Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial.

Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1-32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7-18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 .

Mechanism of Prunella vulgaris L. and luteolin in restoring Tfh/Tfr balance and alleviating oxidative stress in Graves' disease.

BACKGROUND: The pathophysiology of Graves' disease (GD) involves imbalances between follicular helper T (Tfh) and follicular regulatory T (Tfr) cells, as well as oxidative stress (OS). Prunella vulgaris L. (Xia Ku Cao, XKC) and its primary bioactive compound, luteolin, are recognized for their potential in treating GD. Yet, the mechanism accounting for the immune-modulatory and antioxidant effects of XKC remains elusive. PURPOSE: This study aims to evaluate the pharmacological effects and elucidate the underlying mechanism of XKC and luteolin in a GD mouse model induced by recombinant adenovirus of TSH receptor A subunit (Ad-hTSHR-289). METHODS: High-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (HPLC-QTOF MS) was used to detect the constituents of XKC. The GD model was established through inducing female BALB/c mice with three intramuscular injections of Ad-TSHR-289. Thyroid function, autoantibody and OS parameters were measured by ELISA. Changes of Tfh cells and Tfr cells were detected by flow cytometry. RT-qPCR, Western Blotting, immunohistochemistry were used to explore the related molecular mechanisms. RESULTS: A total of 37 chemical components from XKC were identified by HPLC-QTOF MS, represented by flavonoids, steroids, terpenoids, and luteolin. XKC and luteolin reduced T4, TRAb levels and facilitated the recovery from thyroid damage in GD mice. Meanwhile, XKC and luteolin effectively alleviated OS by decreasing the levels of MDA, NOX2, 4-HNE, 8-OHdG, while increasing GSH level. Flow cytometry showed that XKC and luteolin restored the abnormal proportions of Tfh/Tfr and Tfh/Treg, and the mRNA levels of IL-21, Bcl-6 and Foxp3 in GD mice. In addition, XKC and luteolin inhibited PI3K, Akt, p-PI3K and p-Akt, but activated Nrf2 and HO-1. CONCLUSION: XKC and luteolin could inhibit the development of GD in vivo by rebalancing Tfh/Tfr cells and alleviating OS. This therapeutic mechanism may involve the Nrf2/HO-1 and PI3K/Akt signaling pathways. Luteolin is the main efficacy material basis of XKC in countering GD. For the first time, we revealed the mechanism of XKC and luteolin in the treatment of GD from the perspective of autoimmune and OS.

Semi-supervised learning in diagnosis of infant hip dysplasia towards multisource ultrasound images.

Background: Automated diagnosis of infant hip dysplasia is heavily affected by the individual differences among infants and ultrasound machines. Methods: Hip sonographic images of 493 infants from various ultrasound machines were collected in the Department of Orthopedics in Yangzhou Maternal and Child Health Care Service Centre. Herein, we propose a semi-supervised learning method based on a feature pyramid network (FPN) and a contrastive learning scheme based on a Siamese architecture. A large amount of unlabeled data of ultrasound images was used via the Siamese network in the pre-training step, and then a small amount of annotated data for anatomical structures was adopted to train the model for landmark identification and standard plane recognition. The method was evaluated on our collected dataset. Results: The method achieved a mean Dice similarity coefficient (DSC) of 0.7873 and a mean Hausdorff distance (HD) of 5.0102 in landmark identification, compared to the model without contrastive learning, which had a mean DSC of 0.7734 and a mean HD of 6.1586. The accuracy, precision, and recall of standard plane recognition were 95.4%, 91.64%, and 94.86%, respectively. The corresponding area under the curve (AUC) was 0.982. Conclusions: This study proposes a semi-supervised deep learning method following Graf's principle, which can better utilize a large volume of ultrasound images from various devices and infants. This method can identify the landmarks of infant hips more accurately than manual operators, thereby improving the efficiency of diagnosis of infant hip dysplasia.

E4bp4-Cyp3a11 axis in high-fat diet-induced obese mice with weight fluctuation.

OBJECTIVE: Weight regain after weight loss is a challenge in obesity management. The metabolic changes and underlying mechanisms in obese people with weight fluctuation remain to be elucidated. In the present study, we aimed to profile the features and clinical significance of liver transcriptome in obese mice with weight regain after weight loss. METHODS: The male C57BL/6J mice were fed with standard chow diet or high-fat diet (HFD). After 9 weeks, the HFD-induced obese mice were randomly divided into weight gain (WG), weight loss (WL) and weight regain (WR) group. After 10 weeks of dietary intervention, body weight, fasting blood glucose (FBG), intraperitoneal glucose tolerance, triglycerides (TG), total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) were measured. Morphological structure and lipid droplet accumulation in the liver were observed by H&E staining and oil red O staining, respectively. The liver transcriptome was detected by RNA sequencing. Protein expressions of liver cytochrome P450 3a11 (Cyp3a11) and E4 promoter-binding protein 4 (E4bp4) were determined by Western blot. RESULTS: After 10 weeks of dietary intervention, the body weight, FBG, glucose area under the curve, T-CHO and LDL-C in WL group were significantly lower than those in WG group (P < 0.05). At 4 weeks of HFD re-feeding, the mice in WR group presented body weight and T-CHO significantly lower than those in WG group, whereas higher than those in WL group (P < 0.05). Hepatic vacuolar degeneration and lipid droplet accumulation in the liver were significantly alleviated in WL group and WR group, compared to those in WG group. The liver transcriptome associated with lipid metabolism was significantly altered during weight fluctuation in obese mice. Compared with those in WG group, Cyp3a11 in the liver was significantly upregulated, and E4bp4 was significantly downregulated in WL and WR groups. CONCLUSION: Obese mice experience weight regain after weight loss by HFD re-feeding, but their glucose and lipid metabolism disorders are milder than those induced by the persistence of obesity. Downregulated E4bp4 and upregulated Cyp3a11 are detected in obese mice after weight loss, suggesting that the E4bp4-Cyp3a11 axis may involved in metabolic mechanisms underlying weight regulation.

The type V effectors for CRISPR/Cas-mediated genome engineering in plants.

A plethora of CRISPR effectors, such as Cas3, Cas9, and Cas12a, are commonly employed as gene editing tools. Among these, Cas12 effectors developed based on Class II type V proteins exhibit distinct characteristics compared to Class II type VI and type II effectors, such as their ability to generate non-allelic DNA double-strand breaks, their compact structures, and the presence of a single RuvC-like nuclease domain. Capitalizing on these advantages, Cas12 family proteins have been increasingly explored and utilized in recent years. However, the characteristics and applications of different subfamilies within the type V protein family have not been systematically summarized. In this review, we focus on the characteristics of type V effector (CRISPR/Cas12) proteins and the current methods used to discover new effector proteins. We also summarize recent modifications based on engineering of type V effectors. In addition, we introduce the applications of type V effectors for gene editing in animals and plants, including the development of base editors, tools for regulating gene expression, methods for gene targeting, and biosensors. We emphasize the prospects for development and application of CRISPR/Cas12 effectors with the goal of better utilizing toolkits based on this protein family for crop improvement and enhanced agricultural production.

Lymph node metastases in middle and upper mediastinum of Siewert type II adenocarcinoma: A real-world retrospective study.

OBJECTIVE: To explore whether the upper and/or middle mediastinal nodes (UMMN) should be dissected in Siewert type II adenocarcinoma (AC) according to the incidence of lymph node metastasis. Additionally, to investigate the association between the length of esophageal involvement (LEI) and the UMMN metastases. METHODS: A cohort with Siewert type II AC who were operated on by a surgical team that routinely treated esophagogastric junction (EGJ) tumors with esophagectomy and extended lymphadenectomy were assessed retrospectively. The primary endpoint of the research was the metastasis rate of UMMN. RESULTS: A total of 94 patients with EGJ tumor from July 2018 to September 2022 were enrolled. Station 106recR (6.4%, 6/94) was the only station among upper mediastinal nodes (UMN) that presented positive nodes. Middle mediastinal nodes (MMN) metastases of station 107, 109 and station 108 were 2.1% (2/94) and 5.0% (4/80), respectively. Among the 11 patients with MMN or UMN metastases, 63.6% (7/11) had lesser than seven metastatic nodes, and 54.5% (6/11) had a pathological N stage ≤2. LEI >3 cm (p = 0.042) showed a higher risk for MMN metastases in univariable logistic analysis. However, no independent risk factor for mediastinal node metastases was detected. CONCLUSION: This study demonstrated that the incidence of positive MMN and UMN is relatively low in resectable Siewert type II AC, which indicated that it is not necessary to perform a routine dissection upon these stations. LEI >3 cm might be associated with higher risk for mediastinal node metastasis. Certain patients could benefit from extended lymphadenectomy since most of the patients with positive MMN or UMN have a limited number of metastatic nodes.

Neoadjuvant chemotherapy combined with immunotherapy versus neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma.

BACKGROUND: To date, few studies have compared effectiveness and survival rates of neoadjuvant chemotherapy combined with immunotherapy (NACI) and conventional neoadjuvant chemoradiotherapy (NCRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). The present study was conducted to compare therapeutic response and survival between NACI and NCRT. METHODS: The study cohort comprised patients with locally advanced ESCC treated with either NACI or NCRT followed by surgery between June 2018 and March 2021. The 2 groups were compared for treatment response, 3-year overall survival (OS), and disease-free survival (DFS). Survival curves were created using the Kaplan-Meier method, differences were compared using the log-rank test, and potential imbalances were corrected for using the inverse probability of treatment weighting (IPTW) method. RESULTS: Among 202 patients with locally advanced ESCC, 81 received NACI and 121 received conventional NCRT. After IPTW adjustment, the R0 resection rate (85.2% vs 92.3%; P = .227) and the pathologic complete response (pCR) rate (27.5% vs 36.4%; P = .239) were comparable between the 2 groups. Nevertheless, patients who received NACI exhibited both a better 3-year OS rate (91.7% vs 79.8%; P = .032) and a better 3-year DFS rate (87.4% vs 72.8%; P = .039) compared with NCRT recipients. CONCLUSIONS: NACI has R0 resection and pCR rates comparable to those of NCRT and seems to be correlated with better prognosis than NCRT. NACI followed by surgery may be an effective treatment strategy for locally advanced ESCC.

Collaborative multidisciplinary management and expertise of cT2-3 locally advanced operable esophageal squamous cell carcinoma: a report of two cases.

Background: The accurate clinical staging of esophageal squamous cell carcinoma (ESCC) is pivotal for guiding treatment strategies. However, the current precision in staging for clinical T (cT)2 and cT3 stages remains unsatisfactory. This article discusses the role of multidisciplinary teams (MDTs) in the clinical staging and formulation of neoadjuvant treatment strategies for locally advanced operable ESCC. These challenges underscore the importance of precise staging in the decision-making process for appropriate therapeutic interventions. Case Description: Through the lens of two patient case studies with locally advanced resectable ESCC, the article showcases the intricate process of treatment planning undertaken by MDTs. It captures a range of expert perspectives from Japan, China, Hong Kong (China), Korea, the USA, and Europe, focusing on the challenges of differentiating between cT2 and cT3 stages of the disease, which is a critical determinant in the management and therapeutic approach for patients. Conclusions: The article concludes that the accurate staging of ESCC is a cornerstone in determining the most suitable treatment strategies. It underscores the vital role that MDTs play in both clinical staging and the decision-making process for treatment. Highlighting the limitations in current diagnostic methods, the article emphasizes the urgent need for advanced research and the refinement of diagnostic tools to improve the precision of staging, particularly between the cT2 and cT3 stages. It suggests that future research should consider whether a reclassification of these stages could be warranted to enhance treatment planning and outcomes for patients with ESCC.

m6A demethylase FTO stabilizes LINK-A to exert oncogenic roles via MCM3-mediated cell-cycle progression and HIF-1α activation.

RNA N6-methyladenosine (m6A) modification is implicated in cancer progression, yet its role in regulating long noncoding RNAs during cancer progression remains unclear. Here, we report that the m6A demethylase fat mass and obesity-associated protein (FTO) stabilizes long intergenic noncoding RNA for kinase activation (LINK-A) to promote cell proliferation and chemoresistance in esophageal squamous cell carcinoma (ESCC). Mechanistically, LINK-A promotes the interaction between minichromosome maintenance complex component 3 (MCM3) and cyclin-dependent kinase 1 (CDK1), increasing MCM3 phosphorylation. This phosphorylation facilitates the loading of the MCM complex onto chromatin, which promotes cell-cycle progression and subsequent cell proliferation. Moreover, LINK-A disrupts the interaction between MCM3 and hypoxia-inducible factor 1α (HIF-1α), abrogating MCM3-mediated HIF-1α transcriptional repression and promoting glycolysis and chemoresistance. These results elucidate the mechanism by which FTO-stabilized LINK-A plays oncogenic roles and identify the FTO/LINK-A/MCM3/HIF-1α axis as a promising therapeutic target for ESCC.

Dysregulation of MiR-199a/IL8 pathway in chronic Cr (VI)-induced tumor growth and angiogenesis.

Hexavalent chromium [Cr(VI)] is a well-known environmental carcinogen. Recent studies revealed that chronic exposure of human bronchial epithelial cells (BEAS-2B, B2B) to Cr(VI) activated several signaling pathways and induced cell malignant transformation and tumor growth. However, new mechanisms of Cr(VI) in inducing carcinogenesis remains to be elucidated. This study showed that miR-199a expression levels were significantly lower in Cr(VI)-transformed Cr-T cells. By using the mouse model, the expression levels of miR-199a were significantly decreased in blood samples and lung tissues of mice intranasally exposed to Cr(VI) for 12 weeks compared to the solvent exposure control. Overexpression of miR-199a inhibited tube formation and angiogenesis. C-X-C motif chemokine ligand 8 (CXCL8, IL8) levels were significantly higher in blood samples of Cr (VI)-exposed workers compared to normal workers, and forced expression of miR-199a in the cells suppressed IL8 levels. miR-199a suppression induced expression of hypoxia-inducible factor 1α (HIF-1α) and nuclear factor kappa B (NF-κB) p65 to increase IL8 expression. With animal experiment, the results showed that miR-199a overexpression inhibited tumor growth and angiogenesis through inhibiting IL8, HIF-1α and NF-κB p65 expression in vivo. These results show that miR-199a/IL8 pathway is important in Cr(VI)-induced carcinogenesis and angiogenesis.

RPS15 interacted with IGF2BP1 to promote esophageal squamous cell carcinoma development via recognizing m6A modification.

Increased rates of ribosome biogenesis have been recognized as hallmarks of many cancers and are associated with poor prognosis. Using a CRISPR synergistic activation mediator (SAM) system library targeting 89 ribosomal proteins (RPs) to screen for the most oncogenic functional RPs in human esophageal squamous cell carcinoma (ESCC), we found that high expression of RPS15 correlates with malignant phenotype and poor prognosis of ESCC. Gain and loss of function models revealed that RPS15 promotes ESCC cell metastasis and proliferation, both in vitro and in vivo. Mechanistic investigations demonstrated that RPS15 interacts with the K homology domain of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which recognizes and directly binds the 3'-UTR of MKK6 and MAPK14 mRNA in an m6A-dependent manner, and promotes translation of core p38 MAPK pathway proteins. By combining targeted drug virtual screening and functional assays, we found that folic acid showed a therapeutic effect on ESCC by targeting RPS15, which was augmented by the combination with cisplatin. Inhibition of RPS15 by folic acid, IGF2BP1 ablation, or SB203580 treatment were able to suppress ESCC metastasis and proliferation via the p38 MAPK signaling pathway. Thus, RPS15 promotes ESCC progression via the p38 MAPK pathway and RPS15 inhibitors may serve as potential anti-ESCC drugs.

Comparison of neoadjuvant nab-paclitaxel plus immunotherapy versus paclitaxel plus immunotherapy for esophageal squamous cell carcinoma.

BACKGROUND: This study aimed to compare the feasibility of nab-paclitaxel plus platinum-based chemotherapy (nabTP) versus paclitaxel plus platinum-based chemotherapy (TP) with immune checkpoint inhibitors (ICIs) as a neoadjuvant modality for locally resectable esophageal squamous cell carcinoma (ESCC). METHODS: Between April 2019 and March 2022, we identified ESCC patients who received neoadjuvant immunotherapy with both nabTP (n = 213) and TP (n = 98) at our institution and Henan Cancer Hospital. The patients in the ICIs-nabTP and ICIs-TP groups were pair-matched (1:1) for tumor location, sex, smoking, drinking, clinical T and N stage. The primary endpoint was the hazard of 30-day major postoperative complications. Second, logistic models were applied to estimate the risk factors for pathological complete response (pCR) rate. RESULTS: All patients underwent esophagectomy with R0 resection. A statistically significant increase in the risk of developing major pulmonary (odds ratio [OR], 1.182; 95% confidence interval [CI]: 0.530-2.635; p = 0.683), anastomotic (OR, 1.881; 95% CI: 0.607-5.830; p = 0.267), cardiac (OR, 1.000; 95% CI: 0.426-2.349; p = 1.000) complications after neoadjuvant immunotherapy plus nabTP was not observed. The median interval to surgery was 39 days in the ICIs-nabTP group versus 44 days in the ICIs-TP group (p = 0.119). There was no 30-day mortality in each group. However, there was a slight difference in the 30-day readmission rate (p = 0.043) and the incidence of hydropneumothorax (p = 0.027) between the two groups. The pCR rates of the ICIs-nabTP and ICIs-TP group were 36.7 and 21.4%, respectively (p = 0.018). CONCLUSIONS: It appears to be feasible to add immunotherapy to nabTP regimen for locally advanced ESCC. Compared with TP, nabTP plus ICIs can achieve a better pCR rate in ESCC.

Fabrication of Cu/Al/Cu Laminated Composites Reinforced with Graphene by Hot Pressing and Evaluation of Their Electrical Conductivity.

Metal laminated composites are widely used in industrial and commercial applications due to their excellent overall performance. In this study, the copper/graphene-aluminum-copper/graphene (Cu/Gr-Al-Cu/Gr) laminated composites were prepared by ingenious hot pressing design. Raman, optical microscope (OM), scanning electron microscope (SEM), van der Pauw (vdP), and X-Ray Diffractometer (XRD) were used to investigate the graphene status, interface bonding, diffusion layer thickness, electrical conductivity, Miller indices and secondary phases, respectively. The results demonstrate that the Cu-Al interfaces in the Cu/Gr-Al-Cu/Gr composites were free of pores, cracks and other defects and bonded well. The number of graphene layers was varied by regulating the thickness of the Cu/Gr layer, with the Cu/Gr foils fabricated by chemical vapor deposition (CVD). The electrical conductivity of the composite was significantly improved by the induced high-quality interfaces Cu/Gr structure. The increased number of graphene layers is beneficial for enhancing the electrical conductivity of the Cu/Gr-Al-Cu/Gr composite, and the highest conductivity improved by 20.5% compared to that of raw Al.

Pathologic responses and surgical outcomes after neoadjuvant immunochemotherapy versus neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma.

Background: Currently, the role of immunotherapy in neoadjuvant setting for patients with locally advanced esophageal squamous cell carcinoma (ESCC) is gradually attracting attention. Few studies compared the efficacy of neoadjuvant immunochemotherapy (NICT) and neoadjuvant chemoradiotherapy (NCRT). Our study aimed to compare treatment response and postoperative complications after NICT followed by surgery with that after conventional NCRT in patients with locally advanced ESCC. Methods: Of 468 patients with locally advanced ESCC, 154 received conventional NCRT, whereas 314 received NICT. Treatment response, postoperative complications and mortality between two groups were compared. Pathological response of primary tumor was evaluated using the Mandard tumor regression grade (TRG) scoring system. Pathological complete response (pCR) of metastatic lymph nodes (LNs) was defined as no viable tumor cell within all resected metastatic LNs. According to regression directionality, tumor regression pattern was summarized into four categories: type I, regression toward the lumen; type II, regression toward the invasive front; type III, concentric regression; and type IV, scattered regression. Inverse probability propensity score weighting was performed to minimize the influence of confounding factors. Results: After adjusting for baseline characteristics, the R0 resection rates (90.9% vs. 89.0%, P=0.302) and pCR (ypT0N0) rates (29.8% vs. 34.0%, P=0.167) were comparable between two groups. Patients receiving NCRT showed lower TRG score (P<0.001) and higher major pathological response (MPR) rate (64.7% vs. 53.6%, P=0.001) compared to those receiving NICT. However, NICT brought a higher pCR rate of metastatic LNs than conventional NCRT (53.9% vs. 37.1%, P<0.001). The rates of type I/II/III/IV regression patterns were 44.6%, 6.8%, 11.4% and 37.1% in the NICT group, 16.9%, 8.2%, 18.3% and 56.6% in the NCRT group, indicating a significant difference (P<0.001). Moreover, there were no significant differences in the incidence of total postoperative complications (35.8% vs. 39.9%, P=0.189) and 30-d mortality (0.0% vs. 1.1%, P=0.062). Conclusion: For patients with locally advanced ESCC, NICT showed a R0 resection rate and pCR (ypT0N0) rate comparable to conventional NCRT, without increased incidence of postoperative complications and mortality. Notablely, NICT followed by surgery might bring a promising treatment response of metastatic LNs.

Is it necessary for patients with potentially resectable esophageal squamous cell cancer to receive routine preoperative brain MRI/CT?

BACKGROUND: This study aimed to investigate the value and efficiency of routine brain MRI or CT in the preoperative workup for patients with potentially resectable (cT1-4a N0-3 ) thoracic esophageal squamous cell cancer (ESCC). METHODS: This was a prospective cross-sectional clinical trial (ChiCTR1800020304). A total of 385 patients with potentially resectable (cT1-4a N0-3 ) thoracic ESCC diagnosed from October 2018 to August 2020 were included. Plain brain MRI or CT was performed preoperatively to detect brain metastases (BrM). The primary endpoint was BrM detected by imaging. RESULTS: Of all 385 patients, the rate of positive brain MRI/CT findings was 1% (n = 4). BrM Patients received chemoradiotherapy, and the median OS was 6 months (95% CI: 4.303-7.697). All 381 remaining patients with initial negative brain MRI/CT diagnosis revealed no brain-associated symptoms within 6 months. The median follow-up for patients without BrM was 20 months (range, from 6 to 32). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of plain MRI or CT to detect BrM were all 100%. CONCLUSIONS: Preoperative plain MRI or CT is an effective method to detect BrM for potentially resectable (cT1-4a N0-3 ) thoracic ESCC. However, due to the low incidence, the value of brain MRI/CT as a routinely preoperational examination in potentially resectable esophageal squamous cell cancer is rather limited. Therefore, preoperative brain MRI/CT should not be recommended as a routine preoperative examination for ESCC.

Identification and Analysis of Key Barriers of BIM Application for Small- and Medium-Sized Fire Protection Enterprises.

The application of Building Information Modeling (BIM) in fire protection discipline has been sufficiently proved to be useful, but has encountered many barriers in China. Among which, small- and medium-sized enterprises (SMEs), which are considered sensitive to adoption costs and external funding support, play a critical role in the BIM adoption process in fire protection discipline. Therefore, identifying and analyzing the barriers of BIM application are essential to help small- and medium-sized fire protection enterprises to overcome these barriers. In this study, semantic analysis, which includes word frequency analysis and coword analysis, based on literature review was utilized to identify the main barriers. 20 main barriers, which were classified into software, people, organization, and environment group, were obtained. Then, Interpretive Structural Modelling (ISM) approach and Cross-Impact Matrix Multiplication Applied to Classification (MICMAC) analysis were utilized to hierarchically analyze and categorize the main barriers of BIM application in Chinese SMFEs. The findings revealed that the lack of external support and the lack of BIM laws and regulations applicable to fire protection discipline are the key barriers in general for the application of BIM in SMFEs. For the barriers at the enterprise level, through further analysis and discussion based on barriers in the people and organization clusters, the lack of funding support for proper BIM training and the lack of organization culture support were concluded as the key barriers of BIM application inside the scope of SMFEs. According to 80-20 principle, more effort should be focused on the key barriers to gain maximum management effect. The research result categorizes the barriers for easy intervention of fire protection enterprises' managers and policymakers. It contributes to the nascent studies of BIM application and provides guidance for the application of BIM in fire protection discipline.

Development and validation of a nomogram model for the prediction of 4L lymph node metastasis in thoracic esophageal squamous cell carcinoma.

Objectives: The left tracheobronchial (4L) lymph nodes (LNs) are considered as regional LNs for esophageal squamous cell carcinoma (ESCC), but there is a controversy about routine prophylactic 4L LN dissection for all resectable ESCCs. This study aimed to develop a nomogram for preoperative prediction of station 4L lymph node metastases (LNMs). Methods: A total of 522 EC patients in the training cohort and 370 in the external validation cohort were included. The prognostic impact of station 4L LNM was evaluated, and multivariable logistic regression analyses were performed to identify independent risk factors of station 4L LNM. A nomogram model was developed based on multivariable logistic regression analysis. Model performance was evaluated in both cohorts in terms of calibration, discrimination, and clinical usefulness. Results: The incidence of station 4L LNM was 7.9% (41/522) in the training cohort. Patients with station 4L LNM exhibited a poorer 5-year overall survival rate than those without (43.2% vs. 71.6%, p < 0.001). In multivariate logistic regression analyses, six variables were confirmed as independent 4L LNM risk factors: sex (p = 0.039), depth of invasion (p = 0.002), tumor differentiation (p = 0.016), short axis of the largest 4L LNs (p = 0.001), 4L conglomeration (p = 0.006), and 4L necrosis (p = 0.002). A nomogram model, containing six independent risk factors, demonstrated a good performance, with the area under the curve (AUC) of 0.921 (95% CI: 0.878-0.964) in the training cohort and 0.892 (95% CI: 0.830-0.954) in the validation cohort. The calibration curve showed a good agreement on the presence of station 4L LNM between the risk estimation according to the model and histopathologic results on surgical specimens. The Hosmer-Lemeshow test demonstrated a non-significant statistic (p = 0.691 and 0.897) in the training and validation cohorts, which indicated no departure from the perfect fit. Decision curve analysis indicated that the model had better diagnostic power for 4L LNM than the traditional LN size criteria. Conclusions: This model integrated the available clinical and radiological risk factors, facilitating in the precise prediction of 4L LNM in patients with ESCC and aiding in personalized therapeutic decision-making regarding the need for routine prophylactic 4L lymphadenectomy.

The risk and prognostic factors for liver metastases in esophageal cancer patients: A large-cohort based study.

BACKGROUND: This retrospective study aimed to explore risk factors for liver metastases (LiM) in patients with esophageal cancer (EC) and to identify prognostic factors in patients initially diagnosed with LiM. METHODS: A total of 28 654 EC patients were retrieved from the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2018. A multivariate logistic regression model was utilized to identify risk factors for LiM. A Cox regression model was used to identify prognostic factors for patients with LiM. RESULTS: Of 28 654 EC patients, 4062 (14.2%) had LiM at diagnosis. The median overall survival (OS) for patients with and without LiM was 6.00 (95% CI: 5.70-6.30) months and 15.00 (95% CI: 14.64-15.36) months, respectively. Variables significantly associated with LiM included gender, age, tumor site, histology, tumor grade, tumor size, clinical T stage, clinical N stage, bone metastases (BoM), brain metastases (BrM) and lung metastases (LuM). Variables independently predicting survival for EC patients with LiM were age, histology, tumor grade, BoM, BrM, LuM, and chemotherapy. A risk prediction model and two survival prediction models were then constructed revealing satisfactory predictive accuracy. CONCLUSIONS: Based on the largest known cohort of EC, independent predictors of LiM and prognostic indicators of survival for patients with LiM were identified. Two models for predicting survival as well as a risk prediction model were developed with robust predictive accuracy.

99m Tc bone scintigraphy does not affect preoperative workup for patients with potentially resectable esophageal squamous cell carcinoma.

BACKGROUND: 99m Tc bone scintigraphy (BS) is the mainstay and most widely used technique in evaluation of bone metastasis (BM) in China. This study aimed to investigate the value of 99m Tc BS in preoperative workup for patients with potentially resectable (cT1-4a N0-3 ) esophageal squamous cell carcinoma (ESCC). METHODS: This prospective cross-section clinical trial (ChiCTR1800020304) enrolled a total of 385 patients with ESCC diagnosed at thoracic surgery clinic from October 2018 to September 2020. All patients were diagnosed with stage cT1-4a N0-3 and were potential candidates for surgical resection. BS was performed preoperatively and the treatment strategy was changed after confirmation of BM. The primary endpoint was the rate of change of the treatment regimen because of BM, while the secondary endpoint was the rate of positive BS findings. RESULTS: Out of the 385 patients, only two (0.5%) changed their treatment regimen because of BM. The rate of positive BS findings was 1%, while two patients (0.5%) had false-positive or false-negative results. The BS diagnostic performance for BM was sensitivity 50%, specificity 99.5%, positive predictive value 50%, negative predictive value 99.5%, and accuracy 99.0%. There was no significant difference in BM in relation to age, sex, tumor location or clinical stage. CONCLUSION: Our data demonstrated that 99m Tc bone scintigraphy does not significantly affect the preoperative workup in patients with potentially resectable ESCC, especially in early clinical stage patients.