APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling.

BACKGROUND: 5-Fluorouracil(5FU) and oral analogues, such as capecitabine, remain one of the most useful agents for the treatment of colorectal adenocarcinoma. Low toxicity and convenience of administration facilitate use, however clinical resistance is a major limitation. Investigation has failed to fully explain the molecular mechanisms of resistance and no clinically useful predictive biomarkers for 5FU resistance have been identified. We investigated the molecular mechanisms of clinical 5FU resistance in colorectal adenocarcinoma patients in a prospective biomarker discovery project utilising gene expression profiling. The aim was to identify novel 5FU resistance mechanisms and qualify these as candidate biomarkers and therapeutic targets. METHODS: Putative treatment specific gene expression changes were identified in a transcriptomics study of rectal adenocarcinomas, biopsied and profiled before and after pre-operative short-course radiotherapy or 5FU based chemo-radiotherapy, using microarrays. Tumour from untreated controls at diagnosis and resection identified treatment-independent gene expression changes. Candidate 5FU chemo-resistant genes were identified by comparison of gene expression data sets from these clinical specimens with gene expression signatures from our previous studies of colorectal cancer cell lines, where parental and daughter lines resistant to 5FU were compared. A colorectal adenocarcinoma tissue microarray (n = 234, resected tumours) was used as an independent set to qualify candidates thus identified. RESULTS: APRIL/TNFSF13 mRNA was significantly upregulated following 5FU based concurrent chemo-radiotherapy and in 5FU resistant colorectal adenocarcinoma cell lines but not in radiotherapy alone treated colorectal adenocarcinomas. Consistent with APRIL's known function as an autocrine or paracrine secreted molecule, stromal but not tumour cell protein expression by immunohistochemistry was correlated with poor prognosis (p = 0.019) in the independent set. Stratified analysis revealed that protein expression of APRIL in the tumour stroma is associated with survival in adjuvant 5FU treated patients only (n = 103, p < 0.001), and is independently predictive of lack of clinical benefit from adjuvant 5FU [HR 6.25 (95%CI 1.48-26.32), p = 0.013]. CONCLUSIONS: A combined investigative model, analysing the transcriptional response in clinical tumour specimens and cancers cell lines, has identified APRIL, a novel chemo-resistance biomarker with independent predictive impact in 5FU-treated CRC patients, that may represent a target for novel therapeutics.

Is routine blood cross-matching necessary in elective laparoscopic colorectal surgery?

BACKGROUND: Routine pre-operative cross-matching of two units of packed red cells (PRC) is current practice in most hospitals for patients undergoing elective laparoscopic colorectal surgery (LCS). AIMS: To determine the usage of PRC in patients undergoing elective LCS & its cost implications. METHODS: Retrospective analysis of 116 consecutive laparoscopic colorectal resections under the care of 2 consultant surgeons. RESULTS: Surgical procedures were anterior resection (31.9%; n = 37), right hemicolectomy (22.4%; n = 26), sigmoid colectomy (22.4%; n-26), subtotal colectomy (7.8%; n = 9), APR (4.3%; n = 5), panproctocolectomy (3.4%; n = 4), completion proctectomy (1.7%, n = 2), left hemicolectomy (0.9%, n = 1), total colectomy (0.9%; n = 1) & resection rectopexy (0.9%; n = 1). The median age was 65 years, 58% female. The median pre-operative haemoglobin was 131 g/L, median blood loss 100 ml and median post-operative haemoglobin 111.5 g/L. Eleven cases were converted. Three patients required perioperative blood transfusion, 2 of whom underwent open conversion. The cost of carrying out a group & save (G&S) in our hospital is £40.60 excluding laboratory staff labour cost. A 2 unit cross-match costs £294.60. There is potential for substantial cost savings with change of practice to G&S only. CONCLUSION: G&S is sufficient to allow safe & cost-effective operative practice in laparoscopic colorectal surgery.