Construction of a nomogram based on clinicopathologic features to predict the likelihood of No. 253 lymph node metastasis in rectal cancer patients.

PURPOSE: To explore the high-risk factors for rectal cancer No.253 lymph node metastasis (LNM) and to construct a risk nomogram for the individualized prediction of No.253 LNM. METHODS: This was a retrospective analysis of 425 patients with rectal cancer who underwent laparoscopic-assisted radical surgery. Independent risk factors for rectal cancer No.253 LNM was identified using multivariate logistic regression analysis, and a risk prediction nomogram was constructed based on the independent risk factors. In addition, the performance of the model was evaluated by discrimination, calibration, and clinical benefit. RESULTS: Multivariate logistic regression analysis showed that No.253 lymphadenectasis on CT (OR 10.697, P < 0.001), preoperative T4-stage (OR 4.431, P = 0.001), undifferentiation (OR 3.753, P = 0.004), and preoperative Ca199 level > 27 U/ml (OR 2.628, P = 0.037) were independent risk factors for No.253 LNM. A nomogram was constructed based on the above four factors. The calibration curve of the nomogram was closer to the ideal diagonal, indicating that the nomogram had a better fitting ability. The area under the ROC curve (AUC) was 0.865, which indicated that the nomogram had high discriminative ability. In addition, decision curve analysis (DCA) showed that the model could show better clinical benefit when the threshold probability was between 1% and 50%. CONCLUSION: Preoperative No.253 lymphadenectasis on CT, preoperative T4-stage, undifferentiation, and elevated preoperative Ca199 level were found to be independent risk factors for the No.253 LNM. A predictive model based on these risk factors can help surgeons make rational clinical decisions.

Epstein-Barr virus causes vascular abnormalities in epithelial malignancies through upregulating ANXA3-HIF-1α-VEGF pathway.

Angiogenesis is one of the characteristics of malignant tumors, and persistent generation of abnormal tumor blood vessels is an important factor contributing to tumor treatment resistance. Epstein-Barr virus (EBV) is a highly prevalent DNA oncogenic virus that is associated with the development of various epithelial malignancies. However, the relationship between EBV infection and tumor vascular abnormalities as well as its underlying mechanisms is still unclear. In this study, we found that compared to EBV-uninfected tumors, EBV-infected tumors were more angiogenic, but the neovascularization was mostly immature vessels without pericyte attachment in both clinical patient tumor samples and mouse xenograft models; These immature vessels exhibited aberrant functionality, characterized by poor blood perfusion and increased vascular permeability. The vascular abnormalities caused by EBV infection exacerbated tumor hypoxia and was responsible for accelerated tumor growth. Mechanistically, EBV infection upregulated ANXA3-HIF-1α-VEGF pathway. Silencing the ANXA3 gene or neutralizing ANXA3 with an antibody can diminish vascular abnormalities, thereby increasing immune cell infiltration and alleviating treatment resistance. Finally, a new therapy combining ANXA3 blockade and NK cell + PD1 antibody significantly inhibited the growth of EBV-infected xenografts in mice. In conclusion, our study identified a previously unrecognized role for EBV infection in tumor vascular abnormalities and revealed its underlying mechanism that upregulated the ANXA3-HIF-1α-VEGF pathway. ANXA3 is a potential therapeutic target for EBV-infected tumors and ANXA3 blockade to improve vascular conditions, in combination with NK cell + PD1 antibody therapy, holds promise as an effective treatment strategy for EBV-associated epithelial malignancies.

Trimethylamine-N-oxide (TMAO) and predicted risk of cardiovascular events after partial nephrectomy.

INTRODUCTION: Emerging evidence suggests that uremic toxins, in particular trimethylamine-N-oxide(TMAO), indoxyl-sulfate(IS), and p-cresyl-sulfate(PCS), may associate with increased risk of cardiovascular events(CVe). However, whether uremic toxins increase after partial nephrectomy(PN) and their correlation with risk for CVe remains unknown. METHODS: 100 patients managed with PN were retrospectively reviewed. TMAO/IS/PCS levels were examined by liquid chromatography-mass-spectrometry. Renal-parenchymal-volume-preservation(RPVP) was estimated from CT scans. Predicted risks for CVe were obtained using the Framingham score. Linear regression assessed association between uremic toxins, GFR and risk of CVe. Logistic regression evaluated factors associated with post-PN TMAO. RESULTS: TMAO, IS and PCS increased from 1.7, 3.7 and 3.5 µmol/L before PN to 3.6, 5.4 and 7.4 µmol/L at latest follow-up, respectively, while GFR declined from 102 to 93 ml/min/1.73 m2 (all p<0.001). TMAO, IS and PCS levels all negatively correlated with GFR(all p<0.001). Predicted 10-year risk of CVe increased from 1.1% pre-PN to 1.7% post-PN(p<0.001), primarily due to increased age(p<0.001), blood pressure(p = 0.002) and total cholesterol(p = 0.003). TMAO(ß = 0.038) and GFR (ß = -0.02) were independent predictors for predicted 10-year CVe risk on multivariable-analysis. Increased TMAO was an early and sustained finding maintained through 5 years, unlike IS, PCS and eGFR. On multivariable analysis, increased pre-PN TMAO(OR = 2.79) and decreased RPVP(OR = 3.23) were identified as independent risk factors for higher post-PN TMAO, while ischemia type/duration failed to correlate. CONCLUSION: Uremic toxin levels increased after PN correlating with reduced GFR. Higher TMAO independently associated with greater predicted 10-year CVe risk. Parenchymal mass preserved rather than ischemia time or type associated with increased TMAO.

Diagnostic Performance of Modified Contrast-Enhanced Ultrasound Liver Imaging Reporting and Data System in Patients Without Risk Factors for Hepatocellular Carcinoma: Comparison With World Federation for Ultrasound in Medicine and Biology Guideline.

OBJECTIVE: The aim of this study was to assess the ability of the modified contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) to distinguish malignancy in patients without known hepatocellular carcinoma (HCC) risk factors and compare diagnostic accuracy with that of the World Federation for Ultrasound in Medicine and Biology (WFUMB) guideline across radiologists with different levels of CEUS experience. METHODS: A total of 848 individuals with no hepatitis infection presenting with 870 lesions in non-cirrhotic livers were included and divided into the Testing and Validation groups. The modified CEUS LI-RADS was proposed, including downgrading of focal nodular hyperplasia with typical features. Diagnostic performance of the modified CEUS LI-RADS was assessed in the Testing group. In the Validation group, two radiologists with more than 9 y of CEUS experience (Experts) and two radiologists with less than 6 mo of CEUS experience (Novices) used both the modified CEUS LI-RADS and the WFUMB guideline to evaluate performance in diagnosis of the lesions. RESULTS: LR-5 + M (combination of modified LR-5 and modified LR-M) revealed optimal performance with a sensitivity, specificity and area under the curve (AUC) of 99.3%, 81.6% and 0.904, respectively. Novices using the modified CEUS LI-RADS outperformed those using the WFUMB guideline (AUC: 0.858 vs. 0.767, p = 0.005). Additionally, the sensitivity, specificity and AUC of Novices were comparable to those of Experts using the modified CEUS LI-RADS (94.1%, 77.6% and 0.858 vs. 96.1%, 77.6% and 0.868 for experts, respectively). CONCLUSION: The modified CEUS LI-RADS is a valuable method for distinguishing hepatic malignancy in patients without HCC risk factors. This is particularly beneficial for radiologists with limited CEUS expertise.

Effective Antitumor Immunity Can Be Triggered by Targeting VISTA in Combination with a TLR3-Specific Adjuvant.

Resistance to anti-PD-1/PD-L1 treatment is often associated with accumulation of intratumoral inhibitory macrophages. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a nonredundant immune checkpoint that can induce both T-cell and myeloid-cell immunosuppression. In this study, we found that high levels of VISTA+ immune cells were associated with advanced stage bladder cancer and predicted poor survival in patients. A combination of high infiltration of VISTA+ immune cells and PD-L1+ immune cells or PD-1+ T cells predicted the worst survival. Flow cytometry and multiplex immunofluorescence analyses confirmed that VISTA expression was higher in macrophages than in T cells or neutrophils, and only VISTA+CD163+ macrophage density predicted poor prognosis in patients with bladder cancer. Toll-like receptor (TLR) agonists are known to trigger the innate immune response in macrophages. We found that the VISTA-specific mAb 13F3 augmented the ability of a TLR3-specific adjuvant to induce macrophage activation in vitro. In the MB49 syngeneic mouse model of bladder cancer, treatment with 13F3 curbed tumor growth and prolonged survival when combined with a TLR3-specific adjuvant. The combination treatment reduced the intratumoral frequency of CD206+ anti-inflammatory macrophages and levels of the immunosuppressive molecule TGFß1, but it upregulated expression of immunostimulatory molecules (Ifna, Ifnb, and Trail) and increased the CD8+ T cell/regulatory T-cell ratio. These findings indicate that elevated VISTA expression in immune cells, particularly macrophages, is associated with an unfavorable prognosis in patients with bladder cancer and suggest that targeting VISTA in combination with a TLR3-specific adjuvant has translational potential.

Contrast-enhanced US with Sulfur Hexafluoride and Perfluorobutane: LI-RADS for Diagnosing Hepatocellular Carcinoma.

Background Liver Imaging Reporting and Data System (LI-RADS) was designed for contrast-enhanced US (CEUS) with pure blood pool agents to diagnose hepatocellularfcarcinoma (HCC), such as sulfur hexafluoride (SHF), but Kupffer-cell agents, such as perfluorobutane (PFB), allow additional lesion characterization in the Kupffer phase yet remain unaddressed. Purpose To compare the diagnostic performance of three algorithms for HCC diagnosis: two algorithms based on CEUS LI-RADS version 2017 for both SHF and PFB and a modified algorithm incorporating Kupffer-phase findings for PFB. Materials and Methods This multicenter prospective study enrolled high-risk patients for HCC from June 2021 to December 2021. Each participant underwent same-day SHF-enhanced US followed by PFB-enhanced US. Each liver observation was assigned three LI-RADS categories according to each algorithm: LI-RADS SHF, LI-RADS PFB, and modified PFB. For modified PFB, observations at least 10 mm with nonrim arterial phase hyperenhancement were upgraded LR-4 to LR-5 if there was no washout with a Kupffer defect and were reassigned LR-M to LR-5 if there was early washout with mild Kupffer defect. The reference standard was pathologic confirmation or composite (typical CT or MRI features, or 1-year size stability and/or reduction). Diagnostic metrics of LR-5 for HCC using the three algorithms were calculated and compared using the McNemar test. Results Overall, 375 patients (mean age, 56 years ± 11 [SD]; 318 male patients, 57 female patients) with 424 observations (345 HCCs, 40 non-HCC malignancies, 39 benign lesions) were enrolled. PFB and SHF both using LI-RADS showed no significant difference in sensitivity (60% vs 58%; P = .41) and specificity (96% vs 95%; P > .99). The modified algorithm with PFB had increased sensitivity (80% vs 58%; P < .001) and a nonsignificant decrease in specificity (92% vs 95%; P = .73) compared with LI-RADS SHF. Conclusion Based on CEUS LI-RADS version 2017, both SHF and PFB achieved high specificity and relatively low sensitivity for HCC diagnosis. When incorporating Kupffer-phase findings, PFB had higher sensitivity without loss of specificity. Chinese Clinical Trial Registry no. ChiCTR2100047035 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kim in this issue.

Lenvatinib improves anti-PD-1 therapeutic efficacy by promoting vascular normalization via the NRP-1-PDGFRß complex in hepatocellular carcinoma.

Introduction: The limited response to immune checkpoint blockades (ICBs) in patients with hepatocellular carcinoma (HCC) highlights the urgent need for broadening the scope of current immunotherapy approaches. Lenvatinib has been shown a potential synergistic effect with ICBs. This study investigated the optimal method for combining these two therapeutic agents and the underlying mechanisms. Methods: The effect of lenvatinib at three different doses on promoting tissue perfusion and vascular normalization was evaluated in both immunodeficient and immunocompetent mouse models. The underlying mechanisms were investigated by analyzing the vascular morphology of endothelial cells and pericytes. The enhanced immune infiltration of optimal-dose lenvatinib and its synergistic effect of lenvatinib and anti-PD-1 antibody was further evaluated by flow cytometry and immunofluorescence imaging. Results: There was an optimal dose that superiorly normalized tumor vasculature and increased immune cell infiltration in both immunodeficient and immunocompetent mouse models. An adequate concentration of lenvatinib strengthened the integrity of human umbilical vein endothelial cells by inducing the formation of the NRP-1-PDGFRß complex and activating the Crkl-C3G-Rap1 signaling pathway in endothelial cells. Additionally, it promoted the interaction between endothelial cells and pericytes by inducing tyrosine-phosphorylation in pericytes. Furthermore, the combination of an optimal dose of lenvatinib and an anti-PD-1 antibody robustly suppressed tumor growth. Conclusions: Our study proposes a mechanism that explains how the optimal dose of lenvatinib induces vascular normalization and confirms its enhanced synergistic effect with ICBs.

BMP9-induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus-associated hepatocellular carcinoma.

BACKGROUND: In the past decade, the field of tumour immunotherapy has made a great progress. However, the efficacy of immune checkpoint blocking (ICB) in the treatment of hepatocellular carcinoma (HCC) remains limited. Cytotoxic lymphocyte trafficking into tumours is critical for the success of ICB. Therefore, additional strategies that increase cytotoxic lymphocyte trafficking into tumours are urgently needed to improve patient immune responses. METHODS: Paired adjacent tissue and cancerous lesions with HBV-associated HCC were subjected to RNA-seq analysis. Bone morphogenetic protein (BMP9), which reflects vessel normalisation, was identified through Cytoscape software, clinical specimens and Gene Expression Omnibus (GEO) datasets for HCC. The functional effects and mechanism of BMP9 on the tumour vasculature were evaluated in cells and animals. An ultrasound-targeted microbubble destruction (UTMD)-mediated BMP9 delivery strategy was used to normalise the vasculature and evaluate therapeutic efficacy mediated by cytotoxic lymphocytes (NK cells) in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. RESULTS: We discovered that hepatitis B virus (HBV) infection-induced downregulation of BMP9 expression correlated with a poor prognosis and pathological vascular abnormalities in patients with HCC. BMP9 overexpression in HBV-infected HCC cells promoted intra-tumoural cytotoxic lymphocyte infiltration via vascular normalisation by inhibiting the Rho-ROCK-myosin light chain (MLC) signalling cascade, resulting in enhanced efficacy of immunotherapy. Furthermore, UTMD-mediated BMP9 delivery restored the anti-tumour function of cytotoxic lymphocytes (NK cells) and showed therapeutic efficacy in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. CONCLUSIONS: HBV-induced BMP9 downregulation causes vascular abnormalities that inhibit intra-tumoural cytotoxic lymphocyte infiltration, providing a rationale for developing and combining immunotherapy with BMP9-based therapy to treat HBV-associated HCC.

Comparative efficacy of different combinations of acapella, active cycle of breathing technique, and external diaphragmatic pacing in perioperative patients with lung cancer: a randomised controlled trial.

BACKGROUND: Acapella plus active cycle of breathing technique (ACBT), external diaphragm pacemaker (EDP) plus ACBT have been shown to facilitate the recovery of functional capacity and lung function in patients suffering from airway obstruction but the efficacy in perioperative patients with lung cancer has not been proven. METHODS: We conducted a three-arm, prospective, randomized, assessor-blinded, controlled trial in patients with lung cancer who underwent thoracoscopic lobectomy or segmentectomy in the department of thoracic surgery, China. Patients were randomly assigned (1:1:1) to receive Acapella plus ACBT, EDP plus ACBT, or ACBT group (control group) using SAS software. The primary outcome was functional capacity, measured by the 6-minute walk test (6MWT). RESULTS: We recruited 363 participants over 17 months: 123 assigned to the Acapella plus ACBT group, 119 to the EDP plus ACBT group, and 121 to the ACBT group. Statistically significant differences were noted for functional capacity between the EDP plus ACBT and control groups at each follow-up time (1-week follow-up: difference = 47.25 m, 95% CI, 31.56-62.93; P < 0.001; and 1-month follow-up: difference = 49.72 m, 95% CI, 34.04-65.41; P < 0.001), between the Acapella plus ACBT and control groups at postoperative week 1 (difference = 35.23 m, 95% CI, 19.30-51.16; P < 0.001) and postoperative month 1 (difference = 34.96 m, 95% CI, 19.03-50.89; P < 0.001), and between the EDP plus ACBT and Acapella plus ACBT groups at 1-month follow-up (difference = 14.76 m, 95% CI, 1.34-28.19; P = 0.0316). CONCLUSION: EDP plus ACBT and Acapella plus ACBT significantly improved functional capacity and lung function in perioperative patients with lung cancer, compared with single-model ACBT, and the effects of EDP plus ACBT were clearly superior to those of other programs. TRIAL REGISTRATION: The study was registered in the clinical trial database (clinicaltrials.gov) on June 4, 2021 (No. NCT04914624).

Ultrasound-guided core needle biopsy for accessing laryngeal masses with unsatisfactory laryngoscopy and biopsy results.

BACKGROUND: Laryngoscopy and biopsy is the standard techniques to sample and diagnose laryngeal neoplasms, but not all patients with laryngeal neoplasm are eligible for biopsy via laryngoscopy (e.g., submucosal neoplasms). PURPOSE: This study was conducted to evaluate the feasibility and diagnostic yield of ultrasound-guided core needle biopsy (US-CNB) for submucosal laryngeal neoplasms with unsatisfactory laryngoscopy and biopsy results. METHODS: We retrospectively reviewed the medical records of 24 patients with unsatisfactory laryngoscopy and biopsy results who were referred to our center for US-CNB from January 2017 to November 2021. For all enrolled patients, we assessed consistency between the laryngoscopic biopsy, US-CNB, and final results. The final results were determined from the surgical biopsy results or clinical follow-up information (at least 3 month). Differences between biopsy techniques were compared using the Fisher's exact test. A P value less than 0.05 indicated statistical significance. RESULTS: Twenty-four patients (median [range] age: 60.6 [41-76] years, 20 men) were included in our study. Among the 24 patients, 12 were eligible for laryngoscopic biopsy. In total, 24 patients underwent 26 US-CNB. Two patients underwent a repeat US-CNB for conformation of a benign histological result or due to inadequate specimen collection. The results of laryngoscopic biopsy and US-CNB were compared with the final result. The overall accuracy of US-CNB for differentiating benign from malignant lesions was 95.8 % (23/24), and this procedure had a sensitivity, specificity, positive predictive value, and negative predictive value of 95.2 %, 100 %, 100 %, and 75 %, respectively. The results of US-CNB are significantly better than those of laryngoscopic biopsy. CONCLUSIONS: US-CNB is a safe, effective, and feasible technique for investigating suspicious submucosal laryngeal neoplasms and can serve as a complementary method for early and timely diagnosis of those neoplasms.

Predictive Nomogram for Hyperprogressive Disease During Anti-PD-1/PD-L1 Treatment in Patients with Advanced Non-Small Cell Lung Cancer.

Introduction: Various studies have reported that anti-PD-1/PD-L1 treatment may lead to the rapid development of tumors called hyperprogressive disease (HPD). A nomogram for HPD prediction in NSCLC patients is urgently needed. Methods: This retrospective cohort study included 176 cases for establishing a model of HPD prediction and 85 cases for validation in advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. HPD was defined as tumor growth rate (TGR, ≥ 2), tumor growth kinetics (TGK, ≥ 2) or time to treatment failure (TTF, ≤ 2 months). Univariate and multivariate logistic regression were used to estimate the specified factors associated with HPD. Then, the nomogram was developed and validated. Results: Anti-PD-1/PD-L1 therapy resulted in a 9.66% (17/176) incidence of HPD in advanced NSCLC. The overall survival (OS) and progression-free survival (PFS) in patients with HPD were significantly shorter than those in patients without HPD (OS: 7.00 vs 12.00 months, P<0.01; PFS: 2.00 vs 5.00 months, P<0.001, respectively). The HPD prediction nomogram included APTT (P<0.01), CD4+ CD25+ CD127-low cells (Treg cells) (P<0.01), the presence of liver metastasis (P<0.05), and more than two metastatic sites (P<0.05). Then, patients were divided into two groups by the "HPD score" calculated by the nomogram. The C-index was 0.845, while the area under the curve (AUC) was 0.830 (sensitivity 75.00%, specificity 91.70%). The calibration plot of HPD probability showed an optimal agreement between the actual observation and prediction by the nomogram. In the validation cohort, the AUC was up to 0.960 (sensitivity 88.70%, specificity 89.80%). Conclusions: The nomogram was constructed with the presence of liver metastasis, more than two metastatic sites, lengthened APTT and a high level of Treg cells, which could be used to predict HPD risk.

Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study.

PURPOSE: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). PATIENTS AND METHODS: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety. RESULTS: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups. CONCLUSION: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

Investigation on the knowledge level of the rational application of antimicrobial drugs among pharmacists in medical institutions in Shanxi Province.

OBJECTIVE: To investigate the knowledge of the rational use of antibiotics among pharmacists in medical institutions in Shanxi Province, People's Republic of China, in order to determine the problems and provide support for the correct management of antibiotics. METHODS: A questionnaire survey was conducted, which included the basic information of the respondents, the basic knowledge of antimicrobial management, and the related knowledge of antimicrobial drugs. RESULTS: 462 pharmacists were investigated. The average score of the knowledge related to the rational use of antibiotics was 10.49±4.05. It showed that the hospital type, grade, pharmacist's education, professional title and working years all had an effect on the pharmacist's mastery of antimicrobial-related knowledge (p<0.05). Multivariate logistic regression analysis showed that hospital grade and pharmacist's education were the main influencing factors (p<0.05). CONCLUSION: Pharmacists have insufficient knowledge about the rational application of antibacterial drugs. It is essential to strengthen the training of management regulations and the application of antibacterial drugs.

Adagrasib, a KRAS G12C inhibitor, reverses the multidrug resistance mediated by ABCB1 in vitro and in vivo.

BACKGROUND: Multidrug resistance (MDR) is a complex phenomenon that frequently leads to chemotherapy failure during cancer treatment. The overexpression of ATP-binding cassette (ABC) transporters represents the major mechanism contributing to MDR. To date, no effective MDR modulator has been applied in clinic. Adagrasib (MRTX849), a specific inhibitor targeting KRAS G12C mutant, is currently under investigation in clinical trials for the treatment of non-small cell lung cancer (NSCLC). This study focused on investigating the circumvention of MDR by MRTX849. METHODS: The cytotoxicity and MDR reversal effect of MRTX849 were assessed by MTT assay. Drug accumulation and drug efflux were evaluated by flow cytometry. The MDR reversal by MRTX849 in vivo was investigated in two ABCB1-overexpressing tumor xenograft models in nude mice. The interaction between MRTX849 and ABCB1 substrate binding sites was studied by the [125I]-IAAP-photoaffinity labeling assay. The vanadate-sensitive ATPase assay was performed to identify whether MRTX849 would change ABCB1 ATPase activity. The effect of MRTX849 on expression of ABCB1 and PI3K/AKT signaling molecules was examined by flow cytometry, Western blot and Quantitative Real-time PCR analyses. RESULTS: MRTX849 was shown to enhance the anticancer efficacy of ABCB1 substrate drugs in the transporter-overexpressing cells both in vitro and in vivo. The MDR reversal effect was specific against ABCB1 because no similar effect was observed in the parental sensitive cells or in ABCG2-mediated MDR cells. Mechanistically, MRTX849 increased the cellular accumulation of ABCB1 substrates including doxorubicin (Dox) and rhodamine 123 (Rho123) in ABCB1-overexpressing MDR cells by suppressing ABCB1 efflux activity. Additionally, MRTX849 stimulated ABCB1 ATPase activity and competed with [125I]-IAAP for photolabeling of ABCB1 in a concentration-dependent manner. However, MRTX849 did not alter ABCB1 expression or phosphorylation of AKT/ERK at the effective MDR reversal drug concentrations. CONCLUSIONS: In summary, MRTX849 was found to overcome ABCB1-mediated MDR both in vitro and in vivo by specifically attenuating ABCB1 efflux activity in drug-resistant cancer cells. Further studies are warranted to translate the combination of MRTX849 and conventional chemotherapy to clinical application for circumvention of MDR. Video Abstract.

Defect Engineering Triggers Exceptional Sonodynamic Activity of Manganese Oxide Nanoparticles for Cancer Therapy.

Sonodynamic therapy (SDT) has received increasing interest in cancer treatment, but its clinical application is still constrained by the low activity of sonosensitizers and their unclear mechanism. Herein, a kind of oxygen-deficient manganese oxide (MnOx) nanoparticles with greatly enhanced sonodynamic activity and good biocompatibility is developed as an advanced sonosensitizer. The introduced oxygen defects can remarkably enhance the electrical conductivity of manganese oxide (MnO) nanoparticles and serve as charge trapping sites to prohibit the electron-hole pair recombination upon ultrasound (US) irradiation. Such distinct merits promote the generation of reactive oxygen species (ROS), making MnOx as a decent sonosensitizer for SDT, and thus endowing MnOx with higher ROS production under US irradiation. As a demonstration, the MnOx nanoparticles decorated by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (MnOx-DSPE-PEG), a biocompatible coverage to enhance the dispersion ability, achieve a superior tumor killing efficiency of 96%, substantially higher than the MnO-DSPE-PEG counterpart (9%). Our experimental results also reveal that MnOx-DSPE-PEG nanoparticles induce the death of tumor cells by targeting polyunsaturated fatty acids in their membrane with US-triggered ROS. Furthermore, the as-designed sonosensitizers exhibit negligible toxicity toward the treated mice.

Contrast-Enhanced Ultrasound Using Perfluorobutane: Impact of Proposed Modified LI-RADS Criteria on Hepatocellular Carcinoma Detection.

BACKGROUND. Contrast-enhanced ultrasound (CEUS) LI-RADS version 2017 (v2017) applies only to CEUS examinations performed using pure blood pool agents, noting that future versions will address combined blood pool and Kupffer cell agents such as perfluorobutane. Such agents may improve hepatocellular carcinoma (HCC) detection by visualization of a defect in the Kupffer phase (obtained ≥ 10 minutes after injection). OBJECTIVE. The purpose of our study was to compare the diagnostic performance of the LR-5 category for HCC detection in at-risk patients between CEUS LI-RADS v2017 and proposed modified criteria for CEUS examinations performed using perfluorobutane. METHODS. This retrospective study included 293 patients at risk for HCC (259 men, 34 women; mean age, 55 ± 12 [SD] years) who underwent CEUS using perfluorobutane from March 1, 2020, to October 30, 2020, showing a total of 304 observations (274 HCC, 14 non-HCC malignancy, and 16 benign lesions). Two readers independently assessed examinations and assigned categories using both CEUS LI-RADS v2017 and the proposed modified criteria. In the modified criteria, observations 10 mm or greater with not rim arterial phase hyperenhancement (APHE), no washout, and a Kupffer defect were upgraded from LR-4 to LR-5, and observations 10 mm or greater with not rim APHE, early washout, and a mild Kupffer defect were reassigned from LR-M to LR-5. Interreader agreement was assessed, and consensus interpretations were reached. Diagnostic performance was evaluated. RESULTS. Interreader agreement for LI-RADS category assignments, expressed using kappa coefficients, was 0.839 for CEUS LI-RADS v2017 and 0.854 for the modified criteria. Modified criteria upgraded 35 observations from LR-4 to LR-5 on the basis of a Kupffer defect, of which 34 were HCC and one was benign. Modified criteria reassigned 22 observations from LR-M to LR-5 on the basis of a mild Kupffer defect, of which all were HCC. LR-5 using modified criteria, compared with CEUS LI-RADS v2017, had significantly increased sensitivity (89% vs 69%, p < .001), a nonsignificant decrease in specificity (83% vs 87%, p > .99), and significantly increased accuracy (89% vs 71%, p < .001) for HCC. CONCLUSION. When using perfluorobutane for CEUS in at-risk patients, modified criteria incorporating Kupffer defects significantly improve sensitivity without significant loss of specificity in HCC detection. CLINICAL IMPACT. Future CEUS LI-RADS updates seeking to address the use of combined blood pool and Kupffer cell agents should consider adoption of the explored criteria.

Lazertinib improves the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 overexpression cancer cells in vitro, in vivo, and ex vivo.

Multidrug resistance (MDR) is the major cause of chemotherapy failure, which is usually caused by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2. To date, no MDR modulator has been clinically approved. Here, we found that lazertinib (YH25448; a novel third-generation tyrosine kinase inhibitor [TKI]) could enhance the anticancer efficacy of MDR transporter substrate anticancer drugs in vitro，in vivo, and ex vivo. Mechanistically, lazertinib was shown to inhibit the drug efflux activities of ABCB1 and ABCG2 and thus increase the intracellular accumulation of the transporter substrate anticancer drug. Moreover, lazertinib was found to stimulate the ATPase activity of ABCB1/ABCG2 and inhibit the photolabeling of the transporters by 125I-iodoarylazidoprazosin (IAAP). However, lazertinib neither changed the expression or locolization of ABCB1 and ABCG2 nor blocked the signal pathway of Akt or Erk1/2 at a drug concentration effective for MDR reversal. Overall, our results demonstrate that lazertinib effectively reverses ABCB1- or ABCG2-mediated MDR by competitively binding to the ATP-binding site and inhibiting drug efflux function. This is the first report demonstrating the novel combined use of lazertinib and conventional chemotherapeutical drugs to overcome MDR in ABCB1/ABCG2-overexpressing cancer cells.

Advances in artificial intelligence to predict cancer immunotherapy efficacy.

Tumor immunotherapy, particularly the use of immune checkpoint inhibitors, has yielded impressive clinical benefits. Therefore, it is critical to accurately screen individuals for immunotherapy sensitivity and forecast its efficacy. With the application of artificial intelligence (AI) in the medical field in recent years, an increasing number of studies have indicated that the efficacy of immunotherapy can be better anticipated with the help of AI technology to reach precision medicine. This article focuses on the current prediction models based on information from histopathological slides, imaging-omics, genomics, and proteomics, and reviews their research progress and applications. Furthermore, we also discuss the existing challenges encountered by AI in the field of immunotherapy, as well as the future directions that need to be improved, to provide a point of reference for the early implementation of AI-assisted diagnosis and treatment systems in the future.

Intranasal Dexmedetomidine Accompanied by Cartoon Video Preoperation for Reducing Emergence Delirium in Children Undergoing Strabismus Surgery: A Prospective Randomized Trial.

Background: After general anesthesia, many pediatric patients present with emergence delirium (ED). The aim of this study was to determine whether dexmedetomidine intranasal premedication accompanied by a cartoon video 30 min before general anesthesia would have an effect on reducing emergence delirium in preschool children. Methods: One hundred and forty children aged 3-6 year undergoing elective strabismus surgery were randomly to be premedicated with 2 µg kg-1 intranasal dexmedetomidine accompanied by the viewing of a cartoon video (Group DV) or without any premedication as usual (Group C). The primary outcome was the incidence of emergence delirium at the postanesthesia care unit (PACU), evaluated by the Pediatric Anesthesia Emergence Delirium (PAED) scale. The secondary outcomes included: the Modified Yale Preoperative Anxiety Scale (mYPAS) upon separation from parents; the Induction Compliance Checklist score (ICC); the PACU discharge time; the parental satisfaction score; the incidences of the side effects and the Post-Hospital Behavior Questionnaire (PHBQ) score during the first day after surgery. Results: The incidence of emergence agitation (PAED score ≥ 10) was reduced in Group DV compared with Group C [8 (11.4%) vs. 24 (34.3%); P = 0.001]. None of the patients in the DV group experienced severe emergence agitation (PAED score ≥ 15), as compared with the C group (P = 0.006). The mYPAS score upon separation from parents (P < 0.001) and the incidence of poor coordination (ICC ≥ 4) during induction (P < 0.001) were significantly lower in Group DV than in Group C. In Group DV, the PACU discharge time was longer (P < 0.001), and the parental satisfaction score was higher (P < 0.001). However, during the first day after surgery, the PHBQ score was lower in Group DV compared with Group C (P = 0.001). Conclusions: Premedication with 2 µg kg-1 intranasal dexmedetomidine accompanied by cartoon video viewing can dramatically reduce emergence delirium in preschool children undergoing strabismus surgery, relieve preoperative anxiety and improve the parental satisfaction and the postoperative behavior changes during the first day after surgery. Clinical Trial Registration: ChiCTR2000030678.