A modified CEUS risk stratification model for adnexal masses with solid components: prospective multicenter study and risk adjustment.

OBJECTIVES: To evaluate the additional advantages of integrating contrast-enhanced ultrasound (CEUS) into the Ovarian-Adnexal Reporting and Data System (O-RADS) ultrasound (US) for the characterization of adnexal lesions with solid components. MATERIALS AND METHODS: This prospective multicenter study recruited women suspected of having adnexal lesions with solid components between September 2021 and December 2022. All patients scheduled for surgery underwent preoperative CEUS and US examinations. The lesions were categorized according to the O-RADS US system, and quantitative CEUS indexes were recorded. Pathological results served as the reference standard. Univariable and multivariable analyses were performed to identify risk factors for malignancy in adnexal lesions with solid components. Receiver operating characteristic (ROC) curve analysis was employed to assess diagnostic performance. RESULTS: A total of 180 lesions in 175 women were included in the study. Among these masses, 80 were malignant and 100 were benign. Multivariable analysis revealed that serum CA-125, the presence of acoustic shadowing, and peak intensity (PI) ratio (PImass/PIuterus) of solid components on CEUS were independently associated with adnexal malignancy. The modified CEUS risk stratification model demonstrated superior diagnostic value in assessing adnexal lesions with solid components compared to O-RADS US (AUC: 0.91 vs 0.78, p < 0.001) and exhibited comparable performance to the Assessment of Different NEoplasias in the adnexa (ADNEX) model (AUC 0.91 vs 0.86, p = 0.07). CONCLUSION: Our findings underscore the potential value of CEUS as an adjunctive tool for enhancing the precision of diagnostic evaluations of O-RADS US. CLINICAL RELEVANCE STATEMENT: The promising performance of the modified CEUS risk stratification model suggests its potential to mitigate unnecessary surgeries in the characterization of adnexal lesions with solid components. KEY POINTS: • The additional value of CEUS to O-RADS US in distinguishing between benign and malignant adnexal lesions with solid components requires further evaluation. • The modified CEUS risk stratification model displayed superior diagnostic value and specificity in characterizing adnexal lesions with solid components when compared to O-RADS US. • The inclusion of CEUS demonstrated potential in reducing the need for unnecessary surgeries in the characterization of adnexal lesions with solid components.

Ultrasound Microvessel Visualization in Cervical Cancer: Association Between Novel Ultrasound Techniques and Histologic Microvessel Densities.

OBJECTIVE: The aim of the work described here was to evaluate the feasibility of superb microvascular imaging (SMI) and vascular endothelial growth factor receptor 2 (VEGFR2)-targeted microbubble (MBVEGFR2)-based ultrasound molecular imaging (USMI) for visualizing microvessels in cervical cancer. METHODS: Hela cells were used to establish subcutaneous cervical cancer models. SMI and MBVEGFR2-based USMI were performed, and the results were compared with intratumoral microvessel density (MVD) in four groups based on tumor diameter (<3 mm, 3-5 mm, 5-7 mm and ≥7 mm). The vascularization index (VI, %) was evaluated for SMI, and the normalized intensity difference (NID) for USMI. RESULTS: Tumors with diameters ranging from 3 to 5 mm had the highest VI (39.07 ± 1.58) in SMI, and VI significantly decreased with increasing tumor size (all p values <0.001). The strongest signal intensity was observed in very early tumors (d < 3 mm: 43.80 ± 3.58%) after MBVEGFR2 administration; the NID gradually decreased with increasing diameter of tumors (all p values = 0.007). However, no significant differences were observed in NID after administration of non-targeted (control) microbubbles (MBCon) (all p values = 0.125). MBVEGFR2-based USMI had the strongest correlation with MVD in displaying microvessels of cervical cancer compared with SMI and MBCon (R2 = 0.78 vs. R2 = 0.40 and R2 = 0.38). CONCLUSION: These findings validate the superiority and accuracy of MBVEGFR2-based USMI for microvessel imaging and monitoring of angiogenesis in cervical cancer compared with SMI and MBCon. Nonetheless, SMI remains an alternative to microvessel imaging when ultrasonic contrast agent use is contraindicated.

Application of 15N tracing and bioinformatics for estimating microbial-mediated nitrogen cycle processes in oil-contaminated soils.

Crude oil pollution can profoundly alter the nitrogen (N) cycle in the soil. Here, a 30-day incubation with 15N tracer approach was performed to assess the impacts of crude oil concentrations (medium: 10,000 mg kg-1; heavy: 50,000 mg kg-1) on soil N cycling based on a numerical model. Results showed that crude oil pollution significantly increased the gross N-transformation rates, but the rates of oxidation of recalcitrant organic N, the immbolization of NO3- and the adsorption of NH4+ changed differently as a function of hydrocarbon concentrations. There was no significant difference of the oxidation rate of recalcitrant organic N between the medium and heavy oil-contaminated soils (medium: 0.1149 mmol N kg-1 d-1; heavy: 0.1299 mmol N kg-1 d-1), but the rates of NO3- immobilization (0.1135 mmol N kg-1 d-1) and NH4+ adsorption were the highest (0.1148 mmol N kg-1 d-1) in the moderately oil-contaminated soils than those in the heavy polluted soil (0.0849 mmol N kg-1 d-1 and 0.0034 mmol N kg-1 d-1, respectively). The NO3- immobilization rate was 2.5-fold higher than its reduction rate, indicating that NO3- immobilization played a more important role during the process of NO3- transformation. Microbial community structure analysis indicated that phyla of Actinobacteria and Ascomycota respectively promoted the immobilization of NO3- to recalcitrant organic N and the reduction of NO3- to NH4+. The genus of Aspergillus was related to net NH4+ production, and the genera of Penicillium and Acremonium were responsible for oxidation of recalcitrant organic N to NO3-.

Does Combing O-RADS US and CA-125 Improve Diagnostic Accuracy in Assessing Adnexal Malignancy Risk in Women With Different Menopausal Status?

OBJECTIVES: To evaluate the individual and combined performances of the Ovarian-adnexal Reporting and Data System Ultrasound (O-RADS US) and serum cancer antigen 125 (CA-125) in assessing adnexal malignancy risk in women with different menopausal status. METHODS: This retrospective study included patients with adnexal masses scheduled for surgery based on their preoperative US and histopathology results between January 2018 and January 2020. O-RADS were used to assess adnexal malignancy by two experienced radiologists. The area under the receiver operating characteristic curves (AUCs) were used to compare the accuracy of O-RADS and a combination of O-RADS and CA-125. The weighted κ index was used to evaluate the inter-reviewer agreement. RESULTS: Overall, the data of 443 lesions in 443 patients were included, involving 312 benign lesions and 131 malignant lesions. There were 361 premenopausal and 82 postmenopausal patients. The inter-reviewer agreement for the two radiologists was very good (weighted κ: 0.833). Combing O-RADS US and CA-125 significantly increased diagnostic accuracy for classifying malignant from benign adnexal masses, compared with O-RADS US alone (AUC: 0.97 vs 0.95, P < .001 for premenopausal population and AUC: 0.93 vs 0.85, P < .001 for postmenopausal population). The AUCs of O-RADS with and without CA-125 ranged from 0.50 to 0.99 for different adnexal pathology subtypes (ie, benign, borderline, Stage I-IV, and metastatic tumors). CONCLUSION: The addition of CA-125 helps improve discrimination of O-RADS US between benign and malignant adnexal masses, especially in postmenopausal women.

Predictive accuracy and reproducibility of the O-RADS US scoring system among sonologists with different training levels.

PURPOSE: To investigate the predictive performance and reproducibility of Ovarian-Adnexal Reporting and Data System (O-RADS) ultrasound (US) system in evaluating adnexal masses between sonologists with varying levels of expertise. METHODS: This was a single-center retrospective study conducted between May 2019 and May 2020, which included 147 adnexal mases with pathological results. Four sonologists with varying experiences independently assigned an O-RADS US category to each adnexal mass twice. The intra- and inter-observer agreement was assessed using weighted kappa values. The area under the curve (AUC), sensitivity, specificity, positive and negative predictive value (PPV and NPV) were assessed for each sonologist. RESULTS: Of the 147 adnexal mases, 115 (78.2%) lesions were benign and 32 (21.8%) lesions were malignant. Considering O-RADS > 3 as a predictor for adnexal malignancy, the predictive accuracies of the four sonologists were excellent, with AUCs ranging from 0.831 to 0.926. The predictive accuracies of O-RADS US by experienced sonologists were significantly higher compared to inexperienced sonologists (all P values < 0.005). The O-RADS US presented high sensitivity and NPV value for each sonologist. With regard to the reproducibility of O-RADS, the intra- and inter-observer agreement among experienced sonologists performed better than inexperienced sonologists. CONCLUSION: O-RADS showed difference in the predictive accuracy and reproducibility in the evaluation of adnexal masses among sonologists with different levels of expertise. Training is required for inexperienced sonologists before the generalization of O-RADS classification system in clinical practice.

Comparison of contrast-enhanced ultrasonography and magnetic resonance imaging in the evaluation of tumor size and local invasion of surgically treated cervical cancer.

OBJECTIVES: This retrospective study aimed to compare the performance of contrast-enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI) in staging surgically treated early-stage cervical cancer. METHODS: Patients with surgically treated cervical carcinoma confirmed by post-operative pathological findings were included between December 2016 and December 2018. All included patients underwent both CEUS and MRI examinations before the surgery. Post-operative pathology was used as the gold standard. The κ values were calculated to assess the agreements of CEUS and MRI in staging cervical carcinoma in comparison with post-operative pathology. RESULTS: Complete data were available for 39 patients. CEUS showed great inter-observer reproducibility in tumor measurement [Intra-class Correlation Coefficient (ICC) 0.831] and moderate inter-observer reproducibility in the evaluation of vaginal infiltration and parametrial invasion (Cohen's κ 0.692 and 0.624). Tumor size was comparable as measured by CEUS and MRI (ICC 0.769). Both CEUS and MRI presented good concordance with post-operative pathology in staging cervical cancer (weighted κ 0.732 and 0.761). CONCLUSION: CEUS was comparable to MRI in staging surgically treated cervical cancer and might be considered in the pre-treatment work-up for cervical cancer.

Pharmacodynamics, toxicology and toxicokinetics of ropivacaine oil delivery depot.

BACKGROUND: Ropivacaine oil delivery depot (RODD) can be used to treat postoperative incision pain. The aim was to study pharmacodynamics, toxicity and toxicokinetics of RODD. METHODS: The base research of RODD were conducted. Thirty rabbits were randomly divided into saline, solvent, ropivacaine aqueous injection (RAI) 0.9 mg, RODD 0.9 mg and RODD 3 mg groups. The sciatic nerve of rabbits were isolated, dripped with RODD and the effect of nerve block were observed. In toxicity study, the rats were divided into saline, solvent and RODD 75, 150 and 300 mg/kg groups, 30 rats per group. In toxicokinetics, rats were divided into RODD 75, 150 and 300 mg/kg groups, 18 rats per group. The rats were subcutaneously injected drugs. RESULTS: The analgesic duration of RODD 3 mg and RAI 0.9 mg blocking ischiadic nerve lasted about 20 h and 2 h, respectively, and their blocking intensity was similar. The rats in RODD 75 mg/kg did not show any toxicity. Compared with saline group, in RODD 150 mg/kg group neutrophils and mononuclear cells increased, lymphocytes decreased and albumin decreased(P < 0.05), and pathological examination showed some abnormals. In RODD 300 mg/kg group, 10 rats died and showed some abnormalities in central nerve system, hematologic indexes, part of biochemical indexes, and the weights of spleen, liver, and thymus. However, these abnormal was largely recovered on 14 days after the dosing. The results of toxicokinetics of RODD 75 mg/kg group showed that the Cmax was 1.24 ± 0.59 µg/mL and the AUC(0-24 h) was 11.65 ± 1.58 h·µg/mL. CONCLUSIONS: Subcutaneous injection RODD releases ropivacaine slowly, and shows a stable and longer analgesic effect with a large safety range.

Usefulness of New Shear Wave Elastography Technique for Noninvasive Assessment of Liver Fibrosis in Patients with Chronic Hepatitis B: A Prospective Multicenter Study.

PURPOSE: To explore the usefulness of liver stiffness measurements (LSMs) by sound touch elastography (STE) and sound touch quantification (STQ) in chronic hepatitis B (CHB) patients for staging fibrosis. METHODS: This prospective multicenter study recruited normal volunteers and CHB patients between May 2018 and October 2019. The volunteers underwent LSM by STE and supersonic shear imaging (SSI) or by STQ and acoustic radiation force impulse imaging (ARFI). CHB patients underwent liver biopsy and LSM by both STE/STQ. The areas under the receiver operating characteristic curves (AUCs) for staging fibrosis were calculated. RESULTS: Overall, 97 volunteers and 524 CHB patients were finally eligible for the study. The successful STE and STQ measurement rates were both 100 % in volunteers and 99.4 % in CHB patients. The intraclass correlation coefficients (ICCs) for the intra-observer stability of STE and STQ (0.94; 0.90) were similar to those of SSI and ARFI (0.95; 0.87), respectively. STE and STQ showed better accuracy than the aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) (AUC: 0.87 vs 0.86 vs 0.73 vs 0.77) in staging cirrhosis. However, both STE and STQ were not superior to APRI and FIB-4 in staging significant fibrosis (AUC: 0.76 vs 0.73 vs 0.70 vs 0.71, all P-values > 0.05). CONCLUSION: STE and STQ are convenient techniques with a reliable LSM value. They have a similar diagnostic performance and are superior to serum biomarkers in staging cirrhosis in CHB patients.

APS (Age, Platelets, 2D Shear-Wave Elastography) Score Predicts Hepatocellular Carcinoma in Chronic Hepatitis B.

Background Two-dimensional (2D) shear-wave elastography (SWE) has been considered to be useful in predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). Purpose To develop a risk model using 2D SWE to predict HCC in patients with CHB and to compare its predictive value with that of other models. Materials and Methods Patients with biopsy-proven CHB who underwent US and 2D SWE between April 2011 and December 2015 were enrolled in this study. After 2D SWE and biopsy were performed, the patients received regular follow-up for the detection of HCC. The scoring system was developed by dividing the parameters of the Cox proportional hazards model by the smallest parameter and simplifying the assigned points to integers. The predictive performance of the new score was compared with that of other scores. Results Among the 654 patients (mean age, 37 years; range, 30-43 years; 510 men), 26 developed HCC. The variables of age, platelet count, and liver stiffness measurement at 2D SWE were weighted to develop the so-called APS score, with a cutoff of 60 showing the best discrimination for HCC risk. The APS score (area under the receiver operating characteristic curve [AUC], 0.89) was superior to that of the Chinese University HCC prediction score constructed from age, albumin level, bilirubin level, hepatitis B virus (HBV) DNA level, and cirrhosis (AUC, 0.70; P = .005) and slightly higher than that of the guide with age, gender, HBV DNA level, core promoter mutations, and cirrhosis, or GAG-HCC score (AUC, 0.82; P = .052). In patients who underwent transient elastography, the AUC of the APS score was 0.79, compared with 0.82 for the modified risk estimation for HCC in CHB, or mREACH-B, score (P = .05). The APS score performed better in patients regardless of whether antiviral treatment was used, inflammation grade was low or high, or alanine aminotransferase levels were normal or high (all P > .05). Conclusion The APS score based on only the patient's baseline liver stiffness measurement at two-dimensional shear-wave elastography, age, and platelet count is valuable for predicting hepatocellular carcinoma in patients with chronic hepatitis B. © RSNA, 2021 Online supplemental material is available for this article.

Hydrocarbon transformation pathways and soil organic carbon stability in the biostimulation of oil-contaminated soil: Implications of 13C natural abundance.

Mineralization, assimilation, and humification are key processes to detoxify oil-contaminated soil by biostimulation remediation strategies, and these processes are affected by stimulants. In this study, we investigated the effects of either inorganic salts or organic stimulants (organic compost and sawdust) on hydrocarbon transformation. Total petroleum hydrocarbons (TPH) and hydrocarbon components were determined by gravimetry and gas chromatography, and the 13C of CO2, microbial biomass carbon (MBC), and humus were measured by stable isotope mass spectrometry. The results showed that organic compost was the most beneficial for the dissipation of hydrocarbons. After 60 days of remediation, the removal rates of TPH, saturates, aromatics, C7-C30 n-alkanes, and 16 PAHs were 35.7%, 39.6%, 15.9%, 80.5%, and 8.8%, respectively. A total of 84.7%-88.5% of the removed hydrocarbons were mineralized in all the treatments. The hydrocarbon degradation pathway in the control soil (without stimulant addition) was "assimilation → humification → mineralization". The hydrocarbon transformation pathways in the biostimulation treatments were "assimilation → mineralization → humification". The soil organic carbon (SOC) stability decreased during remediation, which was attributed to the enhanced microbial activity and the removal of recalcitrant hydrocarbons.

Deep learning radiomics model accurately predicts hepatocellular carcinoma occurrence in chronic hepatitis B patients: a five-year follow-up.

An early and accurate prediction of hepatocellular carcinoma (HCC) is beneficial for individualized treatment and follow-up of chronic hepatitis B (CHB) patients. We aimed to establish a prediction model for HCC by radiomics analysis in CHB patients and compare performance with liver stiffness measurement (LSM) and other clinical prognostic scores. Initially, 1215 patients were included and finally 434 CHB patients with 5-year follow-up were enrolled, 96.3% of them underwent liver biopsy. Deep learning radiomics analysis was performed on 2170 two-dimensional shear wave elastography (2D-SWE) and corresponding B-mode ultrasound (US) images. These high-throughput imaging features were also combined with low-dimensional serological clinical data by deep learning radiomics to establish different HCC prediction models and to overcome challenges of an unbalanced sample. The best model which is simple with high accuracy was selected. Prediction performance of the selected model was compared with LSM and other clinical prognostic scores. During 5-year follow-up, 32 (7.4%) of 434 patients developed HCC. The best prediction model was HCC-R, which included 2D-SWE and B-mode US images, sex and age. This model showed a high predictive value with areas under the receiver operating characteristic curve (AUCs) of 0.981, 0.942 and 0.900 in training, validation and testing cohorts for predicting 5-year prognosis of HCC. These predictive values were significantly higher than that of LSM (AUC: 0.676~0.784, p < 0.05) and better than that of other clinical prognostic scores (AUC: 0.544~0.869). HCC-R radiomics model based on 2D-SWE and B-mode US images, sex and age comprehensively reflected biomechanical and morphological information of patients and can accurately predict HCC occurrence; thus, this model has great value for treatment and follow-up of CHB patients.

Liver Stiffness Measured with Two-dimensional Shear-Wave Elastography Is Predictive of Liver-related Events in Patients with Chronic Liver Disease Due to Hepatis B Viral Infection.

Background Liver stiffness measurement has been proposed as a noninvasive marker for predicting liver-related complications of cirrhosis. Purpose To evaluate the predictive value of liver stiffness measurement by using two-dimensional (2D) shear-wave elastography (SWE) for liver-related events among patients with chronic hepatitis B. Materials and Methods This retrospective study recruited consecutive patients with chronic hepatitis B who were referred for liver biopsy between May 2011 and May 2015. All patients underwent 2D SWE before biopsy, and a subset of patients underwent transient elastography. Patients were followed up for 4 years through the electronic medical records or telephone interviews. Univariable and multivariable logistic regression analyses were used to determine prognostic factors. Accuracy of prognostic parameters was evaluated by using the area under the receiver operating characteristic curve (AUC). Results Among 430 patients (mean age, 38 years; range, 18-67 years) including 328 men and 102 women, 29 patients developed liver-related events. Multivariable analysis demonstrated that liver stiffness measured with 2D SWE, spleen longitudinal diameter at US, age, and albumin level were predictive factors of liver-related events. The AUC of the multivariable model was higher (0.89; 95% confidence interval [CI]: 0.86, 0.92) but not significantly different from that of 2D SWE (0.86; 95% CI: 0.82, 0.89; P = .23) and was significantly higher than that of the fibrosis stage (0.72; 95% CI: 0.68, 0.76; P < .001), the aspartate aminotransferase-to-platelet ratio index (0.80; 95% CI: 0.76, 0.84; P < .001), and the fibrosis-4 index (0.84; 95% CI: 0.80, 0.87; P = .02). In a subset of patients with available transient elastography (n = 188), the multivariable model, 2D SWE, and transient elastography showed comparable performance (AUC: 0.91 vs 0.86 vs 0.88, respectively). When inflammatory activity was considered, the multivariable model was highly accurate in patients with low-grade inflammation and normal levels of alanine aminotransferase (AUC: 0.97 and 0.94, respectively). Conclusion The multivariable model and two-dimensional shear-wave elastography are more accurate in predicting liver-related events than are the fibrosis stage and serum markers of liver fibrosis tests. © RSNA, 2020 Online supplemental material is available for this article.

Influence of Alanine Transaminase Levels on Alpha-Fetoprotein for Predicting Hepatocellular Carcinoma in Patients with Hepatitis B Infection.

PURPOSE: To investigate the influence of alanine transaminase (ALT) on the accuracy of alpha-fetoprotein (AFP) for detecting hepatocellular carcinoma (HCC). METHODS: This retrospective study recruited 799 patients with HCC, cirrhosis, and chronic hepatitis due to hepatitis B infection and healthy adults between July 2017 and January 2019. Comparisons of the area under the receiver operating characteristic curves (AUCs) for detecting HCC in different ALT levels were calculated. RESULTS: Serum ALT and gamma-glutamyl transferase levels were significantly associated with elevated AFP in patients without HCC. The AUC of AFP was higher in patients with ALT ≤ 2 upper limit of normal (ULN) than in patients with ALT > 2 ULN (0.806 vs. 0.611, P < 0.001). Nevertheless, there were no significant differences in the AUCs of AFP/(ALT × aspartate aminotransferase (AST)) in patients with ALT ≤ 2 ULN and with ALT > 2 ULN (0.745 vs. 0.769, P = 0.68). AFP/(ALT × AST) was better than AFP in patients with ALT > 2 ULN for detecting HCC (P < 0.001). CONCLUSIONS: Higher ALT levels might impair the accuracy of AFP for diagnosing HCC. AFP tests showed better accuracy in patients with ALT ≤ 2 ULN whereas the AFP/(ALT × AST) ratio was recommended in patients with elevated ALT levels.

W941, a new PI3K inhibitor, exhibits preferable anti-proliferative activities against nonsmall cell lung cancer with autophagy inhibitors.

The PI3K pathway is aberrantly activated in many cancers and plays a critical role in tumour cell proliferation and survival, making it a rational therapeutic target. In the present study, the effects and the underlying mechanism of a new PI3K inhibitor, W941, were investigated in non-small-cell lung cancer (NSCLC). The results of this study showed that W941 inhibited the growth of A549 and Hcc827 cells with IC50 values of 0.12 and 0.23 µM, respectively, and that W941 markedly inhibited the growth of A549 xenograft tumours in a nude mouse model without decreasing body weight. Western blotting assays showed that W941 inhibited the phosphorylation of downstream proteins in the PI3K pathway (AKT, mTOR, p70S6K and 4EBP1) in both A549 and Hcc827 cells. In addition, after W941 treatment, a dose-dependent increase in the ratio of the LC3-II/I ratio was observed. When cells were pre-treated with chloroquine or bafilomycin A1, W941 increased the LC3-II/I ratio, suggesting that W941 acted as an autophagy inducer. Moreover, autophagy blockers enhanced apoptosis after W941 treatment, indicating that W941-induced autophagy actually protected the cells against its cytotoxicity. Our findings suggest that the combination of a PI3K inhibitor with an autophagy inhibitor might be a novel option for NSCLC treatment.

[Isolation, Identification and Degradation Characteristics of a 17ß-estradiol Degrading Strain Fusarium sp. KY123915].

A 17ß-estradiol (E2) degrading strain (designated as Wu-SP1) was isolated from the activated sludge collected from a wastewater treatment plant (WWTP) in Xi'an. The strain was identified as Fusarium sp. according to 18S rDNA sequence and phylogenetic analysis. The optimal pH and temperature for E2 degradation were 6 and 30℃, respectively. Under these conditions, the E2 biodegradation rate of 2 mg·L-1 E2 amounted to 92.5% within 48 h by this strain. The kinetics of E2 degradation by the strain KY123915 were in good accord with the first-order equation, with the concentration ranged from 10 to 500 mg·L-1. UV spectrum analysis showed the strength of maximum absorption of metabolites became weak compared to E2, indicating that E2 may be degraded via estrone (E1) by Fusarium sp. KY123915.

Mesenteric CD103+DCs Initiate Switched Coxsackievirus B3 VP1-Specific IgA Response to Intranasal Chitosan-DNA Vaccine Through Secreting BAFF/IL-6 and Promoting Th17/Tfh Differentiation.

Intranasal chitosan-formulated DNA vaccination promotes IgA secretion in the intestine. However, the mechanism whereby chitosan-DNA skews IgA class switch recombination (CSR) of B cells in the Gut-associated lymph tissue (GALT) is not fully resolved. In this study, we investigated the effects of nasally administered chitosan-DNA (pcDNA3.1-VP1 plasmid encoding VP1 capsid protein of Coxsackievirus B3) on IgA production, DC activation and Tfh/Th17 response in the intestine. Compared to DNA immunization, intranasal chitosan-DNA vaccination induced antigen-specific IgA production in feces, a pronounced switching of antigen-specific IgA+ plasmablast B cells in the mesenteric lymph nodes (MLNs) and an enhanced expression of post-recombination Iα-CH transcripts/IgA germline transcript (αGT) as well as activation-induced cytidine deaminase (AID) in MLN B cells. MLN Tfh frequency was markedly enhanced by chitosan-DNA, and was associated with VP1-specific IgA titer. 24 h after immunization, intranasal chitosan-DNA induced a recruitment of CD103+DCs into the MLN that paralleled a selective loss of CD103+DCs in the lamina propria (LP). In vivo activated MLN-derived CD103+DCs produced high levels of IL-6 and BAFF in response to chitosan-DNA, which up-regulated transmembrane activator and CAML interactor (TACI) expression on MLN B cells. Upon co-culture with IgM+B in the presence of chitosan-DNA, MLN CD103+DCs induced IgA production in a T-dependent manner; and this IgA-promoting effect of CD103+DC was blocked by targeting TACI and, to a lower extent, by blocking IL-6. MLN CD103+DCs displayed an enhanced capacity to induce an enhanced CD4+Th17 response in vivo and in vitro, and IL-17A deficient mice had a pronounced reduction of specific intestinal IgA following immunization. Taken together, mesenteric CD103+DCs are indispensable for the adjuvant activity of chitosan in enhancing DNA vaccine-specific IgA switching in gut through activating BAFF-TACI and IL-6-IL-6R signaling, and through inducing Th17/Tfh differentiation in the MLN.

The efficacy and toxicity of afatinib in advanced EGFR-positive non-small-cell lung cancer patients after failure of first-generation tyrosine kinase inhibitors: a systematic review and meta-analysis.

BACKGROUND: The first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, have become the standard first-line treatment for non-small-cell lung cancer (NSCLC) patients with EGFR mutation. However, there was no pooled analysis focused on the usage of the second-generation TKI, afatinib, in advanced EGFR-positive NSCLC patients after failure of first generation TKIs. Therefore, a meta-analysis was conducted to solve the above question. METHODS: Electronic databases were searched for eligible literatures. ORR (objective response rate), DCR (disease controlled rate), PFS (progression-free survival), OS (overall survival) and primary grade 3/4 adverse events were pooled with the corresponding 95% confidence interval using R software. Sensitivity analyses and heterogeneity were quantitatively evaluated. RESULTS: A total of 545 EGFR-positive patients were available for analysis from five studies after detailed screening from 909 relevant studies. The pooled ORR and DCR of afatinib in EGFR-positive patients after failure of the first generation EGFR-TKIs were 0.12 (0.08-0.19) and 0.60 (0.53-0.68), respectively. Besides, the 6 m-PFS rate, 1 y-PFS rate and 6 m-OS rate were 0.26 (0.22-0.30), 0.08 (0.06-0.10) and 0.74 (0.56-0.86). The grade 3/4 rate of diarrhea and that of skin deformity were 0.23 (0.10-0.46) and 0.14 (0.05-0.33), respectively. Sensitivity analyses revealed similar results with lower heterogeneity. CONCLUSIONS: Considering the efficacy, toxicity and current availability, afatinib could be a therapeutic option for advanced EGFR mutated NSCLC patients after the failure of 1st-generation TKIs.

The comparison of EGFR-TKI failure modes and subsequent management between exon 19 deletion and exon 21 L858R mutation in advanced non-small-cell lung cancer.

Background: Advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion (19 Del) and exon 21 L858R mutation (L858R) might be distinct diseases. Therefore, it is necessary to take EGFR mutation subgroups into consideration for making choices of subsequent treatment after tyrosine kinase inhibitors (TKIs) failure. Patients and methods: 174 patients who developed to EGFR-TKI failure were categorized into three cohorts of dramatic progression, gradual progression and local progression. Chi-square was used to compare the distribution of failure modes between 19 Del and L858R. Kaplan-Meier method and Cox Regression were performed for analyses of survival in different subsequent treatments. Results: The distribution of EGFR-TKI failure modes showed no significant difference between 19 Del and L858R. Patients in gradual progression had a longer progression-free survival (PFS) and overall survival (OS) compared with other failure modes in whole population, 19 Del cohort and L858R cohort. 19 Del patients with dramatic progression would obtain survival benefit from chemotherapy, while those with gradual progression got no survival benefit neither from chemotherapy nor previous TKI continuation. However, patients with dramatic or gradual progression would benefit from previous TKI continuation in L858R cohort. Conclusion: For advanced EGFR-positive NSCLC patients with acquired resistance to EGFR-TKI, subsequent treatment should be personalized according to EGFR-TKI failure modes & EGFR mutation subtypes.

Therapeutic Efficacy Comparison of 5 Major EGFR-TKIs in Advanced EGFR-positive Non-Small-cell Lung Cancer: A Network Meta-analysis Based on Head-to-Head Trials.

BACKGROUND: Five major first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including erlotinib, gefitinib, icotinib, afatinib, and dacomitinib, are currently optional for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, there was no head-to-head-based network meta-analysis among all the TKIs in EGFR-mutated populations. METHODS: Eligible literature was searched from an electronic database. Data of objective response rate, disease control rate, progression-free survival, and overall survival were extracted from enrolled studies. Multiple treatment comparisons based on Bayesian network integrated the efficacy of all included treatments. RESULTS: Six phase III randomized trials involving 1055 EGFR-mutated patients with advanced NSCLC were enrolled. Multiple treatment comparisons showed that 5 different EGFR-TKIs shared equivalent therapeutic efficacy in terms of all outcome measures. Rank probabilities indicated that dacomitinib and afatinib had potentially better efficacy compared with erlotinib, gefitinib, and icotinib in the EGFR-mutated patients. When compared with other agents, potential survival benefits (progression-free and overall survival) were observed in dacomitinib, whereas afatinib showed a better rank probability in overall response rate and disease control rate. CONCLUSION: Our study indicated a preferable therapeutic efficacy in the second-generation TKIs (dacomitinib and afatinib) when compared with the first-generation TKIs (erlotinib, gefitinib, and icotinib).

A large, single-center, real-world study of clinicopathological characteristics and treatment in advanced ALK-positive non-small-cell lung cancer.

Crizotinib has achieved astonishing success in advanced non-small-cell lung cancer (NSCLC) patients harboring anaplastic lymphoma kinase (ALK) rearrangement. However, no real-world studies described the clinicopathological characteristics and treatment of such patients in China. Patients were consecutively collected from Sun Yat-sen University Cancer Center. Chi-square test was applied to explore the relationship between ALK fusion status and metastasis sites. Kaplan-Meier methods and multivariable analyses were used to estimate progression-free survival (PFS). A total of 291 advanced NSCLC patients (ALK (+), N = 97; both ALK & epidermal growth factor receptor (EGFR) (-), N = 194) were enrolled. The occurrence of brain metastasis in ALK-positive patients was significantly higher than double-negative ones both at baseline (26.5% vs. 16.5%, P = 0.038) and during treatment (25.8% vs. 11.9%, P = 0.003), but opposite for pleural effusion (6.2% vs. 26.9%, P < 0.001 at baseline; 3.1% vs. 10.3%, P = 0.031 during treatment). ALK-positive patients of 53.6% used crizotinib, whereas others only received chemotherapy (37.1%) or supportive care (9.3%). Usage of crizotinib prolonged PFS compared with chemotherapy in ALK-positive patients (median PFS 17.6 m vs. 4.8 m, P < 0.001). ALK-positive NSCLC had more brain metastasis and less pleural effusion than double-negative ones. Crizotinib showed better PFS than chemotherapy in advanced ALK-positive NSCLC at any line. However, half advanced ALK-positive patients never received crizotinib, which was grim and need improving.