteen of 203 patients in the cohorts exhibited a total of 25 fractures. The LETd in fractured areas is increased (6.1 ± 2.0 keV/µm, mean ± standard deviation), suggesting possible end-of-range radiobiological effects with increased RBE. The D0.5 of the fractured ribs is 80.3 ± 9.4 Gy3(RBE) with a generic factor of 1.1 and is relatively low compared with historical photon results. On the other hand, the D0.5 of the fractured ribs is 100.0 ± 12.5 Gy3(RBE) using the LETd-based model with a dose-response curve that is more consistent with historical photon data. CONCLUSIONS: The increased rib fracture rate seen in our trial is probably associated with the increased LETd and RBE at the distal edge of proton beams. This phenomenon warrants further investigation and possible integration of LETd into treatment planning and optimization in proton therapy.

Risk of Leukemia after Dengue Virus Infection: A Population-Based Cohort Study.

BACKGROUND: Infections account for about 15% of human cancers globally. Although abnormal hematologic profiles and bone marrow suppression are common in patients with dengue, whether dengue is associated with a higher risk of leukemia has not been investigated. METHODS: We conducted a nationwide population-based cohort study by analyzing the National Health Insurance Research Databases in Taiwan. Laboratory-confirmed dengue patients between 2002 and 2011 were identified; five matched non-dengue controls were randomly selected for each patient. Follow-up ended on December 31, 2015. Multivariate Cox proportional hazard regression models were used to evaluate the effect of dengue virus infection on the risk of leukemia. Cancers other than leukemia were used as falsification endpoints to evaluate the validity of this study. RESULTS: We identified 12,573 patients with dengue and 62,865 non-dengue controls. Patients with dengue had a higher risk of leukemia [adjusted HR, 2.03; 95% confidence interval (CI), 1.16-3.53]. Stratified analyses by different follow-up periods showed that dengue virus infection was significantly associated with a higher risk of leukemia only between 3 and 6 years after infection (adjusted HR, 3.22; 95% CI, 1.25-8.32). There was no significant association between dengue and the risk of other cancers. CONCLUSIONS: This study provides the first epidemiologic evidence for the association between dengue virus infection and leukemia. IMPACT: Considering the rapidly increasing global incidence of dengue and the burden of leukemia, further studies are required to verify this association and to unravel the potential mechanisms of pathogenesis.

Evaluation of the Normality Assumption in Meta-Analyses.

Random-effects meta-analysis is one of the mainstream methods for research synthesis. The heterogeneity in meta-analyses is usually assumed to follow a normal distribution. This is actually a strong assumption, but one that often receives little attention and is used without justification. Although methods for assessing the normality assumption are readily available, they cannot be used directly because the included studies have different within-study standard errors. Here we present a standardization framework for evaluation of the normality assumption and examine its performance in random-effects meta-analyses with simulation studies and real examples. We use both a formal statistical test and a quantile-quantile plot for visualization. Simulation studies show that our normality test has well-controlled type I error rates and reasonable power. We also illustrate the real-world significance of examining the normality assumption with examples. Investigating the normality assumption can provide valuable information for further analysis or clinical application. We recommend routine examination of the normality assumption with the proposed framework in future meta-analyses.

Simvastatin and ROCK Inhibitor Y-27632 Inhibit Myofibroblast Differentiation of Graves' Ophthalmopathy-Derived Orbital Fibroblasts via RhoA-Mediated ERK and p38 Signaling Pathways.

Transforming growth factor-ß (TGF-ß)-induced differentiation of orbital fibroblasts into myofibroblasts is an important pathogenesis of Graves' ophthalmopathy (GO) and leads to orbital tissue fibrosis. In the present study, we explored the antifibrotic effects of simvastatin and ROCK inhibitor Y-27632 in primary cultured GO orbital fibroblasts and tried to explain the molecular mechanisms behind these effects. Both simvastatin and Y-27632 inhibited TGF-ß-induced α-smooth muscle actin (α-SMA) expression, which serves as a marker of fibrosis. The inhibitory effect of simvastatin on TGF-ß-induced RhoA, ROCK1, and α-SMA expression could be reversed by geranylgeranyl pyrophosphate, an intermediate in the biosynthesis of cholesterol. This suggested that the mechanism of simvastatin-mediated antifibrotic effects may involve RhoA/ROCK signaling. Furthermore, simvastatin and Y-27632 suppressed TGF-ß-induced phosphorylation of ERK and p38. The TGF-ß-mediated α-SMA expression was suppressed by pharmacological inhibitors of p38 and ERK. These results suggested that simvastatin inhibits TGF-ß-induced myofibroblast differentiation via suppression of the RhoA/ROCK/ERK and p38 MAPK signaling pathways. Thus, our study provides evidence that simvastatin and ROCK inhibitors may be potential therapeutic drugs for the prevention and treatment of orbital fibrosis in GO.

Impact of smoking cessation on clinical outcomes in patients with head and neck squamous cell carcinoma receiving curative chemoradiotherapy: A prospective study.

BACKGROUND: We hypothesized that patients with head and neck squamous cell carcinoma (HNSCC) with smoking cessation during curative chemoradiotherapy (CRT) had fewer complications and lower tumor progression risks. METHODS: Sixty-three patients with nonmetastatic HNSCC who were smokers at diagnosis (carbon monoxide [CO] breath concentrations ≥3 ppm) and underwent curative CRT were prospectively enrolled. Successful smoking cessation throughout CRT was confirmed by CO breath concentrations <3 ppm at CRT completion. RESULTS: Forty-one patients (65%) successfully discontinued smoking throughout CRT. With a median 33-month follow-up, patients with successful smoking cessation during CRT had significantly fewer, greater, and lower probabilities of grade ≥3 acute toxicities (P = .01), progression-free survival (P = .03), and permanent gastrostomy or tracheostomy (P = .04), respectively, than those continuing smoking throughout CRT. In multivariate analysis, successful smoking cessation during CRT significantly reduced tumor progression risks (hazard ratio: 0.4, P = .05). CONCLUSION: Smoking cessation during curative CRT reduced treatment-related toxicities and tumor progression risks in patients with HNSCC.

A simple method to estimate prediction intervals and predictive distributions: Summarizing meta-analyses beyond means and confidence intervals.

A systematic review and meta-analysis is an important step in evidence synthesis. The current paradigm for meta-analyses requires a presentation of the means under a random-effects model; however, a mean with a confidence interval provides an incomplete summary of the underlying heterogeneity in meta-analysis. Prediction intervals show the range of true effects in future studies and have been advocated to be regularly presented. Most commonly, prediction intervals are estimated assuming that the underlying heterogeneity follows a normal distribution, which is not necessarily appropriate. In this article, we provide a simple method with a ready-to-use spreadsheet file to estimate prediction intervals and predictive distributions nonparametrically. Simulation studies show that this new method can provide approximately unbiased estimates compared with the conventional method. We also illustrate the advantage and real-world significance of this approach with a meta-analysis evaluating the protective effect of vaccination against tuberculosis. The nonparametric predictive distribution provides more information about the shape of the underlying distribution than does the conventional method.

Number of Resected Lymph Nodes and Survival of Patients with Locally Advanced Esophageal Squamous Cell Carcinoma Receiving Preoperative Chemoradiotherapy.

BACKGROUND: The association of extended lymph node (LN) dissection with improved outcomes in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who received preoperative chemoradiotherapy (CRT) followed by surgery is debatable. PATIENTS AND METHODS: We reviewed data from patients with esophageal cancer enrolled in three phase II clinical trials of preoperative paclitaxel and cisplatin-based CRT during 2000-2012. Patients with ESCC who underwent planned esophagectomy were enrolled. The number of resected LNs and other clinicopathological factors were analyzed regarding their impact on progression-free (PFS) and overall (OS) survival using Cox proportional hazards model. RESULTS: In total, 139 patients were included. The median PFS and OS were 24.4 and 31.8 months, respectively. The median number of resected and positive LNs were 19 (range=2-96) and 0 (range=0-9), respectively. The mean number of positive LNs did not differ significantly among quartile groups of total resected LNs (quartile 1: 2-12, 2: 13-19, 3: 20-29, and 4: 30-96). The resected LN number analyzed as dichotomies divided by the median or as continuous variables was not associated with PFS or OS. However, in an exploratory analysis, patients of quartiles 2 and 3 had longer PFS and OS than those with quartiles of 1 and 4 in multivariate analysis (p=0.019 and 0.005, respectively). CONCLUSION: Although extensive LN dissection was not associated with improved survival, resection of 13-29 LNs was associated with improved survival in patients with locally advanced ESCC receiving preoperative paclitaxel and cisplatin-based CRT.