Search

The accepted importance of a positive circumferential resection margin (CRM) (defined as R1 in the TNM classification) is based on histopathology of the resection specimen obtained after primary surgery in esophageal cancer patients. The aim of this study is to look for the prognostic value of CRM after neoadjuvant chemoradiotherapy and to compare the clinical significance of a histologically CRM < 1 mm from the cut margin (Royal College of Pathologists definition of R1) to a positive cut margin (College of American Pathologists definition of R1) and to ≥1 mm margin (R0) resections in patients with ypT3-esophageal tumors after neoadjuvant chemoradiotherapy. Between 2000 and 2014, 458 patients who received esophagectomy after neoadjuvant chemoradiation therapy were selected. Overall (OS) and disease-free survival (DFS) were calculated by means of Kaplan-Meier curves and compared by Cox regression analysis. There were 163 (35.9%) patients who had a ypT3 tumor; in 118 (72.4%) resection was complete (R0). In 37 (22.7%) patients a CRM < 1 mm was found and 8 (4.9%) had a circumferential R1-resection. CRM involvement was inversely correlated with tumor regression grading, lymph node capsular involvement, and number of positive lymph nodes. On univariate analysis, no statistically significant difference was found between R0-resection and CRM < 1 mm (P = 0.103) for OS, but DFS showed a significant difference (P = 0.025). Circumferential R1-resections showed a significant difference compared to R0-resections for OS and DFS (both P = 0.002). In multivariate analysis, extracapsular lymph node involvement and circumferential R1-resection were withheld as independent prognosticators for OS, whereas extracapsular lymph node involvement, absence of regression on the primary tumor and circumferential R1-resection were withheld for DFS. After correcting for different variables in the multivariate model, CRM < 1 mm showed no statistical difference compared to R0-resections neither for OS nor for DFS. After neoadjuvant chemoradiotherapy, CRM is correlated with biological behavior of the tumor and with therapy response. Furthermore it is an independent prognosticator for OS and DFS. HoweverCRM<1mm itself is no independent prognosticator for OS nor DFS survival in multivariable analysis. These results suggest that the definition of R1-resection should be limited to true invasion of the section plane. [ABSTRACT FROM AUTHOR]

Background:Microsatellite instability (MSI) accounts for 15% of all colorectal tumours. Several specific clinicopathologicals (e.g., preference for the proximal colon over the distal colon, improved prognosis and altered response to chemotherapeutics) are described for this subset of tumours. This study aimed to analyse morphological, inflammatory and angiogenic features of MSI vs microsatellite stable (MSS) tumours.Methods:Twenty-seven MSS and 29 MSI, TNM stage matched, colorectal tumours were selected from the archive of the Department of Pathology, UZ Leuven. Morphology was analysed on haematoxylin-eosin sections. Immunohistochemistry for CD3, CD4, CD8, CD20 and CD68 was used to map tumour infiltration in both a digital and traditional microscope-based manner for all distinct morphological components of the tumour. CD31 immunostains were performed to assess angiogenesis.Results:Morphological tumour heterogeneity was a marked feature of MSI tumours, occurring in 53% of the cases as compared with 11% of the MSS tumours (P<0.001). Digital immune quantification showed an increased number of tumour-infiltrating cytotoxic T-lymphocytes (CD8+) in MSI compared with MSS tumours for both the tumour (P=0.02) and peritumoural area (P=0.03). Traditional microscope-based quantification confirmed these results (P<0.001 for both) and, in addition, revealed large numbers of CD68+ macrophages in the peritumoural area of MSI cancers (P=0.001). Moreover, traditional microscope-based analysis was able to distinguish between lymphocytes directly infiltrating the tumoural glands (intra-epithelial) and those infiltrating only the neoplastic stroma around the glands (intratumoural). Quantification showed high numbers of intra-epithelial CD3+, CD4+, CD8+, CD20+ and CD68+ cells in MSI compared with MSS cancers (P<0.001, P=0.01, P<0.001, P<0.001 and P=0.006, respectively). Higher microvessel density (MVD) was observed in MSI tumours compared with their MSS counterpart.Conclusions:Mixed morphology, reflecting tumour heterogeneity, is an important feature of MSI tumours and may have both diagnostic and therapeutic impact. The inflammatory reaction also presented with significant differences in MSI vs MSS colorectal tumours. MSI cancers showed mainly infiltration by cytotoxic T-cells in both the tumour and the close border around the tumour, as well as increased intra-epithelial infiltration in contrast to MSS tumours. The type of immune cell and the compartment it resides in (intratumoural or intra-epithelial) depend both on MSI status and morphology. Finally, MSI tumours showed a higher angiogenic capacity represented by an increased MVD, hinting for possible therapeutic consequences. [ABSTRACT FROM AUTHOR]

Background:This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT).Methods:From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients.Results:One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response.Conclusions:We could not support the 'normalization hypothesis' and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed. [ABSTRACT FROM AUTHOR]