A novel fluorescent c-met targeted imaging agent for intra-operative colonic tumour mapping: Translation from the laboratory into a clinical trial.

BACKGROUND: The c-Met protein is overexpressed in many gastrointestinal cancers. We explored EMI-137, a novel c-Met targeting fluorescent probe, for application in fluorescence-guided colon surgery, in HT-29 colorectal cancer (CRC) cell line and an in vivo murine model. METHODS: HT-29 SiRNA transfection confirmed specificity of EMI-137 for c-Met. A HT-29 CRC xenograft model was developed in BALB/c mice, EMI-137 was injected and biodistribution analysed through in vivo fluorescent imaging. Nine patients, received a single intravenous EMI-137 bolus (0.13 mg/kg), 1-3 h before laparoscopic-assisted colon cancer surgery (NCT03360461). Tumour and LN fluorescence was assessed intraoperatively and correlated with c-Met expression in eight samples by immunohistochemistry. FINDINGS: c-Met expression HT-29 cells was silenced and imaged with EMI-137. Strong EMI-137 uptake in tumour xenografts was observed up to 6 h post-administration. At clinical trial, no serious adverse events related to EMI-137 were reported. Marked background fluorescence was observed in all participants, 4/9 showed increased tumour fluorescence over background; 5/9 had histological LN metastases; no fluorescent LN were detected intraoperatively. All primary tumours (8/8) and malignant LN (15/15) exhibited high c-Met protein expression. INTERPRETATION: EMI-137, binds specifically to the human c-Met protein, is safe, and with further refinement, shows potential for application in fluorescence-guided surgery.

The utility of c-Met as a diagnostic tissue biomarker in primary colorectal cancer.

The transmembrane protein, c-Met, is thought to be overexpressed and activated in colorectal cancer (CRC). This study explored its potential as a diagnostic tissue biomarker for CRC in a large human CRC tissue collection obtained from a randomized clinical trial. Tissue microarrays of matched normal colorectal epithelium and primary cancer were prepared from specimens obtained from 280 patients recruited to the MRC CLASICC trial (ISRCTN 74883561) and interrogated using immunohistochemistry for c-Met expression. The distribution and intensity of immunopositivity was graded using a validated, semi-quantifiable score, and differences in median scores analysed using the Wilcoxon signed-rank test. A receiver operating characteristic (ROC) curve was plotted to measure the diagnostic accuracy of c-Met as a biomarker in CRC. Epithelial cell membrane expression of c-Met differed significantly between CRC and normal colorectal tissue: median 12.00 (Interquartile range (IQR) 6-15) versus median 6.00 (IQR 2.70-12.00) respectively (P = <.0001). ROC-AUC analysis of c-Met expression yielded a CRC diagnostic probability of 0.66 (95% CI: 0.61 to 0.70; P < .0001). A score of ≥14.50 showed high specificity at 85.32% (95% CI 80.33%-89.45%) but sensitivity of only 30.92% (CI 25.37%-36.90%). Thus c-Met is consistently overexpressed in human CRC as compared to normal colorectal epithelium tissue. c-Met expression may have a role in diagnosis and prognostication if combined with other biomarkers.

Is medullary carcinoma of the colon underdiagnosed? An audit of poorly differentiated colorectal carcinomas in a large national health service teaching hospital.

AIMS: Medullary carcinoma is an uncommon colorectal tumour which appears poorly differentiated histologically. Consequently, it may be confused with poorly differentiated adenocarcinoma not otherwise specified (NOS). The principal aim of this study was to review a large series of poorly differentiated colorectal cancers resected at a large National Health Service (NHS) Teaching Hospital to determine how often medullary carcinomas were misclassified . Secondary aims were to investigate how often neuroendocrine differentiation or metastatic tumours were considered in the differential diagnosis, and compare clinico-pathological features between medullary and poorly differentiated adenocarcinoma NOS. METHODS AND RESULTS: Histology slides from 302 colorectal cancer resections originally reported as poorly differentiated adenocarcinoma were reviewed and cases fulfilling World Health Organisation (WHO) criteria for medullary carcinoma identified. The original pathology report was examined for any mention of medullary phenotype, consideration of neuroendocrine differentiation or consideration of metastasis from another site. Clinico-pathological features were compared to poorly differentiated adenocarcinoma NOS. Only one-third of medullary carcinomas were correctly identified between 1997 and 2018. The other two-thirds were reported as poorly differentiated adenocarcinoma NOS. The possibility of an extracolonic origin or neuroendocrine carcinoma was considered in 21 and 27% of reports. Most medullary carcinomas exhibited mismatch repair deficiency, were located in ascending colon and caecum and had a lower rate of vascular channel invasion and lymph node metastasis compared to poorly differentiated adenocarcinoma. CONCLUSIONS: Medullary carcinoma of the colon is often mistaken for poorly differentiated adenocarcinoma NOS and occasionally for neuroendocrine or metastatic carcinoma. Greater familiarity with morphological criteria and use of mismatch repair protein staining should improve diagnosis.

CT assessment of right colonic arterial anatomy pre and post cancer resection - a potential marker for quality and extent of surgery?

BACKGROUND: There is conflicting opinion as to the optimum extent of resection for right-sided colonic cancer, which is currently graded by pathological analysis of the resected specimen. It is not known if computed tomography (CT) analysis of residual post-resection arterial stump length could be used as an alternative in vivo marker for extent of mesenteric resection. Ileocolic artery stumps have been demonstrated previously on CT after right hemicolectomy, but only in the early postoperative period. PURPOSE: To analyze preoperative right colonic arterial anatomy using portal venous colorectal cancer staging CT and subsequently determine if post-resection arterial stumps (a potential in vivo marker of surgical resection) could be consistently identified using routine follow-up CT scans many months after cancer resection. MATERIAL AND METHODS: A retrospective analysis of routine staging and follow-up CT scans for 151 patients with right-sided colorectal cancer was performed. Preoperative right colonic arterial anatomy and postoperative arterial stumps were analyzed and measured. RESULTS: Preoperative ileocolic (98.8%), middle (94.7%), and right colic artery (23.8%) identification was comparable to catheter angiogram studies. Postoperative ileocolic stumps were consistently demonstrated (88.3%) many months (average, 2 years and 42 days) after resection and were significantly longer than expected for a standard D2 resection (paired t-test, t(127) = -11.45, P ≤ 0.001). CONCLUSION: This is the first study to successfully demonstrate ileocolic arterial stumps many months (and years) after cancer resection using routine portal venous CT. Further prospective research should assess whether arterial stumps can be used as an in vivo marker of surgical quality and extent.

Histopathological work-up of resection specimens, local excisions and biopsies in colorectal cancer.

The pathological examination of material removed from patients with colorectal neoplasia is important. It provides a wide range of information on, for example, the quality and completeness of excision, the stage and biological aggressiveness, the need for further therapy, and response to therapy. Molecular testing adds valuable information on genetic risk and is required before treatment with anti-EGF-r antibodies. This article highlights the value derived from macroscopic inspection of surgical specimens, careful microscopy and excellent reporting according to national guidelines. Increasing use of a number of preoperative therapies and combinations in rectal cancer change the pathological features found and a standardised approach to the diagnosis of complete response is required. It touches upon the issues with frequent changes in TNM staging and the difficulties these changes are causing. The widespread introduction of bowel cancer screening is changing the stage of presentation of colorectal cancer leading to increasing numbers of local excisions and polyp cancers.