Background: Approximately 15% of patients undergoing resection for presumed perihilar cholangiocarcinoma (PHC) have benign disease at final pathological assessment. Molecular imaging targeting... Show moreBackground: Approximately 15% of patients undergoing resection for presumed perihilar cholangiocarcinoma (PHC) have benign disease at final pathological assessment. Molecular imaging targeting tumor-specific biomarkers could serve as a novel diagnostic tool to reduce these futile surgeries. Imaging agents have been developed, selectively binding integrin alpha(nu)beta 6, a cell receptor upregulated in pancreatobiliary malignancies, for both (preoperative) PET and (intraoperative) fluorescent imaging. Here, expression of integrin alpha(nu)beta 6 is evaluated in PHC, intrahepatic cholangiocarcinoma (ICC), hepatocellular carcinoma (HCC) and benign disease mimicking PHC using immunohistochemistry.Materials & methods: Three tissue microarrays (TMA) including 103 PHC tumor cores and sixty tissue samples were selected from resection specimens of pathologically proven PHC (n = 20), ICC (n = 10), HCC (n = 10), metastatic PHC lymph nodes (n = 10) and benign disease (presumed PHC with benign disease at pathological assessment, n = 10). These samples were stained for integrin anb6 and quantified using the H-score.Results: Immunohistochemical staining for integrin alpha(nu)beta 6 showed membranous expression in all twenty PHC whole mount slides (100%) and 93 out of 103 (92%) PHC tumor cores. Mean H-score of PHC samples was 195 +/- 71, compared to a mean H-score of 126 +/- 57 in benign samples (p = 0.013). In both benign and PHC samples, inflammatory infiltrates and pre-existent peribiliary glands showed integrin anb6 expression. The mean H-score across ten ICC was 33 +/- 53, which was significantly lower compared to PHC (p < 0.001) but too weak to consistently discriminate ICC from HCC (H-score 0)(p = 0.062).Conclusion: Integrin anb6 is abundantly expressed in PHC and associated metastatic lymph nodes. Expression is significantly higher in PHC as compared to benign disease mimicking PHC, ICC and HCC, emphasizing its potential as a target for tumor-specific molecular imaging. (C) 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/ Show less
Tummers, W.S.; Miller, S.E.; Teraphongphom, N.T.; Berg, N.S. van den; Hasan, A.; Longacre, T.A.; ... ; Poultsides, G.A. 2019
Background: Although most patients with PDAC experience distant failure after resection, a significant portion still present with local recurrence. Intraoperative fluorescent imaging can... Show moreBackground: Although most patients with PDAC experience distant failure after resection, a significant portion still present with local recurrence. Intraoperative fluorescent imaging can potentially facilitate the visualization of involved peritumoral LNs and guide the locoregional extent of nodal dissection. Here, the efficacy of targeted intraoperative fluorescent imaging was examined in the detection of metastatic lymph nodes (LNs) during resection of pancreatic ductal adenocarcinoma (PDAC).Methods: A dose-escalation prospective study was performed to assess feasibility of tumor detection within peripancreatic LNs using cetuximab-IRDye800 in PDAC patients. Fluorescent imaging of dissected LNs was analyzed ex vivo macroscopically and microscopically and fluorescence was correlated with histopathology.Results: A total of 144 LNs (72 in the low-dose and 72 in the high-dose cohort) were evaluated. Detection of metastatic LNs by fluorescence was better in the low-dose (50 mg) cohort, where sensitivity and specificity was 100% and 78% macroscopically, and 91% and 66% microscopically. More importantly, this method was able to detect occult foci of tumor (measuring < 5 mm) with a sensitivity of 88% (15/17 LNs).Conclusion: This study provides proof of concept that intraoperative fluorescent imaging with cetuximab-IRDye800 can facilitate the detection of peripancreatic lymph nodes often containing subclinical foci of disease. Show less
Human embryonic stemcells (hESCs) can serve as a potentially limitless source of cells that may enable regeneration of diseased tissue and organs. Here we investigate the use of human embryonic... Show moreHuman embryonic stemcells (hESCs) can serve as a potentially limitless source of cells that may enable regeneration of diseased tissue and organs. Here we investigate the use of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) in promoting recovery from cardiac ischemia reperfusion injury in a mouse model. Using microarrays, we have described the hESC-CM transcriptome within the spectrum of changes that occur between undifferentiated hESCs and fetal heart cells. The hESC-CMs expressed cardiomyocyte genes at levels similar to those found in 20-week fetal heart cells, making this population a good source of potential replacement cells in vivo. Echocardiographic studies showed significant improvement in heart function by 8 weeks after transplantation. Finally, we demonstrate long-term engraftment of hESC-CMs by using molecular imaging to track cellular localization, survival, and proliferation in vivo. Taken together, global gene expression profiling of hESC differentiation enables a systems-based analysis of the biological processes, networks, and genes that drive hESC fate decisions, and studies such as this will serve as the foundation for future clinical applications of stem cell therapies. Show less
