No abstract

Metastatic uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years. There are no standard-of-care therapies available for the treatment of metastatic UM, hence it is a clinical area of urgent unmet need. Here, the clinical relevance and therapeutic potential of cysteinyl leukotriene receptors (CysLT1 and CysLT2) in UM was evaluated. High expression of CYSLTR1 or CYSLTR2 transcripts is significantly associated with poor disease-free survival and poor overall survival in UM patients. Digital pathology analysis identified that high expression of CysLT1 in primary UM is associated with reduced disease-specific survival (p = 0.012; HR 2.76; 95% CI 1.21–6.3) and overall survival (p = 0.011; HR 1.46; 95% CI 0.67–3.17). High CysLT1 expression shows a statistically significant (p = 0.041) correlation with ciliary body involvement, a poor prognostic indicator in UM. Small molecule drugs targeting CysLT1 were vastly superior at exerting anti-cancer phenotypes in UM cell lines and zebrafish xenografts than drugs targeting CysLT2. Quininib, a selective CysLT1 antagonist, significantly inhibits survival (p < 0.0001), long-term proliferation (p < 0.0001), and oxidative phosphorylation (p < 0.001), but not glycolysis, in primary and metastatic UM cell lines. Quininib exerts opposing effects on the secretion of inflammatory markers in primary versus metastatic UM cell lines. Quininib significantly downregulated IL-2 and IL-6 in Mel285 cells (p < 0.05) but significantly upregulated IL-10, IL-1β, IL-2 (p < 0.0001), IL-13, IL-8 (p < 0.001), IL-12p70 and IL-6 (p < 0.05) in OMM2.5 cells. Finally, quininib significantly inhibits tumour growth in orthotopic zebrafish xenograft models of UM. These preclinical data suggest that antagonism of CysLT1, but not CysLT2, may be of therapeutic interest in the treatment of UM.

Many recent reports in the North American literature have documented an increase in the ratio of proximal to distal colorectal cancers with an increase in right-sided lesions. In order to assess trends in the distribution of large bowel carcinoma at our hospital we reviewed the files of 1553 patients who presented with primary colorectal carcinoma over a 30-year period. Thirty-nine percent of patients were over 70 years old and 51% were in the 50-69 year age group. Seventy five percent of the carcinomas were left-sided, 22% right-sided and caecal carcinomas accounted for 18%. This distribution varied only slightly over the study period. Left-sided lesions were more common in males (55%: p less than 0.005), and right-sided lesions were more common in females (57%: p less than 0.005). Caecal carcinoma was more common in patients over 69 years old than in younger patients (p less than 0.001). In elderly females (greater than 69 years) 30% of colorectal carcinomas occurred in the caecum. These findings may have important implications for the investigation of patients with suspected colorectal disease or for screening programmes.

No abstract