US-based Sequential Algorithm Integrating an AI Model for Advanced Liver Fibrosis Screening.

Background Noninvasive tests can be used to screen patients with chronic liver disease for advanced liver fibrosis; however, the use of single tests may not be adequate. Purpose To construct sequential clinical algorithms that include a US deep learning (DL) model and compare their ability to predict advanced liver fibrosis with that of other noninvasive tests. Materials and Methods This retrospective study included adult patients with a history of chronic liver disease or unexplained abnormal liver function test results who underwent B-mode US of the liver between January 2014 and September 2022 at three health care facilities. A US-based DL network (FIB-Net) was trained on US images to predict whether the shear-wave elastography (SWE) value was 8.7 kPa or higher, indicative of advanced fibrosis. In the internal and external test sets, a two-step algorithm (Two-step#1) using the Fibrosis-4 Index (FIB-4) followed by FIB-Net and a three-step algorithm (Three-step#1) using FIB-4 followed by FIB-Net and SWE were used to simulate screening scenarios where liver stiffness measurements were not or were available, respectively. Measures of diagnostic accuracy were calculated using liver biopsy as the reference standard and compared between FIB-4, SWE, FIB-Net, and European Association for the Study of the Liver guidelines (ie, FIB-4 followed by SWE), along with sequential algorithms. Results The training, validation, and test data sets included 3067 (median age, 42 years [IQR, 33-53 years]; 2083 male), 1599 (median age, 41 years [IQR, 33-51 years]; 1124 male), and 1228 (median age, 44 years [IQR, 33-55 years]; 741 male) patients, respectively. FIB-Net obtained a noninferior specificity with a margin of 5% (P < .001) compared with SWE (80% vs 82%). The Two-step#1 algorithm showed higher specificity and positive predictive value (PPV) than FIB-4 (specificity, 79% vs 57%; PPV, 44% vs 32%) while reducing unnecessary referrals by 42%. The Three-step#1 algorithm had higher specificity and PPV compared with European Association for the Study of the Liver guidelines (specificity, 94% vs 88%; PPV, 73% vs 64%) while reducing unnecessary referrals by 35%. Conclusion A sequential algorithm combining FIB-4 and a US DL model showed higher diagnostic accuracy and improved referral management for all-cause advanced liver fibrosis compared with FIB-4 or the DL model alone. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Ghosh in this issue.

Association between human blood metabolome and the risk of pre-eclampsia.

Pre-eclampsia is a complex multi-system pregnancy disorder with limited treatment options. Therefore, we aimed to screen for metabolites that have causal associations with preeclampsia and to predict target-mediated side effects based on Mendelian randomization (MR) analysis. A two-sample MR analysis was firstly conducted to systematically assess causal associations of blood metabolites with pre-eclampsia, by using metabolites related large-scale genome-wide association studies (GWASs) involving 147,827 European participants, as well as GWASs summary data about pre-eclampsia from the FinnGen consortium R8 release data that included 182,035 Finnish adult female subjects (5922 cases and 176,113 controls). Subsequently, a phenome-wide MR (Phe-MR) analysis was applied to assess the potential on-target side effects associated with hypothetical interventions that reduced the burden of pre-eclampsia by targeting identified metabolites. Four metabolites were identified as potential causal mediators for pre-eclampsia by using the inverse-variance weighted method, including cholesterol in large HDL (L-HDL-C) [odds ratio (OR): 0.88; 95% confidence interval (95% CI): 0.83-0.93; P = 2.14 × 10-5), cholesteryl esters in large HDL (L-HDL-CE) (OR: 0.88; 95% CI: 0.83-0.94; P = 5.93 × 10-5), free cholesterol in very large HDL (XL-HDL-FC) (OR: 0.88; 95% CI: 0.82-0.94; P = 1.10 × 10-4) and free cholesterol in large HDL (L-HDL-FC) (OR: 0.89; 95% CI: 0.84-0.95; P = 1.45 × 10-4). Phe-MR analysis showed that targeting L-HDL-CE had beneficial effects on the risk of 24 diseases from seven disease chapters. Based on this systematic MR analysis, L-HDL-C, L-HDL-CE, XL-HDL-FC, and L-HDL-FC were inversely associated with the risk of pre-eclampsia. Interestingly, L-HDL-CE may be a promising drug target for preventing pre-eclampsia with no predicted detrimental side effects. The study consists of a two-stage design that conducts MR at both stages. First, we assessed the causality for the associations between 194 blood metabolites and the risk of pre-eclampsia. Second, we investigated a broad spectrum of side effects associated with the targeting identified metabolites in 693 non-preeclampsia diseases. Our results suggested that Cholesteryl esters in large HDL may serve as a promising drug target for the prevention or treatment of pre-eclampsia with no predicted detrimental side effects.

Tailoring Oxidation Responsiveness of Gold Nanoclusters via Ligand Engineering for Imaging Acute Kidney Injury.

Gold nanoclusters (AuNCs) have shown great promise for in vivo imaging because of their definable structure, tunable photoluminescence (PL), and desired renal clearance. However, current understanding of the responsiveness of AuNCs to biological substances is still limited, which may hamper their biomedical applications. Herein, we explore the oxidation responsiveness of near-infrared II (NIR-II) luminescent AuNCs capped with two different ligands, which can be optimized for high-efficiency NIR-II PL imaging of mice acute kidney injury (AKI) featuring high-level peroxynitrite anions (ONOO-). We found that in the presence of ONOO-, N-acetylcysteine-capped AuNCs (NAC-AuNCs) tended to be oxidized more easily than that capped with the macromolecular mercapto-ß-cyclodextrin (CDS-AuNCs), resulting in the aggregation of NAC-AuNCs into large-sized assemblies, which was not observed in CDS-AuNCs. The oxidation-triggered morphology, composition, and NIR-II PL changes in NAC-AuNCs were then systematically studied. We finally demonstrated that NAC-AuNCs can be implemented for sensitive NIR-II PL imaging of mice AKI, facilitated by the synergetic in situ AuNC aggregation and decreased glomerular filtration rate (GFR) in the injured kidney, which outperforms the methods solely based on the decreased GFR effect. Therefore, this work highlights the critical significance of ligand engineering in AuNCs and may motivate future design of AuNCs for diverse bioimaging applications.

Needs and influence factors of medical-nursing-pension of disabled elderly.

As the population ages, the incidence of disabled elderly persons increases, and the need for medical-nursing-pension services among disabled senior persons increases. The purpose of this study is to determine the needs and affecting factors of disabled elderly living in community homes in Nanning, Guangxi, China. The study utilized the descriptive comparative cross-sectional study. Stratified random sampling was utilized, based on inclusion and exclusion criteria, a total of 168 disabled elderly were randomly selected and investigated using a self-designed questionnaire which included basic nursing services domain, professional nursing services domain, rehabilitative nursing services domain, living nursing services domain, and spiritual nursing services domain. The t test, one-way ANOVA, and multivariate logistic regression were used to determine the influencing factors of medical-nursing-pension demands for community-dwelling disabled elderly. Majority of impaired seniors have a moderate to high-level of demand for medical-nursing-pension services. Age (t = 2.369, 95% confidence interval [CI]: 0.673-7.414), educational level (t = -16.946, 95% CI: -31.247 to -24.726), monthly income (t = -16.273, 95% CI: -22.104 to -17.320), economic source (t = 8.891, 95% CI: 16.850-26.470), time spent disabled (t = -11.151, 95% CI: -31.845 to -22.264), living with children (t = 10.852, 95% CI: 24.491-35.521), and medical insurance participation (t = 4.556, 95% CI: 9.032-22.848) all influence the demand for medical-nursing-pension services for disabled seniors in the community ( P = .05). Majority of community-dwelling impaired seniors have a moderate to high demand for medical-nursing-pension services. Relevant departments and community nurses should pay increased attention to the elderly who are older, have a low educational level, a low monthly income, have an economic source of pension from their own, have been disabled for long period of time, are single, and do not have children, to improve the health care system for disabled elderly by implementing more personalized home visits in medical-nursing-pension on health education about oxygen inhalation and wound dressing.

American college of radiology ovarian-adnexal reporting and data system ultrasound (O-RADS): Diagnostic performance and inter-reviewer agreement for ovarian masses in children.

Objective: To evaluate the diagnostic performance and inter-observer agreement of the American College of Radiology Ovarian-Adnexal Reporting and Data System Ultrasound (O-RADS) in the diagnosis of ovarian masses in children. Methods: From June 2012 to December 2021, 163 ovarian masses in 159 patients with pathologic results were retrospectively analyzed. Each mass was classified into an O-RADS category according to the criteria. The diagnostic performance of O-RADS for detecting malignant ovarian masses was assessed using histopathology as the reference standard. Kappa (k) statistic was used to assess inter-observer agreement between a less-experienced and a well-experienced radiologist. Results: Out of 163 ovarian masses, 18 (11.0%) were malignant and 145 (89.0%) were benign. The malignancy rates of O-RADS 5, O-RADS 4, and O-RADS 3 masses were 72.7%, 34.6%, and 4.8%, respectively. The area under the receiver operating characteristic curve was 0.944 (95% CI, 0.908-0.981). The optimal cutoff value for predicting malignant ovarian masses was > O-RADS 3 with a sensitivity, specificity, and accuracy of 94.4%, 86.2% and 86.2% respectively. The inter-observer agreement of the O-RADS category was good (k = 0.777). Conclusions: O-RADS has a high diagnostic performance for children with ovarian masses. It provides an effective malignant risk classification for ovarian masses in children, which shows high consistency between radiologists with different levels of experience.

Association between growth differentiation factor 15 levels and gestational diabetes mellitus: A combined analysis.

Objective: Gestational diabetes mellitus (GDM) is a common glucose metabolism disease occurs in pregnancy that affects both maternal and neonatal health. Recently, increasing studies have attached importance to the relationship between growth differentiation factor 15 (GDF-15) and GDM, but the results were inconclusive. Therefore, we conducted a meta-analysis to examine the association between GDF-15 and GDM. Materials and methods: A systematical search was performed in Gene Expression Omnibus (GEO), PubMed and Google Scholar till Oct 27, 2022. We first calculated the mean and standard deviation of GDF-15 expression levels from the included eligible datasets and articles. Then, a meta-analysis was conducted to depict the difference in GDF-15 mRNA or GDF-15 protein expression between case and control groups by using conservative random effect model. Moreover, the potential publication bias was checked with the aid of Begg's test and Egger's test. Finally, sensitivity analyses were performed by changing the inclusion criteria. Results: In summary, 12 GEO datasets and 5 articles were enrolled in our study, including 789 GDM patients and 1202 non-GDM pregnant women. It was found that the expression levels of GDF-15 mRNA and GDF-15 protein in late pregnancy were significantly higher in GDM patients compared with non-GDM pregnant women, with the standard mean difference (SMD) and 95% confidence interval (95% CI) of 0.48 (0.14, 0.83) and 0.82 (0.32-1.33), respectively. Meanwhile, a slightly weakened association between GDF-15 protein levels and GDM was also observed in the middle pregnancy, with SMD (95% CI) of 0.53 (0.04-1.02). Conclusion: In all, our results suggested that the expression levels of GDF-15 were significantly higher in GDM patients compared with non-GDM pregnant women, especially in the late pregnancy.

Aspirin 75 mg to prevent preeclampsia in high-risk pregnancies: a retrospective real-world study in China.

BACKGROUND: Several randomized clinical trials showed that aspirin could decrease the incidence of preeclampsia (PE) in women at high risk, but data from sources other than traditional clinical trials that investigating the preventive effect of aspirin 75 mg on PE is still lacking, especially in mainland China. We aimed to use Chinese real-world data to estimate the preventive effect of low-dose aspirin (LDA) on PE. METHODS: Clinical data of pregnant women who were at high risk of PE and had their first prenatal visit at the affiliated Taicang People's Hospital of Soochow University during November 31, 2018 and May 10, 2021 was retrospectively analyzed. Among the 266 included pregnant women, 115 individuals treated with aspirin 75 mg per day and the other 151 without such treatment were considered as the LDA group and the control group, respectively. RESULTS: In the LDA group, 64 (55.65%) of 115 pregnant women took aspirin before 16 weeks of gestation. Besides, 12 (10.43%) and 34 (22.52%) women developed PE in the LDA group and control group, respectively; the aspirin prophylaxis was associated with a lower risk of PE (odds ratio = 0.40, 95% confidence interval = 0.20-0.82, P = 0.0098). In addition, LDA is slightly more effective when initiated before 16 weeks of gestation or in those without chronic hypertension, when compared with their counterparts. CONCLUSION: Prophylaxis with 75 mg per day of aspirin in high-risk women resulted in a significantly lower incidence of PE than that in the control group.

Identification of Novel Hypoxia Subtypes for Prognosis Based on Machine Learning Algorithms.

Objective: A reduced level or tension or the deprivation of oxygen is termed hypoxia. It is common for tumours to outgrow their natural source of nutrients, which causes hypoxia in some tumour regions. Hypoxia affects ovarian cancer (OC) in several ways. Methods: In this study, the expression patterns of prognostic hypoxia-related genes were curated, and consensus clustering analyses were performed to determine hypoxia subtypes in OC included in The Cancer Genome Atlas cohort. Two hypoxia-related subtypes were observed and considered for further investigation. The analyses of differentially expressed genes (DEGs), gene ontology, mutation, and immune cell infraction were performed to explore the underlying molecular mechanisms. Results: In total, 377 patients with OC were classified into two subgroups based on the subtype of hypoxia. The clinical outcome was considerably poor for patients with hypoxia subtype 2. DEG and protein-protein interaction analyses revealed that the expression levels of CLIP2 and SH3PXD2A were low in OC tissues. Immune cell infarction analysis revealed that the subtypes were associated with the tumour microenvironment (TME). Conclusion: Our findings established the existence of two distinctive, complex, and varied hypoxia subtypes in OC. Findings from the quantitative analysis of hypoxia subtypes in patients improved our understanding of the characteristics of the TME and may facilitate the development of more efficient treatment regimens.

Prenatal ultrasonic features of a mediastinal teratoma: A case report and literature review.

Fetal mediastinal teratomas represent only 10% of congenital teratomas in children and 2.6% of all mediastinal masses in children. Teratomas have multifactorial etiology, such as chromosomal abnormalities. Fetal mediastinal teratomas are rare. Mediastinal teratomas can cause hydrops fetalis, fetal demise, and neonatal respiratory distress; therefore, accurate perinatal management and interventions are very important. We describe a case of fetal mediastinal teratoma wherein the cystic fluid in the fetal tumor was aspirated and confirmed by surgical pathology after birth at the authors' center. The teratoma in this case was characterized by a large single cystic mass with clear borders in the anterosuperior mediastinum, which grew rapidly and was closely related to the thymus. The infant was healthy at birth, and the tumor was surgically removed the age of 1 year. The postoperative course was uneventful, and the patient was in good health 6 years postoperatively. This case and literature review suggests that ultrasound examination can accurately diagnose fetal mediastinal teratomas, which is beneficial to provide an accurate basis for fetal prenatal intervention and treatment. Additionally, an important ultrasound feature of a fetal unicystic mediastinal teratoma is a saddle-shaped mass with clear boundaries, which provided an accurate reference for the diagnosis of a fetal cystic mediastinal teratoma by prenatal ultrasonography.

Near-Infrared II Gold Nanocluster Assemblies with Improved Luminescence and Biofate for In Vivo Ratiometric Imaging of H2S.

Ultrasmall gold nanoclusters (AuNCs) are emerging as promising luminescent nanoprobes for bioimaging due to their fantastic photoluminescence (PL) and renal-clearable ability. However, it remains a great challenge to design them for in vivo sensitive molecular imaging in desired tissues. Herein, we have developed a strategy to tailor the PL and biofate of near-infrared II (NIR-II)-emitting AuNCs via ligand anchoring for improved bioimaging. By optimizing the ligand types in AuNCs and using Er3+-doped lanthanide (Ln) nanoparticles as models, core-satellite Ln@AuNCs assemblies were rationally constructed, which enabled 2.5-fold PL enhancement of AuNCs at 1100 nm and prolonged blood circulation compared to AuNCs. Significantly, Ln@AuNCs with dual intense NIR-II PL (from AuNCs and Er3+) can effectively accumulate in the liver for ratiometric NIR-II imaging of H2S, facilitated by H2S-mediated selective PL quenching of AuNCs. We have then demonstrated the real-time imaging evaluation of liver delivery efficacy and dynamics of two H2S prodrugs. This shows a paradigm to visualize liver H2S delivery and its prodrug screening in vivo. Note that Ln@AuNCs are body-clearable via the hepatobiliary excretion pathway, thus reducing potential long-term toxicity. Such findings may propel the engineering of AuNC nanoprobes for advancing in vivo bioimaging analysis.

Pipeline In-Line Inspection Method, Instrumentation and Data Management.

Pipelines play an important role in the national/international transportation of natural gas, petroleum products, and other energy resources. Pipelines are set up in different environments and consequently suffer various damage challenges, such as environmental electrochemical reaction, welding defects, and external force damage, etc. Defects like metal loss, pitting, and cracks destroy the pipeline's integrity and cause serious safety issues. This should be prevented before it occurs to ensure the safe operation of the pipeline. In recent years, different non-destructive testing (NDT) methods have been developed for in-line pipeline inspection. These are magnetic flux leakage (MFL) testing, ultrasonic testing (UT), electromagnetic acoustic technology (EMAT), eddy current testing (EC). Single modality or different kinds of integrated NDT system named Pipeline Inspection Gauge (PIG) or un-piggable robotic inspection systems have been developed. Moreover, data management in conjunction with historic data for condition-based pipeline maintenance becomes important as well. In this study, various inspection methods in association with non-destructive testing are investigated. The state of the art of PIGs, un-piggable robots, as well as instrumental applications, are systematically compared. Furthermore, data models and management are utilized for defect quantification, classification, failure prediction and maintenance. Finally, the challenges, problems, and development trends of pipeline inspection as well as data management are derived and discussed.

Dynamic Contrast-Enhanced Ultrasound Radiomics for Hepatocellular Carcinoma Recurrence Prediction After Thermal Ablation.

PURPOSE: To develop a radiomics model based on dynamic contrast-enhanced ultrasound (CEUS) to predict early and late recurrence in patients with a single HCC lesion ≤ 5 cm in diameter after thermal ablation. PROCEDURES: We enrolled patients who underwent thermal ablation for HCC in our hospital from April 2004 to April 2017. Radiomics based on two branch convolution recurrent network was utilized to analyze preoperative dynamic CEUS image of HCC lesions to establish CEUS model, in comparison to the conventional ultrasound (US), clinical, and combined models. Clinical follow-up of HCC recurrence after ablation were taken as reference standard to evaluate the predicted performance of CEUS model and other models. RESULTS: We finally analyzed 318 patients (training cohort: test cohort = 255:63). The combined model showed better performance for early recurrence than CUES (in training cohort, AUC, 0.89 vs. 0.84, P < 0.001; in test cohort, AUC, 0.84 vs. 0.83, P = 0.272), US (P < 0.001), or clinical model (P < 0.001). For late recurrence prediction, the combined model showed the best performance than the CEUS (C-index, in training cohort, 0.77 vs. 0.76, P = 0.009; in test cohort, 0.77 vs. 0.68, P < 0.001), US (P < 0.001), or clinical model (P < 0.001). CONCLUSIONS: The CEUS model based on dynamic CEUS radiomics performed well in predicting early HCC recurrence after ablation. The combined model combining CEUS, US radiomics, and clinical factors could stratify the high risk of late recurrence.

Prenatal sonographic diagnosis of partial left pulmonary artery sling: A rare case report.

Pulmonary artery sling is a rare congenital vascular anomaly. Partial anomalous left pulmonary artery is even rarer and no in utero observation has yet been reported. Here, we present the ultrasonographic findings of a 38-year-old woman at 32 weeks of gestation whose fetus showed a normal bifurcation of the pulmonary trunk into the right and left pulmonary arteries, but an anomalous origin of the left lower lobe pulmonary artery from the right pulmonary artery. These findings were confirmed by postnatal echocardiography and thoracic computed tomography.

Intraprocedural computed tomography/magnetic resonance-contrast-enhanced ultrasound fusion imaging improved thermal ablation effect of hepatocellular carcinoma: Comparison with conventional ultrasound.

AIM: To retrospectively compare the treatment effect of intraprocedural computed tomography/magnetic resonance-contrast-enhanced ultrasound (CT/MR-CEUS) fusion imaging (FI) with that of conventional ultrasound (US) in the guidance and assessment of thermal ablation of hepatocellular carcinoma (HCC). METHODS: The FI group (112 patients with 129 HCC) was treated between April 2010 and December 2012, whereas the US group (83 patients with 90 HCC) was treated between January 2008 and March 2010. Either CT/MR-CEUS FI or US was used to guide puncture, provide immediate assessment, and guide supplementary ablation. Technical efficacy, cumulative local tumor progression rate (LTP), recurrence-free survival (RFS), and overall survival (OS) were evaluated and compared during follow-up. Technical success rate of CT/MR-CEUS FI was also recorded. RESULTS: Technical efficacy was significantly higher in the FI group than in the US group (100% vs. 86.7%, P < 0.001). The 1-, 2-, 3-, 4-, 5-, and 6-year cumulative LTP rates in the FI group were significantly lower than in the US group (3.8%, 4.9%, 6.0%, 6.0%, 7.2%, and 7.2% vs. 16.9%, 20.1%, 25%, 25%, 25%, and 25%, respectively; P < 0.001); RFS and OS were significantly higher in the FI group than in the US group (P = 0.027 and P = 0.049, respectively). The technical success rate of FI was 85.3%. CONCLUSIONS: Intraprocedural CT/MR-CEUS FI improved the treatment effect of thermal ablation of HCC by immediately assessing treatment response and guiding supplementary ablation relative to those resulting from the use of conventional US.

Purification of chlorogenic acid from Heijingang potatoes and evaluation of its binding properties to recombinant human serum albumin.

The aim of the present study was to purify the natural chlorogenic acid (CGA) monomer from Heijingang potatoes and investigate its interaction with recombinant human serum albumin (rHSA). The potato extract (PE) was purified using macroporous resins and solvent, and the CGA monomer was subsequently isolated using semipreparative liquid chromatography (SP-LC). The purity and structure of the CGA monomer was analyzed by high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR). The interaction between the CGA monomer and rHSA was studied using fluorescence spectroscopy and molecular docking. HPLC analysis indicates that the CGA monomer had a retention time of 5.368 min and a purity of 97.9%, the presence of which was confirmed by NMR. The molecular docking and fluorescence spectroscopy demonstrate that CGA had a static quenching effect on rHSA with one binding site, and the range of K values was 7.14 × 103 to 1.56 × 104 M-1. This simple and efficient extract coupled with SP-LC has the potential for use in the extraction and purification of CGA in pilot or large-scale operations.

Prenatal sonographic diagnosis of nondysraphic intramedullary lipomas: A case report.

Nondysraphic intramedullary lipomas of the spinal cord are rare, and there are currently no reports of their observation in utero. Here, we present the sonographic (US) findings in such a case. Four intraspinal hyperechoic masses were observed on US on the dorsal aspect of the fetal spine in a 30-year-old woman at 30 weeks' gestation. Findings were consistent with those of prenatal MRI and were confirmed on autopsy after induced abortion. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:278-281, 2018.

Laparoscopic Partial Nephrectomy for T1 Renal Cell Carcinoma: Comparison of Two Resection Techniques in a Multi-institutional Propensity Score-Matching Analysis.

BACKGROUND: Enucleoresection is defined as presence of a minimal paratumor parenchyma that allows for clear visualization of the tumor's contours during partial nephrectomy (PN). Because there is variability in published reports regarding resection techniques during PN before the surface-intermediate-base (SIB) margin score reporting system, the association between postoperative outcomes and resection techniques are rarely reported. This study was designed to compare the perioperative, oncologic, and functional outcomes between laparoscopic enucleoresection (LER) (SIB score 1 + 1 + 1 = 3) and traditional laparoscopic partial nephrectomy (TLPN) (SIB score 1 + 2 + 2 = 5). METHODS: Data from 270 consecutive patients who underwent laparoscopic partial nephrectomy for single T1 RCC at 3 medical centers were prospectively collected. Propensity score matching was performed on age, gender, body mass index, American Society of Anesthesiologists score, preoperative estimated glomerular filtration rate (eGFR), tumor size, RENAL nephrometry score, Charlson score, and solitary kidney status. Normal parenchyma width of each patient was evaluated right after the surgery, and SIB score was assigned retrospectively. Ninety-eight matched patients undergoing LER or TLPN were compared for perioperative, oncologic, and functional outcomes. RESULTS: After matching, warm ischemia time (WIT) and operative time were significantly shorter in LER than TLPN group (20.8 vs. 23.8 min, P = 0.003 and 130.8 vs. 152.1 min, P = 0.005, respectively). Estimated blood loss (EBL) also was lower in LER than TLPN group (50 vs. 90 mL, P = 0.045). Complication rates, positive surgical margin rates, and local recurrence rates were comparable between groups (P = 0.3, P = 0.62, and P = 1.0, respectively). At last follow-up, the eGFRs also were comparable in both groups (P = 0.6). CONCLUSIONS: LER has similar oncologic, functional outcomes and complication rates with the advantage of a shorter WIT, operative time, and lower EBL compared with TLPN.

Src mutation induces acquired lapatinib resistance in ERBB2-amplified human gastroesophageal adenocarcinoma models.

ERBB2-directed therapy is now a routine component of therapy for ERBB2-amplified metastatic gastroesophageal adenocarcinomas. However, there is little knowledge of the mechanisms by which these tumors develop acquired resistance to ERBB2 inhibition. To investigate this question we sought to characterize cell line models of ERBB2-amplified gastroesophageal adenocarcinoma with acquired resistance to ERBB2 inhibition. We generated lapatinib-resistant (LR) subclones from an initially lapatinib-sensitive ERBB2-amplified esophageal adenocarcinoma cell line, OE19. We subsequently performed genomic characterization and functional analyses of resistant subclones with acquired lapatinib resistance. We identified a novel, acquired SrcE527K mutation in a subset of LR OE19 subclones. Cells with this mutant allele harbour increased Src phosphorylation. Genetic and pharmacologic inhibition of Src resensitized these subclones to lapatinib. Biochemically, Src mutations could activate both the phosphatidylinositol 3-kinase and mitogen activated protein kinase pathways in the lapatinib-treated LR OE19 cells. Ectopic expression of SrcE527K mutation also was sufficient to induce lapatinib resistance in drug-naïve cells. These results indicate that pathologic activation of Src is a potential mechanism of acquired resistance to ERBB2 inhibition in ERBB2-amplified gastroesophageal cancer. Although Src mutation has not been described in primary tumor samples, we propose that the Src hyperactivation should be investigated in the settings of acquired resistance to ERBB2 inhibition in esophageal and gastric adenocarcinoma.

SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas.

The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology.