Contrast-enhanced CT radiomics features to preoperatively identify differences between tumor and proximal tumor-adjacent and tumor-distant tissues of resectable esophageal squamous cell carcinoma.

BACKGROUND: Esophagectomy is the main treatment for esophageal squamous cell carcinoma (ESCC), and patients with histopathologically negative margins still have a relatively higher recurrence rate. Contrast-enhanced CT (CECT) radiomics might noninvasively obtain potential information about the internal heterogeneity of ESCC and its adjacent tissues. This study aimed to develop CECT radiomics models to preoperatively identify the differences between tumor and proximal tumor-adjacent and tumor-distant tissues in ESCC to potentially reduce tumor recurrence. METHODS: A total of 529 consecutive patients with ESCC from Centers A (n = 447) and B (n = 82) undergoing preoperative CECT were retrospectively enrolled in this study. Radiomics features of the tumor, proximal tumor-adjacent (PTA) and proximal tumor-distant (PTD) tissues were individually extracted by delineating the corresponding region of interest (ROI) on CECT and applying the 3D-Slicer radiomics module. Patients with pairwise tissues (ESCC vs. PTA, ESCC vs. PTD, and PTA vs. PTD) from Center A were randomly assigned to the training cohort (TC, n = 313) and internal validation cohort (IVC, n = 134). Univariate analysis and the least absolute shrinkage and selection operator were used to select the core radiomics features, and logistic regression was performed to develop radiomics models to differentiate individual pairwise tissues in TC, validated in IVC and the external validation cohort (EVC) from Center B. Diagnostic performance was assessed using area under the receiver operating characteristics curve (AUC) and accuracy. RESULTS: With the chosen 20, 19 and 5 core radiomics features in TC, 3 individual radiomics models were developed, which exhibited excellent ability to differentiate the tumor from PTA tissue (AUC: 0.965; accuracy: 0.965), the tumor from PTD tissue (AUC: 0.991; accuracy: 0.958), and PTA from PTD tissue (AUC: 0.870; accuracy: 0.848), respectively. In IVC and EVC, the models also showed good performance in differentiating the tumor from PTA tissue (AUCs: 0.956 and 0.962; accuracy: 0.956 and 0.937), the tumor from PTD tissue (AUCs: 0.990 and 0.974; accuracy: 0.952 and 0.970), and PTA from PTD tissue (AUCs: 0.806 and 0.786; accuracy: 0.760 and 0.786), respectively. CONCLUSION: CECT radiomics models could differentiate the tumor from PTA tissue, the tumor from PTD tissue, and PTA from PTD tissue in ESCC.

Inflammation- and Metastasis-Related Proteins Expression Changes in Early Stages in Tumor and Non-Tumor Adjacent Tissues of Colorectal Cancer Samples.

Chronic inflammation can induce malignant cell transformation, having an important role in all colorectal cancer (CRC) phases. Non-tumor adjacent tissue plays an important role in tumor progression, but its implication in CRC has not yet been fully elucidated. The aim was to analyze the expression of inflammatory, epithelial-mesenchymal transition (EMT), and metastasis-related proteins in both tumor and non-tumor adjacent tissues from CRC patients by western blot. Tumor tissue presented an increase in metastasis and EMT-related proteins compared to non-tumor adjacent tissue, especially in stage II. Tumor tissue stage II also presented an increase in inflammatory-related proteins compared to other stages, which was also seen in non-tumor adjacent tissue stage II. Additionally, the relapse-free survival study of Vimentin and VEGF-B expression levels in stage II patients showed that the higher the expression levels of each protein, the lower 10-year relapse-free survival. These could suggest that some metastasis-related signalling pathways may be activated in stage II in tumor tissue, accompanied by an increase in inflammation. Furthermore, non-tumor adjacent tissue presented an increase of the inflammatory status that could be the basis for future tumor progression. In conclusion, these proteins could be useful as biomarkers of diagnosis for CRC at early stages.

Apparent diffusion coefficient derived from diffusion-weighted imaging to differentiate between tumor, tumor-adjacent and tumor-distant tissues in resectable rectal adenocarcinoma.

PURPOSE: To evaluate feasibility of apparent diffusion coefficient (ADC) at different b-values to differentiate between tumor, tumor-adjacent and tumor-distant tissues in rectal adenocarcinoma (RA). MATERIALS AND METHODS: Seventy consecutive patients with RA undergoing preoperative diffusion-weighted imaging were retrospectively enrolled. ADCs of tumor, proximal tumor-adjacent tissue (PTA) and tumor-distant tissue (PTD), and distal tumor-adjacent tissue (DTA) and tumor-distant tissue (DTD) were calculated with b-values of 0 and 800 sec/mm2, 0 and 1000 sec/mm2, 0 and 1500 sec/mm2, and multiple b-values of 0, 50, 100, 800, 1000 and 1500 sec/mm2. Statistical analysis was performed to determine feasibility of ADC to differentiate between pairwise tissues. RESULTS: Mean ADC of tumor was lower than those of PTA, PTD, DTA and DTD; and mean ADCs of PTA and DTA were lower than those of PTD and DTD at all b-values, respectively (all P-values < 0.001). ADC cut-offs of 1.089 × 10-3 mm2/sec (b = 0, 1000 sec/mm2) or 1.215 × 10-3 mm2/sec (b = 0, 800 sec/mm2), and 1.142 × 10-3 mm2/sec (b = 0, 1000 sec/mm2) or 0.995 × 10-3 mm2/sec (b = 0, 1500 sec/mm2) achieved excellent performance in differentiating tumor from PTA or PTD, and tumor from DTA or DTD (area under receiver operating characteristic curves [AUCs]: 0.813 or 0.952, and 0.970 or 0.996), respectively. ADC cut-offs of 1.625 × 10-3 mm2/sec (b = 0, 800 sec/mm2), and 1.165 × 10-3 mm2/sec (b = 0, 1500 sec/mm2) could differentiate PTA from PTD, and DTA from DTD (AUCs: 0.709 and 0.673), respectively. CONCLUSION: ADC can help differentiate between tumor, tumor-adjacent and tumor-distant tissues in RA.

Tumor budding and adjacent tissue at the invasive front correlate with delayed neck metastasis in clinical early-stage tongue squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: Some patients with early-stage oral cancer have a poor prognosis owing to the delayed neck metastasis (DNM). Tumor budding is reportedly a promising prognostic marker in many cancers. Moreover, the tissue surrounding a tumor is also considered to play a prognostic role. In this study, we evaluated whether tumor budding and adjacent tissue at the invasive front can be potential novel predictors of DNM in early tongue cancer. METHODS: In total, 337 patients with early-stage tongue squamous cell carcinoma were retrospectively reviewed. The patient characteristics and histopathological factors were evaluated for association with DNM. DNM rates were calculated; items which were significant in the univariate analysis were used as explanatory variables, and independent factors for DNM were identified by the multivariate analysis. RESULTS: The univariate analysis identified T classification, depth of invasion, tumor budding, vascular invasion, and adjacent tissue at the invasive front as significant predictors of DNM; the multivariate analysis using these factors revealed all the above variables except vascular invasion, which are independent predictors of DNM. CONCLUSION: In addition to conventional predictors, high grade tumor budding and adjacent tissue at the invasive front can serve as useful predictors of DNM in early tongue cancer.

Non-tumor adjacent tissue of advanced stage from CRC shows activated antioxidant response.

Colorectal cancer (CRC) is a leading cause of malignant cancer-related morbidity and mortality, with a higher incidence in developed countries and a high mortality rate mainly attributable to metastases. The aim of the present study was to determine the metabolic adaptations related to oxidative stress in tumor tissue from advanced stages (III and IV) of CRC and whether they could be used as potential biomarkers for clinical applications. To tackle this aim, we have analyzed the protein expression levels related to oxidative stress and the enzymatic activities of MnSOD and catalase, comparing samples of non-tumor adjacent tissue and tumor tissue of CRC patients in stages III and IV. The results showed no differences between stage III and IV in tumor tissues for any of the proteins studied. However, some differences were found between samples of non-tumor adjacent tissue and tumor tissue for some of the antioxidant enzymes. Overwhelmingly, the greatest differences were detected when comparing samples of non-tumor adjacent tissue from stage III and stage IV. To the best of our knowledge, this is the first study where differences between the non-tumor adjacent tissues of CRC patients from different cancer stages were determined. This study suggests that the parameters analyzed should be evaluated as biomarkers for the evolution of CRC. Furthermore, tumor tissue status should not be of sole importance for the prognosis of CRC, as the non-tumor adjacent tissues could also merit consideration.

Breast Cancers Activate Stromal Fibroblast-Induced Suppression of Progenitors in Adjacent Normal Tissue.

Human breast cancer cells are known to activate adjacent "normal-like" cells to enhance their own growth, but the cellular and molecular mechanisms involved are poorly understood. We now show by both phenotypic and functional measurements that normal human mammary progenitor cells are significantly under-represented in the mammary epithelium of patients' tumor-adjacent tissue (TAT). Interestingly, fibroblasts isolated from TAT samples showed a reduced ability to support normal EGF-stimulated mammary progenitor cell proliferation in vitro via their increased secretion of transforming growth factor ß. In contrast, TAT fibroblasts promoted the proliferation of human breast cancer cells when these were co-transplanted in immunodeficient mice. The discovery of a common stromal cell-mediated mechanism that has opposing growth-suppressive and promoting effects on normal and malignant human breast cells and also extends well beyond currently examined surgical margins has important implications for disease recurrence and its prevention.

Hypermethylation of CDKN2A exon 2 in tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients.

BACKGROUND: Breast carcinogenesis is a multistep process involving genetic and epigenetic changes. Tumor tissues are frequently characterized by gene-specific hypermethylation and global DNA hypomethylation. Aberrant DNA methylation levels have, however, not only been found in tumors, but also in tumor-surrounding tissue appearing histologically normal. This phenomenon is called field cancerization. Knowledge of the existence of a cancer field and its spread are of clinical relevance. If the tissue showing pre-neoplastic lesions is not removed by surgery, it may develop into invasive carcinoma. METHODS: We investigated the prevalence of gene-specific and global DNA methylation changes in tumor-adjacent and tumor-distant tissues in comparison to tumor tissues from the same breast cancer patients (n = 18) and normal breast tissues from healthy women (n = 4). Methylation-sensitive high resolution melting (MS-HRM) analysis was applied to determine methylation levels in the promoters of APC, BRCA1, CDKN2A (p16), ESR1, HER2/neu and PTEN, in CDKN2A exon 2 and in LINE-1, as indicator for the global DNA methylation extent. The methylation status of the ESR2 promoter was determined by pyrosequencing. RESULTS: Tumor-adjacent and tumor-distant tissues frequently showed pre-neoplastic gene-specific and global DNA methylation changes. The APC promoter (p = 0.003) and exon 2 of CDKN2A (p < 0.001) were significantly higher methylated in tumors than in normal breast tissues from healthy women. For both regions, significant differences were also found between tumor and tumor-adjacent tissues (p = 0.001 and p < 0.001, respectively) and tumor and tumor-distant tissues (p = 0.001 and p < 0.001, respectively) from breast cancer patients. In addition, tumor-adjacent (p = 0.002) and tumor-distant tissues (p = 0.005) showed significantly higher methylation levels of CDKN2A exon 2 than normal breast tissues serving as control. Significant correlations were found between the proliferative activity and the methylation status of CDKN2A exon 2 in tumor (r = -0.485, p = 0.041) and tumor-distant tissues (r = -0.498, p = 0.036). CONCLUSIONS: From our results we can conclude that methylation changes in CDKN2A exon 2 are associated with breast carcinogenesis. Further investigations are, however, necessary to confirm that hypermethylation of CDKN2A exon 2 is associated with tumor proliferative activity.