RESUMO
The expression of the protein Mesothelin (MSLN) is highly variable in several malignancies including colorectal cancer (CRC) and high levels are associated with aggressive clinicopathological features and worse patient survival. CRC is both a common and deadly cancer; being the third most common in incidence and second most common cause of cancer related death. While systemic therapy remains the primary therapeutic option for most patients with stage IV (metastatic; m) CRC, their disease eventually becomes treatment refractory, and 85% succumb within 5 years. Microsatellite-stable (MSS) CRC tumors, which affect more than 90% of patients with mCRC, are generally refractory to immunotherapeutic interventions. In our current work, we characterize MSLN levels in CRC, specifically correlating expression with clinical outcomes in relevant CRC subtypes and explore how MSLN expression impacts the status of immune activation and suppression in the peritumoral microenvironment. High MSLN expression is highly prevalent in CMS1 and CMS4 CRC subtypes as well as in mCRC tissue and correlates with higher gene mutation rates across the patient cohorts. Further, MSLN-high patients exhibit increased M1/M2 macrophage infiltration, PD-L1 staining, immune-inhibitory gene expression, enrichment in inflammatory, TGF-ß, IL6/JAK/STAT3, IL2/STAT5 signaling pathways and mutation in KRAS and FBXW7. Together, these results suggest MSLN protein is a potential target for antigen-specific therapy and supports investigation into its tumorigenic effects to identify possible therapeutic interventions for patients with high MSLN expressing MSS CRC.
RESUMO
Background/Aims@#Endoscopic resection has become the preferred treatment approach for select early esophageal adenocarcinoma (EAC); however, the epidemiology of early stage disease has not been well defined. @*Methods@#Surveillance Epidemiology and End Results (SEER) data were analyzed to determine age-adjusted incidence rates among major epithelial carcinomas, including EAC, from 1973 to 2017. The percent change in incidence over time was compared according to tumor subtype. Early T-stage, node-negative EAC without metastasis was examined from 2004 to 2017 when precise T-stage data were available. @*Results@#The percent change in annual incidence from 1973 to 2017 was 767% for EAC. Joinpoint analysis showed that the average annual percent change in EAC from 1973 to 2017 was 5.11% (95% confidence interval, 4.66%–5.56%). The annual percent change appeared to plateau between 2004 and 2017; however, early EAC decreased from 2010 to 2017, with an annual percent change of -5.78%. @*Conclusions@#There has been a 7-fold increase in the incidence of EAC, which was significantly greater than that of the other major epithelial malignancies examined. More recently, the incidence of early EAC has been decreasing. Approximately one in five patients has node negative, potentially resectable early stage disease.
