Stem Cell Marker Expression in Early Stage Colorectal Cancer is Associated with Recurrent Intestinal Neoplasia.

BACKGROUND: Colorectal cancer (CRC) ranks second in cancer deaths worldwide and presents multiple management challenges, one of which is identifying high risk stage II disease that may benefit from adjuvant therapy. Molecular biomarkers, such as ones that identify stem cell activity, could better stratify high-risk cohorts for additional treatment. METHODS: To identify possible biomarkers of high-risk disease in early-stage CRC, a discovery set (n = 66) of advanced-stage tumors were immunostained with antibodies to stemness proteins (CD166, CD44, CD26, and LGR5) and then digitally analyzed. Using a second validation cohort (n = 54) of primary CRC tumors, we analyzed protein and gene expression of CD166 across disease stages, and extended our analyses to CD166-associated genes (LGR5, ASCL2, BMI1, POSTN, and VIM) by qRT-PCR. RESULTS: Stage III and metastatic CRC tumors highly expressed stem cell-associated proteins, CD166, CD44, and LGR5. When evaluated across stages, CD166 protein expression was elevated in advanced-stage compared to early-stage tumors. Notably, a small subset of stage I and II cancers harbored elevated CD166 protein expression, which correlated with development of recurrent cancer or adenomatous polyps. Gene expression analyses of CD166-associated molecules revealed elevated ASCL2 in primary tumors from patients who recurred. CONCLUSIONS: We identified a protein signature prognostic of aggressive disease in early stage CRC. Stem cell-associated protein and gene expression identified a subset of early-stage tumors associated with cancer recurrence and/or subsequent adenoma formation. Signatures for stemness offer promising fingerprints for stratifying early-stage patients at high risk of recurrence.

Hepatic resection of solitary HCC in the elderly: A unique disease in a growing population.

BACKGROUND: Management of elderly patients with solitary hepatocellular carcinoma (sHCC) is challenging with perceived clinicopathologic differences driving treatment options. We sought to determine factors predictive of disease control and survival after hepatic resection of sHCC in elderly patients. METHODS: We identified n = 45 elderly patients (³≥65 yo) with sHCC treated with hepatic resection alone from our prospective database from 2003-16. Clinicopathologic data were analyzed and survival was assessed from the time of hepatic resection. RESULTS: The median age was 75-years-old. Less than half of patients (47%) had viral hepatitis. At resection, the median Child-Pugh score was A6, median tumor size 5 cm, and mean AFP of 1050 (ng/mL). Major hepatectomy was performed in 23 patients (51%) with R0 resection achieved in 96%. Two patients (4%) had Grade III complications with no mortalities at 30 days and one death (2%) at 90-days. After R0 resection 44% (n = 20) had intrahepatic recurrence at a median of 32 months (95% CI: 15-46) with 20% (n = 9) developing extrahepatic recurrence at a median of 78 months (95% CI: 78-.). The median survival was 72 months (95% CI: 30-108 months). For patients with at least 3 years of follow-up, the 1-, 3-, and 5-year overall survival was 74%, 59%, and 50%, respectively. Mortality was associated with higher AFP and lower Prognostic Nutritional Index (PNI). CONCLUSION: Carefully selected elderly patients with sHCC appear to have unique disease that is amenable to hepatic resection with low morbidity and mortality with excellent overall and recurrence-free survival.

Colorectal Cancer Liver Metastasis: Evolving Paradigms and Future Directions.

In patients with colorectal cancer (CRC) that metastasizes to the liver, there are several key goals for improving outcomes including early detection, effective prognostic indicators of treatment response, and accurate identification of patients at high risk for recurrence. Although new therapeutic regimens developed over the past decade have increased survival, there is substantial room for improvement in selecting targeted treatment regimens for the patients who will derive the most benefit. Recently, there have been exciting developments in identifying high-risk patient cohorts, refinements in the understanding of systemic vs localized drug delivery to metastatic niches, liquid biomarker development, and dramatic advances in tumor immune therapy, all of which promise new and innovative approaches to tackling the problem of detecting and treating the metastatic spread of CRC to the liver. Our multidisciplinary group held a state-of-the-science symposium this past year to review advances in this rapidly evolving field. Herein, we present a discussion around the issues facing treatment of patients with CRC liver metastases, including the relationship of discrete gene signatures with prognosis. We also discuss the latest advances to maximize regional and systemic therapies aimed at decreasing intrahepatic recurrence, review recent insights into the tumor microenvironment, and summarize advances in noninvasive multimodal biomarkers for early detection of primary and recurrent disease. As we continue to advance clinically and technologically in the field of colorectal tumor biology, our goal should be continued refinement of predictive and prognostic studies to decrease recurrence after curative resection and minimize treatment toxicity to patients through a tailored multidisciplinary approach to cancer care.

Macrophage-Dependent Cytoplasmic Transfer during Melanoma Invasion In Vivo.

Interactions between tumor cells and tumor-associated macrophages play critical roles in the initiation of tumor cell motility. To capture the cellular interactions of the tumor microenvironment with high-resolution imaging, we directly visualized tumor cells and their interactions with macrophages in zebrafish. Live imaging in zebrafish revealed that macrophages are dynamic, yet maintain sustained contact with tumor cells. In addition, the recruitment of macrophages to tumor cells promotes tumor cell dissemination. Using a Cre/LoxP strategy, we found that macrophages transfer cytoplasm to tumor cells in zebrafish and mouse models. Remarkably, macrophage cytoplasmic transfer correlated with melanoma cell dissemination. We further found that macrophages transfer cytoplasm to tumor cells upon cell contact in vitro. Thus, we present a model in which macrophage/tumor cell contact allows for the transfer of cytoplasmic molecules from macrophages to tumor cells corresponding to increased tumor cell motility and dissemination.