Brief report: Lymph node morphology in stage II colorectal cancer.

BACKGROUND: Colorectal cancer is one of the leading causes of cancer-associated morbidity and mortality worldwide. The local anti-tumour immune response is particularly important for patients with stage II where the tumour-draining lymph nodes have not yet succumbed to tumour spread. The lymph nodes allow for the expansion and release of B cell compartments such as primary follicles and germinal centres. A variation in this anti-tumour immune response may influence the observed clinical heterogeneity in stage II patients. AIM: The aim of this study was to explore tumour-draining lymph node histomorphological changes and tumour pathological risk factors including the immunomodulatory microRNA-21 (miR-21) in a small cohort of stage II CRC. METHODS: A total of 23 stage II colorectal cancer patients were included. Tumour and normal mucosa samples were analysed for miR-21 expression levels and B-cell compartments were quantified from Haematoxylin and Eosin slides of lymph nodes. These measures were compared to clinicopathological risk factors such as perforation, bowel obstruction, T4 stage and high-grade. RESULTS: We observed greater Follicle density in patients with a lower tumour T stage and higher germinal centre density in patients with higher pre-operative carcinoembryonic antigen levels. Trends were also detected between tumours with deficiency in mismatch repair proteins, lymphatic invasion and both the density and size of B-cell compartments. Lastly, elevated tumour miR-21 was associated with decreased Follicle and germinal centre size. CONCLUSION: Variation in B-cell compartments of tumour-draining lymph nodes is associated with clinicopathological risk factors in stage II CRC patients.

Neoadjuvant therapy in rectal cancer: how are we choosing?

BACKGROUND: Neoadjuvant therapy has revolutionized the management of rectal cancer; however, there is a need to examine the factors driving neoadjuvant treatment allocation. This study aimed to describe patterns of treatment allocation for patients with rectal cancer at our institution and identify predictors for receiving neoadjuvant therapy, and for choice of short- or long-course therapy. METHODS: A retrospective review of a prospectively maintained database of 122 patients undergoing surgical resection for rectal cancer with curative intent, between 1 November 2012 and 31 October 2017. Univariate and multivariate analyses were performed to identify factors that determined which patients received neoadjuvant therapy, and whether it was short or long course. RESULTS: Eighty-six patients (70%) received neoadjuvant therapy. Independent predictors for receiving neoadjuvant therapy were T3-4 tumours (P < 0.001), node-positive disease (P = 0.005) and mid (P = 0.045) or low rectal cancers (P < 0.001). Of those receiving neoadjuvant therapy, 38 (44%) received short course and 48 (56%) received long course. Node-positive disease was the only predictor for receiving long rather than short-course neoadjuvant therapy (P = 0.002). Overall, these factors predicted 76% of neoadjuvant treatment allocation. Our predictor model identified important areas of variance in our decision-making. CONCLUSION: Utilizing the identified factors, it appears that consistent decisions regarding neoadjuvant therapy are being made the majority of the time. These decisions are largely driven by T and N stage as well as tumour height. Mesorectal fascia involvement, pre-treatment carcinoembryonic antigen, age and comorbidity also influenced decision-making to a lesser and more variable extent.

Pre-operative carcinoembryonic antigen predicts survival following colorectal cancer surgery with curative intent.

BACKGROUND: Circulating biomarkers may be of value in providing additional prognostic information to the TNM staging system. Previous population-level studies suggest a prognostic role for pre-operative carcinoembryonic antigen (CEA). The purpose of this study is to verify the prognostic role of pre-operative CEA at the individual level, in a New Zealand cohort of colorectal cancer patients. METHODS: Retrospective cohort study of patients undergoing potentially curative surgery for colorectal adenocarcinoma between 2010 and 2012 at a tertiary hospital in New Zealand. One hundred and thirty-nine patients had pre-operative CEA data available and were included in the study. The main outcomes measured were overall survival (OS) and disease-free survival (DFS) over a minimum of 5 years of follow up. RESULTS: Pre-operative CEA was requested in 138 out of 237 (58.2%) patients undergoing surgery. The median age was 71 years and median follow-up duration 61 months. High CEA was not associated with the incidence of disease recurrence (P = 0.69). A significant difference was found between high and low CEA for OS (P = 0.09) and DFS (P = 0.04). On multi-variate survival analysis, pre-operative CEA was identified as an independent predictor of OS (HR 2.50, 95% CI 1.17-5.36, P = 0.02) and DFS (HR 1.78, 95% CI 1.02-3.13, P = 0.04). CONCLUSION: We identified pre-operative CEA as an independent predictor of OS and DFS on an individual level. CEA offers additional prognostic value to TNM staging and should be requested routinely as part of the pre-operative work-up.

Disease recurrence following surgery for colorectal cancer: five-year follow-up.

AIM: To describe the patterns of recurrence in a contemporaneous cohort of patients undergoing surgery with curative intent for colorectal adenocarcinoma at a New Zealand hospital with five-year follow-up. METHODS: Patients with colorectal cancer undergoing potentially curative surgery between January 2010 and December 2012 were followed up for a median of 61 months with three-monthly CEA (carcinoembryonic antigen), a colonoscopy after one year and yearly computed tomography scans of the chest, abdomen and pelvis for the first three years. RESULTS: Overall, 59/237 (24.9%) of patients experienced disease recurrence, the most common sites being the liver, followed by the lung and local recurrence. Recurrence rates did not differ significantly between colon and rectal cancer and ranged from 5.1% in stage I to 60% in stage IV. Seventy-three percent of all recurrences were observed within the first 24 months post-operatively. CONCLUSION: While New Zealand outcomes in colorectal cancer have historically compared unfavourably against international standards, the outcomes observed in this cohort are encouraging and may reflect advances in care, including multidisciplinary team discussion, increased use of adjuvant therapy, surgical subspecialisation and protocolled surveillance and follow-up.

The expression of S100A8 in pancreatic cancer-associated monocytes is associated with the Smad4 status of pancreatic cancer cells.

The cross-talk between tumour cells and the surrounding supporting host cells (stroma) is a key regulator of cancer growth and progression. By undertaking 2-DE analysis of laser capture microdissected malignant and stromal components of pancreatic tumours and benign ductal elements, we have identified high levels of S100A8 and S100A9 in tumour-associated stroma but not in benign or malignant epithelia. Immunohistochemical analysis (n = 71 patients) revealed strong expression of both proteins in stromal myeloid cells, subsequently identified as CD14(+)/CD68(- )monocytes/macrophages. Co-immunofluorescence revealed that S100A8 was expressed in a subset of S100A9-positive cells. Correlation of the expression of S100A8 and S100A9 to patient parameters revealed that the microenvironments of tumours which lacked expression of the tumour suppressor protein, Smad4, had significantly reduced numbers of S100A8-immunoreactive (p = 0.023) but not S100A9-immunoreactive (p = 0.21) cells. The ratio of S100A8- to S100A9-positive cells within individual tumours was significantly lower in Smad4-negative tumours than in Smad4-positive tumours (p<0.003). Pancreatitic specimens also contained S100A8- and S100A9-expressing cells, although this was not observed in regions displaying extensive fibrosis. In conclusion, our study provides an extensive analysis of S100A8 and S100A9 in pancreatic disease and highlights a potentially important relationship between pancreatic cancer cells and their surrounding microenvironment.

Application of laser capture microdissection combined with two-dimensional electrophoresis for the discovery of differentially regulated proteins in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal of all the common malignancies and markers for early detection or targets for treatment of this disease are urgently required. The disease is characterised by a strong stromal response, with cancer cells usually representing a relatively small proportion of the cells in the tumor mass. We therefore performed laser capture microdissection (LCM) to enrich for both normal and malignant pancreatic ductal epithelial cells. Proteins extracted from these cells were then separated by two-dimensional gel electrophoresis (2-DE). The limited amounts of protein in the LCM procured samples necessitated the detection of 2-DE resolved proteins by silver staining. Consequently, loading equivalent amounts of protein onto gels was essential. However, we found that conventional means of measuring total protein in the samples were not sufficiently accurate. We therefore adopted a strategy in which the samples were first separated by one-dimensional sodium dodecyl sulphate-polyacrylamide gel electrophoresis, stained with silver stain and subjected to densitometry. Evaluation of the staining intensity was then used to normalise the samples. We found that the protein profiles from undissected normal pancreas and LCM-acquired non-malignant ductal epithelial cells from the same tissue block were different, underpinning the value of LCM in our analysis. The comparisons of protein profiles from nonmalignant and malignant ductal epithelial cells revealed nine protein spots that were consistently differentially regulated. Five of these proteins showed increased expression in tumor cells while four showed diminished expression in these cells. One of the proteins displaying enhanced expression in tumor cells was identified as the calcium-binding protein, S100A6. To determine the incidence of S100A6 overexpression in pancreatic cancer, we carried out immunohistochemical analysis on sections from a pancreas cancer tissue array containing 174 duplicate normal and malignant pancreatic tissue samples, from 46 pancreas cancer patients. Normal pancreatic ductal epithelia were either devoid of detectable S100A6 or showed weak expression only. Moderately or poorly differentiated tumors, by contrast, showed a higher incidence and a higher level of S100A6 expression. These observations indicate that the combination of LCM with 2-DE provides an effective strategy to discover proteins that are differentially expressed in PDAC.

Update on pancreatic cancer.

Pancreatic cancer is one of the commonest causes of cancer death worldwide. Patients with pancreatic cancer benefit from resectional surgery (improved quality of life) and adjuvant treatment (enhanced survival). This review covers advances in the understanding of the development of pancreatic cancer, state-of-the-art clinical management and, finally, novel treatment and screening techniques.