tumor invasiveness
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Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6038
Author(s):  
Liudmyla Zurnadzhy ◽  
Tetiana Bogdanova ◽  
Tatiana I. Rogounovitch ◽  
Masahiro Ito ◽  
Mykola Tronko ◽  
...  

Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAFV600E-positive PTCs, whose proportion is growing with time, are not well described yet. We analyzed the relationship between the BRAFV600E status (determined immunohistochemically with the VE1 antibody) and the clinicopathological features of 247 radiogenic and 138 sporadic PTCs from young Ukrainian patients aged ≤28 years. The frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences. In contrast, the BRAFV600E-negative radiogenic PTCs displayed less frequent dominant papillary and more frequent solid growth patterns, lower Ki67 labeling index, and higher invasiveness than the BRAFV600E-negative sporadic tumors. Thus, BRAFV600E is not associated with a more aggressive course of PTC in young patients regardless of etiology. The major clinicopathological differences between the radiogenic and sporadic PTCs are observed among the BRAFV600E-negative tumors.


Author(s):  
Rajkumar Venkatramani ◽  
Wei Xue ◽  
R. Lor Randall ◽  
Suzanne Wolden ◽  
James Anderson ◽  
...  

PURPOSE Synovial sarcoma (SS) is the second most common malignant soft tissue tumor in children. ARST0332 evaluated a risk-based treatment strategy for young patients with soft tissue sarcoma designed to limit therapy for low-risk (LR) disease and to test neoadjuvant chemoradiotherapy for unresected higher-risk disease. METHODS Newly diagnosed patients with SS age < 30 years were assigned to four treatment arms based on disease features: A (surgery only), B (55.8 Gy radiotherapy [RT]), C (ifosfamide and doxorubicin [ID] chemotherapy plus 55.8 Gy RT), and D (neoadjuvant ID and 45 Gy RT, then surgery and RT boost based on margins followed by adjuvant ID). Patients treated in Arms A and B were considered LR, arms C and D without metastases as intermediate-risk (IR), and those with metastases as high-risk (HR). RESULTS Of the 146 patients with SS enrolled, 138 were eligible and evaluable: LR (46), IR (71), and HR (21). Tumors were 80% extremity, 70% > 5 cm, 70% high-grade, 62% invasive, 95% deep, and 15% metastatic. Treatment was on arm A (29.7%), B (3.6%), C (16.7%), and D (50%). There were no toxic deaths and four unexpected grade 4 adverse events. By risk group, at a median follow-up of 6.8 years, estimated 5-year event-free survival was LR 82%, IR 70%, and HR 8%, and overall survival was LR 98%, IR 89%, and HR 13%. After accounting for the features that defined risk category, none of the other patient or disease characteristics (age, sex, tumor site, tumor invasiveness, and depth) improved the risk stratification model. CONCLUSION The risk-based treatment strategy used in ARST0332 produced favorable outcomes in patients with nonmetastatic SS relative to historical controls despite using RT less frequently and at lower doses. The outcome for metastatic SS remains unsatisfactory and new therapies are urgently needed.


2021 ◽  
pp. 1-9
Author(s):  
Shashwat Tripathi ◽  
Tito Vivas-Buitrago ◽  
Ricardo A. Domingo ◽  
Gaetano De Biase ◽  
Desmond Brown ◽  
...  

OBJECTIVE Recent studies have proposed resection of the T2 FLAIR hyperintensity beyond the T1 contrast enhancement (supramarginal resection [SMR]) for IDH–wild-type glioblastoma (GBM) to further improve patients’ overall survival (OS). GBMs have significant variability in tumor cell density, distribution, and infiltration. Advanced mathematical models based on patient-specific radiographic features have provided new insights into GBM growth kinetics on two important parameters of tumor aggressiveness: proliferation rate (ρ) and diffusion rate (D). The aim of this study was to investigate OS of patients with IDH–wild-type GBM who underwent SMR based on a mathematical model of cell distribution and infiltration profile (tumor invasiveness profile). METHODS Volumetric measurements were obtained from the selected regions of interest from pre- and postoperative MRI studies of included patients. The tumor invasiveness profile (proliferation/diffusion [ρ/D] ratio) was calculated using the following formula: ρ/D ratio = (4π/3)2/3 × (6.106/[VT21/1 − VT11/1])2, where VT2 and VT1 are the preoperative FLAIR and contrast-enhancing volumes, respectively. Patients were split into subgroups based on their tumor invasiveness profiles. In this analysis, tumors were classified as nodular, moderately diffuse, or highly diffuse. RESULTS A total of 101 patients were included. Tumors were classified as nodular (n = 34), moderately diffuse (n = 34), and highly diffuse (n = 33). On multivariate analysis, increasing SMR had a significant positive correlation with OS for moderately and highly diffuse tumors (HR 0.99, 95% CI 0.98–0.99; p = 0.02; and HR 0.98, 95% CI 0.96–0.99; p = 0.04, respectively). On threshold analysis, OS benefit was seen with SMR from 10% to 29%, 10% to 59%, and 30% to 90%, for nodular, moderately diffuse, and highly diffuse, respectively. CONCLUSIONS The impact of SMR on OS for patients with IDH–wild-type GBM is influenced by the degree of tumor invasiveness. The authors’ results show that increasing SMR is associated with increased OS in patients with moderate and highly diffuse IDH–wild-type GBMs. When grouping SMR into 10% intervals, this benefit was seen for all tumor subgroups, although for nodular tumors, the maximum beneficial SMR percentage was considerably lower than in moderate and highly diffuse tumors.


Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1328
Author(s):  
Carolina Noronha ◽  
Ana Sofia Ribeiro ◽  
Ricardo Taipa ◽  
Diogo S. Castro ◽  
Joaquim Reis ◽  
...  

Cadherins are calcium-binding proteins with a pivotal role in cell adhesion and tissue homeostasis. The cadherin-dependent mechanisms of cell adhesion and migration are exploited by cancer cells, contributing to tumor invasiveness and dissemination. In particular, cadherin switch is a hallmark of epithelial to mesenchymal transition, a complex development process vastly described in the progression of most epithelial cancers. This is characterized by drastic changes in cell polarity, adhesion, and motility, which lead from an E-cadherin positive differentiated epithelial state into a dedifferentiated mesenchymal-like state, prone to metastization and defined by N-cadherin expression. Although vastly explored in epithelial cancers, how these mechanisms contribute to the pathogenesis of other non-epithelial tumor types is poorly understood. Herein, the current knowledge on cadherin expression in normal development in parallel to tumor pathogenesis is reviewed, focusing on epithelial to mesenchymal transition. Emphasis is taken in the unascertained cadherin expression in CNS tumors, particularly in gliomas, where the potential contribution of an epithelial-to-mesenchymal-like process to glioma genesis and how this may be associated with changes in cadherin expression is discussed.


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Kimihide Kusafuka ◽  
Masaru Yamashita ◽  
Tomohiro Iwasaki ◽  
Chinatsu Tsuchiya ◽  
Aki Kubota ◽  
...  

Abstract Background Thyroid tumors are often difficult to histopathologically diagnose, particularly follicular adenoma (FA) and follicular carcinoma (FC). Papillary carcinoma (PAC) has several histological subtypes. Periostin (PON), which is a non-collagenous extracellular matrix molecule, has been implicated in tumor invasiveness. We herein aimed to elucidate the expression status and localization of PON in thyroid tumors. Method We collected 105 cases of thyroid nodules, which included cases of adenomatous goiter, FA, microcarcinoma (MIC), PAC, FC, poorly differentiated carcinoma (PDCa), and undifferentiated carcinoma (UCa), and immunohistochemically examined the PON expression patterns of these lesions. Results Stromal PON deposition was detected in PAC and MIC, particularly in the solid/sclerosing subtype, whereas FA and FC showed weak deposition on the fibrous capsule. However, the invasive and/or extracapsular regions of microinvasive FC showed quite strong PON expression. Except for it, we could not find any significant histopathological differences between FA and FC. There were no other significant histopathological differences between FA and FC. Although PDCa showed a similar PON expression pattern to PAC, UCa exhibited stromal PON deposition in its invasive portions and cytoplasmic expression in its carcinoma cells. Although there was only one case of UCa, it showed strong PON immunopositivity. PAC and MIC showed similar patterns of stromal PON deposition, particularly at the invasive front. Conclusions PON may play a role in the invasion of thyroid carcinomas, particularly PAC and UCa, whereas it may act as a barrier to the growth of tumor cells in FA and minimally invasive FC.


2021 ◽  
Vol 11 ◽  
Author(s):  
Yao Xu ◽  
Yu Li ◽  
Hongkun Yin ◽  
Wen Tang ◽  
Guohua Fan

IntroductionTumors are continuously evolving biological systems which can be monitored by medical imaging. Previous studies only focus on single timepoint images, whether the performance could be further improved by using serial noncontrast CT imaging obtained during nodule follow-up management remains unclear. In this study, we evaluated DL model for predicting tumor invasiveness of GGNs through analyzing time series CT imagesMethodsA total of 168 pathologically confirmed GGN cases (48 noninvasive lesions and 120 invasive lesions) were retrospectively collected and randomly assigned to the development dataset (n = 123) and independent testing dataset (n = 45). All patients underwent consecutive noncontrast CT examinations, and the baseline CT and 3-month follow-up CT images were collected. The gross region of interest (ROI) patches containing only tumor region and the full ROI patches including both tumor and peritumor regions were cropped from CT images. A baseline model was built on the image features and demographic features. Four DL models were proposed: two single-DL model using gross ROI (model 1) or full ROI patches (model 3) from baseline CT images, and two serial-DL models using gross ROI (model 2) or full ROI patches (model 4) from consecutive CT images (baseline scan and 3-month follow-up scan). In addition, a combined model integrating serial full ROI patches and clinical information was also constructed. The performance of these predictive models was assessed with respect to discrimination and clinical usefulness.ResultsThe area under the curve (AUC) of the baseline model, models 1, 2, 3, and 4 were 0.562 [(95% confidence interval (C)], 0.406~0.710), 0.693 (95% CI, 0.538–0.822), 0.787 (95% CI, 0.639–0.895), 0.727 (95% CI, 0.573–0.849), and 0.811 (95% CI, 0.667–0.912) in the independent testing dataset, respectively. The results indicated that the peritumor region had potential to contribute to tumor invasiveness prediction, and the model performance was further improved by integrating imaging scans at multiple timepoints. Furthermore, the combined model showed best discrimination ability, with AUC, sensitivity, specificity, and accuracy achieving 0.831 (95% CI, 0.690–0.926), 86.7%, 73.3%, and 82.2%, respectively.ConclusionThe DL model integrating full ROIs from serial CT images shows improved predictive performance in differentiating noninvasive from invasive GGNs than the model using only baseline CT images, which could benefit the clinical management of GGNs.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Markus Eckstein ◽  
Charlotte Kimmel ◽  
Johannes Bruendl ◽  
Florian Weber ◽  
Stefan Denzinger ◽  
...  

AbstractTumor budding is defined as a single cell or a cluster of up to 5 tumor cells at the invasion front. Due to the difficulty of identifying patients at high risk for pT1 non-muscle-invasive bladder cancer (NMIBC) and the difficulties in T1 substaging, tumor budding was evaluated as a potential alternative and prognostic parameter in these patients. Tumor budding as well as growth pattern, invasion pattern and lamina propria infiltration were retrospectively evaluated in transurethral resection of the bladder (TURB) specimens from 92 patients with stage pT1 NMIBC. The presence of tumor budding correlated with multifocal tumors (p = 0.003), discontinuous invasion pattern (p = 0.039), discohesive growth pattern (p < 0.001) and extensive lamina propria invasion (p < 0.001). In Kaplan–Meier analysis, tumor budding was associated with significantly worse RFS (p = 0.005), PFS (p = 0.017) and CSS (p = 0.002). In patients who received BCG instillation therapy (n = 65), the absence of tumor budding was associated with improved RFS (p = 0.012), PFS (p = 0.011) and CSS (p = 0.022), with none of the patients suffering from progression or dying from the disease. Tumor budding is associated with a more aggressive and invasive stage of pT1 NMIBC and a worse outcome. This easy-to-assess parameter could help stratify patients into BCG therapy or early cystectomy treatment groups.


2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii37-ii38
Author(s):  
G Pavlova ◽  
S Pavlova ◽  
S Drozd ◽  
E Savchenko ◽  
L Zakharova ◽  
...  

Abstract BACKGROUND Gliomas are still one of the most aggressive human cancers, and even despite modern therapeutic approaches, the prognosis for patients with this disease is not favorable. It is known that glioma cells are capable of local invasiveness, when glioma cells migrate into healthy brain tissue. A lack of any definite markers, characterizing migrating glioma cells and allowing them to be distinguished from healthy brain cells, requires a thorough investigation. In case it would be possible to characterize invasive glioma cells, then a development of targeted therapy could be feasible. MATERIAL AND METHODS Cell cultures of human gliomas Gr II, III and IV were developed with 5 cultures for each Grade. MTT, RT-PCR, Western and Nosern blot, transcriptome analysis were applied. RESULTS Three cultures of human gliomas had a high degree of migration, within the range of 6% - 14%. These cultures were developed from gliomas of Grade III and Grade IV, and with IDH1- (minus) phenotype. Moreover, cell cultures with IDH1 + (plus) phenotype had a low migration rate within 1%. An intensity of migration correlated with the degree of malignancy, and an average rate decreased with a decrease of the Grade. Moreover, an analysis of the proliferative activity of cell cultures of human gliomas of various degrees of malignancy did not reveal a relationship with a migratory properties of cultures. A number of actively proliferating cultures did not show high migration, while cultures with medium proliferative activity could show a high level of migration. The low level of proliferation of cultures of gliomas of Grade II and I at the beginning of cultivation, in some cases, subsequently increased, but an inherent low migration activity did not change. In actively migrating cultures, a significant decrease in the expression of Sox2 and Nestin is detected. A positive correlation was found between migration abilities of human glioma cell culture cells and the marker Ki67, GFAP, Sox2, and Oct4. The difference was statistically significant by the one-sided Mann-Whitney test. CONCLUSION Conclusions: Cell cultures derived from glioma tumor tissue can be used to predict invasive properties of the tumor. High tumor invasiveness is characteristic for Grade III and Grade IV, and with IDH1- (minus) phenotype, and it also correlates with elevated expression of GFAP, Sox2 and Oct4The reported study was funded by RFBR according to the research project № 18-29-01012 and by the Ministry of Science and Higher Education of the Russian Federation, grant number 075-15-2020-809 (13.1902.21.0030).


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eitan Rabinovitch ◽  
Koishiro Mihara ◽  
Amiram Sananes ◽  
Marianna Zaretsky ◽  
Michael Heyne ◽  
...  

AbstractProteinase-activated receptor-1 (PAR1), triggered by thrombin and other serine proteinases such as tissue kallikrein-4 (KLK4), is a key driver of inflammation, tumor invasiveness and tumor metastasis. The PAR1 transmembrane G-protein-coupled receptor therefore represents an attractive target for therapeutic inhibitors. We thus used a computational design to develop a new PAR1 antagonist, namely, a catalytically inactive human KLK4 that acts as a proteinase substrate-capture reagent, preventing receptor cleavage (and hence activation) by binding to and occluding the extracellular R41-S42 canonical PAR1 proteolytic activation site. On the basis of in silico site-saturation mutagenesis, we then generated KLK4S207A,L185D, a first-of-a-kind ‘decoy’ PAR1 inhibitor, by mutating the S207A and L185D residues in wild-type KLK4, which strongly binds to PAR1. KLK4S207A,L185D markedly inhibited PAR1 cleavage, and PAR1-mediated MAPK/ERK activation as well as the migration and invasiveness of melanoma cells. This ‘substrate-capturing’ KLK4 variant, engineered to bind to PAR1, illustrates proof of principle for the utility of a KLK4 ‘proteinase substrate capture’ approach to regulate proteinase-mediated PAR1 signaling.


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