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PurposeUnderstanding the complex bidirectional interactions between neurons and glioma cells could help to identify new therapeutic targets. Herein, the techniques and application of novel neuroscience tools implemented to study the complex interactions between brain and malignant gliomas, their results, and the potential therapeutic opportunities were reviewed.MethodsLiterature search was performed on PubMed between 2001 and 2023 using the keywords "glioma", "glioblastoma", "circuit remodeling", "plasticity", "neuron networks" and "cortical networks". Studies including grade 2 to 4 gliomas, diffuse midline gliomas, and diffuse intrinsic pontine gliomas were considered.ResultsGlioma cells are connected through tumour microtubes and form a highly connected network within which pacemaker cells drive tumorigenesis. Unconnected cells have increased invasion capabilities. Glioma cells are also synaptically integrated within neural circuitry. Neurons promote tumour growth via paracrine and direct electrochemical mechanisms, including glutamatergic AMPA-receptors. Increased glutamate release in the tumor microenvironment and loss of peritumoral GABAergic inhibitory interneurons result in network hyperexcitability and secondary epilepsy. Functional imaging, local field potentials and subcortical mapping, performed in awake patients, have defined patterns of malignant circuit remodeling. Glioma-induced remodeling is frequent in language and even motor cortical networks, depending on tumour biological parameters, and influences functional outcomes.ConclusionThese data offer new insights into glioma tumorigenesis. Future work will be needed to understand how tumor intrinsic molecular drivers influence neuron-glioma interactions but also to integrate these results to design new therapeutic options for patients.

BACKGROUND: Loss of AZGP1 expression is a biomarker associated with progression to castration resistance, development of metastasis, and poor disease-specific survival in prostate cancer. However, high expression of AZGP1 cells in prostate cancer has been reported to increase proliferation and invasion. The exact role of AZGP1 in prostate cancer progression remains elusive. METHOD: AZGP1 knockout and overexpressing prostate cancer cells were generated using a lentiviral system. The effects of AZGP1 under- or over-expression in prostate cancer cells were evaluated by in vitro cell proliferation, migration, and invasion assays. Heterozygous AZGP1± mice were obtained from European Mouse Mutant Archive (EMMA), and prostate tissues from homozygous knockout male mice were collected at 2, 6 and 10 months for histological analysis. In vivo xenografts generated from AZGP1 under- or over-expressing prostate cancer cells were used to determine the role of AZGP1 in prostate cancer tumor growth, and subsequent proteomics analysis was conducted to elucidate the mechanisms of AZGP1 action in prostate cancer progression. AZGP1 expression and microvessel density were measured in human prostate cancer samples on a tissue microarray of 215 independent patient samples. RESULT: Neither the knockout nor overexpression of AZGP1 exhibited significant effects on prostate cancer cell proliferation, clonal growth, migration, or invasion in vitro. The prostates of AZGP1-/- mice initially appeared to have grossly normal morphology; however, we observed fibrosis in the periglandular stroma and higher blood vessel density in the mouse prostate by 6 months. In PC3 and DU145 mouse xenografts, over-expression of AZGP1 did not affect tumor growth. Instead, these tumors displayed decreased microvessel density compared to xenografts derived from PC3 and DU145 control cells, suggesting that AZGP1 functions to inhibit angiogenesis in prostate cancer. Proteomics profiling further indicated that, compared to control xenografts, AZGP1 overexpressing PC3 xenografts are enriched with angiogenesis pathway proteins, including YWHAZ, EPHA2, SERPINE1, and PDCD6, MMP9, GPX1, HSPB1, COL18A1, RNH1, and ANXA1. In vitro functional studies show that AZGP1 inhibits human umbilical vein endothelial cell proliferation, migration, tubular formation and branching. Additionally, tumor microarray analysis shows that AZGP1 expression is negatively correlated with blood vessel density in human prostate cancer tissues. CONCLUSION: AZGP1 is a negative regulator of angiogenesis, such that loss of AZGP1 promotes angiogenesis in prostate cancer. AZGP1 likely exerts heterotypical effects on cells in the tumor microenvironment, such as stromal and endothelial cells. This study sheds light on the anti-angiogenic characteristics of AZGP1 in the prostate and provides a rationale to target AZGP1 to inhibit prostate cancer progression.

Objective Methods Results Conclusions One‐third of head and neck squamous cell carcinomas are early‐stage oral cavity squamous cell carcinomas (OCSCC). Despite a high curative rate, 20% of early‐stage OCSCC patients do not achieve long‐term survival. This study evaluates the role of adjuvant therapy (ADJ) in delaying disease progression and prolonging survival.This single‐institute retrospective cohort study enrolled 481 early‐stage OCSCC patients, 16% (78/481) of whom received ADJ. It was reported according to the STROBE guidelines. Cox proportional hazards regression and Kaplan–Meier survival curves were employed to identify suitable candidates for ADJ.The 5‐year locoregional recurrence‐free survival (LR‐RFS) and overall survival rates were 73.2% and 84.9%, respectively. Positive margins and advanced depth of invasion (DOI) were independent predictors of LR‐RFS. For patients with positive margins, adjuvant chemoradiotherapy (CRT) was superior to adjuvant radiotherapy alone in improving LR‐RFS (hazard ratios for adjuvant CRT vs. none, 0.042; adjuvant radiotherapy alone vs. none, 0.702). Excluding positive margins, advanced DOI was the most critical factor in assessing the need for ADJ. Positive margins and advanced DOI were more appropriate criteria than EORTC 22931/RTOG 9501 for evaluating adjuvant CRT.Adjuvant CRT was indicated for patients with positive margins and advanced DOI to improve survival outcomes. [ABSTRACT FROM AUTHOR]

Background: The Union for International Cancer Control and American Joint Committee on Cancer tumor staging system is used globally for treatment planning. As it may be insufficient for tumor staging of lower gingival carcinomas, we proposed the mandibular canal tumor staging system. In this study, we aimed to compare the two systems for such tumor staging and to identify prognostic markers. Methods: This multicenter, retrospective study included patients with lower gingival squamous cell carcinoma who underwent radical surgery during 2001–2018. We compared survival rates (Kaplan–Meier estimator) and patient stratification according to the two systems. Results: The proposed system yielded more balanced patient stratification than the existing system. Progression in the tumor grade according to the proposed system was associated with a poorer prognosis. The 5-year overall and disease-specific survival rates for the entire cohort were 74.9% and 81.8%, respectively. Independent factors affecting overall survival were tumor stage according to the proposed system, excision margins, and number of positive nodes, whereas those affecting disease-specific survival were excision margins and number of positive nodes. Conclusions: Subsite-specific tumor classification should be used for patients with oral cancer, and our results suggest that mandibular canal tumor classification may be effective for patients with lower gingival carcinoma. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of platelet-derived growth factor (PDGF) on the activity and invasion ability of choroidal melanoma (CM) cells. Methods CM cells were divided into groups A and B and were transfected with empty vector and PDGF knockdown lentivirus, respectively. RT-qPCR was used to measure the relative expression level of PDGF mRNA; XTT assay was used to measure cell activity; Transwell assay was used to test the invasion ability of cells in the two groups; Western blot was used to measure the relative expression levels of epithelial-mesenchymal transition (EMT) marker proteins and matrix metalloproteinases (MMPs). GEPIA database was used to investigate the association between PDGF and the prognosis of CM patients. Results Compared with group A, group B had significant reductions in the relative expression level of PDGF RNA (t=176.30,P

Objective To investigate the expression level of long non-coding RNA (lncRNA) AL365181.2 in cholangiocarcinoma (CHOL) and its effect on the functional characteristics of CHOL cells. Methods The Cancer Genome Atlas (TCGA) database was used to compare the expression level of lncRNA AL365181.2 between cancerous tissue and paracancerous tissue in CHOL patients, and the association between the expression level of lncRNA AL365181.2 and immune cell infiltration in CHOL tissue was analyzed. The Gene Set Enrichment Analysis (GSEA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed for lncRNA AL365181.2. EdU assay, wound healing assay, Transwell assay, and xenograft tumor formation experiment were used to investigate the impact of lncRNA AL365181.2 on the proliferation, migration, invasion, and tumorigenic abilities of CHOL cells. Results The analysis of TCGA data showed that the expression level of lncRNA AL365181.2 in CHOL tissue was significantly higher than that in paracancerous tissue (Z=4.00,P

Perineural invasion (PNI) is the phenomenon whereby cancer cells invade the space surrounding nerves. PNI occurs frequently in epithelial malignancies, but is especially characteristic of pancreatic ductal adenocarcinoma (PDAC). The presence of PNI portends an increased incidence of local recurrence, metastasis and poorer overall survival. While interactions between tumor cells and nerves have been investigated, the etiology and initiating cues for PNI development is not well understood. Here, we used digital spatial profiling to reveal changes in the transcriptome and to allow for a functional analysis of neural-supportive cell types present within the tumor-nerve microenvironment of PDAC during PNI. We found that hypertrophic tumor-associated nerves within PDAC express transcriptomic signals of nerve damage including programmed cell death, Schwann cell proliferation signaling pathways, as well as macrophage clearance of apoptotic cell debris by phagocytosis. Moreover, we identified that neural hypertrophic regions have increased local neuroglial cell proliferation which was tracked using EdU tumor labeling in KPC mice, as well as frequent TUNEL positivity, suggestive of a high turnover rate. Functional calcium imaging studies using human PDAC organotypic slices confirmed nerve bundles had neuronal activity, as well as contained NGFR+ cells with high sustained calcium levels, which are indicative of apoptosis. This study reveals a common gene expression pattern that characterizes solid tumor-induced damage to local nerves. These data provide new insights into the pathobiology of the tumor-nerve microenvironment during PDAC as well as other gastrointestinal cancers.

Objective To investigate the effect of STX5 on the metastasis of hepatocellular carcinoma (HCC) and its mechanism. Methods Clinical data were collected from 36 patients who were diagnosed with HCC in our hospital from January to December 2015, and the correlation between the expression level of STX5 in tumor tissue and the clinicopathological features of HCC patients was analyzed. Human hepatoma cells MHCC97H were divided into groups A and B and were transfected with negative control plasmid and STX5 overexpression plasmid, respectively. Human hepatoma cells Huh7 were divided into groups C and D and were transfected with negative control lentivirus and STX5 knockdown virus, respectively. Western blot was used to measure the protein expression level of STX5 in groups A, B, C, and D, wound healing was used to measure the migration ability of cells in groups A, B, C, and D, and Transwell assay was used to measure the migration ability of cells in groups A, B, C, and D. Gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis were performed for the differentially expressed genes in groups A and B obtained by transcriptomic sequencing, and RT-qPCR was used to measure the levels of the most significantly differentially expressed genes in group A and B. MHCC97H cells were divided into groups E, F, G, and H and were transfected with negative control plasmid, STX5 overexpression plasmid, negative control plasmid+Sarilumab, and STX5 overexpression plasmid+Sarilumab, respectively. Scratch assay was used to measure the migration ability of cells in groups E, F, G, and H, and Transwell assay was used to measure the migration ability of cells in groups E, F, G, and H. Results The expression level of STX5 in tumor tissue was associated body mass index, presence or absence of hepatitis B virus infection, and the number of tumors (P

Objective To investigate the effect of different concentrations of bufotalin (BT) on the proliferation, migration, invasion, and epithelial-mesenchymal transition of human colorectal cancer HCT116 cells. Methods CCK-8 assay was used to measure cell viability after 24 and 48 h of BT treatment at different concentrations (0, 10, 20, 40, 80, 160, and 320 nmol/L), and the half-maximal inhibitory concentration (IC50) was calculated. The plate colony formation assay was used to verify the effect of BT treatment at the concentrations of 0, 12.5, and 25.0 nmol/L for 14 days on the colony formation ability of HCT116 cells (established as groups A, B, and C). The wound healing assay and the Transwell assay were used to verify the effect of BT treatment at the concentrations of 0, 25, and 50 nmol/L for 24 h on the migration and invasion abilities of HCT116 cells (established as groups A, C, and D). Western blot was used to measure the protein expression levels of E-cadherin and N-cadherin in HCT116 cells after 24 h of treatment in groups A, C and D. Results CCK-8 assay showed that after HCT116 cells were treated by BT for 24 or 48 h, the inhibitory effect of BT on the proliferation of HCT116 cells increased significantly with the increase in the concentration of BT (F=2 106.00,3 725.00,P

To explore and compare the performance of LI-RADS® and radiomics from multiparametric MRI in predicting microvascular invasion (MVI) preoperatively in patients with solitary hepatocellular carcinoma (HCC) < 5 cm. We enrolled 143 patients with pathologically proven HCC and randomly stratified them into training (n = 100) and internal validation (n = 43) cohorts. Besides, 53 patients were enrolled to constitute an independent test cohort. Clinical factors and imaging features, including LI-RADS and three other features (non-smooth margin, incomplete capsule, and two-trait predictor of venous invasion), were reviewed and analyzed. Radiomic features from four MRI sequences were extracted. The independent clinic-imaging (clinical) and radiomics model for MVI-prediction were constructed by logistic regression and AdaBoost respectively. And the clinic-radiomics combined model was further constructed by logistic regression. We assessed the model discrimination, calibration, and clinical usefulness by using the area under the receiver operating characteristic curve (AUC), calibration curve, and decision-curve analysis respectively. Incomplete tumor capsule, corona enhancement, and radiomic features were related to MVI in solitary HCC ＜ 5 cm. The clinical model achieved AUC of 0.694/0.661 (training/internal validation). The single-sequence-based radiomic model's AUCs were 0.753–0.843/0.698–0.767 (training/internal validation). The combination model exhibited superior diagnostic performance to the clinical model (AUC: 0.895/0.848 [training/ internal validation]) and yielded an AUC of 0.858 in an independent test cohort. Incomplete tumor capsule and corona enhancement on preoperative MRI were significantly related to MVI in solitary HCC ＜5 cm. Multiple-sequence radiomic features potentially improve MVI-prediction-model performance, which could potentially help determining HCC's appropriate therapy. [ABSTRACT FROM AUTHOR]

Objective To explore the effect of HIF-1α on the migration and invasion of gallbladder cancer cells and its related regulatory mechanism. Methods GBC-SD cells were constructed and transfected with lentivirus, and the experimental group (HIF-1α shRNA), negative control group (empty lentivirus transfection) and blank control group (untreated) were obtained respectively. The expression levels of E-Cadherin, and N-Cadherin proteins were detected by Western blotting assay, Cell scratch assay was ued to detect the migratory ability of GBC-SD cells, and Transwell invasion assay was uesd to detect the invasive ability of GBC-SD cells. Results Compared with the control group, the expression level of E-Cadherin protein in the experimental group was significantly increased (P < 0.001), while the expression level of N-Cadherin protein was significantly decreased (P < 0.001), and there was no remarkable difference in the expression level of E-Cadherin and N-Cadherin proteins between the control groups (P both>0.05). In the experimental group, the cell scratch healing degree was inferior to the control group (P < 0.001), and the number of penetrating molds was also inferior to the control group (P < 0.001), while there was no obvious otherness in the cell scratch healing degree and the number of penetrating molds between the control groups (P > 0.05). Conclusion Targeted knockdown of HIF-1α can reduce the migration and invasion ability of gallbladder cancer cells, and its mechanism of action may be related to the regulation of epithelial mesenchymal transition. [ABSTRACT FROM AUTHOR]

Objective: This study aims to develop a CT-based method for quantifying tracheal shape and evaluating its ability to distinguish between cases with or without tracheal invasion in patients with thyroid carcinoma. Methods: A total of 116 quantitative shape features, including 56 geometric moments and 60 bounding shape features, were defined. The tracheal lumen was semi-automatically defined with a CT threshold of less than − 500 HU. Three contiguous slices with the 1st, 2nd, and 3rd smallest trachea lumen areas were contiguously selected, and the appropriate number of slices to be included was determined. Fifty-six patients with differentiated thyroid carcinoma (DTC) invading the trachea and 22 patients with DTC but without invasion were retrospectively included. A receiver operating characteristic (ROC) curve was applied to select the representative shape features and determine the optimal threshold. Results: 23.3%, 25.9%, and 24.1% of the features displayed an area under the ROC curve (AUC) ≥ 0.800 when derived from 1, 2, and 3 slices, respectively. Calculating feature values from two slices with the 1st and 2nd smallest tracheal lumen area were considered appropriate. Six final features, including 3 geometric moments and 3 bounding shape features, were selected to determine the tracheal invasion status of DTC and displayed AUCs of 0.875–0.918, accuracies of 0.821–0.891, sensitivities of 0.813–0.893, and specificities of 0.818–0.932, outperforming the visual evaluation results. Conclusions: Geometric moments and bounding shape features can quantify the tracheal shape and are reliable for identifying DTC tracheal invasion. The selected features quantified the extent of tracheal deformity in DTC patients with and without tracheal invasion. Clinical relevance statement: Six geometric features provide a non-invasive, semi-automated evaluation of the tracheal invasion status of thyroid cancer. Key Points: • A novel method for quantifying tracheal shape using 56 geometric moments and 60 bounding shape features was developed. • Six features identify tracheal invasion by thyroid carcinoma. • The selected features quantified the extent of tracheal deformity in differentiated thyroid carcinoma patients with and without tracheal invasion. [ABSTRACT FROM AUTHOR]

BackgroundThis study aims to construct and verify a nomogram model for microvascular invasion (MVI) based on hepatocellular carcinoma (HCC) tumor characteristics and differential protein expressions, and explore the clinical application value of the prediction model.MethodsThe clinicopathological data of 200 HCC patients were collected and randomly divided into training set and validation set according to the ratio of 7:3. The correlation between MVI occurrence and primary disease, age, gender, tumor size, tumor stage, and immunohistochemical characteristics of 13 proteins, including GPC3, CK19 and vimentin, were statistically analyzed. Univariate and multivariate analyzes identified risk factors and independent risk factors, respectively. A nomogram model that can be used to predict the presence of MVI was subsequently constructed. Then, receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were conducted to assess the performance of the model.ResultsMultivariate logistic regression analysis indicated that tumor size, GPC3, P53, RRM1, BRCA1, and ARG were independent risk factors for MVI. A nomogram was constructed based on the above six predictors. ROC curve, calibration, and DCA analysis demonstrated the good performance and the clinical application potential of the nomogram model.ConclusionsThe predictive model constructed based on the clinical characteristics of HCC tumors and differential protein expression patterns could be helpful to improve the accuracy of MVI diagnosis in HCC patients.

Objective To investigate the value of preoperative CT evaluation of extramural vascular invasion in evaluating the prognosis of gastric cancer patients. Methods The patients who underwent gastrectomy in our hospital from January 2016 to December 2018 were enrolled as subjects, and preoperative CT examination was performed to evaluate extramural vascular invasion. The patients were followed up after surgery to observe overall survival (OS) and disease-free survival (DFS); the K-M curve and the log-rank test were used to analyze the association of extramural vascular invasion with OS and DFS, and the COX regression model was used to investigate the influencing factors for OS and DFS. Results The patients with a tumor diameter of ≥5 cm and TNM stage Ⅲ gastric cancer had a significantly higher incidence rate of extramural vascular invasion on preoperative CT evaluation than those with a tumor diameter of

PurposeIdentification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non-muscle-invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied.Experimental designGermline analysis was conducted on paired tumor/normal sequencing results from two distinct cohorts of patients initially diagnosed with NMIBC. Associations between clinicopathologic features and clinical outcomes with the presence of P/LP germline variants in ≥76 hereditary cancer predisposition genes were analyzed.ResultsA similar frequency of P/LP germline variants were seen in our two NMIBC cohorts [12% (12/99) vs. 8.7% (10/115), P = 0.4]. In the combined analysis, P/LP germline variants were found only in patients with high-grade NMIBC (22/163), but none of the 46 patients with low-grade NMIBC (13.5% vs. 0%, P = 0.005). Fifteen (9.2%) patients with high-grade NMIBC had P/LP variants in DNA damage response genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in patients with NMIBC not receiving Bacillus Calmette-Guerin (BCG), P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG or with risk of developing upper tract urothelial carcinoma.ConclusionsOur results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of initial tumor stage. Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.

Objectives Materials and Methods Results Conclusions Ameloblastoma (AM), a locally aggressive tumor with extensive growth capacity, causes significant damage to the jaw and affects facial appearance. Although the high prevalence of BRAF V600E mutation in AM is known, its specific impacts on patients with AM remain unclear. Thus, the present study investigated the role of BRAF V600E mutation, thereby focusing on its impact on AM invasion and growth.Immunohistochemical analysis was used to compare BRAF V600E, MMP2, MMP9, and Ki‐67 expressions in AM (n = 49), normal oral mucosa (NOM) (n = 10), and odontogenic keratocyst (OKC) (n = 15) tissues. AM was further classified according to the presence or absence of BRAF V600E. The relationship between BRAF V600E and invasion as well as growth was evaluated. In addition, correlation analysis was performed using immunohistochemistry and confirmed via double‐labeling immunofluorescence. Finally, comparative analyses using mass spectrometry, immunohistochemistry, and immunofluorescence were performed to explore and identify underlying mechanisms.AM exhibited a higher incidence of BRAF V600E mutation than NOM and OKC. BRAF V600E expression was positively correlated with the invasion‐associated proteins MMP2 and MMP9 and the growth‐related protein Ki‐67. Proteomic data revealed that BRAF V600E primarily activates the MAPK signaling pathway in AM, particularly driving the phosphorylation of extracellular signal‐regulated kinase 1/2 (ERK1/2).In summary, the findings suggested that the BRAF V600E mutation enhances the invasion and growth abilities of AM via the MAPK/ERK signaling pathway. Thus, targeting BRAF V600E or the MAPK/ERK pathway may be a potential AM therapy. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the imaging features indicating portal vein invasion (PVI) of hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced MRI and to create more accurate diagnostic criteria than the presence of portal vein tumor thrombosis (PVTT) on MRI. Methods: This retrospective study included patients with surgically resected HCC larger than 5 cm, and the presence of PVI was investigated. On MRI, we evaluated the image findings of portal vein occlusion, the parenchymal signal change caused by hemodynamic alterations of the portal vein, and their combination showing the highest odds ratio (OR) to define the diagnostic criteria for radiological PVI detection (rPVI criteria). The diagnostic performance and recurrence-free survival were compared between the rPVI criteria and the presence of PVTT using McNemar's test and Kaplan–Meier method, respectively. Interobserver agreement was evaluated using Cohen's weighted ĸ statistics. Results: Of 189 enrolled patients, 25 (13.2%) had PVI on histology. To diagnose PVI on MRI, either peripheral wedge-shaped arterial peritumoral hyperemia with an abrupt cut-off of a portal vein or the presence of PVTT had the highest OR (41.67, p < 0.001). The sensitivity of PVI was significantly increased under this diagnostic criterion (64.0% to 88.0%; p = 0.031) with comparable accuracy (95.2% vs. 94.7%; p > 0.999). In terms of recurrence-free survival, the patient group with rPVI was significantly worse (p = 0.017) compared with the patients without rPVI. Interobserver agreement of radiologic findings was substantial (ĸ = 0.64). Conclusion: Diagnostic criteria for radiologically PVI detection increase the sensitivity more than the only presence of PVTT. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of long non-coding ribonucleic acid (LncRNA) repulsive guidance molecules B-antisense chain (RGMB-AS1) on the proliferation, migration and invasion of human prostate cancer cells (DU145), and explore its targeting effect on miR-574-3p. Methods Human prostate cancer cells (DU145) were cultured and used in the study. Cell tests were divided into 9 groups including RGMB-AS1 upregulation group (transfected with pcDNA3. 1-RGMB-AS1), RGMB-AS1 upregulation control group (transfected with pcDNA3. 1 control), RGMB-AS1 downregulation group (transfected with si-RGMB-ASl), RGMB-AS1 downregulation control group (transfected with si-NC), miR-574-3p upregulation group (transfected with miR-574-3p mimics), miR-574-3p upregulation control group (transfected with miR mimics NC ), miR-574-3p downregulation group (transfected with miR-574-3 p inhibitor), miR-574-3p downregulated control group (transfected with miR inhibitor NC) and blank group, and 3 wells in each group. After 48 hours culture, cell proliferation activity was detected by CCK-8 assay. Cell migration ability was evaluated by wound healing assay. Cell invasive ability was assessed by Matrigel invasion assay (Transwell chamber). The expression of LncRNA RGMB-AS1, the expression of miR-574-3p, and the gene expressions of Cyclin D1, P21, ZEB1, N-cadherin, E-cadherin, and Vimentin were detected by LncRNA-RT-qPCR, miRNA-RT-qPCR and RT-qPCR, respectively. The protein expressions of Cyclin Dl, P21, ZEB1, N-cadherin, E-cadherin, and VIM were measured by western blot. The dual luciferase gene reporter assay was used to determine whether LncRNA RGMB-AS1 targets miR-574-3p. Results Compared with those in the blank group, RGMB-AS1 up-regulated control group, RGMB-AS1 down-regulated control group, miR-574-3p up-regulated control group, and miR-574-3p down-regulated control group, the D value, scratch healing rates, invasive cell counts, Cyclin Dl, ZEB1, N-cadherin, and VIM expressions in the RGMB-AS1 up-regulated group and miR-574-3p up-regulated group were all decreased (P <0. 05), while the proliferation inhibition rates, P21, and E-cadherin expressions were all increased (P <0.05). Simultaneously, the D value, scratch healing rates, invasive cell counts, Cyclin Dl, ZEB1, N-cadherin, and VIM expressions in the RGMB-AS1 down-regulated group and miR-574-3p down-regulated group were all increased (P <0. 05), while the proliferation inhibition rates, P21, and E-cadherin expressions were all decreased (P<0.05). Compared with the miR-NC group, the miR-574-3p mimics group showed a decrease in Wt-RGMR-AS1 luciferase activity (P<0. 05), but little change in Mut RGMB-AS1-luciferase activity (P > 0. 05). Conclusion Upregulation of LncRNA RGMB-AS1 can target upregulation of miR-574-3p to inhibit the proliferation, migration, and invasion of human prostate cancer cells, which may be attributed to downregulation of Cyclin D1, ZEB1, N-cadherin, VIM expressions, and upregulation of P21 and E-cadherin expressions. [ABSTRACT FROM AUTHOR]

Abstract Pseudoinvasion is a phenomenon in which adenomatous tissue deviates into the submucosa with the mucosal lamina propria in colorectal epithelial tumors. A relatively large, stalked, neoplastic lesion of the sigmoid colon is considered at high risk of pseudoinvasion. A few reports have described endoscopic mucosal resection or polypectomy for colorectal tumors with pseudoinvasion, but the vertical margins were not sufficiently assessed. Because a positive margin can be a risk factor for recurrence, endoscopic treatment for pseudoinvasion should be carefully considered. We herein report a case in which even endoscopic submucosal dissection (ESD) was not adequate for curative resection of pseudoinvasion in early colorectal cancer. The endoscopic findings of a 25‐mm Type 0‐Is lesion in the sigmoid colon suggested a low possibility of carcinoma invasion into the deep submucosa. Although ESD was considered to be indicated in this case, laparoscopic sigmoid colon resection was eventually performed because we observed a broadly pulled muscle layer and an almost undetectable submucosal layer during ESD. The surgical specimen showed that the tumor glands of pseudoinvasion existed beyond the planned ESD dissection line, indicating that the vertical margin would have been positive if we had continued ESD. Whether pseudoinvasion was associated with the infeasibility of ESD remains unclear. This case indicates that diagnosing the presence and depth of pseudoinvasion by magnified endoscopy with narrow‐band imaging is challenging and that preoperative examinations, such as endoscopic ultrasound, may be needed for a tumor with a high risk of pseudoinvasion.

Surgical management of head and neck cancer requires a careful balance between complete resection of malignancy and preservation of function. Surgeons must also determine whether to resect important cranial nerves that harbor perineural invasion (PNI), as sacrificing nerves can result in significant morbidity including facial paralysis. Our group has previously reported that Dynamic Optical Contrast Imaging (DOCI), a novel non-invasive imaging system, can determine margins between malignant and healthy tissues. Herein, we use an in vivo murine model to demonstrate that DOCI can accurately identify cancer margins and perineural invasion, concordant with companion histology. Eight C3H/HeJ male mice were injected subcutaneously into the bilateral flanks with SCCVIISF, a murine head and neck cancer cell line. DOCI imaging was performed prior to resection to determine margins. Both tumor and margins were sent for histologic sectioning. After validating that DOCI can delineate HNSCC margins, we investigated whether DOCI can identify PNI. In six C3H/HeJ male mice, the left sciatic nerve was injected with PBS and the right with SCCVIISF. After DOCI imaging, the sciatic nerves were harvested for histologic analysis. All DOCI images were acquired intraoperatively and in real-time (10 s per channel), with an operatively relevant wide field of view. DOCI values distinguishing cancer from adjacent healthy tissue types were statistically significant (P

ObjectivesThis study sought to identify tumor characteristics that associate with regional lymph node metastases in squamous cell carcinomas originating in the upper gingiva.Materials and methodsData from 113 patients from Osaka University Dental Hospital were included. We measured each primary tumor's width, length, depth, and the extent of bone invasion. Additionally, tumor signal intensity for T1 and T2-weighted images as well as the center of the tumor's location and T classification was assessed, and a histopathological analysis was performed.ResultsTumor signal intensity was not found to be a significant prognostic factor. However, bucco-lingual width, histopathological classification as well as the tumor's location were significantly different between metastatic and non-metastatic groups in both univariate and multivariate analysis. Superior-inferior depth and T classification were significant only in the univariate (and not the multivariate) analysis.ConclusionsBucco-lingual width, histopathological grading as well as the tumor's location are likely to be important predictors for the occurrence of LN metastasis in upper gingival carcinoma patients and should be considered when managing care for these patients.

Objective To investigate the expression of COL6A1 in sarcoma tissue and its significance based on bioinformatics analysis. Methods The GEO database was used to download the GSE16088, GSE21122, and GSE49972 datasets to analyze the expression level of COL6A1-3. The Kaplan-Meier survival curves were used to analyze the impact of the expression level of COL6A1-3 on the prognosis of patients with sarcoma. A Spearman correlation analysis was performed using GSVA package to investigate the correlation between the expression level of COL6A1 and immune cell infiltration. The LinkedOmics database was used to analyze the genes co-expressed with COL6A1, and the ggstatsplot package of R software was used to investigate the correlation between COL6A1 and COL6A2. The ClusterProfiler package of R software was used to perform GO functional enrichment analysis and KEGG pathway analysis of the genes co-expressed with COL6A1. The GSEA analysis was used to investigate the important kinase, miRNA, and transcription factor targets of the genes co-expressed with COL6A1. Results Compared with normal tissue, there was a significant increase in the expression level of COL6A1 in osteosarcoma, soft tissue sarcoma, and clear cell sarcoma of the kidney. The survival analysis showed that the high expression of COL6A1 was associated with low overall survival rate and di-sease-specific survival rate (χ2=6.37,4.57,P

The success of anticancer therapies is often limited by heterogeneity within and between tumors. While much attention has been devoted to understanding the intrinsic molecular diversity of tumor cells, the surrounding tissue microenvironment is also highly complex and coevolves with tumor cells to drive clinical outcomes. Here, we propose that diverse types of solid tumors share common physical motifs that change in time and space, serving as universal regulators of malignancy. We use breast cancer and glioblastoma as instructive examples and highlight how invasion in both diseases is driven by the appropriation of structural guidance cues, contact-dependent heterotypic interactions with stromal cells, and elevated interstitial fluid pressure and flow. We discuss how engineering strategies show increasing value for measuring and modeling these physical propertiesfor mechanistic studies. Moreover, engineered systems offer great promise for developing and testing novel therapies that improve patient prognosis by normalizing the physical tumor microenvironment.

Lung adenocarcinoma with lepidic growth pattern (LPA) is characterized by tumor cell proliferation along intact alveolar walls, and further classified as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive lepidic predominant adenocarcinoma (iLPA). Accurate diagnosis of lepidic lesions is critical for appropriate prognostication and management as five-year survival in patients with iLPA is lower than in those with AIS and MIA. We aimed to evaluate the accuracy of CT-guided core needle lung biopsy classifying LPA lesions and identify clinical and radiologic predictors of invasive disease in biopsied lesions. Thirty-four cases of adenocarcinoma with non-invasive lepidic growth pattern on core biopsy pathology that subsequently were resected between 2011 and 2018 were identified. Invasive LPA vs. non-invasive LPA (AIS or MIA) was defined based on explant pathology. Histopathology of core biopsy and resected tumor specimens was compared for concordance, and clinical, radiologic and pathologic variables were analyzed to assess for correlation with invasive disease. The majority of explanted tumors (70.6%) revealed invasive disease. Asian race (p = 0.03), history of extrathoracic malignancy (p = 0.02) and absence of smoking history (p = 0.03) were associated with invasive disease. CT-measured tumor size was not associated with invasiveness (p = 0.15). CT appearance of density (p = 0.61), shape (p = 0.78), and margin (p = 0.24) did not demonstrate a significant difference between the two subgroups. Invasiveness of tumors with lepidic growth patterns can be underestimated on transthoracic core needle biopsies. Asian race, absence of smoking, and history of extrathoracic malignancy were associated with invasive disease.

Objectives: To evaluate the performance of a radiomics nomogram developed based on gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) MRI for preoperative prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC), and to identify patients who may benefit from the postoperative adjuvant transarterial chemoembolization (PA-TACE). Methods: A total of 260 eligible patients were retrospectively enrolled from three hospitals (140, 65, and 55 in training, standardized external, and non-standardized external validation cohort). Radiomics features and image characteristics were extracted from Gd-EOB-DTPA MRI image before hepatectomy for each lesion. In the training cohort, a radiomics nomogram which incorporated the radiomics signature and radiological predictors was developed. The performance of the radiomics nomogram was assessed with respect to discrimination calibration, and clinical usefulness with external validation. A score (m-score) was constructed to stratify the patients and explored whether it could accurately predict patient who benefit from PA-TACE. Results: A radiomics nomogram integrated with the radiomics signature, max-D(iameter) > 5.1 cm, peritumoral low intensity (PTLI), incomplete capsule, and irregular morphology had favorable discrimination in the training cohort (AUC = 0.982), the standardized external validation cohort (AUC = 0.969), and the non-standardized external validation cohort (AUC = 0.981). Decision curve analysis confirmed the clinical usefulness of the novel radiomics nomogram. The log-rank test revealed that PA-TACE significantly decreased the early recurrence in the high-risk group (p = 0.006) with no significant effect in the low-risk group (p = 0.270). Conclusions: The novel radiomics nomogram combining the radiomics signature and clinical radiological features achieved preoperative non-invasive MVI risk prediction and patient benefit assessment after PA-TACE, which may help clinicians implement more appropriate interventions. Clinical relevance statement: Our radiomics nomogram could represent a novel biomarker to identify patients who may benefit from the postoperative adjuvant transarterial chemoembolization, which may help clinicians to implement more appropriate interventions and perform individualized precision therapies. Key Points: • The novel radiomics nomogram developed based on Gd-EOB-DTPA MRI achieved preoperative non-invasive MVI risk prediction. • An m-score based on the radiomics nomogram could stratify HCC patients and further identify individuals who may benefit from the PA-TACE. • The radiomics nomogram could help clinicians to implement more appropriate interventions and perform individualized precision therapies. [ABSTRACT FROM AUTHOR]

Background/Aim. The depth of invasion of oral cavity carcinoma (OCC) and the nodal involvement define the treatment selection, outcome, and prognosis of the disease. In determining the stage of OCC, the most widely applied methods are computerized tomography (CT) and magnetic resonance imaging (MRI), whose limitations can be overcome to some extent by using intraoral ultrasound (IOUS). The aim of the study was to evaluate the imaging presentation of early-stage OCC, determine the depth of invasion (DOI) and the greatest diameter (GD) of the tumor using the IOUS and CT methods, and compare them with histopathological (HP) findings. Methods. The study was designed as a prospective one, with a time limitation of three months. Eleven patients with clinical early-stage OCC underwent a native CT examination of the head and neck as well as a contrast-enhanced phase, and then IOUS of the lesion was performed. Using both methods, DOI and GD values were measured, and the values were correlated with HP findings. The analysis of the obtained data was performed using the statistical package SPSS 22 and Pearson correlation coefficient. Results. A significant correlation (p = 0.001) was established between the DOI values measured by IOUS and CT examination with the measurements obtained by HP processing. On the other hand, by comparing the GD measured on IOUS and CT examination, no correlation was established with the HP report. Conclusion. Measurements of DOI obtained by IOUS significantly correlated with those in the HP report, while overcoming the limitations of the CT method in the evaluation of small-sized tumors and tumors that cannot be shown due to artifacts. [ABSTRACT FROM AUTHOR]

Objective: In the 2018 FIGO staging system, cervical cancers with ≥5 mm depth of invasion (DOI) and a diameter of >7 mm, first classified as stage IB, are classified as stage IA. In this group, it is unclear what the risk of lymph node metastasis (LNM) is. This retrospective cohort study aims to determine the incidence of LNM and to study the association between disease-related characteristics and LNM. Methods: Women diagnosed with FIGO 2009 IB cervical cancer, with ≤5 mm DOI and a diameter >7 mm, treated with a radical hysterectomy and pelvic lymphadenectomy between 1985 and 2020 were selected from the databases of the Amsterdam University Medical Center and the University Medical Center Groningen. The specimens of patients with LNM were revised by expert pathologists. The incidence of LNM was calculated. The associations between LNM and DOI, diameter, histological type, clinical visibility and lymphovascular space invasion (LVSI) were evaluated by calculating odds ratios using logistic regression. Results: Of the 389 patients included, 10 had pathologically confirmed LNM (2.6%, 95% confidence interval=1.3%-4.5%). In case of LVSI, univariate analysis showed an increased risk of LNM (p=0.003 and p=0.012, respectively). No difference in LNM was found between lesions diagnosed by microscopy and clinically visible lesions. No LNM were found in patients without LVSI and a DOI of ≤3 mm. Conclusion: For patients with stage IA cervical cancer with a diameter >7 mm, we recommend considering a pelvic lymph node assessment in case of DOI >3 mm and/or presence of LVSI. [ABSTRACT FROM AUTHOR]

Objective To investigate the mechanism of miR-338-5p regulating the proliferation, migration and invasion of bladder cancer cells by targeting TSHZ3. Methods The expression of miR-338-5p in 33 samples of bladder cancer tissue and paracancerous tissue was detected by qRT-PCR. Bladder cancer T24 and UM-UC-3 cells were transfected with mimics-NC, miR-338-5p mimics, inhibitor-NC and miR-338-5p inhibitor, and the transfection efficiency was detected by qRT-PCR. CCK-8 assay was used to detect the effect of overexpression or knockdown of miR-338-5p on the proliferation of bladder cancer cells. Transwell assay was used to detect the effect of miR-338-5p on migration and invasion of bladder cancer cells. The potential target genes of miR-338-5p were predicted by TargetScan, miRDB and Targetminer databases, and TSHZ3 was chosen for the target gene. The targeting relationship between miR-338-5p and TSHZ3 was verified by dual-luciferase reporter gene assay and Western blot assay. miR-338-5p mimics and TSHZ3 overexpression plasmids were co-transfected in bladder cancer cells, and the proliferation, migration and invasion of cells were detected by CCK-8 and Transwell assays. Western blot assay was used to detect the overexpression of miR-338-5p or TSHZ3 against Wnt/ β-catenin signaling pathway. Results miR-338-5p was significantly upregulated in bladder cancer (P＜0.05). Overexpression of miR-338-5p increased the proliferation, migration and invasion of bladder cancer cells (P＜ 0.05), while transfection of miR-338-5p inhibitor decreased the proliferation, migration and invasion of bladder cancer cells (P＜0.05). Bioinformatics analysis and the dual-luciferase reporter gene assay showed that there was a targeting relationship between miR-338-5p and TSHZ3. The rescue experiment showed that co-transfection of miR-338-5p mimics and TSHZ3 overexpression plasmid partially eliminated the promoting effect of overexpression of miR-338-5p on the proliferation, migration and invasion of bladder cancer cells (P＜0.05). Western blot results showed that overexpression of miR-338-5p significantly decreased the expression level of TSHZ3 protein and increased Wnt3a and β-catenin protein expression levels (P＜0.05). In addition, overexpression of TSHZ3 reduced Wnt3a and β -catenin protein expression levels (P＜0.05). Conclusion miR-338-5p is upregulated in bladder cancer, and promotes the proliferation, migration and invasion of bladder cancer by targeting TSHZ3 expression. The mechanism may be related to the activation of Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

ABSTRACT Schwannomas commonly develop in the cervical region, 25% – 45% of cases are diagnosed in this anatomical region. Tracheal neurogenic tumors are exceedingly rare and can be misdiagnosed as invasive thyroid carcinomas or other infiltrating malignancies when present at the level of the thyroid gland. Here, we present a case of synchronous benign cervical schwannoma with tracheal invasion and papillary thyroid carcinoma in a patient who was initially hospitalized for COVID-19. The patient presented with dyspnea that was later found to be caused by tracheal extension of a cervical tumor. Surgical excision was performed, and the surgical team proceeded with segmental tracheal resection, removal of the cervical mass, and total thyroidectomy. The specimen was sent for pathological analysis, which revealed synchronous findings of a benign cervical schwannoma with tracheal invasion and papillary thyroid carcinoma. The literature on this subject, together with the present case report, suggests that neurogenic tumors should be included in the differential diagnosis of obstructing tracheal cervical masses. Surgical excision is the first-line of treatment for benign cervical schwannomas.

PURPOSE: Low-grade intermediate-risk nonmuscle-invasive bladder cancer (LG IR NMIBC) is a recurrent disease, thus requiring repeated transurethral resection of bladder tumor under general anesthesia. We evaluated the efficacy and safety of UGN-102, a mitomycin-containing reverse thermal gel, as a primary chemoablative therapeutic alternative to transurethral resection of bladder tumor for patients with LG IR NMIBC. MATERIALS AND METHODS: This prospective, phase 2b, open-label, single-arm trial recruited patients with biopsy-proven LG IR NMIBC to receive 6 once-weekly instillations of UGN-102. The primary end point was complete response (CR) rate, defined as the proportion of patients with negative endoscopic examination, negative cytology and negative for-cause biopsy 3 months after treatment initiation. Patients with CR were followed quarterly up to 12 months to assess durability of treatment effect. Safety and adverse events were monitored throughout the trial. RESULTS: A total of 63 patients (38 males and 25 females 33-96 years old) enrolled and received ≥1 instillation of UGN-102. Among the patients 41 (65%) achieved CR at 3 months, of whom 39 (95%), 30 (73%) and 25 (61%) remained disease-free at 6, 9 and 12 months after treatment initiation, respectively. A total of 13 patients had documented recurrences. The probability of durable response 9 months after CR (12 months after treatment initiation) was estimated to be 73% by Kaplan-Meier analysis. Common adverse events (incidence ≥10%) included dysuria, urinary frequency, hematuria, micturition urgency, urinary tract infection and fatigue. CONCLUSIONS: Nonsurgical primary chemoablation of LG IR NMIBC using UGN-102 resulted in significant treatment response with sustained durability. UGN-102 may provide an alternative to repetitive surgery for patients with LG IR NMIBC.

The major biological methyl donor, S-adenosylmethionine (adoMet) synthesis occurs mainly in the liver. Methionine adenosyltransferase 1A (MAT1A) and glycine N-methyltransferase (GNMT) are two key enzymes involved in the functional implications of that variation. We collected 42 RNA-seq data from paired hepatocellular carcinoma (HCC) and its adjacent normal liver tissue from the Cancer Genome Atlas (TCGA). There was no mutation found in MAT1A or GNMT RNA in the 42 HCC patients. The 11,799 genes were annotated in the RNA-Seq data, and their expression levels were used to investigate the phenotypes of low MAT1A and low GNMT by Gene Set Enrichment Analysis (GSEA). The REACTOME_TRANSLATION gene set was enriched and visualized in a heatmap along with corresponding differences in gene expression between low MAT1A versus high MAT1A and low GNMT versus high GNMT. We identified 43 genes of the REACTOME_TRANSLATION gene set that are powerful prognosis factors in HCC. The significantly predicted genes were referred into eukaryotic translation initiation (EIF3B, EIF3K), eukaryotic translation elongation (EEF1D), and ribosomal proteins (RPs). Cell models expressing various MAT1A and GNMT proved that simultaneous restoring the expression of MAT1A and GNMT decreased cell proliferation, invasion, as well as the REACTOME_TRANSLATION gene EEF1D, consistent with a better prognosis in human HCC. We demonstrated new findings that downregulation or defect in MAT1A and GNMT genes can enrich the protein-associated translation process that may account for poor HCC prognosis. This is the first study demonstrated that MAT1A and GNMT, the 2 key enzymes involved in methionine cycle, could attenuate the function of ribosome translation. We propose a potential novel mechanism by which the diminished GNMT and MAT1A expression may confer poor prognosis for HCC.

Abstract Background Ameloblastoma (AME) is a benign odontogenic tumour of epithelial origin characterised by slow but aggressive growth, infiltration, and recurrence; it is capable of reaching large dimensions and invading adjacent structures. Stem cell research has proven to be significant in the sphere of tumour biology through these cells’ possible involvement in the aetiopathogenesis of this tumour. Methods Immunohistochemistry was performed on AME, dentigerous cyst (DC), and dental follicle (DF) samples, and indirect immunofluorescence was performed on the AME-hTERT cell line to determine the expression of SALL4, LIN28A, and KLF4. Results Expression of proteins related to cellular pluripotency was higher in AME cells than in DC and DF cells. The analysis revealed that the proteins in question were mainly expressed in the parenchyma of AME tissue samples and were detected in the nuclei of AME-hTERT cells. Conclusions Stem cells may be related to the origin and progression of AME.

Metastasis is a major obstacle in the therapeutic intervention of melanoma, and several GTP-binding proteins were found to play important roles in regulating cancer metastasis. To assess systematically the regulatory roles of these proteins in melanoma metastasis, we employed a targeted chemoproteomic method, which relies on the application of stable isotope-labeled desthiobiotin-GTP acyl phosphate probes in conjunction with scheduled multiple-reaction monitoring (MRM), for profiling quantitatively the GTP-binding proteins. Following probe labeling, tryptic digestion, and affinity pull-down of desthiobiotin-conjugated peptides, differences in expression levels of GTP-binding proteins in two matched pairs of primary/metastatic melanoma cell lines were measured using liquid chromatography-MRM analysis. We also showed that among the top upregulated proteins in metastatic melanoma cells, AK4 promotes the migration and invasion of melanoma cells; overexpression of AK4 in primary melanoma cells leads to augmented migration and invasion, and reciprocally, knockdown of AK4 in metastatic melanoma cells results in repressed invasiveness. In summary, we examined the relative expression levels of GTP-binding proteins in two pairs of primary/metastatic melanoma cell lines. Our results confirmed some previously reported regulators of melanoma metastasis and revealed a potential role of AK4 in promoting melanoma metastasis.

The Hippo and mTOR signaling cascades are major regulators of cell growth and division. Aberrant regulation of these pathways has been demonstrated to contribute to gliomagenesis and result in enhanced glioblastoma proliferation and invasive characteristics. Several crosstalk mechanisms have been described between these two pathways, although a complete picture of these signaling interactions is lacking and is required for effective therapeutic targeting. Here we report the ability of mTORC2 to directly phosphorylate YAP at serine 436 (Ser436) positively regulating YAP activity. We show that mTORC2 activity enhances YAP transcriptional activity and the induction of YAP-dependent target gene expression while its ablation via genetic or pharmacological means has the opposite affects on YAP function. mTORC2 interacts with YAP via Sin1 and mutational analysis of serine 436 demonstrates that this phosphorylation event affects several properties of YAP leading to enhanced transactivation potential. Moreover, YAP serine 436 mutants display altered glioblastoma growth, migratory capacity and invasiveness both in vitro and in xenograft experiments. We further demonstrate that mTORC2 is able to regulate a Hippo pathway resistant allele of YAP suggesting that mTORC2 can regulate YAP independent of Hippo signaling. Correlative associations between the expression of these components in GBM patient samples also supported the presence of this signaling relationship. These results advance a direct mTORC2/YAP signaling axis driving GBM growth, motility and invasiveness.

PurposeThe Sedlis criteria define risk factors for recurrence warranting post-hysterectomy radiation for early-stage cervical cancer; however, these factors were defined for squamous cell carcinoma (SCC) at an estimated recurrence risk of ≥30%. Our study evaluates and compares risk factors for recurrence for cervical SCC compared with adenocarcinoma (AC) and develops histology-specific nomograms to estimate risk of recurrence and guide adjuvant treatment.MethodsWe performed an ancillary analysis of GOG 49, 92, and 141, and included stage I patients who were surgically managed and received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were used to evaluate independent risk factors for recurrence by histology and to generate prognostic histology-specific nomograms for 3-year recurrence risk.ResultsWe identified 715 patients with SCC and 105 with AC; 20% with SCC and 17% with AC recurred. For SCC, lymphvascular space invasion (LVSI: HR 1.58, CI 1.12-2.22), tumor size (TS ≥4 cm: HR 2.67, CI 1.67-4.29), and depth of invasion (DOI; middle 1/3, HR 4.31, CI 1.81-10.26; deep 1/3, HR 7.05, CI 2.99-16.64) were associated with recurrence. For AC, only TS ≥4 cm, was associated with recurrence (HR 4.69, CI 1.25-17.63). For both histologies, there was an interaction effect between TS and LVSI. For those with SCC, DOI was most associated with recurrence (16% risk); for AC, TS conferred a 15% risk with negative LVSI versus a 25% risk with positive LVSI.ConclusionsCurrent treatment standards are based on the Sedlis criteria, specifically derived from data on SCC. However, risk factors for recurrence differ for squamous cell and adenocarcinoma of the cervix. Histology-specific nomograms accurately and linearly represent risk of recurrence for both SCC and AC tumors and may provide a more contemporary and tailored tool for clinicians to base adjuvant treatment recommendations to their patients with cervical cancer.

BackgroundThe aim of this study was to determine how Stathmin-1 and Heat Shock Protein 27 (HSP27) can be used as adjunctive biomarkers to differentiate high-grade dysplasia from benign/reactive lesions in cervical tissues. In addition, we aimed to see if any of these markers can differentiate endometrial from endocervical adenocarcinomas.MethodsFifty cases including benign cervical tissue, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), adenocarcinoma in situ of the endocervix, invasive endocervical adenocarcinoma, and endometrial adenocarcinoma were selected. Stathmin-1 and HSP27 immunohistochemistry (IHC) were performed for each case and the results were compared to the previously available p16 IHC stains.Resultsp16 stained positively in 100% of HSIL, endocervical adenocarcinoma in situ, and invasive endocervical cases. Stathmin-1 stained positively in 43% of HSIL and 90% of endocervical adenocarcinoma in situ and all invasive endocervical cases. Stathmin-1 and p16 were negative in all benign cervical samples. Stathmin-1, HSP27, and p16 stained 100% of LSIL cases. HSP27 stained indiscriminately, including 100% of benign cervical tissue. 87% of the endometrial adenocarcinomas stained positively for p16, Stathmin-1, and HSP27.Conclusionp16 remains superior to both Stathmin-1 and HSP27 in differentiating dysplasia from benign, reactive changes of the cervix.

OBJECTIVE: The 2017 World Health Organization classification of pituitary adenomas identified the plurihormonal PIT-1-positive (PP1) adenoma as a distinct subtype. The reported data suggest that PP1 adenomas encompass the former class of silent subtype 3 (SS3) adenomas and might have an aggressive phenotype. In the present study, we summarized the current clinical data on PP1 and SS3 adenomas and compared the reported data with the data from a single institutional cohort. METHODS: Medline and Google Scholar were searched from 1990 to 2020 for clinical series of PP1 and SS3 adenomas in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. Studies were included if they had reported pituitary pathology as PP1 or SS3 adenomas and had reported the clinical outcomes after surgical intervention. To better define the PP1 phenotype compared with non-PP1 adenomas, we also reviewed the adenomas treated surgically at our institution from 2012 to 2019. RESULTS: Of all the tumors reported in the studies as PP1 or SS3, 99% were macroadenomas and 18% were giant adenomas (>4 cm). Of the reported patients, 31.8% had received radiotherapy, and 22.9% had undergone multiple surgeries for their pituitary tumor. In our single-center experience, 20 patients had an adenoma that met the criteria for a PP1 adenoma. Compared with the 1146 non-PP1 tumors, the PP1 tumors did not show statistically significant differences in the extent of resection, size, number of previous surgeries, future reoperations, rate of radiotherapy, p53 staining, or MIB-1 labeling index. CONCLUSIONS: The findings from the present large, single-center study comparing PP1 and non-PP1 adenomas do not suggest that PP1 tumors are more aggressive. Further work is warranted to identify the pathologic subtypes of pituitary adenomas that are consistently more clinically aggressive.

Objective To investigate the effect of FXX-W-12-4, a novel heat shock protein 90 (Hsp90)/histone deacetylase (HDAC) dual-target inhibitor, on the proliferation, invasion, and migration of breast cancer MDA-MB-231 cells. Methods CCK-8 assay was used to observe the effect of FXX-W-12-4 on the viability of MDA-MB-231 cells, and its half-maximal inhibitory concentration (IC50) was calculated as the reference value for concentration in follow-up experiment. On the basis of the IC50 value, FXX-W-12-4 with a final concentration of 0, 100, 200, and 300 nmol/L was added to MDA-MB-231 cells and was established as groups A, B, C, and D, respectively. Cell scratch assay and Transwell assay were used to observe the effect of FXX-W-12-4 on the invasion and migration of MDA-MB-231 cells in each group. Western blot was used to measure the relative expression levels of proteins such as ac-H3 and Hsp70 in MDA-MB-231 cells. Results CCK-8 assay showed that the viability of MDA-MB-231 cells gradually decreased with the increase in FXX-W-12-4 concentration (F=2 663.00,P

Aims. The objective of this study was to compare bone invasion type with histopathological, clinical and immunohistochemical prognostic factors. Methods. The study included 49 patients who were treated for oral squamous cell carcinoma. Of which, 30 patients, with presence of bone invasion on histopathology, were divided according to the type of bone invasion (erosive, infiltrative, mixed). Each invasion type was compared to microvascular density using the CD34 marker. Results. The bone invasion was observed in 30 out of 49 patients (61.22%). On McNemar's test, statistically significant association was observed between bone invasion types and histopathological grade. In contrast, no significant correlation was observed between bone invasion type, and tumour volume or nodal metastases. In tumours with bone invasion of the infiltrative type, higher frequency of locoregional relapses was observed. The 5-year survival, since diagnosis, was approximately 60% in the erosive group, 40% in the mixed group, and merely 15% in the infiltrative group. Conclusion. Peritumoural microvascular density was not significantly related to bone invasion types. Whereas, a significantly higher intratumoural microvascular density was observed in infiltrative type of the bone invasion, when compared to the erosive and mixed type.

Objective To investigate the effect of the long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) on the migration, invasion, and epithelial-mesenchymal transition (EMT) of breast cancer cells and its mechanism. Methods Breast cancer tissue samples and adjacent normal tissue samples were collected from 20 patients with breast cancer, and normal human breast epithelial cell MCF-10A and breast cancer cell lines MCF-7, BT-549, MDA-MB-231, and MDA-MB-468 were cultured. RT-qPCR was used to measure the expression levels of SNHG1 and miR-641 in tissue samples and cells. BT-549 cells were divided into groups A to D and were transfected with si-NC (group A), si-SNHG1 (group B), si-SNHG1+anti-miR-641-NC (group C), and si-SNHG1+anti-miR-641 (group D), respectively. RT-qPCR was used to measure the expression levels of SNHG1 and miR-641 in cells; Transwell assay was used to observe cell invasion and migration abilities; Western blot was used to measure the expression levels of the EMT-related proteins E-cadherin, N-cadherin, and Vimentin. BT-549 cells were divided into groups E to H and were co-transfected with SNHG1-WT and miR-641 mimics (group E), SNHG1-WT and miR-NC (group F), SNHG1-MUT and miR-641 mimics (group G), and SNHG1-MUT and miR-NC (group H), respectively, and dual-luciferase reporter assay was used to determine the interaction between SNHG1 and miR-641. Results SNHG1 was highly expressed in breast cancer tissue (t=4.81,P0.05). Conclusion cSNHG1 is highly expressed in breast cancer tissue and cells, and downregulation of its expression can inhibit the migration, invasion, and EMT of breast cancer cells by targeting miR-641.

Introduction. Around 2% of all cutaneous neoplasms arise in the scalp and can be classified as either primary or metastatic. The intracranial extension is rare in cutaneous malignancies but can generally occur if left untreated. Squamous cell carcinoma (SCC) is the second most common type of nonmelanoma skin cancer after basal cell carcinoma. About 3 –8% of SCCs are located on the scalp and can cause skull and dural invasion in rare cases. Case report. A 49-year-old male patient presented with a large and painful lesion in the parietooccipital region of the head. Magnetic resonance imaging (MRI) revealed a large inhomogeneous, necroti c lesion with infiltration of the underlying skull and dura. The patient underwent surgical removal of the tumor with excision of invaded skin, bone, and dura with a safety margin of 1 cm, followed by custom prefabricated 3D-printed cranioplasty with polymethylmetacrilate. Pathohistological analysis revealed invasive SCC with immunohistochemistry staining revealing CK5/6 and CK7 positivity. Conclusion. Some cases of scalp SCCs can cause invasion of the underlying skull and dura if left untreated. Imaging modalities like computed tomography (CT) and MRI play a crucial role in evaluating the degree of neoplastic extension and potential calvarial and dural invasion, thus being of significant importance in preoperative planning and management. [ABSTRACT FROM AUTHOR]

Hilar cholangiocarcinoma is the most common malignant tumor of the biliary tract， and radical surgery is still the only possible means for patients to obtain long－term survival. This article briefly describes the features of lymph node metastasis and nerve plexus invasion in hilar cholangiocarcinoma and reviews the current viewpoints on lymph node dissection and nerve plexus dissection in China and globally. It is shown that the regional lymph node dissection and nerve plexus dissection are generally accepted in China and globally， but there are still controversies over extended lymph node dissection. [ABSTRACT FROM AUTHOR]

Tongue carcinoma constitutes 10.4–46.9% of all oral squamous cell carcinomas (OSCCs) and is notoriously known for invading tissues deeper than the evident gross margins. The deeper the tumor invades, the higher are its chances of future morbidity and mortality due to extensive neck dissection and risk of recurrence. Magnetic resonance imaging (MRI) is a noninvasive diagnostic aid used for measuring a preoperative tumor's depth of invasion (DOI) as it can efficiently outline soft tissue tumors from adjacent normal tissue. To assess various MRI modalities used in measuring DOI in tongue carcinoma and their reliability compared with other DOI measuring modalities. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022330866), and the following Preferred Reporting Items for a Systematic Review and Meta-Analysis (PRISMA) Diagnostic Test Accuracy guidelines were performed. PubMed electronic database was searched using a combination of keywords for relevant articles in the English language since 2016. Critical appraisal was carried out using the Quality Assessment of Diagnostic Accuracy Studies-Comparative (QUADAS-C) risk-of-bias (RoB) assessment tool. A weighted mean difference (WMD) was calculated between MRI and histopathological DOI along with pooled correlation and subgroup analysis, where possible. A total of 795 records were retrieved of which 17 were included in the final review with 13 included for meta-analysis. A high RoB was found for most studies for all parameters except flow and timing. WMD showed a statistically significant MRI overestimation of 1.90 mm compared with histopathology. Subgroup analysis showed the 1.5 Tesla machine to be superior to the 3.0 Tesla machine, while imaging sequence subgroup analysis could not be performed. MRI is a viable preoperative DOI measurement modality that can help in efficient treatment planning to decrease surgical morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: Ameloblastoma (AME) is a benign odontogenic tumour of epithelial origin characterised by slow but aggressive growth, infiltration, and recurrence; it is capable of reaching large dimensions and invading adjacent structures. Stem cell research has proven to be significant in the sphere of tumour biology through these cells' possible involvement in the aetiopathogenesis of this tumour. Methods: Immunohistochemistry was performed on AME, dentigerous cyst (DC), and dental follicle (DF) samples, and indirect immunofluorescence was performed on the AME-hTERT cell line to determine the expression of SALL4, LIN28A, and KLF4. Results: Expression of proteins related to cellular pluripotency was higher in AME cells than in DC and DF cells. The analysis revealed that the proteins in question were mainly expressed in the parenchyma of AME tissue samples and were detected in the nuclei of AME-hTERT cells. Conclusions: Stem cells may be related to the origin and progression of AME. [ABSTRACT FROM AUTHOR]

To investigate the impact of nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA) axis on the proliferation, apoptosis and invasion of cervical cancer SiHa cells. Methods Normal cervical epithelial cells HUCEC and cervical cancer cells SiHa were cultured in vitro. SiHa cells were grouped into the control group (normal culture), the L-NGF group (50 µg/L recombinant human NGF protein), the H-NGF group (100 µg/L recombinant human NGF protein), the H-NGF+L-K252a group (100 µg/L recombinant human NGF protein+50 µg/L K252a) and H-NGF+HK252a group (100 µg/L recombinant human NGF protein+100 µg/L K252a). The protein expression levels of NGF, TrkA, Ecadherin, N-cadherin and Vimentin were detected by Western blot assay. The proliferation of SiHa cells was detected by CCK-8 method. Apoptosis of SiHa cells was detected by flow cytometry. Cell migration was determined by scratch healing test. Cell invasion was measured by Transwell assay. Results The levels of NGF and TrkA were obviously higher in SiHa cells than those in HUCEC cells (P＜0.01). Compared with the control group, levels of NGF and TrkA, proliferative activity, migration rate, number of invasive cells and N-cadherin and Vimentin proteins were obviously higher in the L-NGF group and the H-NGF group (P＜0.05), and the apoptosis rate and the level of E-cadherin protein were obviously lower (P＜0.05). The above indexes were more obviously different in the H-NGF group than those of the L-NGF group (P＜0.05). Compared with the H-NGF group, levels of NGF, TrkA, proliferative activity, migration rate, number of invasive cells and N-cadherin and Vimentin proteins were obviously lower in the H-NGF+L-K252a group and the H-NGF+H-K252a group (P＜0.05), and the apoptosis rate and the level of E-cadherin protein were obviously higher (P＜0.05). The above indexes in the HNGF+H-K252a group were more obviously different than those in the H-NGF+L-K252a group (P＜0.05). Conclusion Down-regulation of NGF/TrkA axis can inhibit the proliferation and invasion of cervical cancer SiHa cells and promote their apoptosis. [ABSTRACT FROM AUTHOR]

Objectives: To compare between the diagnostic performance of 3.0-T MRI and CT for aorta and tracheobronchial invasion in patients with esophageal cancer (EC). Methods: We prospectively included patients with pathologically confirmed EC from November 2018 to June 2021, who had baseline stage of T3-4N0-2M0 and restaging after neoadjuvant chemotherapy. All patients underwent contrast-enhanced CT and MRI of the thorax. Two independent blinded radiologists scored image quality and the presence of invasion. Agreements between the two readers were calculated using kappa test. The sensitivity, specificity, accuracy, positive predict value (PPV), and negative predict value (NPV) of MRI and CT in evaluating invasion were calculated. The net reclassification index (NRI) was used to evaluate the change in the number of patients correctly classified by MRI and CT. Results: A total of 70 patients (64.8 ± 9.0 years; 53 men) were enrolled. Inter-reader agreements of image quality scores and presence of invasion by MRI and CT between the two readers were almost perfect (kappa > 0.80). The accuracy of MRI in evaluating thoracic aorta invasion was significantly higher than that of CT (reader 1: 90.0% vs. 71.4%; reader 2: 92.9% vs. 70.0%, respectively), and the accuracy of MRI in evaluating tracheobronchial invasion also was significantly higher than that of CT (reader 1: 92.9% vs. 72.9%; reader 2: 95.7% vs. 70.0%, respectively). NRI values were positive in both the evaluation of aorta and tracheobronchial invasion. Conclusions: The accuracy of 3-T MRI in determining thoracic aorta and tracheobronchial invasion is significantly higher than that of CT. Key Points: • 3.0-T MRI was significantly more accurate than CT in assessing invasion of the thoracic aorta in patients with esophageal cancer. • 3.0-T MRI was also significantly more accurate than CT in assessing tracheobronchial invasion in patients with esophageal cancer. • 3.0-T MRI has a higher diagnostic performance than CT in evaluating patients with suspected aortic or tracheobronchial invasion in esophageal cancer. [ABSTRACT FROM AUTHOR]

Breast cancer invasion and metastasis result from a complex interplay between tumor cells and the tumor microenvironment (TME). Key oncogenic changes in the TME include aberrant synthesis, processing, and signaling of hyaluronan (HA). Hyaluronan‐mediated motility receptor (RHAMM, CD168; HMMR) is an HA receptor enabling tumor cells to sense and respond to this aberrant TME during breast cancer progression. Previous studies have associated RHAMM expression with breast tumor progression; however, cause and effect mechanisms are incompletely established. Focused gene expression analysis of an internal breast cancer patient cohort confirmed that increased RHAMM expression correlates with aggressive clinicopathological features. To probe mechanisms, we developed a novel 27‐gene RHAMM‐related signature (RRS) by intersecting differentially expressed genes in lymph node (LN)‐positive patient cases with the transcriptome of a RHAMM‐dependent model of cell transformation, which we validated in an independent cohort. We demonstrate that the RRS predicts for poor survival and is enriched for cell cycle and TME‐interaction pathways. Further analyses using CRISPR/Cas9‐generated RHAMM−/− breast cancer cells provided direct evidence that RHAMM promotes invasion in vitro and in vivo. Immunohistochemistry studies highlighted heterogeneous RHAMM protein expression, and spatial transcriptomics associated the RRS with RHAMM‐high microanatomic foci. We conclude that RHAMM upregulation leads to the formation of 'invasive niches', which are enriched in RRS‐related pathways that drive invasion and could be targeted to limit invasive progression and improve patient outcomes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]