Assessing Detection Accuracy of Computerized Sonographic Features and Computer-Assisted Reading Performance in Differentiating Thyroid Cancers.

For ultrasound imaging of thyroid nodules, medical guidelines are all based on findings of sonographic features to provide clinicians management recommendations. Due to the recent development of artificial intelligence and machine learning (AI/ML) technologies, there have been computer-assisted detection (CAD) software devices available for clinical use to detect and quantify the sonographic features of thyroid nodules. This study is to validate the accuracy of the computerized sonographic features (CSF) by a CAD software device, namely, AmCAD-UT, and then to assess how the reading performance of clinicians (readers) can be improved providing the computerized features. The feature detection accuracy is tested against the ground truth established by a panel of thyroid specialists and a multiple-reader multiple-case (MRMC) study is performed to assess the sequential reading performance with the assistance of the CSF. Five computerized features, including anechoic area, hyperechoic foci, hypoechoic pattern, heterogeneous texture, and indistinct margin, were tested, with AUCs ranging from 0.888~0.946, 0.825~0.913, 0.812~0.847, 0.627~0.77, and 0.676~0.766, respectively. With the five CSFs, the sequential reading performance of 18 clinicians is found significantly improved, with the AUC increasing from 0.720 without CSF to 0.776 with CSF. Our studies show that the computerized features are consistent with the clinicians' findings and provide additional value in assisting sonographic diagnosis.

The management of postoperative upper alimentary tract fistulas: A single-center experience of endoscopic tissue glue repair and recommendations of a systematic review.

BACKGROUND/PURPOSE: The appropriate management of postoperative upper alimentary tract fistula (UATF) remains uncertain. The efficacy of esophagogastroduodenoscopy (EGD) tissue glue repair in the treatment of patients with postoperative UATF was explored. We also conducted a systematic review of the literature regarding the inpatient management of UATF. METHODS: Totally 24 patients received EGD tissue glue repair for postoperative UATF at our institute from April 2014 to April 2020. Independent characteristics of size of fistula, location of the UATF, complications, and recurrences were analyzed. PubMed and Cochrane Library databases were reviewed. A pooled analysis was performed, and subgroup analysis was conducted separately for different anatomic locations and techniques. RESULTS: With a mean follow-up of 40 months, the fistula failed to close with EGD tissue glue repair in 2 of 24 patients (8.3%). Eight patients required repeated EGD tissue glue repair, which was more frequent in oral or thoracic UATF (p = 0.053), but all achieved a successful seal in the EGD tissue after glue repair alone (n = 22). The fistula size was correlated with the demand for repeated EGD tissue glue repair (p = 0.017). Besides, a total of 30 studies regarding 2356 cases of postoperative UATF between 2010 and 2021 were retrieved and analyzed. Several non-operative methods were generally accepted as the initial approach, with a non-inferior success rate compared to operative techniques. CONCLUSION: The results suggest that no single approach toward UATF is superior in terms of success rate and healing time. The potential advantages of EGD tissue glue repair after drainage were more suitable for patients with postoperative UATF and multiple comorbidities.

Assessing efficacy of antiviral therapy for COVID-19 patients: A case study on remdesivir with bayesian synthesis design and multistate analysis.

BACKGROUND/PURPOSE: A synthesis design and multistate analysis is required for assessing the clinical efficacy of antiviral therapy on dynamics of multistate disease progression and in reducing the mortality and enhancing the recovery of patients with COVID-19. A case study on remdesivir was illustrated for the clinical application of such a novel design and analysis. METHODS: A Bayesian synthesis design was applied to integrating the empirical evidence on the one-arm compassion study and the two-arm ACTT-1 trial for COVID-19 patients treated with remdesivir. A multistate model was developed to model the dynamics of hospitalized COVID-19 patients from three transient states of low, medium-, and high-risk until the two outcomes of recovery and death. The outcome measures for clinical efficacy comprised high-risk state, death, and discharge. RESULTS: The efficacy of remdesivir in reducing the risk of death and enhancing the odds of recovery were estimated as 31% (95% CI, 18-44%) and 10% (95% CI, 1-18%), respectively. Remdesivir therapy for patients with low-risk state showed the efficacy in reducing subsequent progression to high-risk state and death by 26% (relative rate (RR), 0.74; 95% CI, 0.55-0.93) and 62% (RR, 0.38; 95% CI, 0.29-0.48), respectively. Less but still statistically significant efficacy in mortality reduction was noted for the medium- and high-risk patients. Remdesivir treated patients had a significantly shorter period of hospitalization (9.9 days) compared with standard care group (12.9 days). CONCLUSION: The clinical efficacy of remdesvir therapy in reducing mortality and accelerating discharge has been proved by the Bayesian synthesis design and multistate analysis.

Classification of community-acquired outbreaks for the global transmission of COVID-19: Machine learning and statistical model analysis.

BACKGROUND: As Coronavirus disease 2019 (COVID-19) pandemic led to the unprecedent large-scale repeated surges of epidemics worldwide since the end of 2019, data-driven analysis to look into the duration and case load of each episode of outbreak worldwide has been motivated. METHODS: Using open data repository with daily infected, recovered and death cases in the period between March 2020 and April 2021, a descriptive analysis was performed. The susceptible-exposed-infected-recovery model was used to estimate the effective productive number (Rt). The duration taken from Rt > 1 to Rt < 1 and case load were first modelled by using the compound Poisson method. Machine learning analysis using the K-means clustering method was further adopted to classify patterns of community-acquired outbreaks worldwide. RESULTS: The global estimated Rt declined after the first surge of COVID-19 pandemic but there were still two major surges of epidemics occurring in September 2020 and March 2021, respectively, and numerous episodes due to various extents of Nonpharmaceutical Interventions (NPIs). Unsupervised machine learning identified five patterns as "controlled epidemic", "mutant propagated epidemic", "propagated epidemic", "persistent epidemic" and "long persistent epidemic" with the corresponding duration and the logarithm of case load from the lowest (18.6 ± 11.7; 3.4 ± 1.8)) to the highest (258.2 ± 31.9; 11.9 ± 2.4). Countries like Taiwan outside five clusters were classified as no community-acquired outbreak. CONCLUSION: Data-driven models for the new classification of community-acquired outbreaks are useful for global surveillance of uninterrupted COVID-19 pandemic and provide a timely decision support for the distribution of vaccine and the optimal NPIs from global to local community.

Differences in the ultrasonographic appearance of thyroid nodules after radiofrequency ablation.

CONTEXT: Radiofrequency ablation (RFA) is a well-tolerated approach to treating benign thyroid nodules (TNs), but no index can predict its success. Other than size decrease, little is known about TN appearance on ultrasonography (US) after RFA. OBJECTIVE: This study aimed to (a) assess the effectiveness of single-session RFA treatment, (b) determine whether pre-ablation US characteristics correlate with its effectiveness, and (c) demonstrate TN characteristics on baseline and follow-up US. DESIGN: Retrospective cohort study among the patients who underwent single-session RFA for the treatment of benign TNs at a referral medical center between January 2018 and April 2019. PATIENTS: A total of 116 patients (137 nodules) were included in the study. MEASUREMENTS: Characteristics were quantified using commercial software. TNs were classified into 2015 American Thyroid Association (ATA) sonographic patterns and American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TI-RADS) categories. RESULTS: The average volume reduction ratio (VRR) was 74.51% in 1 year (95% confidence interval, 70.63%-78.39%). The only pre-ablation US feature significantly different between nodules with VRR <50% and VRR >50% was the cyst composition (0.05 vs. 0.02, p-value = .02). The VRR and margin change in the first 3 months after ablation were found to be leading indicators significantly correlated to the VRR in 6 months with correlation coefficients (r) = .72 and -.28 (p-value < .0001 and = .0008) and VRR in 1 year with r = .65 and -.17 (p-value < .0001 and = .046), respectively. After RFA, more TNs became ATA high suspicion (2.9% vs. 19.7%, p < .0001) and more appeared to be the non-ATA patterns (12.4% vs. 23.4%, p < .0001). Also, a greater number of post-RFA TNs were classified as ACR-TI-RADS categories 4 and 5 (40.1% vs. 70.1%, p < .0001). CONCLUSIONS: Radiofrequency ablation therapy is effective for treating TNs. Pre-ablation cyst components, 3-month post-ablation volume reduction and margin change of TNs were related to the 6-month and 1-year response. Clinicians should consider that TNs would appear peculiar on US after RFA, mistakenly suggesting malignant potential.

Early weight loss as a predictor of 3-year weight loss and weight regain in patients with good compliance after sleeve gastrectomy.

BACKGROUND: Sleeve gastrectomy (SG) is the most common surgery for severe obesity. Patients lose weight post SG and regain some weight in the following years. Early weight loss predicts weight loss after SG. However, etiologies of weight loss and regain after SG remain unclear. OBJECTIVES: To investigate the effects of early weight loss on medium-term weight regain post SG. SETTING: Two university hospitals in Taiwan. METHODS: Patients with records within 1 and at 3 years after SG were enrolled retrospectively. Preoperative clinical variables and percentage of total weight loss (%TWL) were analyzed. Weight regain was defined as a weight increase from 1 year postoperatively of >25% of the lost weight. Linear and multiple logistic regression were applied to examine the associations of early weight loss, weight loss, and weight regain. RESULTS: A total of 363 patients were included. Body mass indexes before and 1, 3, 6, 12, and 36 months postoperatively were 40.7 ± 6.8 kg/m2, 36.6 ± 6.2 kg/m2, 33.5 ± 5.8 kg/m2, 30.9 ± 5.5 kg/m2, 28.4 ± 5.2, and 29.3 ± 5.4 kg/m2, respectively. At 3 years after SG, 73 patients (20.1%) had weight regain. In multivariate linear analyses, initial age, waist circumference, type 2 diabetes, and %TWL at 1 or 3 months were associated with either 1-year or 3-year %TWL. Multiple logistic regression revealed %TWL at 3 months to be a predictor for 3-year weight regain after SG (odds ratio, .927; P = .02). CONCLUSION: Early weight loss predicted weight loss and regain 3 years after SG. Early lifestyle and behavioral interventions are suggested in patients at high risk of poor weight loss and weight regain outcomes after SG.

Evaluating medical capacity for hospitalization and intensive care unit of COVID-19: A queue model approach.

BACKGROUND: The surge of COVID-19 pandemic has caused severe respiratory conditions and a large number of deaths due to the shortage of intensive care unit (ICU) in many countries. METHODS: We developed a compartment queue model to describe the process from case confirmation, home-based isolation, hospitalization, ICU, recovery, and death. By using public assessed data in Lombardy, Italy, we estimated two congestion indices for isolation wards and ICU. The excess ICU needs were estimated in Lombardy, Italy, and other countries when data were available, including France, Spain, Belgium, New York State in the USA, South Korea, and Japan. RESULTS: In Lombardy, Italy, the congestion of isolation beds had increased from 2.2 to the peak of 6.0 in March and started to decline to 3.9 as of 9th May, whereas the demand for ICU during the same period has not decreased yet with an increasing trend from 2.9 to 8.0. The results showed the unmet ICU need from the second week in March as of 9th May. The same situation was shown in France, Spain, Belgium, and New York State, USA but not for South Korea and Japan. The results with data until December 2020 for Lombardy, Italy were also estimated to reflect the demand for hospitalization and ICU after the occurrence of viral variants. CONCLUSION: Two congestion indices for isolation wards and ICU beds using open assessed tabulated data with a compartment queue model underpinning were developed to monitor the clinical capacity in hospitals in response to the COVID-19 pandemic.

Risk Stratification in Patients With Follicular Neoplasm on Cytology: Use of Quantitative Characteristics and Sonographic Patterns.

Objectives: Differentiating thyroid nodules with a cytological diagnosis of follicular neoplasm remains an issue. The goal of this study was to determine whether ultrasonographic (US) findings obtained preoperatively from the computer-aided detection (CAD) system are sufficient to further stratify the risk of malignancy for this diagnostic cytological category. Methods: From September 2016 to September 2018 in our hospital, patients diagnosed with Bethesda category IV (follicular neoplasm or suspicion of follicular neoplasm) thyroid nodules and underwent surgical excisions were include in the study. Quantification and analysis of tumor features were performed using CAD software. The US findings of the region of interest, including index of composition, margin, echogenicity, texture, echogenic dots indicative of calcifications, tall and wide orientation, and margin were calculated into computerized values. The nodules were further classified into American Thyroid Association (ATA) and American College of Radiology Thyroid Imaging Reporting & Data System (TI-RADS) categories. Results: 92 (10.1%) of 913 patients were diagnosed with Bethesda category IV thyroid nodules. In 65 patients, the histological type of the nodule was identified. The quantitative features between patients with benign and malignant conditions differed significantly. The presence of heterogeneous echotexture, blurred margins, or irregular margins was shown to have the highest diagnostic value. The risks of malignancy for nodules classified as having very low to intermediate suspicion ATA, non-ATA, and high suspicion ATA patterns were 9%, 35.7%, and 51.7%, respectively. Meanwhile, the risks of malignancy were 12.5%, 26.1%, and 53.8% for nodules classified as TIRADS 3, 4, and 5, respectively. When compared to human observers, among whom poor agreement was noticeable, the CAD software has shown a higher average accuracy. Conclusions: For patients with nodules diagnosed as Bethesda category IV, the software-based characterizations of US features, along with the associated ATA patterns and TIRADS system, were shown helpful in the risk stratification of malignancy.

Adjuvant tegafur-uracil (UFT) or S-1 monotherapy for advanced gastric cancer: a single center experience.

BACKGROUND: Adjuvant tegafur-gimeracil-oteracil (S-1) is commonly used for gastric cancer in Asia, and tegafur-uracil (UFT) is another oral fluoropyrimidine when S-1 is unavailable. The real-world data of adjuvant UFT has less been investigated. METHODS: Patients with pathological stage II-IIIB (except T1) gastric cancer receiving adjuvant UFT or S-1 monotherapy after D2 gastrectomy were included. Usage of UFT or S-1 was based on reimbursement policy of the Taiwanese healthcare system. The characteristics, chemotherapy completion rates, and 5-year recurrence-free survival (RFS) and overall survival (OS), were compared between these two groups. RESULTS: From 2005 to 2016, 86 eligible patients were included. Most tumor characteristics were similar between the UFT group (n = 37; age 59.1 ± 13.9 years) and S-1 group (n = 49; age 56.3 ± 10.7 years), except there were significantly more Borrmann type III/IV (86.5% versus 67.3%; p = 0.047) and T4 (56.8% versus 10.2%; p < 0.001) lesions in the UFT group than in the S-1 group. The chemotherapy complete rates were similar in the two groups. The 5-year RFS was 56.1% in the UFT group and 59.6% in the S-1 group (p = 0.71), and the 5-year OS was 78.3% in the UFT group and 73.1% in the S-1 group (p = 0.48). The hazard ratio of adjuvant chemotherapy (S-1 versus UFT) on RFS was 1.25 (95% confidence interval = 0.53-2.94) when Borrmann type and T and N stages were adjusted. CONCLUSIONS: This small cohort study showed adjuvant UFT, and S-1 monotherapy had a comparable long-term outcome for pathological stage II-IIIB gastric cancer following D2 gastrectomy.

Software-Based Analysis of the Taller-Than-Wide Feature of High-Risk Thyroid Nodules.

BACKGROUND: Shape is one of the most important features in the diagnosis of malignant thyroid nodules. This characteristic has been described qualitatively, but only shapes that appear markedly different can be easily differentiated at first interpretation. This study sought to clarify whether software-based shape indexes are useful for the detection of thyroid cancers. METHODS: In the final analysis, 200 participants with 231 pathologically proven nodules participated in the study. Ultrasound features were assessed by clinicians. The tumor contour was auto-defined, and shape indexes were calculated using commercial software. RESULTS: Of the 231 nodules, 134 were benign and 97 were malignant. The presence of taller-than-wide (TTW) dimensions differed significantly between the benign and malignant thyroid tumors. Designation of TTW assessed by the software had a higher kappa value and proportional agreement than TTW assessed by clinicians. Disagreement between the clinician and software in designating nodules as TTW occurred for 28 nodules. The presence of other ultrasonic characteristics and small differences in the height and width measurements were causes for the incorrect interpretation of the TTW feature. CONCLUSION: The proposed software-based quantitative analysis of tumor shape seems to be promising as an important advance compared with conventional TTW features evaluated by operators because it allows for a more reliable and consistent distinction and is less influenced by other ultrasonic features.

Parenteral glutamine supplementation improves serum albumin values in surgical cancer patients.

INTRODUCTION: Patients with gastric adenocarcinoma (GA) often develop malnutrition, which deteriorates after cancer surgery and negatively affects surgical outcomes. Despite being an abundant and versatile amino acid involved in the immune system and metabolic functions, glutamine levels are significantly depleted among patients who are critically ill or hypercatabolic. Therefore, this study aimed to investigate whether parenteral glutamine supplementation may improve nutritional status and surgical outcomes. METHODS: This retrospective, single-center cohort study included patients with GA who underwent gastrectomy between January 2007 and June 2019. Patients were classified into either the non-glutamine or glutamine group. Propensity score matching was used to minimize the bias in patient demographics. Furthermore, the average parenteral glutamine dose from the day of surgery to postoperative day four was calculated in g/kg/day. Surgical outcomes (length of hospitalization, major complication, and mortality) and changes in lymphocyte count and serum albumin levels 7 days post-surgery were assessed in both matched groups using adjusted models. RESULTS: A total of 1950 patients were reviewed, among whom 522 (26.8%) received parenteral glutamine supplementation (glutamine dose ranging from 0.05 to 0.49 g/kg/day). Among the included patients, 57.2% were males, and the median age was 64.9 years. After matching, there were 478 cases in each group. No differences in surgical outcomes and changes in lymphocyte count were observed between both matched groups. The glutamine group exhibited a smaller decrease in serum albumin levels compared to the non-glutamine group (-0.6 vs. -1.1 g/dL; P < 0.001). The adjusted matched model showed that glutamine dose contributed significantly toward increasing serum albumin levels (coefficient = 0.08 per 0.1 g/day/kg increment in glutamine; 95% confidence interval: 0.04 to 0.10; P < 0.001). CONCLUSIONS: Perioperative parenteral glutamine supplementation had a positive dose-dependent impact on the recovery of serum albumin levels among patients with GA undergoing gastrectomy, implying that glutamine supplementation improved postoperative nutritional suppression and ameliorated stress-associated inflammation. Although glutamine supplementation was not associated with surgical outcomes, further studies should be conducted to evaluate the clinical significance of serum albumin restoration.

Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFß signaling through TGFBR1 stabilization.

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFß1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFß1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.

Impact of 3D-CT-Based Gastric Wall Volume on Weight Loss after Laparoscopic Sleeve Gastrectomy.

PURPOSE: There are several debates on the association between gastric anatomy and weight loss after laparoscopic sleeve gastrectomy (LSG). There is a paucity of data on the impact of gastric wall volume (GWV) on weight loss. This study therefore aimed to investigate the effect of GWV on weight loss response after LSG. MATERIALS AND METHODS: Thirty-two patients with body mass index (BMI) of ≧ 40 kg/m2 who underwent LSG between November 2016 and August 2018 were enrolled. Three-dimensional computed tomography (3D-CT) was performed pre-operatively and 1 year after LSG to assess gastric volumes. The population was divided into two groups: the first 20% (n = 7) with the largest GWV, defined as LGWV group, and the rest of the population (n = 25), defined as the small GWV (SGWV) group. Percentage total weight loss (%TWL) was compared. RESULTS: The mean preoperative GWV was 216.9 ± 47.7 ml in the SGWV group, versus 336.3 ± 24.1 ml in the LGWV group. Patients with LGWV had significantly lower 1-year %TWL (34.9.1% versus 27.9%, p = 0.0439). Multilinear regression identified LGWV as a significant prognostic factor after adjusting for BMI and early weight loss response. Repeated measure mixed effect model showed that the LGWV group had a significantly slower %TWL change, particularly after 3 months postoperatively. No association was found between 1-year %TWL and preoperative and postoperative gastric luminal volume or resected gastric volume. CONCLUSION: 3D-CT disclosed GWV, but not other gastric anatomical characteristics, was an independent predictor of %TWL after 1-year post LSG.

A 2-Phase Merge Filter Approach to Computer-Aided Detection of Breast Tumors on 3-Dimensional Ultrasound Imaging.

OBJECTIVES: The role of image analysis in 3-dimensional (3D) automated breast ultrasound (ABUS) images is increasingly important because of its widespread use as a screening tool in whole-breast examinations. However, reviewing a large number of images acquired from ABUS is time-consuming and sometimes error prone. The aim of this study, therefore, was to develop an efficient computer-aided detection (CADe) algorithm to assist the review process. METHODS: The proposed CADe algorithm consisted of 4 major steps. First, initial tumor candidates were formed by extracting and merging hypoechoic square cells on 2-dimensional (2D) transverse images. Second, a feature-based classifier was then constructed using 2D features to filter out nontumor candidates. Third, the remaining 2D candidates were merged longitudinally into 3D masses. Finally, a 3D feature-based classifier was used to further filter out nontumor masses to obtain the final detected masses. The proposed method was validated with 176 passes of breast images acquired by an Acuson S2000 automated breast volume scanner (Siemens Medical Solutions USA, Inc., Malvern, PA), including 44 normal passes and 132 abnormal passes containing 162 proven lesions (79 benign and 83 malignant). RESULTS: The proposed CADe system could achieve overall sensitivity of 100% and 90% with 6.71 and 5.14 false-positives (FPs) per pass, respectively. Our results also showed that the average number of FPs per normal pass (7.16) was more than the number of FPs per abnormal pass (6.56) at 100% sensitivity. CONCLUSIONS: The proposed CADe system has a great potential for becoming a good companion tool with ABUS imaging by ensuring high sensitivity with a relatively small number of FPs.

Circulating Diabetic Candidate Neurotrophic Factors, Brain-Derived Neurotrophic Factor and Fibroblast Growth Factor 21, in Sleeve Gastrectomy.

Recent studies show brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 21 (FGF21) are neurotrophic factors associated with obesity and diabetes mellitus (DM). Laparoscopic sleeve gastrectomy (LSG) can significantly reduce weight and improve DM. In this study, we enrolled 78 patients with obesity and evaluated the change of BDNF and FGF21 6 months after LSG. At baseline, the BDNF level was similar between the preoperative DM (n = 30) (17.1 ± 7.7 ng/ml) and non-DM (n = 48) (17.0 ± 6.9 ng/ml) patients with obesity, but FGF21 was significantly higher in the DM patients (201.5 ± 204.3 versus 107.6 ± 63.8 pg/ml). At 6 months after LSG, most of the preoperative DM patients (96.7%) had DM either resolved (66.7%) or improved (30%). BDNF increased and FGF21 decreased significantly regardless of the preoperative DM status, while FGF21 decreased more prominently in the preoperative DM patients (-92.6 ± 179.8 versus -4.6 ± 63.4 pg/ml). After adjusted for age, sex, and preoperative DM status, FGF21 became significantly and positively related to C-peptide (ß = 18.887), insulin (ß = 2.399), and homeostasis model assessment of insulin resistance index (ß = 8.566) after surgery. In conclusion, diabetic patients with obesity had higher FGF21 and similar BDNF levels compared to non-diabetic obese patients. BDNF increased and FGF21 decreased significantly after LSG. FGF21 became positively associated with several insulin-related profiles after surgery.

Multi-Reader Multi-Case Study for Performance Evaluation of High-Risk Thyroid Ultrasound with Computer-Aided Detection.

Physicians use sonographic characteristics as a reference for the possible diagnosis of thyroid cancers. The purpose of this study was to investigate whether physicians were more effective in their tentative diagnosis based on the information provided by a computer-aided detection (CAD) system. A computer compared software-defined and physician-adjusted tumor loci. A multicenter, multireader, and multicase (MRMC) study was designed to compare clinician performance without and with the use of CAD. Interobserver variability was also analyzed. Excellent, satisfactory, and poor segmentations were observed in 25.3%, 58.9%, and 15.8% of nodules, respectively. There were 200 patients with 265 nodules in the study set. Nineteen physicians scored the malignancy potential of the nodules. The average area under the curve (AUC) of all readers was 0.728 without CAD and significantly increased to 0.792 with CAD. The average standard deviation of the malignant potential score significantly decreased from 18.97 to 16.29. The mean malignant potential score significantly decreased from 35.01 to 31.24 for benign cases. With the CAD system, an additional 7.6% of malignant nodules would be suggested for further evaluation, and biopsy would not be recommended for an additional 10.8% of benign nodules. The results demonstrated that applying a CAD system would improve clinicians' interpretations and lessen the variability in diagnosis. However, more studies are needed to explore the use of the CAD system in an actual ultrasound diagnostic situation where much more benign thyroid nodules would be seen.

Ultrasonographic features for differentiating follicular thyroid carcinoma and follicular adenoma.

BACKGROUND: Preoperative differentiation of follicular thyroid carcinoma (FTC) from follicular adenoma (FA) remains an unsolved puzzle. Patients sometimes undergo unnecessary lobectomy for histology confirmation inevitably. OBJECTIVE: In this retrospective study, we propose new gray-scale ultrasonographic (US) features that may help to differentiate FTC from FA. METHOD: Medical charts and US images of follicular thyroid neoplasms were collected prospectively. Gray-scale US features including conventional parameters adding tubercle-in-nodule and trabecular formation were recorded. RESULTS: The histopathologic diagnosis was FA in 139 and FTC in 49 patients. In patients with FTC, minimally invasive follicular carcinoma (MIFC) was seen in 36 patients and widely invasive follicular carcinoma (WIFC) in 13. The incidences of calcifications (p < 0.0001), tubercle-in-nodule signs (p < 0.0001), spiculated margins (p = 0.014), and trabecular formations (p = 0.03) were significantly higher in FTC. Tubercle-in-nodule (p < 0.01) and calcification (p < 0.001) were independent factors in the differentiation of FTC in multivariate analysis (area under the curve = 0.689). CONCLUSIONS: US characteristics of tubercle-in-nodule in combination with calcification help to differentiate FTC from FA.

Calreticulin regulates vascular endothelial growth factor-A mRNA stability in gastric cancer cells.

Calreticulin (CRT) and vascular endothelial growth factor-A (VEGF-A) are crucial for angiogenesis, and mediate multiple malignant behaviors in gastric cancer. In this study, we report that CRT is positively correlated with VEGF-A in gastric cancer patients. Moreover, high expressions of both CRT and VEGF-A are markedly associated with the pathological stage, progression, and poor prognosis in the patients. Therefore, we sought to elucidate the mechanism by which CRT affects VEGF-A in gastric cancer. Firstly, we demonstrate the novel finding that knockdown of CRT reduced VEGF-A mRNA stability in two gastric cancer cell lines, AGS and MKN45. The AU-Rich element (ARE) is believed to play a crucial role in the maintenance of VEGF-A mRNA stability. Luciferase reporter assay shows that knockdown of CRT significantly decreased the activity of renilla luciferase with VEGF-A ARE sequence. Additionally, competition results from RNA-binding/electrophoretic mobility shift assay indicate that CRT forms an RNA-protein complex with the VEGF-A mRNA by binding to the ARE. In addition, the proliferation rate of human umbilical vein endothelial cells (HUVEC) was significantly reduced when treated with conditioned medium from CRT knockdown cells; this was rescued by exogenous VEGF-A recombinant protein. Our results demonstrate that CRT is involved in VEGF-A ARE binding protein complexes to stabilize VEGF-A mRNA, thereby promoting the angiogenesis, and progression of gastric cancer.

B-Cell Activating Factor Enhances Hepatocyte-Driven Angiogenesis via B-Cell CLL/Lymphoma 10/Nuclear Factor-KappaB Signaling during Liver Regeneration.

B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through BAFF-R. However, the roles of BAFF during liver regeneration are not well defined. In this study, C57/B6 mice with 70% partial hepatectomy were used as a liver regeneration model. BAFF expression was determined by enzyme immunoassay, and anti-BAFF-neutralizing antibodies were administered to confirm the effects of BAFF on liver regeneration. Western blotting, immunohistochemistry, and florescence staining determined the expression of B-cell CCL/lymphoma 10 (BCL10). The angiogenesis promoting capability was evaluated after the transfection of cells with siRNA targeting BCL10 expression, and the role of NF-κB was assessed. The results revealed that the BAFF and BCL10 levels were upregulated after partial hepatectomy. Treatment with anti-BAFF-neutralizing antibodies caused death in mice that were subjected to 70% partial hepatectomy within 72 h. In vitro, recombinant BAFF protein did not enhance hepatocyte proliferation; however, transfection with BCL10 siRNA arrested hepatocytes at the G2/M phase. Interestingly, conditioned medium from BAFF-treated hepatocytes enhanced angiogenesis and endothelial cell proliferation. Moreover, Matrix metalloproteinase-9 (MMP-9), Fibroblast growth factor 4 (FGF4), and Interleukin-8 (IL-8) proteins were upregulated by BAFF through BCL10/NF-κB signaling. In mice that were treated with anti-BAFF-neutralizing antibodies, the microvessel density (MVD) of the remaining liver tissues and liver regeneration were both reduced. Taken together, our study demonstrated that an increased expression of BAFF and activation of BCL10/NF-κB signaling were involved in hepatocyte-driven angiogenesis and survival during liver regeneration.

Quantitative Proteomics of Th-MYCN Transgenic Mice Reveals Aurora Kinase Inhibitor Altered Metabolic Pathways and Enhanced ACADM To Suppress Neuroblastoma Progression.

Neuroblastoma is a neural crest-derived embryonal tumor and accounts for about 15% of all cancer deaths in children. MYCN amplification is associated with aggressive and advanced stage of high-risk neuroblastoma, which remains difficult to treat and exhibits poor survival under current multimodality treatment. Here, we analyzed the transcriptomic profiles of neuroblastoma patients and showed that aurora kinases lead to poor survival and had positive correlation with MYCN amplification and high-risk disease. Further, pan-aurora kinase inhibitor (tozasertib) treatment not only induces cell-cycle arrest and suppresses cell proliferation, migration, and invasion ability in MYCN-amplified (MNA) neuroblastoma cell lines, but also inhibits tumor growth and prolongs animal survival in Th-MYCN transgenic mice. Moreover, we performed quantitative proteomics and identified 150 differentially expressed proteins after tozasertib treatment in the Th-MYCN mouse model. The functional and network-based enrichment revealed that tozasertib alters metabolic processes and identified a mitochondrial flavoenzyme in fatty acid ß-oxidation, ACADM, which is correlated with aurora kinases and neuroblastoma patient survival. Our findings indicate that the aurora kinase inhibitor could cause metabolic imbalance, possibly by disturbing carbohydrate and fatty acid metabolic pathways, and ACADM may be a potential target in MNA neuroblastoma.