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BackgroundThis study was designed to characterize gut microbiota changes of the patients with gastric cancer before and after the gastrectomy during their hospital staying periods.Methods16S ribosomal RNA (rRNA) gene sequencing was used to evaluate differences in gut microbiota among patients with gastric cancer before and after the gastrectomy by comparing gut microbiota α diversity, β diversity, and structure composition at different taxonomic levels.ResultsA total of 120 fecal specimens were collected from 60 patients. There was no significant difference in Chao1 index, Shannon index, and Simpson index before and after gastrectomy (all P > 0.05). At the phylum level, the gut microbiota in the gastrectomy group showed less abundance of Bacteroidota, Synergistota, and Verrucomicrobiota but with higher abundance of Campylobacter, Actinobacteria, and Bacillota. At the genus level, the gut microbiota in the gastrectomy group showed less abundance of flora Bacteroides, Faecalibacterium, Blautia, and Lachnospiraceae nk4a136 group but with higher abundance of Campylobacter, Porphyromona, Finegordia, Dialist, Anaerococcus, and Corynebacterium.ConclusionsThere was no significant change in the diversity of intestinal flora before and after surgery. However, significant changes in the structure of intestinal flora before and after surgery were occurred.

ObjectiveTo assess the effectiveness and tolerability of both PD-1 and PD-L1 inhibitors in advanced cervical cancer (CC), focusing on varying PD-L1 levels.MethodsA comprehensive exploration was carried out on EMBASE, PubMed, Cochrane Library databases as well as Web of Science up to May 25, 2024, for studies involving advanced CC patients receiving PD-1/PD-L1 inhibitors. Inclusion criteria were studies reporting objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), as well as median overall survival (OS). Data extraction and quality assessment were performed by two reviewers using the JBI Case Series Critical Appraisal Checklist, followed by a meta-analysis via STATA/MP 16.0.ResultsFive eligible studies comprising 223 patients were chosen. ORR and DCR were 42% (95% CI: 17%-66%, P = 0.00) and 70% (95% CI: 22%-117%, P = 0.00), respectively, in the PD-L1 positive patients and were 36% (95% CI: 17%-54%, P = 0.00) and 47% (95% CI: 30%-63%, P = 0.00), respectively, in patients with PD-L1 negativity. For patients exhibiting PD-L1 positivity, median PFS and median OS were 3.98 months (95% CI: 0.80–7.16, P = 0.01) and 11.26 months (95% CI: 3.01–12.58, P = 0.00), respectively.ConclusionWith PD-1/PD-L1 inhibitors, PD-L1 positive CC patients demonstrate superior ORR, DCR, median PFS, and median OS, underscoring PD-L1 as one biomarker for immunotherapy response.

BackgroundMetastasis remains the leading cause of mortality among colorectal cancer (CRC) patients. Identification of new metastasis-related genes are critical to improve colorectal cancer prognosis.MethodsData on mRNA expression in metastatic and primary CRC was obtained from the Gene Expression Omnibus (GEO) database, including GSE81986, GSE41568, GSE71222, GSE21510, and GSE14333. Additionally, data concerning mRNA expression in colon cancer (COAD) and adjacent normal tissues were acquired from The Cancer Genome Atlas (TCGA) database. Hub genes were identified by weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis. Moreover, we assessed the impact of hub gene expression on both overall survival (OS) and disease-free survival (DFS) in patients and identified ZG16 as a potential target. We generated CRC cell lines transfected with lentivirus OE-ZG16 to investigate proliferation, invasion, and migration in vitro. To further elucidate the involvement of ZG16, we utilized gene set enrichment analysis (GSEA) to identify enriched pathways, which were subsequently validated via Western blot analysis.ResultsFive datasets containing primary and metastatic CRC samples from GEO database and CRC samples from TCGA database were included in this study and 29 hub genes were identified by WGCNA and differentially expressed gene (DEG) analysis. Low expression of the hub genes (CLCA1 and ZG16) was associated with poor DFS and OS. We confirmed the low expression of ZG16 in CRC using external database and IHC analysis at both transcriptional and protein levels. In addition, the expression of ZG16 was notably elevated in NCM460 cells in comparison to CRC cell lines. The overexpression of ZG16 in CRC cells has been shown to inhibit the proliferation, invasion, and migration of CRC cells. Furthermore, the overexpression of ZG16 has been found to suppress the activation of the epithelial-mesenchymal transition (EMT) and Wnt/β-catenin signaling pathways in CRC.ConclusionZG16 may serve as a promising therapeutic target for metastatic CRC treatment.

As one lethal malignancy in women’s reproductive systems, ovarian cancer (OC) is frequently detected at an advanced phase during diagnosis. when the disease has spread widely. The absence of obvious symptoms and powerful screening tools in the early stages makes treatment difficult and the prognosis poor. Despite the clinical remission that can be achieved in some patients after initial treatment, the recurrence rate is conspicuous, posing a considerable challenge in treating recurrent OC (ROC). In the retrospective analysis, we compared the effects of two treatment regimens, aqupla combined with paclitaxel liposome (NP group) versus aqupla combined with docetaxel (ND group), on survival and biomarkers in patients with ROC. The study included 121 OC patients, and clinical data were collected through an electronic medical record system, outpatient review records, and a follow-up record system. The results revealed a notably higher overall remission rate in the ND group than the NP group, but revealed no notable inter-group discrepancy in toxicities, implying that the aqupla combined with docetaxel regimen may be more effective in platinum-sensitive ROC patients. Additionally, post-treatment CA125 levels were lower in patients in the ND group, suggesting that the regimen may be more effective in reducing tumour load. Survival analysis further revealed that treatment regimen, FIGO stage, number of recurrent lesions, and pretreatment CA125 level were independent prognostic factors affecting patients’ 5-year OS and PFS. Overall for ROC patients, especially platinum-sensitive patients, the aqupla in combination with docetaxel regimen provided an improved survival benefit with a comparable safety profile, highlighting the importance of individualised treatment strategies.

ObjectiveCurrently, there are no studies showing which neoadjuvant therapy modality can provide better prognosis for patients after pancreatic cancer surgery. This study explores the optimal neoadjuvant therapy model by comparing the survival differences between patients with non-metastatic pancreatic cancer (cT1-4N0-1M0) who received neoadjuvant chemotherapy (NACT) and neoadjuvant chemoradiotherapy (NARCT).MethodsWe retrospectively analyzed the clinical data of 723 patients with cT1-4N0-1M0 pancreatic cancer who received neoadjuvant therapy before surgery from the Surveillance, Epidemiology, and End Results (SEER) database. After propensity score matching (PSM), we compared the effects of NACT and NARCT on overall survival (OS) and cancer-specific survival (CSS) in patients with non-metastatic pancreatic cancer, and then performed subgroup analyze. Finally, we used univariate and multivariate Cox regression analysis to explore potential risk factors for OS and CSS in patients with non-metastatic pancreatic cancer treated with preoperative neoadjuvant therapy.ResultBefore PSM, mOS (30.0 months VS 26.0 months, P=0.122) and mCSS (30.0 months VS 26.0 months, P=0.117) were better in patients with non-metastatic pancreatic cancer treated with NACT compared with NARCT, but this was not statistically significant (P>0.05). After PSM, mOS (30.0 months VS 25.0 months, P=0.032) and mCSS (33.0 months VS 26.0 months, P=0.028) were better in patients with non-metastatic pancreatic cancer treated with NACT compared with NARCT, and this difference was statistically significant (P

ObjectiveThis study aimed to develop and validate a nomogram based on ultrasonographic features and clinical indicators to differentiate mass-forming intrahepatic cholangiocarcinoma (MF-ICC) from hepatic metastatic colorectal adenocarcinoma.Materials and methodsA total of 343 patients with pathologically confirmed MF-ICC or metastatic colorectal adenocarcinoma were enrolled between October 2018 and July 2022. Patients were randomly assigned to training and validation sets at a ratio of 7:3. Preoperative ultrasound features and clinical indicators were retrieved. Univariate logistic regression analysis was employed to select relevant features. Multivariate logistic regression analysis was used to establish a predictive model, which was presented as a nomogram in training sets. The model’s performance was assessed in terms of discrimination, calibration, and clinical usefulness.ResultsThe study included 169 patients with MF-ICC and 174 with liver metastatic colorectal adenocarcinoma, assigned to training (n=238) and validation (n=105) cohorts. The nomogram incorporated ultrasound features (tumor size, lesion number, echogenicity, tumor necrosis, and rim arterial phase hyperenhancement) and clinical information (serum levels of CEA, CA19-9, CA125). The nomogram demonstrated promising performance in differentiating these two entities in both training and validation sets, with an AUC value of 0.937 (95%CI: 0.907,0.969) and 0.916 (95%CI: 0.863,0.968), respectively. The Hosmer–Lemeshow test and calibration curves confirmed good consistency between predictions and observations. Additionally, decision curve analysis confirmed the nomogram’s high clinical practicability.ConclusionThe nomogram based on ultrasound features and clinical indicators demonstrated good discrimination performance in differentiating MF-ICC from metastatic colorectal adenocarcinoma, which may enhance clinical decision-making process in managing these challenging diagnostic scenarios.

ObjectiveTo establish machine learning (ML) prediction models for prostate cancer (PCa) using transrectal ultrasound videos and multi-parametric magnetic resonance imaging (mpMRI) and compare their diagnostic performance.Materials and methodsWe systematically collated the data of 383 patients, including 187 with PCa and 196 with benign lesions. Of them, 307 patients (150 with PCa and 157 with benign lesions) were randomly selected to train and validate the ML models, 76 patients were used as test set. B-Ultrasound videos (BUS), mpMRI T2 sequence (T2), and ADC sequence (ADC) were obtained from all patients. We extracted 851 features of each patient in the BUS, T2, and ADC groups and used a t-test, the Mann–Whitney U test, and LASSO regression to screen the features. Support vector machine (SVM), random forest (RF), adaptive boosting (ADB), and gradient boosting machine (GBM) models were used to establish radiomics models. In addition, we fused the features screened via LASSO regression from three groups as new features and rebuilt ML models. The performance of the ML models in diagnosing PCa in the BUS, T2, ADC, and fusion groups was compared using the area under the ROC curve (AUC), sensitivity, specificity, and accuracy.ResultsIn the test cohort, the AUC of each model in the ADC group was higher than that of in the.BUS and T2 groups. Among the models, the RF model had the best diagnostic performance, with an AUC of 0.85, sensitivity of 0.78 (0.61–0.89), specificity of 0.84 (0.69–0.94), and accuracy of 0.83 (0.66–0.93). The SVM model in both the BUS and T2 groups performed best. Based on the features screened in the BUS, T2, and ADC groups fused to construct the models, the SVM model was found to perform best, with an AUC of 0.87, sensitivity of 0.73 (0.56–0.86), specificity of 0.79 (0.63–0.90), and accuracy of 0.77 (0.59–0.89). The difference in the results was statistically significant (p

BackgroundAlthough laparoscopic hepatectomy has been widely used in the treatment of benign and malignant liver diseases, its applicability in intrahepatic cholangiocarcinoma (ICC) is controversial. We conducted a meta-analysis to compare the short-term and long-term outcomes of laparoscopic hepatectomy (Lap-ICC) and open hepatectomy (Open-ICC) in ICC patients.MethodsThe PubMed, Web of science, Cochrane Library, China National Knowledge Infrastructure and other databases were searched for the relevant literature. The research data were extracted according to the inclusion and exclusion criteria.ResultsSeventeen studies, including 3975 ICC patients, were selected for the meta-analysis. Compared to Open-ICC, Lap-ICC had lower rates of lymph node dissection (OR=0.44, P=0.01) and metastasis (OR=0.58, P=0.03), along with less intraoperative bleeding (MD=-128.43 ml, P

ObjectivesAdenocarcinoma at the gastroesophageal junction (ACGEJ) refers to a malignant tumor that occurs at the esophagogastric junction. Despite some progress in targeted therapies for HER2, FGFR2, EGFR, MET, Claudin 18.2 and immune checkpoints in ACGEJ tumors, the 5-year survival rate of patients remains poor. Thus, it is urgent to explore genomic alterations and neoantigen characteristics of tumors and identify CD8+ T-cell infiltration-associated genes to find potential therapeutic targets and develop a risk model to predict ACGEJ patients’ overall survival (OS).MethodsWhole-exome sequencing (WES) was performed on 55 paired samples from Chinese ACGEJ patients. Somatic mutations and copy number variations were detected by Strelka2 and FACETS, respectively. SigProfiler and SciClone were employed to decipher the mutation signature and clonal structure of each sample, respectively. Neoantigens were predicted using the MuPeXI pipeline. RNA sequencing (RNA-seq) data of ACGEJ samples from our previous studies and The Cancer Genome Atlas (TCGA) were used to identify genes significantly associated with CD8+ T-cell infiltration by weighted gene coexpression network analysis (WGCNA). To construct a risk model, we conducted LASSO and univariate and multivariate Cox regression analyses.ResultsRecurrent MAP2K7, RNF43 and RHOA mutations were found in ACGEJ tumors. The COSMIC signature SBS17 was associated with ACGEJ progression. CCNE1 and VEGFA were identified as putative CNV driver genes. PI3KCA and TP53 mutations conferred selective advantages to cancer cells. The Chinese ACGEJ patient neoantigen landscape was revealed for the first time, and 58 potential neoantigens common to TSNAdb and IEDB were identified. Compared with Siewert type II samples, Siewert type III samples had significant enrichment of the SBS17 signature, a lower TNFRSF14 copy number, a higher proportion of samples with complex clonal architecture and a higher neoantigen load. We identified 10 important CD8+ T-cell infiltration-related Hub genes (CCL5, CD2, CST7, GVINP1, GZMK, IL2RB, IKZF3, PLA2G2D, P2RY10 and ZAP70) as potential therapeutic targets from the RNA-seq data. Seven CD8+ T-cell infiltration-related genes (ADAM28, ASPH, CAMK2N1, F2R, STAP1, TP53INP2, ZC3H3) were selected to construct a prognostic model. Patients classified as high risk based on this model had significantly worse OS than low-risk patients, which was replicated in the TCGA-ACGEJ cohort.ConclusionsThis study provides new neoantigen-based immunotherapeutic targets for ACGEJ treatment and effective disease prognosis biomarkers.

Irreversible electroporation (IRE) is a soft tissue ablation technique that uses short electrical fields which induce the death of target cells. To evaluate the safety and efficacy of an IRE-based device compared to regular radiofrequency ablation (RFA) of solid liver tumors, in this multicenter, randomized, parallel-arm, non-inferiority study, 152 patients with malignant liver tumors were randomized into IRE (n = 78) and RFA (n = 74) groups. The primary endpoint was the success rate of tumor ablation; the secondary endpoints included the tumor ablation time, complications, tumor recurrence rates and treatment-related adverse events (TRAE). The success rate of tumor ablation using IRE was 94.9% and was non-inferior to the RFA group (96.0%) (P = 0.761). For the secondary endpoints, the average ablation time was 34.29 ± 30.38 min for the IRE group, which was significantly longer than for the RFA group (19.91 ± 16.08 min) (P < 0.001). The incidences of postoperative complications after 1 week (P = 1.000), 1 month (P = 0.610) and 3 months (P = 0.490) were not significantly different between the 2 groups. The recurrence rates of liver tumor at 1, 3 and 6 months after ablation were 0 (0.0%), 10 (13.9%) and 10 (13.3%) in the IRE group and 2.9%, 7.3% and 19.7% in the RFA control group (all P > 0.05), respectively. For safety assessments, 51 patients experienced 191 AEs (65.4%) in the IRE group, which was not different from the RFA group (73.0%, 54/184) (P = 0.646). In 7 IRE patients, 8 TRAEs (7.9%) occurred, the most common being edema of the limbs (mild grade) and fever (severe grade), while no TRAEs occurred in the RFA group. This study proved that the excellent safety and efficacy of IRE was non-inferior to the regular radiofrequency device in ablation performance for the treatment of solid liver tumors. Clinical trial registration: Chinese Clinical Trial Registry: ChiCTR1800017516

Next-generation sequencing technology has enabled the identification of fusion partners of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer, and various ALK fusion partners have been confirmed. Here, a novel rhabdomyosarcoma 2-associated transcript (RMST)-ALK rearrangement was identified in an 80-year-old Chinese man with advanced lung adenocarcinoma. The patient was prescribed ceritinib and achieved a partial response, which has been sustained for more than 18 months. This is the first report of the RMST-ALK rearrangement, and we showed that a patient with lung adenocarcinoma carrying this rearrangement can benefit from ceritinib treatment; therefore, this is a significant finding in clinical practice.

Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers and our ability to target them specifically are not well understood. We demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple independent patient cohorts comprising both high- and low-grade gliomas. Knockdown of PDPN radiosensitized glioma cell lines and glioma-stem-like cells (GSCs). Clonogenic assays and xenograft experiments revealed that PDPN expression was associated with radiotherapy resistance and tumor aggressiveness. We further demonstrate that knockdown of PDPN in GSCs in vivo is sufficient to improve overall survival in an intracranial xenograft mouse model. PDPN therefore identifies a subset of aggressive, treatment-resistant glioma cells responsible for radiation resistance and may serve as a novel therapeutic target.

ObjectiveTo build a machine learning (ML) prediction model for prostate cancer (PCa) from transrectal ultrasound video clips of the whole prostate gland, diagnostic performance was compared with magnetic resonance imaging (MRI).MethodsWe systematically collated data from 501 patients—276 with prostate cancer and 225 with benign lesions. From a final selection of 231 patients (118 with prostate cancer and 113 with benign lesions), we randomly chose 170 for the purpose of training and validating a machine learning model, while using the remaining 61 to test a derived model. We extracted 851 features from ultrasound video clips. After dimensionality reduction with the least absolute shrinkage and selection operator (LASSO) regression, 14 features were finally selected and the support vector machine (SVM) and random forest (RF) algorithms were used to establish radiomics models based on those features. In addition, we creatively proposed a machine learning models aided diagnosis algorithm (MLAD) composed of SVM, RF, and radiologists’ diagnosis based on MRI to evaluate the performance of ML models in computer-aided diagnosis (CAD). We evaluated the area under the curve (AUC) as well as the sensitivity, specificity, and precision of the ML models and radiologists’ diagnosis based on MRI by employing receiver operator characteristic curve (ROC) analysis.ResultsThe AUC, sensitivity, specificity, and precision of the SVM in the diagnosis of PCa in the validation set and the test set were 0.78, 63%, 80%; 0.75, 65%, and 67%, respectively. Additionally, the SVM model was found to be superior to senior radiologists’ (SR, more than 10 years of experience) diagnosis based on MRI (AUC, 0.78 vs. 0.75 in the validation set and 0.75 vs. 0.72 in the test set), and the difference was statistically significant (p< 0.05).ConclusionThe prediction model constructed by the ML algorithm has good diagnostic efficiency for prostate cancer. The SVM model’s diagnostic efficiency is superior to that of MRI, as it has a more focused application value. Overall, these prediction models can aid radiologists in making better diagnoses.

BackgroundCombining two immune checkpoint inhibitors (ICIs) instead of using one can effectively improve the prognosis of advanced malignant tumors. At present, ipilimumab alongside nivolumab is the most widely used combinatorial regimen of ICIs. However, the risk of treatment-related adverse events is higher in combinatorial regimens than in single-drug regimens. Thus, this study aimed to evaluate the risks of common adverse events associated with the combinatorial regimen of ipilimumab and nivolumab by using meta-analysis.MethodsWe searched Pubmed, Medline, EMBASE, and Cochrane Library for reports published by 30 September 2021. A randomized controlled study was developed and analyzed using the statistical software R to determine the efficacy of the combinatorial treatment. Risk estimates (hazard ratios, RR) and 95% confidence intervals for various common serious adverse events were used.ResultsA total of 23 randomized control trials (n = 3970 patients) were included. Our meta-analysis indicated the risks of adverse events of any grade and grade ≥ 3 as 90.42% (95%CI: 85.91% ~ 94.18%) and 46.46% (95%CI: 39.37% ~ 53.69%), respectively; the risks of treatment-related death and adverse events leading to discontinuation were estimated at 0.42% (95% CI, 0.18% ~ 0.72%) and 19.11% (95% CI, 14.99% ~ 24.38%), respectively. Classification of 19 common adverse events. The top 5 grade 1-2 adverse events were found to be fatigue (30.92%, 95% CI: 24.59% ~ 37.62%), pruritus (26.05%, 95%CI: 22.29%~29.99%), diarrhea (23.58%, 95% CI: 20.62% ~ 26.96%), rash (19.90%, 95%CI: 15.75% ~ 25.15%), and nausea (17.19%, 95% CI:13.7% ~ 21.57%). The top 5 grade ≥ 3 adverse events were identified as increased alanine aminotransferase(8.12%, 95% CI: 5.90%~10.65%), increased lipase(7.62%, 95% CI: 4.88% ~ 10.89%), and colitis (6.39%, 95%CI: 3.98% ~ 10.25%), increased aspartate aminotransferase (6.30%, 95% CI: 4.61% ~ 8.22%), and diarrhea(5.72%, 95%CI: 3.50% ~ 8.44%). Subgroup analysis revealed some differences in the adverse events between the N1-I3 and N3-I1 subgroups and between subgroups of different cancer types.ConclusionThis study summarized the risks of common adverse events in the co-treatment of malignant-tumor patients with ipilimumab and nivolumab and identified the impacts of various initial administration schemes on the risks of such events, thereby providing an important reference for the toxicity of co-treatment with ipilimumab and nivolumab.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42020181350.

BackgroundThere is no consensus for the management of epithelioid trophoblastic tumor (ETT) up to date.ObjectiveETT is the rarest form of gestational trophoblastic neplasia (GTN). Our goal was to assess the outcomes and explore the prognostic factors of patients with ETT through this multicenter retrospective analysis and to devise a risk-adapted approach to clinical management.MethodsA total of 31 patients were validated as ETT pathologically between January 2004 and June 2021 from three tertiary hospitals. We retrospectively analyzed the characteristics, treatments, outcomes, and prognostic factors.ResultsEight patients experienced a recurrence, and 6 patients died of ETT, resulting in a mortality rate of 19.4%. Five patients with stage I disease had a fertility-preserving treatment. Among them, one patient had a full-term delivery, whereas a 23-year-old patient who declined a hysterectomy died of a recurrent disease. Eight patients of extrauterine ETT with isolated pulmonary lesion were at a young age at diagnosis (median: 30.5 vs. 41, p = 0.003) and had a smaller tumor size (median: 2.4 vs. 4.8 cm, p = 0.003) compared with other patients who had a metastatic disease, and none of them died. The multivariate analyses showed that the number of metastases ≥3 [hazard ratio (HR), 28.16, p = 0.003] was the only significant predictor associated with adverse overall survival, while the number of metastases ≥3 (HR 9.59, p = 0.005) and chemotherapy alone (HR 16.42, p = 0.001) were associated with adverse recurrence-free survival. Patients in stage I or with number of metastases

This study aimed to investigate whether magnetic resonance imaging (MRI) features could differentiate non-hypervascular pancreatic neuroendocrine tumors (PNETs) from pancreatic ductal adenocarcinomas (PDACs). In this study, 131 patients with surgically and pathologically proven non-hypervascular PNETs (n = 44) or PDACs (n = 87) were enrolled. Two radiologists independently analyzed MRI imaging findings and clinical features. Relevant features in differentiating non-hypervascular PNETs from PDACs were identified via univariate and multivariate logistic regression models. The MRI feature-based nomogram was constructed based on multivariable logistic analysis and the reliability of the constructed nomogram was further validated. The results showed that tumor margin (P = 0.012; OR: 6.622; 95% CI: 1.510, 29.028), MPD dilation (P = 0.047; OR: 4.309; 95% CI: 1.019, 18.227), and signal in the portal phase (P < 0.001; OR: 53.486; 95% CI: 10.690, 267.618) were independent discriminative MRI features between non-hypervascular PNETs and PDACs. The discriminative performance of the developed nomogram was optimized compared with single imaging features. The calibration curve, C-index, and DCA validated the superior practicality and usefulness of the MRI-based nomogram. In conclusion, the radiologically discriminative model integrating various MRI features could be preoperatively and easily utilized to differentiate non-hypervascular PNETs from PDACs.

Patients with non-small cell lung cancer harboring the epidermal growth factor receptor (EGFR)-sensitive mutations are known to benefit significantly from EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, icotinib, or afatinib. However, the efficacy of EGFR-TKIs against rare mutations has not yet been well investigated. Here, we report a female patient with advanced lung adenocarcinoma (LUAD), carrying a rare mutation of EGFR Exon19 E746_L747delinsIP, who was administered first-generation EGFR-TKIs as the first-line treatment. The patient continued to progress slowly until peritoneal metastases have occurred. Subsequently, the patient was treated with anlotinib for 5 months until disease progression. Given the finding of the same EGFR rare mutation in peritoneal effusion without other EGFR-TKI resistance mutations, the patient received afatinib with a tremendous response. Our results may be of clinical relevance for patients with LUAD carrying this rare mutation, and these findings warrant further investigation.

BackgroundBevacizumab is the representative drug in antiangiogenic therapy for lung cancer. However, it induced resistance in some neoplasm. Anlotinib, a novel multi-target tyrosine kinase inhibitor which has an inhibitory action on both angiogenesis and malignancy, is possible to reverse the resistance.MethodsTranswell migration and invasion experiments of bevacizumab with or without anlotinib were conducted to verify the activated/inhibited ability of lung adenocarcinoma cells. We sequenced A549 cells with enhanced migration and invasion abilities after bevacizumab treatment, screened out the differentially expressed gene and further confirmed by western blot and q-PCR assays. We also investigated immunohistochemical staining of tumor tissue in mice and human lung adenocarcinoma.ResultsBevacizumab facilitated migration and invasion of lung adenocarcinoma cells. Differentially expressed gene RGC32 was screened out. Bevacizumab upregulated the expression of RGC32, N-cadherin, and MMP2 through ERK-MAPK and PI3K-AKT pathways. Anlotinib downregulated their expression and reversed the effect of bevacizumab on A549 cells. In vivo experiments confirmed that higher-dose bevacizumab facilitated metastasis in tumor-bearing nude mice and upregulated the expression of RGC32, N-cadherin, and MMP2, whereas anlotinib abrogated its effect. Expression of both RGC32 and N-cadherin positively correlated with lymph node metastasis and stage in lung adenocarcinoma was found. Survival analysis revealed that higher expressions of RGC32 and N-cadherin were associated with poor progression-free survival and overall survival.ConclusionsBevacizumab may promote invasion and metastasis of lung adenocarcinoma cells by upregulating RGC32 through ERK-MAPK and PI3K-AKT pathways to promote epithelial–mesenchymal transition, whereas anlotinib reverses the effect. RGC32 and N-cadherin are independent prognostic factors in lung adenocarcinoma.

PurposeCommercial independent monitor unit (IMU) check systems for high-magnetic-field MR-guided radiation therapy (RT) systems are lacking. We investigated the feasibility of adopting an existing treatment planning system (TPS) as an IMU check for online adaptive radiotherapy using 1.5-Tesla MR-Linac.MethodsThe 7-MV flattening filter free (FFF) beam and multi-leaf collimator (MLC) models of a 1.5-T Elekta Unity MR-Linac within Monte Carlo-based Monaco TPS were used to generate an optimized beam model in Eclipse TPS. The MLC dosimetric leaf gap of the beam in Eclipse was determined by matching the dose distribution of Eclipse-generated intensity-modulated radiation therapy (IMRT) plans using the Analytical Anisotropic Algorithm (AAA) algorithm to Monaco plans. The plans were automatically adjusted for different source-to-axis distances (SADs) between the two systems. For IMU check, the treatment plans developed in Monaco were transferred to Eclipse to recalculate the dose using AAA. A plug-in within Eclipse was created to perform a 2D gamma analysis of the AAA and Monte Carlo dose distribution on a beam’s eye view parallel plane. Monaco dose distribution was shifted laterally by 2 mm during gamma analysis to account for the impact of magnetic field on electron trajectories. Eclipse doses for posterior beams were corrected for both the Unity couch and the posterior MR coil attenuation. Thirteen patients, each with 4–5 fractions for a variety of tumor sites (pancreas, rectum, and prostate), were tested.ResultsAfter thorough commissioning, the method was implemented as part of the standard clinical workflow. A total of 62 online plans, each with approximately 15 beams, were evaluated. The average per-beam gamma (3%/3 mm) pass rate for plans was 97.9% (range, 95.9% to 98.8%). The average pass rate per beam for all 932 beams used in these plans was 97.9% ± 1.9%, with the lowest per-beam gamma pass rate at 88.4%. The time for the process was within 3.2 ± 0.9 min.ConclusionThe use of a second planning system provides an efficient way to perform IMU checks with clinically acceptable accuracy for online adaptive plans on Unity MR-Linac. This is essential for meeting the safety requirements for second checks as outlined in American Association of Physicists in Medicine Task Group (AAPM TG) reports 114 and 219.

SRSF3, an important member of the serine/arginine-rich protein (SRp) family, is highly expressed in various tumors and plays an important role in tumor cell proliferation, migration and invasion. However, it is still unclear whether SRSF3 is involved in tumor angiogenesis. In this study, we first revealed that SRSF3 regulated the expression of numerous genes related to angiogenesis, including proangiogenic SRF. Then, we confirmed that SRSF3 was highly expressed in colorectal cancer (CRC) and was positively correlated with SRF. Mechanistic studies revealed that SRSF3 directly bound to the “CAUC” motif in exon 6 of SRF and induced the exclusion of introns. Knockdown of SRSF3 significantly reduced the secretion of VEGF from CRC cells. Conditioned medium from SRSF3-knockdown CRC cells significantly inhibited the migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). In addition, SRF silencing inhibited angiogenesis, while SRF overexpression reversed the antiangiogenic effects of SRSF3 knockdown on tube formation. These findings indicate that SRSF3 is involved in the splicing of SRF and thereby regulates the angiogenesis of CRC, which offers novel insight into antiangiogenic therapy in CRC.

PurposeTo evaluate the efficacy and safety of induction chemotherapy (IC) combined with concurrent chemoradiotherapy (CCRT) versus CCRT combined with adjuvant chemotherapy (AC) in patients with stage II–IVA nasopharyngeal carcinoma (NPC), we conducted a retrospective study and a meta-analysis combining the results of our studies.Patients and MethodsWe used the propensity score matching (PSM) to balance variables. A total of 168 patients were chosen by one-to-two PSM, including 101 patients with IC + CCRT and 67 cases with CCRT + AC. We used the Kaplan–Meier curve to compare survival outcomes and also used Cox regression analysis to determine independent prognostic factors. For meta-analysis, we determined the related studies by searching the PubMed database. We used STATA v12 software to perform meta-analysis of the extracted data and calculate pooled hazard ratios, 95% confidence intervals of survival outcomes, and risk ratios for the toxicities.ResultsIn this retrospective study, there was no significant difference in 5-year overall survival (76.9% vs. 79.0%, P = 0.966), progression-free survival (71.3% vs. 68.5%, P = 0.332), distant metastasis-free survival (80.5% vs. 74.2%, P = 0.140), and locoregional relapse-free survival (91.5% vs. 91.8%, P = 0.894) among patients with NPC with IC + CCRT versus CCRT + AC after PSM. For meta-analysis, six articles (including our study) reporting 1,052 cases of IC + CCRT and 883 cases of CCRT + AC were included in the meta-analysis. There was no difference of OS (pooled HR = 0.90, 95% CI: 0.63–1.29, P = 0.561), PFS (pooled HR = 1.07, 95% CI: 0.87–1.33, P = 0.633), DMFS (pooled HR= 0.98, 95% CI: 0.76-1.25, P=0.861), and LRRFS (pooled HR = 1.06, 95% CI: 0.76–1.48, P = 0.724).ConclusionThe efficacy of IC + CCRT and CCRT + AC was comparable in patients with stage II–IVA NPC. In terms of compliance and acute adverse reactions, IC + CCRT may be a potential therapeutic strategy.

Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy with increasing mortality and high recurrence. Ferroptosis is an emerging programed cell death and plays an essential role in tumorigenesis. Circular RNAs (circRNAs) have been reported as a type of critical regulators in OSCC development. In this study, we identified the function of circular RNA FNDC3B (circFNDC3B) in regulating ferroptosis during the malignant progression of OSCC. Our data demonstrated that the silencing of circFNDC3B by shRNA inhibited GPX4 and SLC7A11 expression and enhanced ROS, iron, and Fe2+ levels in OSCC cells. CircFNDC3B knockdown reinforced erastin-induced inhibitory effect on OSCC cells. The depletion of circFNDC3B repressed cell proliferation and enhanced cell apoptosis of OSCC cells. Mechanically, circFNDC3B was able to increase SLC7A11 by targeting miR-520d-5p. The overexpression of SLC7A11 reversed circFNDC3B depletion or miR-520d-5p-induced ferroptosis phenotypes of OSCC cells. Moreover, tumorgenicity assays in nude mice showed that the depletion of circFNDC3B repressed OSCC cell growth in vivo. Taken together, we concluded that circFNDC3B attenuated ferroptosis of OSCC cells and contributed to OSCC progression by regulating the miR-520d-5p/SLC7A11 axis. CircFNDC3B, miR-520d-5p, and SLC7A11 may serve as potential therapeutic targets of OSCC.

ObjectivesTo establish and validate an effective nomogram to predict clinical outcomes for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC).Materials and MethodsThe clinicopathological parameters and follow-up information of 402 locoregionally advanced NPC patients (training cohort, n = 302; validation cohort, n = 100) were retrospectively enrolled. The nomogram was built with the important prognostic variables identified by Cox regression analysis. Overall survival (OS) and progression-free survival (PFS) were the primary and secondary endpoints, respectively. The predictive power and clinical utility of the nomogram were assessed using the Harrell concordance index (C-index), calibration curve, and decision curve analysis. We compared the eighth staging system model with the nomogram to analyze whether the model could improve the accuracy of prognosisResultsEpstein–Barr virus (EBV) DNA load, the gross tumor volume (GTVnx), and cervical lymph node tumor volume (GTVnd) after induction chemotherapy were the independent predictors of OS and PFS. The calibration curves indicated superb agreement between the nomogram-predicted probabilities and observed actual probabilities of survival. The C-index and area under the receiver operator characteristic curve (AUC) of the nomogram integrating these significant factors and N stage, and TNM stage were higher than those of the eighth TNM system alone. In addition, the decision curve analyses demonstrated the clinical value and higher overall net benefit of the nomogram. High-risk groups identified by the nomogram had significantly poorer OS and PFS than the low-risk group (p < 0.05).ConclusionsThe multidimensional nomogram incorporating TNM stage, EBV DNA load, and tumor volume after induction chemotherapy led to a more precise prognostic prediction and could be helpful for stratifying risk and guiding treatment decisions in locoregionally advanced NPC patients who have undergone induction chemotherapy and concurrent chemoradiation.

BackgroundPancreatic cancer (PC) has a dismal prognosis due to its insidious early symptoms and poor early detection rate. Exosomes can be released by various cell types and tend to be a potential novel biomarker for PC detection. In this study, we explored the proteomic profiles of plasma exosomes collected from patients with PC at different stages and other pancreatic diseases.MethodsPlasma samples were collected from six groups of patients, including PC at stage I/II, PC at stage III/IV, well-differentiated pancreatic neuroendocrine tumor (P-NET), pancreatic cystic lesions (PCLs), chronic pancreatitis (CP), and healthy controls (HCs). Plasma-derived exosomes were isolated by ultracentrifugation and identified routinely. Isobaric tags for relative and absolute quantification (iTRAQ) based proteomic analysis along with bioinformatic analysis were performed to elucidate the biological functions of proteins. The expression of exosomal ALIX was further confirmed by enzyme-linked immunosorbent assay in a larger cohort of patients. Furthermore, receiver operating characteristic curve analysis was applied to evaluate the potential of ALIX as a novel diagnostic biomarker.ResultsThe proteomic profile revealed a total of 623 proteins expressed among the six groups, and 16 proteins with differential degrees of abundance were found in PC vs. other pancreatic diseases (including P-NET, PCLs, and CP). Based on the results of proteomic and bioinformatic analyses, exosomal ALIX was subsequently selected as a novel biomarker for PC detection and validated in another clinical cohort. We noticed that ALIX expression was elevated in PC patients compared with patients with other pancreatic diseases or HC, and it was also closely associated with TNM stage and distant metastasis. Interestingly, the combination of exosomal ALIX and serum CA199 has greater values in differentiating both early vs. late PC (AUC value 0.872) and PC vs. other pancreatic diseases (AUC value 0.910) than either ALIX or CA199 alone.ConclusionIn summary, our study demonstrated that based on proteomic profiling, proteins isolated from the plasma-derived exosomes may function as ideal non-invasive biomarkers for the clinical diagnosis of PC. Importantly, exosomal ALIX combined with CA199 has great potentials in detection of PC, especially in distinguishing PC patients at early stages from advanced stages.

IntroductionEmerging evidence has suggested that inherited factors are also involved in lung cancer development. However, most studies focused on well-elucidated cancer predisposition genes, the majority of which are tumor suppressor genes. The profile of germline mutations in oncogenic driver genes remains unrevealed, which might also provide potential clinical implications for lung cancer management.MethodsSequencing data from 36,813 unselected lung cancer patients who underwent somatic mutation profiling were retrospectively reviewed. All recruited patients had matched white blood cell samples sequenced in parallel using a capture-based panel including eight key lung cancer driver genes (epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), MET proto-oncogene, receptor tyrosine kinase (MET), Kirsten rat sarcoma viral oncogene homolog (KRAS), Erb-B2 receptor tyrosine kinase 2(ERBB2), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), ret proto-oncogene (RET), and B-Raf proto-oncogene, serine/threonine kinase (BRAF)). Likely pathogenic/pathogenic (LP/P) variants were called according to the classification criteria of the American College of Medical Genetics and Genomics. Variants of uncertain significance (VUS) located in the kinase domains of driver genes and occurring recurrently (n ≥3) were also included for further analyses.ResultsSeven different LP/P variants in EGFR, MET, or RET were identified in 0.03% of lung cancer patients (n = 14) and 25 different VUS in the kinase domains of seven driver genes (except KRAS) were found with a prevalence of 0.3% (n = 117).Collectively, germline mutations were most frequently seen in ROS1 (n = 31, 0.084%), followed by MET (n = 23, 0.062%), EGFR (n = 22, 0.06%), ALK (n = 22, 0.06%) and RET (n = 17, 0.046%). LP/P variants and VUS fell the most commonly in EGFR (n = 10, 72%) and ROS1 (n = 31, 26%), respectively. Of the 10 patients with EGFR LP/P germline mutation, 70% also acquired somatic EGFR driver mutation exon21 p.L858R or exon19 deletion at baseline; while the three patients with pathogenic germline RET mutation displayed distinct baseline somatic profiles of rare EGFR mutation or KRAS exon2 p.G12C. We discovered 11 germline mutations that also occurred somatically, including four LP/P variants and seven VUS.ConclusionWe present the first study to systemically characterize the germline mutation in oncogenic driver genes in a large cohort of unselected patients with lung cancers.

Recent evidences indicated that miRNAs played core role in the progression of clear cell renal cell carcinoma (ccRCC). However, its molecular mechanism in ccRCC is still remained unclear. The study was designed to identify the role and regulatory mechanism of miR-582-5p in ccRCC. In this study, the low expression level of miR-582-5p were detected by qRT-PCR in ccRCC patient tumor samples and ccRCC cell lines, respectively. The expression level of miR-582-5p was associated with tumor stage and metastasis. In vivo and in vitro experiments found miR-582-5p inhibit tumor growth via suppressing COL5A1 expression. Additionally, RUNX1 was identified as the negative regulator of miR-582-5p through database prediction and chromatin immunoprecipitation. Finally, the negative relation of RUNX1 and miR-582-5p was verified through rescue experiment both in vitro and in vivo. In summary, miR-582-5p, which was regulated by RUNX1, inhibited tumor growth and invasion by targeting COL5A1, indicating that miR-582-5p may act as a biomarker and that the RUNX1/miR-582-5p/COL5A1 axis could be a potential therapeutic target for ccRCC.

Curcumin [(1E,6E) ‑1,7‑bis(4‑hydroxy‑3‑methoxyphenyl) hepta‑1,6‑diene‑3,5‑ dione] is a natural polyphenol derived from the rhizome of the turmeric plant Curcuma longa. Accumulated evidences have presented curcumin’s function in terms of anti-inflammatory, antioxidant properties, and especially anti-tumor activities. Studies demonstrated that curcumin could exert anti-tumor activity via multiple biological signaling pathways, such as PI3K/Akt, JAK/STAT, MAPK, Wnt/β-catenin, p53, NF-ĸB and apoptosis related signaling pathways. Moreover, Curcumin can inhibit tumor proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), invasion and metastasis by regulating tumor related non-coding RNA (ncRNA) expression. In this review, we summarized the roles of curcumin in regulating signaling pathways and ncRNAs in different kinds of cancers. We also discussed the regulatory effect of curcumin through inhibiting carcinogenic miRNA and up regulating tumor suppressive miRNA. Furthermore, we aim to illustrate the cross regulatory relationship between ncRNA and signaling pathways, further to get a better understanding of the anti-tumor mechanism of curcumin, thus lay a theoretical foundation for the clinical application of curcumin in the future.

Background: To investigate the impact of alpha-2-macroglobulin (A2M), a suspected intrinsic radioprotectant, on radiation pneumonitis and esophagitis using multifactorial predictive models.Materials and Methods: Baseline A2M levels were obtained for 258 patients prior to thoracic radiotherapy (RT). Dose-volume characteristics were extracted from treatment plans. Spearman's correlation (Rs) test was used to correlate clinical and dosimetric variables with toxicities. Toxicity prediction models were built using least absolute shrinkage and selection operator (LASSO) logistic regression on 1,000 bootstrapped datasets.Results: Grade ≥2 esophagitis and pneumonitis developed in 61 (23.6%) and 36 (14.0%) patients, respectively. The median A2M level was 191 mg/dL (range: 94–511). Never/former/current smoker status was 47 (18.2%)/179 (69.4%)/32 (12.4%). We found a significant negative univariate correlation between baseline A2M levels and esophagitis (Rs = −0.18/p = 0.003) and between A2M and smoking status (Rs = 0.13/p = 0.04). Further significant parameters for grade ≥2 esophagitis included age (Rs = −0.32/p < 0.0001), chemotherapy use (Rs = 0.56/p < 0.0001), dose per fraction (Rs = −0.57/p < 0.0001), total dose (Rs = 0.35/p < 0.0001), and several other dosimetric variables with Rs > 0.5 (p < 0.0001). The only significant non-dosimetric parameter for grade ≥2 pneumonitis was sex (Rs = −0.32/p = 0.037) with higher risk for women. For pneumonitis D15 (lung) (Rs = 0.19/p = 0.006) and D45 (heart) (Rs = 0.16/p = 0.016) had the highest correlation. LASSO models applied on the validation data were statistically significant and resulted in areas under the receiver operating characteristic curve of 0.84 (esophagitis) and 0.78 (pneumonitis). Multivariate predictive models did not require A2M to reach maximum predictive power.Conclusion: This is the first study showing a likely association of higher baseline A2M values with lower risk of radiation esophagitis and with smoking status. However, the baseline A2M level was not a significant risk factor for radiation pneumonitis.

Background: Testicular germ cell tumors (TGCTs) are commonly diagnosed tumors in young men. However, a satisfactory approach to predict relapse of stage I TGCTs is still lacking. Therefore, this study aimed to develop a robust risk score model for stage I TGCTs.Method: RNA-sequence data of stage I TGCTs and normal testis samples were downloaded and analyzed to identify different expression genes. Gene-based prognostic model was constructed in The Cancer Genome Atlas (TCGA) using least absolute shrinkage and selection operator (LASSO) regression analysis and validated in GSE99420 dataset. Potential biological functions of the genes in prognostic model were determined via Gene Set Enrichment Analysis (GSEA) between high-risk and low-risk patients.Results: A total of 9,391 differentially expressed genes and 84 prognosis-related genes were identified. An eight-gene-based risk score model was constructed to divide patients into high or low risk of relapse. The low-risk patients had a significantly better relapse-free survival (RFS) than high-risk patients in both training and validation cohorts (HR = 0.129, 95% CI = 0.059–0.284, P < 0.001; HR = 0.277, 95% CI = 0.116–0.661, P = 0.004, respectively). The area under the receiver operating characteristic curve (AUC) values at 5 years was 0.805 and 0.724 in the training and validation cohorts, respectively. Functional enrichment analyses showed that DNA replication, ribosome, cell cycle, and TGF-beta signaling pathway may contribute to the relapse process.Conclusion: In summary, our analysis provided a novel eight-gene signature that could predict RFS in stage I TGCT patients.

Background: Osteosarcoma (OS) is the most common primary bone tumor. The disease has a poor prognosis due to the delay in the diagnosis and the development of metastasis. N6-Methyladenosine (m6A)-related regulators play an essential role in various tumors. In this study, a comprehensive analysis was conducted to elucidate the relationship between the expression profiles of m6A-related molecules and the clinical outcome of OS patients.Materials and Methods: Public genome datasets and a tissue microarray (TMA) cohort were used to analyze the mRNA and protein expression levels of m6A regulators. Next, immunofluorescence (IF) analysis was used to determine the subcellular localization of m6A-related molecules. Kaplan–Meier and Cox regression analyses were performed to confirm the prognostic value of m6A-related molecules in OS. A comprehensive bioinformatic analysis was conducted to identify the potential molecular mechanisms mediated by m6A modification in OS.Results: We found that m6A-related regulator expression was dysregulated in OS tissues, especially in metastatic tumor tissues. Low expression of METTL3, METTL14, and YTHDF2 and high expression of KIAA1429 and HNRNPA2B1 were significantly associated with poor prognosis in the TMA cohort. Simultaneously, the genome meta-cohort analysis revealed that low expression of FTO and METTL14 and high expression of METTL3, HNRNPA2B1, and YTHDF3 were associated with poor prognosis in OS. Cox regression analysis showed that HNRNPA2B1 might be an independent risk factor for OS. Bioinformatic analysis indicated that m6A regulators might be involved in OS progression through humoral immune response and cell cycle pathways.Conclusion: M6A-related regulators are frequently dysregulated and correlate with metastasis and prognosis in OS. M6A-related regulators may serve as novel therapeutic targets and prognostic biomarkers for OS.

Study Objective: To compare the surgical and oncologic outcomes between open abdomen radical hysterectomy (ARH) and laparoscopic radical hysterectomy (LRH) for cervical cancer.Methods: Retrospective observational study with propensity score matching was used to ensure balanced groups for ARH and LRH. One-hundred-and-ninety-eight women with cervical cancer, 99 treated using ARH and 99 using LRH, between January 2012 and December 2014. Outcomes included disease-free survival (DFS), overall survival (OS), intra-operative factors, post-operator recovery, urinary retention, and adverse events. Moreover, the inverse probability of the treatment weighting (IPTW) method was also used.Main Results: Compared with ARH, LRH was associated with a lower volume of blood loss (P < 0.001) and transfusion rate (P < 0.001), with a broader resection of the parametrium (P < 0.001). Post-operatively, the time to first flatus was shorter for LRH than ARH (P < 0.001) but the rate of urinary retention was higher for LRH (22.2%) than ARH (8.1%; P = 0.009). DFS and OS were similar between groups. By IPTW, laparoscopy was also not associated with poorer survival in terms of DFS (HR 1.52, CI 0.799–2.891, P = 0.202) or OS (HR 0.942, HR 0.425–2.09, P = 0.883).Conclusion: Compared with ARH, LRH provided better intra-operative and post-operative outcomes, with no significant difference in oncologic outcomes and survival. Urinary retention remains a clinical issue to improve with LRH. The technology of LRH has been improved in China to address the inconsistent results of oncologic outcomes in previous studies. Whether these improvements could be effective needs to be investigated in the future.

Background: Treatment effectiveness and overall prognosis for glioma patients depend heavily on the genetic and epigenetic factors in each individual tumor. However, intra-tumoral genetic heterogeneity is known to exist and needs to be managed. Currently, evidence for genetic changes varying spatially within the tumor is qualitative, and quantitative data is lacking. We hypothesized that a greater genetic diversity or “genetic distance” would be observed for distinct tumor samples taken with larger physical distances between them.Methods: Stereotactic biopsies were obtained from untreated primary glioma patients as part of a clinical trial between 2011 and 2016, with at least one biopsy pair collected in each case. The physical (Euclidean) distance between biopsy sites was determined using coordinates from imaging studies. The tissue samples underwent whole exome DNA sequencing and epigenetic methylation profiling and genomic distances were defined in three separate ways derived from differences in number of genes, copy number variations (CNV), and methylation profiles.Results: Of the 31 patients recruited to the trial, 23 were included in DNA methylation analysis, for a total of 71 tissue samples (14 female, 9 male patients, age range 21–80). Samples from an 8 patient subset of the 23 evaluated patients were further included in whole exome and copy number variation analysis. Physical and genomic distances were found to be independently and positively correlated for each of the three genomic distance measures. The correlation coefficients were 0.63, 0.65, and 0.35, respectively for (a) gene level mutations, (b) copy number variation, and (c) methylation status. We also derived quantitative linear relationships between physical and genomic distances.Conclusion: Primary brain tumors are genetically heterogeneous, and the physical distance within a given glioma correlates to genomic distance using multiple orthogonal genomic assessments. These data should be helpful in the clinical diagnostic and therapeutic management of glioma, for example by: managing sampling error, and estimating genetic heterogeneity using simple imaging inputs.

Objective: To profile the serum metabolites and metabolic pathways in colorectal cancer (CRC) patients associated with spleen-deficiency and qistagnation syndrome (SDQSS) or damp-heat syndrome (DHS). Methods: From May 2020 to January 2021, CRC patients diagnosed with traditional Chinese medicine (TCM) syndromes of SDQSS or DHS were enrolled. The clinicopathological data of the SDQSS and DHS groups were compared. The serum samples were analyzed by liquid chromatography-mass spectrometry (LC-MS). The variable importance in the projection >1, fold change ≥3 or ≤0.333, and P value ≤0.05 were used to identify differential metabolites between the two groups. Furthermore, areas under the receiver operating characteristic (ROC) curve > 0.9 were applied to select biomarkers with good predictive performance. The enrichment metabolic pathways were searched through the database of Kyoto Encyclopedia of Genes and Genomes. Results: 60 CRC patients were included (30 SDQSS and 30 DHS). The level of alanine aminotransferase was marginally significantly higher in the DHS group than the SDQSS group (P = 0.051). The other baseline clinicopathological characteristics were all comparable between the two groups. 23 differential serum metabolites were identified, among which 16 were significantly upregulated and 7 were significantly down-regulated in the SDQSS group compared with the DHS group. ROC curve analysis showed that (S)-3-methyl-2-oxopentanoic acid, neocembrene, 1-aminocyclopropanecarboxylic acid, 3- methyl-3-hydroxypentanedioate, and nicotine were symbolic differential metabolites with higher predictive power. The top five enrichment signalling pathways were valine, leucine and isoleucine biosynthesis; lysosome; nicotine addiction; fructose and mannose metabolism; and pertussis. Conclusion: Our study identifies the differential metabolites and characteristic metabolic pathways among CRC patients with SDQSS or DHS, offering the possibility of accurate and objective syndrome differentiation and TCM treatment for CRC patients. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety and efficacy of interventional therapy (iodine-125[125I] seed strand and portal vein stent [PVS] implantation plus transarterial chemoembolization [TACE]) combined with systemic therapy (lenvatinib plus anti-PD-1 antibody) as first-line treatment for hepatocellular carcinoma (HCC) patients with Vp4 portal vein tumor thrombus (PVTT). Patients and methods: From December 2018 to October 2021, 87 HCC patients with Vp4 PVTT were included in this single-center retrospective study. Forty-seven patients underwent interventional therapy combined with lenvatinib and anti-PD-1 antibody (group A), while 40 cases underwent interventional therapy combined with lenvatinib only (group B). Overall response rate (ORR), stent occlusion rates (SOR), median overall survival (OS), median progression-free survival (PFS) and median stent patency time (SPT) were compared between the 2 groups. Results: The mean intended dose (r = 10 mm; z = 0; 240 days) was 64.9 ± 1.0 Gy and 64.5 ± 1.1 Gy in group A and B, respectively (p = 0.133). ORR and SOR were significantly different between group A and B (ORR, 55.3% vs 17.5%, p < 0.001; SOR, 12.8% vs 35.0%, p = 0.014). In the propensity-score matching (PSM) cohort, the median OS, median PFS and median SPT were significantly longer in group A compared with group B (32 PSM pairs; OS, 17.7 ± 1.7 vs 12.0 ± 0.8 months, p = 0.010; PFS, 17.0 ± 4.3 vs 8.0 ± 0.7 months, p < 0.001; SPT, not-reached vs 12.5 ± 1.1 months, p = 0.028). Conclusion: This interventional therapy combined with lenvatinib and anti-PD-1 antibody is safe and effective for HCC patients with Vp4 PVTT. [ABSTRACT FROM AUTHOR]

Irreversible electroporation (IRE) is a soft tissue ablation technique that uses short electrical fields which induce the death of target cells. To evaluate the safety and efficacy of an IRE-based device compared to regular radiofrequency ablation (RFA) of solid liver tumors, in this multicenter, randomized, parallel-arm, non-inferiority study, 152 patients with malignant liver tumors were randomized into IRE (n = 78) and RFA (n = 74) groups. The primary endpoint was the success rate of tumor ablation; the secondary endpoints included the tumor ablation time, complications, tumor recurrence rates and treatment-related adverse events (TRAE). The success rate of tumor ablation using IRE was 94.9% and was noninferior to the RFA group (96.0%) (P = 0.761). For the secondary endpoints, the average ablation time was 34.29 ± 30.38 min for the IRE group, which was significantly longer than for the RFA group (19.91 ± 16.08 min) (P < 0.001). The incidences of postoperative complications after 1 week (P = 1.000), 1 month (P = 0.610) and 3 months (P = 0.490) were not significantly different between the 2 groups. The recurrence rates of liver tumor at 1, 3 and 6 months after ablationwere 0 (0.0%), 10 (13.9%) and 10 (13.3%) in the IRE group and 2.9%, 7.3% and 19.7% in the RFA control group (all P > 0.05), respectively. For safety assessments, 51 patients experienced 191 AEs (65.4%) in the IRE group, whichwas not different from the RFA group (73.0%, 54/184) (P = 0.646). In 7 IRE patients, 8 TRAEs (7.9%) occurred, the most common being edema of the limbs (mild grade) and fever (severe grade), while no TRAEs occurred in the RFA group. This study proved that the excellent safety and efficacy of IRE was non-inferior to the regular radiofrequency device in ablation performance for the treatment of solid liver tumors. [ABSTRACT FROM AUTHOR]

Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers and our ability to target them specifically are not well understood. We demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple independent patient cohorts comprising both high- and low-grade gliomas. Knockdown of PDPN radiosensitized glioma cell lines and glioma-stem-like cells (GSCs). Clonogenic assays and xenograft experiments revealed that PDPN expression was associated with radiotherapy resistance and tumor aggressiveness. We further demonstrate that knockdown of PDPN in GSCs in vivo is sufficient to improve overall survival in an intracranial xenograft mouse model. PDPN therefore identifies a subset of aggressive, treatment-resistant glioma cells responsible for radiation resistance and may serve as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Next-generation sequencing technology has enabled the identification of fusion partners of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer, and various ALK fusion partners have been confirmed. Here, a novel rhabdomyosarcoma 2-associated transcript (RMST)-ALK rearrangement was identified in an 80-year-old Chinese man with advanced lung adenocarcinoma. The patient was prescribed ceritinib and achieved a partial response, which has been sustained for more than 18 months. This is the first report of the RMST-ALK rearrangement, and we showed that a patient with lung adenocarcinoma carrying this rearrangement can benefit from ceritinib treatment; therefore, this is a significant finding in clinical practice. [ABSTRACT FROM AUTHOR]

BackgroundFerroptosis is a novel form of regulated cell death involved in tumor progression. The role of ferroptosis-related lncRNAs in hepatocellular carcinoma (HCC) remains unclear.MethodsRNA-seq and clinical data for HCC patients were downloaded from The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC) portal. Bioinformatics methods, including weighted gene coexpression network analysis (WGCNA), Cox regression, and least absolute shrinkage and selection operator (LASSO) analysis, were used to identify signature markers for diagnosis/prognosis. The tumor microenvironment, immune infiltration and functional enrichment were compared between the low-risk and high-risk groups. Subsequently, small molecule drugs targeting ferroptosis-related signature components were predicted via the L1000FWD and PubChem databases.ResultsThe prognostic model consisted of 2 ferroptosis-related mRNAs (SLC1A5 and SLC7A11) and 8 ferroptosis-related lncRNAs (AC245297.3, MYLK-AS1, NRAV, SREBF2-AS1, AL031985.3, ZFPM2-AS1, AC015908.3, MSC-AS1). The areas under the curves (AUCs) were 0.830 and 0.806 in the training and test groups, respectively. Decision curve analysis (DCA) revealed that the ferroptosis-related signature performed better than all pathological characteristics. Multivariate Cox regression analysis showed that the risk score was an independent prognostic factor. The survival probability of low- and high-risk patients could be clearly distinguished by the principal component analysis (PCA) plot. The risk score divided HCC patients into two distinct groups in terms of immune status, especially checkpoint gene expression, which was further supported by the Gene Ontology (GO) biological process, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, several small molecule drugs (SIB-1893, geldanamycin and PD-184352, etc) targeting ferroptosis-related signature components were identified for future reference.ConclusionWe constructed a new ferroptosis-related mRNA/lncRNA signature for HCC patients. The model can be used for prognostic prediction and immune evaluation, providing a reference for immunotherapies and targeted therapies.