Suboptimal performance of LI-RADS v2018 on gadoxetic acid-enhanced MRI for detecting hepatocellular carcinoma in liver transplant candidates.

OBJECTIVES: To evaluate the diagnostic performance for hepatocellular carcinoma (HCC) detection of the Liver Imaging Reporting and Data System (LI-RADS) version 2018 on gadoxetic acid-enhanced MRI, comparing liver transplant candidates (LT group) with patients who underwent surgical resection (SR group), and to determine significant clinical factors for diagnostic performance of LI-RADS v2018. METHODS: Patients who underwent gadoxetic acid-enhanced MRI and subsequent SR or LT for HCC were retrospectively included between January 2019 and December 2020. The sensitivity and specificity of LI-RADS LR-5 for HCC were compared between the two groups using generalized estimating equations. The accuracy of patient allocation according to the Milan criteria was calculated for the LT group. Univariable and multivariable logistic regression analyses were performed to determine significant clinical factors associated with the sensitivity of LI-RADS. RESULTS: Of the 281 patients, 237 were assigned to the SR group, and 44 were assigned to the LT group. The LT group showed significantly lower per-patient (48.5% vs. 79.6%, p < .001) and per-lesion sensitivity (31.0% vs. 75.9%, p < .001) than the SR group, whereas no significant difference in both per-patient (100.0% vs. 91.7%, p > .99) and per-lesion specificities (100.0% vs. 94.1%, p > .99). The accuracy of patient allocation was 50.0%. Sensitivity was significantly lower in patients with a smaller lesion size (p < .001), a larger lesion number (p = .002), and a higher Child-Pugh score (p = .009). CONCLUSION: LI-RADS v2018 on gadoxetic acid-enhanced MRI might be insufficient in liver transplant candidates and other diagnostic imaging tests should be considered in patients with these significant clinical factors. CLINICAL RELEVANCE STATEMENT: In liver transplant candidates with a smaller lesion size, a larger lesion number, and a higher Child-Pugh score, imaging tests other than gadoxetic acid-enhanced MRI may be clinically useful to determine the transplant eligibility. KEY POINTS: • The sensitivity of the Liver Imaging Reporting and Data System (LI-RADS) was lower in liver transplant candidates than in those who underwent surgical resection. • With the use of gadoxetic acid-enhanced MRI, the accuracy of patient allocation for liver transplantation on the basis of the Milan criteria was suboptimal. • The sensitivity of LI-RADS v2018 was significantly associated with lesion size, lesion number, and Child-Pugh classification.

Does total omentectomy prevent peritoneal seeding for advanced gastric cancer with serosal invasion?

BACKGROUND: Radical gastrectomy is composed of gastrectomy, lymph node dissection, and omentectomy. Total omentectomy (TO) is expected to reduce the incidence of peritoneal recurrence. We aimed to investigate the necessity of TO for advanced gastric cancer (AGC) with serosal invasion. METHODS: We retrospectively reviewed 310 patients who underwent radical gastrectomy with TO and 93 patients who underwent partial omentectomy (PO) for gastric cancer with serosal invasion between August, 2005 and December, 2017. Finally, 91 patients in the PO group and 91 in the TO group were enrolled based on a 1:1 propensity-score matching analysis. We evaluated surgical and oncological outcomes, including 5-year overall and recurrence-free survival rates. RESULTS: There was no statistically significant difference between the two groups in postoperative complications. Recurrence sites showed similar patterns in both groups, including peritoneal recurrence (PO vs. TO, 18.7% vs. 28.6%; p = 0.188). Five-year overall survival was better in the PO group (p = 0.018), while 5-year recurrence-free survival was similar in both groups (p = 0.066). CONCLUSION: TO might not be an essential part of preventing peritoneal recurrence for AGC with serosal invasion. PO could be considered a radical gastrectomy for T4a gastric cancer.

A Fast and Accurate Method for Genome-Wide Time-to-Event Data Analysis and Its Application to UK Biobank.

With increasing biobanking efforts connecting electronic health records and national registries to germline genetics, the time-to-event data analysis has attracted increasing attention in the genetics studies of human diseases. In time-to-event data analysis, the Cox proportional hazards (PH) regression model is one of the most used approaches. However, existing methods and tools are not scalable when analyzing a large biobank with hundreds of thousands of samples and endpoints, and they are not accurate when testing low-frequency and rare variants. Here, we propose a scalable and accurate method, SPACox (a saddlepoint approximation implementation based on the Cox PH regression model), that is applicable for genome-wide scale time-to-event data analysis. SPACox requires fitting a Cox PH regression model only once across the genome-wide analysis and then uses a saddlepoint approximation (SPA) to calibrate the test statistics. Simulation studies show that SPACox is 76-252 times faster than other existing alternatives, such as gwasurvivr, 185-511 times faster than the standard Wald test, and more than 6,000 times faster than the Firth correction and can control type I error rates at the genome-wide significance level regardless of minor allele frequencies. Through the analysis of UK Biobank inpatient data of 282,871 white British European ancestry samples, we show that SPACox can efficiently analyze large sample sizes and accurately control type I error rates. We identified 611 loci associated with time-to-event phenotypes of 12 common diseases, of which 38 loci would be missed within a logistic regression framework with a binary phenotype defined as event occurrence status during the follow-up period.

Concordance indices with left-truncated and right-censored data.

In the context of time-to-event analysis, a primary objective is to model the risk of experiencing a particular event in relation to a set of observed predictors. The Concordance Index (C-Index) is a statistic frequently used in practice to assess how well such models discriminate between various risk levels in a population. However, the properties of conventional C-Index estimators when applied to left-truncated time-to-event data have not been well studied, despite the fact that left-truncation is commonly encountered in observational studies. We show that the limiting values of the conventional C-Index estimators depend on the underlying distribution of truncation times, which is similar to the situation with right-censoring as discussed in Uno et al. (2011) [On the C-statistics for evaluating overall adequacy of risk prediction procedures with censored survival data. Statistics in Medicine 30(10), 1105-1117]. We develop a new C-Index estimator based on inverse probability weighting (IPW) that corrects for this limitation, and we generalize this estimator to settings with left-truncated and right-censored data. The proposed IPW estimators are highly robust to the underlying truncation distribution and often outperform the conventional methods in terms of bias, mean squared error, and coverage probability. We apply these estimators to evaluate a predictive survival model for mortality among patients with end-stage renal disease.

Estimating postsurgical outcomes of patients with a single hepatocellular carcinoma using gadoxetic acid-enhanced MRI: risk scoring system development and validation.

OBJECTIVES: To develop and validate risk scoring systems using gadoxetic acid-enhanced liver MRI features and clinical factors that predict recurrence-free survival (RFS) of a single hepatocellular carcinoma (HCC). METHODS: Consecutive 295 patients with treatment-naïve single HCC who underwent curative surgery were retrospectively enrolled from two centers. Cox proportional hazard models developed risk scoring systems whose discriminatory powers were validated using external data and compared to the Barcelona Clinic Liver Cancer (BCLC) or American Joint Committee on Cancer (AJCC) staging systems using Harrell's C-index. RESULTS: Independent variables-tumor size (per cm; hazard ratio [HR], 1.07; 95% confidence interval [CI]: 1.02-1.13; p = 0.005), targetoid appearance (HR, 1.74; 95% CI: 1.07-2.83; p = 0.025), radiologic tumor in vein or tumor vascular invasion (HR, 2.59; 95% CI: 1.69-3.97; p < 0.001), the presence of a nonhypervascular hypointense nodule on the hepatobiliary phase (HR, 4.65; 95% CI: 3.03-7.14; p < 0.001), and pathologic macrovascular invasion (HR, 2.60; 95% CI: 1.51-4.48; p = 0.001)-with tumor markers (AFP ≥ 206 ng/mL or PIVKA-II ≥ 419 mAU/mL) derived pre- and postoperative risk scoring systems. The risk scores showed comparably good discriminatory powers in the validation set (C-index, 0.75-0.82) and outperformed the BCLC (C-index, 0.61) and AJCC staging systems (C-index, 0.58; ps < 0.05). The preoperative scoring system stratified the patients into low-, intermediate-, and high-risk for recurrence, whose 2-year recurrence rate was 3.3%, 31.8%, and 85.7%, respectively. CONCLUSION: The developed and validated pre- and postoperative risk scoring systems can estimate RFS after surgery for a single HCC. KEY POINTS: • The risk scoring systems predicted RFS better than the BCLC and AJCC staging systems (C-index, 0.75-0.82 vs. 0.58-0.61; ps < 0.05). • Five variables-tumor size, targetoid appearance, radiologic tumor in vein or vascular invasion, the presence of a nonhypervascular hypointense nodule on the hepatobiliary phase, and pathologic macrovascular invasion-combined with tumor markers derived risk scoring systems predicting postsurgical RFS for a single HCC. • In the risk scoring system using preoperatively-available factors, patients were classified into three distinct risk groups, with 2-year recurrence rates in the low-, intermediate-, and high-risk groups being 3.3%, 31.8%, and 85.7% in the validation set.

Proliferative hepatocellular carcinomas in cirrhosis: patient outcomes of LI-RADS category 4/5 and category M.

OBJECTIVES: We aimed to compare Liver Imaging Reporting and Data System (LI-RADS) category 4/5 and category M (LR-M) of proliferative hepatocellular carcinomas (HCCs) in cirrhotic patients and evaluate their impacts on prognosis. METHODS: This retrospective multi-reader study included cirrhotic patients with single treatment-naïve HCC ≤ 5.0 cm who underwent contrast-enhanced CT, MRI, and subsequent hepatic resection within 2 months. The percentages of CT/MRI LR-4/5 and LR-M in proliferative and non-proliferative HCCs were compared. Univariable and multivariable Cox proportional hazards regression analyses were performed to assess the association of LI-RADS categories (LR-4/5 vs. LR-M) and pathologic classification (proliferative vs. non-proliferative) with overall survival (OS) and recurrence-free survival (RFS). Subgroups of patients with proliferative and non-proliferative HCCs were analyzed to compare OS and RFS between LR-4/5 and LR-M. RESULTS: Of the 204 included patients, 38 were classified as having proliferative HCC. The percentages of LR-M were higher in proliferative than non-proliferative HCC on both CT (15.8% vs. 3.0%, p = 0.007) and MRI (26.3% vs. 9.6%, p = 0.016). Independent of pathologic classification, CT and MRI LR-M were significantly associated with poorer OS (hazard ratio (HR) = 4.58, p = 0.013, and HR = 6.45, p < 0.001) and RFS (HR = 3.66, p = 0.005, and HR = 6.44, p < 0.001) than LR-4/5. MRI LR-M was associated with significantly poorer OS (p ≤ 0.003) and RFS (p < 0.001) than MRI LR-4/5 in both proliferative and non-proliferative HCCs. CONCLUSIONS: This multi-reader study showed that the percentages of LR-M were significantly higher in proliferative than non-proliferative HCCs. CT/MRI LR-M was significantly associated with poor OS and RFS, independent of the pathologic classification of proliferative versus non-proliferative HCCs. CLINICAL RELEVANCE STATEMENT: CT and MRI LI-RADS category M can be clinically useful in predicting poor outcomes in patients with proliferative and non-proliferative hepatocellular carcinomas. KEY POINTS: • The percentages of LR-M tumors on both CT and MRI were significantly higher in proliferative than non-proliferative hepatocellular carcinomas. • Independent of pathologic classification, CT/MRI LR-M categories were correlated with poor overall survival and recurrence-free survival. • Patients with both proliferative and non-proliferative hepatocellular carcinomas categorized as MRI LR-M had significantly poorer overall survival and recurrence-free survival than those categorized as MRI LR-4/5.

Pitfalls of the concordance index for survival outcomes.

Prognostic models are useful tools for assessing a patient's risk of experiencing adverse health events. In practice, these models must be validated before implementation to ensure that they are clinically useful. The concordance index (C-Index) is a popular statistic that is used for model validation, and it is often applied to models with binary or survival outcome variables. In this paper, we summarize existing criticism of the C-Index and show that many limitations are accentuated when applied to survival outcomes, and to continuous outcomes more generally. We present several examples that show the challenges in achieving high concordance with survival outcomes, and we argue that the C-Index is often not clinically meaningful in this setting. We derive a relationship between the concordance probability and the coefficient of determination under an ordinary least squares model with normally distributed predictors, which highlights the limitations of the C-Index for continuous outcomes. Finally, we recommend existing alternatives that more closely align with common uses of survival models.

Encapsulating lithium at the microscale: selective deposition in carbon-doped graphitic carbon nitride spheres.

For stable lithium deposition without dendrites, three-dimensional (3D) porous structure has been intensively investigated. Here, we report the use of carbon-doped graphitic carbon nitride (C-doped g-C3N4) microspheres as a 3D host for lithium to suppress dendrite formation, which is crucial for stable lithium deposition. The C-doped g-C3N4microspheres have a high surface area and porosity, allowing for efficient lithium accommodation with high accessibility. The carbon-doping of the g-C3N4microspheres confers lithiophilic properties, which facilitate the regulation of Li+flux and dense filling of cavities with nucleated lithium, thereby preventing volume expansion and promoting dendrite-free Li deposition. The electrochemical performance was improved with cyclic stability and high Coulombic efficiency over 260 cycles at 1.0 mA cm-2for 1.0 mAh cm-2, and even over 70 cycles at 5.0 mA cm-2for 3.0 mAh cm-2. The use of C-doped g-C3N4microspheres as a 3D Li host shows promising results for stable lithium deposition without dendrite formation.

Minimally invasive versus open pancreaticoduodenectomy for distal bile duct cancer: an inverse probability of treatment weighting analysis of outcomes.

BACKGROUND: Minimally invasive pancreaticoduodenectomy (MIPD) has been extended to periampullary cancers, but the oncologic outcome of MIPD for distal bile duct cancer (DBDC) has not been confirmed yet. METHODS: Patients who underwent pancreaticoduodenectomy (PD) for DBDC of stage I-IIb from 2015 to 2019 at a tertiary referral center were identified and divided into open PD (OPD) and MIPD groups, the latter including laparoscopic and robotic procedures. Survival was compared between the two groups after inverse probability of treatment weighting (IPTW) using predetermined factors, and exploratory mediation analysis was performed using surgery-derived outcomes. RESULTS: MIPD (n = 81) group had more female patients (46.9% vs 31.6%, p = 0.011) and longer operation time (366.2 min vs. 279.1 min, p < 0.001) than the OPD (n = 288) group before IPTW. Otherwise, intraoperative and immediate postoperative outcomes were comparable between the two groups. In oncologic outcomes, MIPD group showed comparable 3-year overall survival (78.2% vs 75.0%, p = 0.062) and recurrence-free survival (51.2% vs 53.4%, p = 0.871) rates with OPD group before IPTW, and MIPD was not related with survival (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.29-1.26, p = 0.18) and recurrence (HR 1.01, 95% CI 0.67-1.53, p = 0.949) after IPTW with consideration of potential mediators. Sensitivity analysis using propensity score matching also showed similar results for survival (HR 0.68, 95% CI 0.32-1.44, p = 0.312) and recurrence (HR 1.12, 95% CI 0.67-1.88, p = 0.653). CONCLUSION: MIPD and OPD groups showed similar postoperative and oncologic outcomes. MIPD could be a considerable treatment option without oncological compromise in high-volume centers.

Analysis of risk factors affecting long-term survival in elderly patients with advanced gastric cancer.

BACKGROUND: Factors predicting postoperative complications after gastrectomy for elderly patients with gastric cancer have been analyzed in several previous studies. However, there is limited research available on risk factors related to long-term survival. AIMS: This study aimed to analyze factors affecting long-term survival after curative gastrectomy in elderly patients with advanced gastric cancer. METHODS: This study included patients aged > 75 years with histologically confirmed advanced gastric cancer stage II or greater. Before analysis, risk factors were categorized into four groups: baseline characteristics, underlying diseases, surgical and pathologic factors, and nutritional factors. RESULTS: The mean follow-up duration was 71.0 months. The 5-year overall survival and disease-specific survival rates were 51.5% and 58.3%, respectively. Kaplan-Meier curves showed that patients who were female and overweight had significantly longer survival rates than those who were male and underweight. Elderly patients who underwent a total gastrectomy had poorer survival rates than those who underwent a distal gastrectomy. Multivariate analysis demonstrated that tumor stage, extent of gastrectomy, overweight status and overall complication were independent risk factors for overall survival. DISCUSSION: Our study show that the overweight patients, the extent of gastrectomy, tumor stage and overall complications are significant risk factors affecting long-term survival. CONCLUSIONS: Therefore, surgeons may be cautious in performing total gastrectomy in elderly gastric cancer patients. Additionally, it is important to focus on improving nutritional status and mitigating overall complications.

A comparison of the continuous supraclavicular brachial plexus block using the proximal longitudinal oblique approach and the interscalene brachial plexus block for arthroscopic shoulder surgery: A randomised, controlled, double-blind trial.

BACKGROUND: Continuous interscalene brachial plexus block (ISB) is widely used for arthroscopic shoulder surgery, but the incidence of hemidiaphragmatic paresis (HDP) has been reported to reach 100%. Several methods, including injections distal to the C5-C6 nerve roots, have been attempted to reduce the HDP incidence. However, catheter placement distal to the C5-C6 nerve roots interferes with the surgical site. OBJECTIVE: Our primary objective was to describe a new technique, the supraclavicular brachial plexus block (SCB), using the proximal longitudinal oblique approach (PLO-SCB), which can facilitate catheter placement and, when compared with ISB, to test whether this would provide noninferior analgesia and spare the phrenic nerve. DESIGN: Prospective, randomised, double-blind study. SETTING: Operating rooms, postanaesthesia care unit, and wards. PATIENTS: Seventy-six patients aged 20 to 80 years scheduled for arthroscopic shoulder surgery. INTERVENTIONS: Patients were randomly assigned to the continuous PLO-SCB (n = 40) or the continuous ISB (n = 40) groups. All patients received an initial low-volume single-injection (5 ml 0.75% ropivacaine) followed by a patient-controlled infusion of 0.15% ropivacaine. MAIN OUTCOME MEASURES: The primary outcomes were the incidence of HDP and pain scores. Secondary outcomes were respiratory function, postoperative analgesic consumption, sensory and motor function, and complications. RESULTS: The HDP incidence was significantly lower in the PLO-SCB group than in the ISB group at 30 min after block injection: 0% (0 of 38 patients) and 73.7% (28 of 38 patients), respectively (P < 0.001). Similarly, at 24 h after surgery, the incidences were 23.7% (9 of 38 patients) and 47.4% (18 of 38 patients) in the PLO-SCB and ISB groups, respectively (P = 0.002). Median [IQR] NRS pain scores at rest measured after surgery in the ISB and PLO-SCB groups were similar: immediately after surgery, 1 [0 to 2] vs. 1 [0 to 1], P = 0.06); at 30 min, 2 [0.25 to 2] vs. 1 [0 to 2], P = 0.065); and at 24 h 2 [0.25 to 3] vs. 1 [0 to 3], P = 0.47, respectively. CONCLUSION: For major shoulder surgery, compared with continuous ISB, continuous PLO-SCB was more sparing of diaphragmatic and respiratory function while providing noninferior analgesia. Catheter placement via the PLO approach is feasible without interfering with the surgical field. TRIAL REGISTRATION: Registered by the Clinical Trial Registry of Korea (Seoul, Korea; KCT0004759, http: cris.nih.go.kr, principal investigator: Hyungtae Kim).

Peak systolic myocardial velocity in patients undergoing surgical aortic valve replacement for severe aortic stenosis: prognostic value and natural course.

Myocardial systolic longitudinal function has been known to decrease in patients with severe aortic stenosis (AS). Preoperative peak systolic myocardial velocity at the septal mitral valve annulus (S'), measured using Doppler tissue imaging, was used as an indicator for myocardial systolic longitudinal function. The prognostic value and natural course of S' after surgical aortic valve replacement for severe AS have not been elucidated. This retrospective observational study included patients from January 2006 to December 2018. The patients were divided to 2 groups (pre-S'HIGH vs. pre-S'LOW) with a cut-off 5.4 cm/s of preoperative S' (pre-S') that was identified by restricted cubic spline curve. The primary outcome was postoperative long-term all-cause mortality. Nine hundred and five patients were analyzed. All-cause mortality rate at the median follow-up period of 5.2 years was 12% in pre-S'LOW and 8% in pre-S'HIGH. Multivariate analysis showed that pre-S'LOW was associated with an increased all-cause mortality (hazard ratio, 1.60; 95% confidence interval, 1.04-2.48; P = 0.032). Significantly different trajectories of postoperative S' (post-S') were found between two groups (P < 0.001 for difference): In pre-S'LOW, post-S' increased within 6 months after surgery, and gradually decreased over time, whereas it slowly decreased up to 5 years after surgery and then reached a plateau in pre-S'HIGH. The difference in pre-S' level maintained over time, and remained consistent in the adjusted analysis. Pre-S' < 5.4 cm/s was found to be associated with an increased long-term all-cause mortality. In addition, the trajectories for post-S' were different according to pre-S', which remained after adjustment.

Clinical Significance of Combined Epithelial-Mesenchymal Transition Markers Expression and Role of Rac1 in Hepatocellular Carcinoma.

Epithelial-mesenchymal transition (EMT) has been implicated in cancer progression, invasion, and metastasis. We aimed to evaluate the correlations between clinicopathological characteristics and EMT markers in patients with hepatocellular carcinoma (HCC) who underwent surgical resection and to identify the key regulator in EMT process. Fresh-frozen HCC tissues and adjacent nontumor liver tissues from 30 patients who underwent surgical resection were provided by the Gachon University Gil Medical Center Bio Bank. Human HCC cell lines, Hep3B, SNU449, and Huh7 cells were transfected with Rac1 siRNA and exposed to hypoxic conditions. The combined EMT markers expression (down-expression of E-cadherin and overexpression of p21-activated kinases 1 (PAK1)/Snail) by Western blot in HCC tissues when compared to adjacent nontumor liver tissues was significantly associated with macrovascular invasion (p = 0.021), microvascular invasion (p = 0.001), large tumor size (p = 0.021), and advanced tumor stage (p = 0.015). Patients with combined EMT markers expression showed early recurrence and poor overall survival. In vitro studies showed that Rac1 knockdown decreased the expression of EMT markers including PAK1 and Snail in hypoxia-induced Hep3B cells and suppressed the migration and invasion of hypoxia-induced HCC cells. Rac1 may be a potential therapeutic target for inhibition of EMT process through the inhibition of PAK1 and Snail in HCC.

Improved Wound Healing and Skin Regeneration Ability of 3,2'-Dihydroxyflavone-Treated Mesenchymal Stem Cell-Derived Extracellular Vesicles.

Flavonoids enhance the self-renewal and differentiation potential of mesenchymal stem cells (MSCs) and have therapeutic activities, including regenerative, anti-oxidative, and anti-inflammatory effects. Recent studies have revealed that MSC-derived extracellular vesicles (MSC-EVs) have therapeutic effects on tissue regeneration and inflammation. To facilitate further research on the therapeutic potential of MSC-EVs derived from flavonoid-treated MSCs, we surveyed the production of EVs and their therapeutic applications in wound regeneration. MSCs treated with flavonoids enhanced EV production twofold compared with naïve MSCs. EVs produced by MSCs treated with flavonoids (Fla-EVs) displayed significant anti-inflammatory and wound-healing effects in vitro. The wound-healing capacity of EVs was mediated by the upregulation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling. Interestingly, the protein level of p-ERK under inhibition of MEK signals was maintained in Fla-EV-treated fibroblasts, suggesting that Fla-EVs have a higher therapeutic potential than naïve MSC-EVs (Cont-EVs) in wound healing. Moreover, the in vivo wound closure effect of the Fla-EVs showed significant improvement compared with that of the flavonoid-only treatment group and the Cont-EVs. This study provides a strategy for the efficient production of EVs with superior therapeutic potential using flavonoids.

Comparison of Standard D2 and Limited Lymph Node Dissection in Elderly Patients with Advanced Gastric Cancer.

BACKGROUND: Knowledge on the optimal extent of lymphadenectomy among elderly patients with advanced gastric cancer is limited. This study was designed to compare standard D2 and limited lymphadenectomy for evaluating the appropriate extent of lymphadenectomy. PATIENTS AND METHODS: We retrospectively reviewed patient's data based on a prospectively collected gastric cancer registry. The inclusion criteria were age above 75 years and histologically confirmed stage II or more advanced gastric cancer. In this study, 103 patients who underwent limited lymph node dissection and 134 patients who underwent standard D2 lymph node dissection were included to evaluate surgical and oncological outcomes using propensity score matching (PSM) analysis. RESULTS: The mean age after PSM was approximately 78 years in both groups. The Charlson Comorbidity Index was 5.81 ± 0.87 and 5.75 ± 0.76, respectively, and 12.5% of the patients in both groups had American Society of Anesthesiologists scores of more than 3. The limited lymphadenectomy group showed a shorter operation time and fewer retrieved lymph. However, other surgical outcomes and pathological data were not significantly different between the groups. No postoperative mortality within 30 days was observed. There were no significant differences in overall complications between the groups. The 3-year overall survival rates of the limited and standard lymphadenectomy groups were 58.3% and 73.6%, respectively. The 3-year recurrence-free survival rate of the limited lymphadenectomy group was lower than that of the standard lymphadenectomy group; however, the difference was not statistically significant. CONCLUSIONS: Standard D2 lymphadenectomy has better oncological outcomes in elderly patients with advanced gastric cancer.

Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice.

OBJECTIVE: Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children and young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% of bAVMs are sporadic without family history, the pathogenesis of sporadic bAVMs is largely unknown, which may account for the lack of therapeutic options. KRAS mutations are frequently observed in cancer, and a recent unprecedented finding of these mutations in human sporadic bAVMs offers a new direction in the bAVM research. Using a novel adeno-associated virus targeting brain endothelium (AAV-BR1), the current study tested if endothelial KRASG12V mutation induces sporadic bAVMs in mice. METHODS: Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRASG12V . At 8 weeks after the AAV injection, bAVM formation and characteristics were addressed by histological and molecular analyses. The effect of MEK/ERK inhibition on KRASG12V -induced bAVMs was determined by treatment of trametinib, a US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor. RESULTS: The viral-mediated KRASG12V overexpression induced bAVMs, which were composed of a tangled nidus mirroring the distinctive morphology of human bAVMs. The bAVMs were accompanied by focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, and impaired sensory/cognitive/motor functions. Finally, we confirmed that bAVM growth was inhibited by trametinib treatment. INTERPRETATION: Our innovative approach using AAV-BR1 confirms that KRAS mutations promote bAVM development via the MEK/ERK pathway, and provides a novel preclinical mouse model of bAVMs which will be useful to develop a therapeutic strategy for patients with bAVM. ANN NEUROL 2021;89:926-941.

Bevacizumab and anexelekto inhibitor, TP-0903 inhibits TGF-ß1-induced epithelial-mesenchymal transition of colon cancer cells.

The incidence of colorectal cancer (CRC) is reported to be increasing nowadays, with a large proportion of newly diagnosed CRC patients being affected by metastasis. Epithelial-mesenchymal transition (EMT) is an important event in the development of metastasis of CRC. In this study, we investigated whether the anticancer drug bevacizumab and anexelekto inhibitor, TP-0903, regulate EMT of colon cancer cells induced by transforming growth factor-beta 1 (TGF-ß1). Using quantitative real-time PCR and western blot analysis, we found that bevacizumab and TP-0903 decreased the expression levels of fibronectin, alpha-smooth muscle actin, and vimentin, whereas they restored E-cadherin expression in TGF-ß1-exposed SW480 and HCT116 cells. In addition, we elucidated that bevacizumab and TP-0903 inhibited the migration and invasion of TGF-ß1-exposed colon cancer cells using scratched wound healing, transwell migration, and Matrigel-coated invasion assays. Finally, we discovered that bevacizumab and TP-0903 inactivated the Smad 2/3 signaling pathway in TGF-ß1-exposed SW480 and HCT116 cells. Therefore, we suggest that treatment of bevacizumab and TP-0903 inhibits TGF-ß1-induced EMT of colon cancer cells through inactivation of the Smad 2/3 signaling pathway.

Differences in the prognostic implication of ground-glass opacity on CT according to pathological nodal status in lung cancers treated with lobectomy or pneumonectomy.

OBJECTIVES: To clarify the prognostic significance of a ground-glass opacity (GGO) component according to T category and pathological nodal status in patients with resectable non-small cell lung cancer (NSCLC). METHODS: Patients who underwent lobectomy or pneumonectomy for NSCLC between July 2010 and December 2017 were retrospectively included. Patients were divided into GGO and solid groups based on the presence of a GGO component on CT. The effects on survival of interactions between GGO and (a) pathological nodal status (pN) and (b) cT category were evaluated using Cox regression. RESULTS: Out of 1545 patients, 548 were classified into the GGO group (pN0: 457, pN1/2: 91) and 997 into the solid group (pN0: 660, pN1/2: 337). There were interactions between the presence of GGO and pathological nodal status on 5-year disease-free survival (DFS; p = .006) and 5-year overall survival (OS; p = .02). In multivariate analysis, better survival of patients in the GGO group than in the solid group was observed only in pN0 category (adjusted hazard ratio [HR], 0.63 for 5-year DFS; p = .002 and 0.47 for 5-year OS; p = .002), but not in pN1/2 category. Moreover, in those with pN0 category, the favorable prognostic value of GGO was limited to those with cT1 category for 5-year DFS (adjusted HR, 0.48; p < .001) and those with cT1/2 category for 5-year OS (adjusted HR, 0.37; p = .002). CONCLUSIONS: GGO was a favorable predictor of survival only in patients with pN0 category, showing an advantage in DFS for those with cT1 category and OS for those with cT1/2 category. KEY POINTS: • The presence of ground-glass opacity was associated with a favorable prognosis, only in pathological node-negative patients (5-year disease-free survival, p = .002; 5-year overall survival, p = .002). • Within pathological node-negative patients, the effect of ground-glass opacity on 5-year disease-free survival was valid in patients with cT1 category (adjusted hazard ratio, 0.48; 95% confidence interval, 0.32-0.72; p < .001), but not in patients with cT2 or above category. • Within pathological node-negative patients, the effect of ground-glass opacity on 5-year overall survival was valid in patients with cT1/2 category (adjusted hazard ratio, 0.37; 95% confidence interval, 0.20-0.68; p = .002), but not in patients with cT3/4 category.

Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction.

Increased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlying mechanism of sENG-induced vascular malformations is not clear. The evidence suggests the role of sENG as a pro-inflammatory modulator, and increased microglial accumulation and inflammation have been observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that the presence of sENG along with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, we observed increased microglial activation around dysplastic vessels with the expression of NLRP3, an inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1ß), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased levels of angiogenic factors (Notch-1 and TGFß) and pERK1/2 in ECs but it decreased the level of IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to express angiogenic/inflammatory molecules which may be involved in EC dysfunction. Our study corroborates the contribution of microglia to the pathology of sENG-associated vascular malformations.

Ethnic Differences in Informal Caregiving After Stroke.

BACKGROUND AND PURPOSE: Informal (unpaid) caregiving usually provided by family is important poststroke. We studied whether the prevalence of informal caregiving after stroke differs between Mexican Americans (MAs) and non-Hispanic Whites (NHWs). METHODS: Between October 2014 and December 2018, participants in the BASIC (Brain Attack Surveillance in Corpus Christi) project in Nueces County, Texas, were interviewed 90 days after stroke to determine which activities of daily living they required help with and whether family provided informal caregiving. Ethnic differences between MAs and NHWs were determined by logistic regression. The logistic models were stratified by formal (paid) care status. Odds ratios (95% CIs) are reported with NHW as the referent group. Fisher exact tests were used to assess the association of ethnicity with relationship of caregiver and with individual activities of daily living. RESULTS: Eight hundred thirty-one patients answered the caregiving questions. Of these, 242 (29%) received family caregiving (33% of MAs and 23% of NHWs), and 142 (17%) received paid caregiving (21% of MAs and 10% of NHWs). There were no ethnic differences in stroke severity. In logistic regression analyses, among those without formal, paid care, MAs were more likely to have informal caregiving (odds ratio, 1.75 [95% CI, 1.12-2.73]) adjusted for age, National Institutes of Health Stroke Scale, prestroke modified Rankin Scale, and insurance. No ethnic differences in informal care were found among those who had formal care. There were no differences between ethnic groups in which family members provided the informal care. MAs were more likely to require help compared with NHWs for walking (P<0.0001), bathing (P<0.0001), hygiene (P=0.0012), eating (P=0.0004), dressing (P<0.0001), ambulating (P=0.0304), and toileting (P=0.0003). CONCLUSIONS: MAs required more help poststroke than NHWs for assistance with activities of daily living. MAs received more help for activities of daily living through informal, unpaid caregiving than NHWs if they were not also receiving formal, paid care. Efforts to help minority and low-resource populations provide stroke care are needed.