Stump Appendicitis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140214/1/sur.2013.163.pd

Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages

Pancreatic ductal adenocarcinoma (PDA) is accompanied by reprogramming of the local microenvironment, but changes at distal sites are poorly understood. We implanted biomaterial scaffolds, which act as an artificial premetastatic niche, into immunocompetent tumor-bearing and control mice, and identified a unique tumor-specific gene expression signature that includes high expression of C1qa, C1qb, Trem2, and Chil3 Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated C1qa, C1qb, and Trem2, the other with high Chil3, Ly6c2 and Plac8 In mice, expression of these genes in the corresponding populations was elevated in tumor-associated macrophages compared with macrophages in the normal pancreas. We then analyzed single-cell RNA sequencing from patient samples, and determined expression of C1QA, C1QB, and TREM2 is elevated in human macrophages in primary tumors and liver metastases. Single-cell sequencing analysis of patient blood revealed a substantial enrichment of the same gene signature in monocytes. Taken together, our study identifies two distinct tumor-associated macrophage and monocyte populations that reflects systemic immune changes in pancreatic ductal adenocarcinoma patients

Clinical Utility of Epigenetic Changes in Pancreatic Adenocarcinoma

Pancreatic cancer is a molecularly heterogeneous disease. Epigenetic changes and epigenetic regulatory mechanisms underlie at least some of this heterogeneity and contribute to the evolution of aggressive tumor biology in patients and the tumor’s intrinsic resistance to therapy. Here we review our current understanding of epigenetic dysregulation in pancreatic cancer and how it is contributing to our efforts in early diagnosis, predictive and prognostic biomarker development and new therapeutic approaches in this deadly cancer

Survival benefit with adjuvant radiotherapy after resection of distal cholangiocarcinoma: A propensity-matched National Cancer Database analysis.

BACKGROUND No convincing evidence for the benefit of adjuvant radiotherapy (RT) following resection of distal cholangiocarcinoma (dCCA) exists, especially for lower-risk (margin- or node-negative) disease. Hence, the association of adjuvant RT on survival after surgical resection of dCCA was compared with no adjuvant RT (noRT). METHODS Using National Cancer Database data from 2004 to 2016, patients undergoing pancreatoduodenectomy for nonmetastatic dCCA were identified. Patients with neoadjuvant RT and chemotherapy and survival <6 months were excluded. Propensity score matching was used to account for treatment-selection bias. A multivariable Cox proportional hazards model was then used to analyze the association of adjuvant RT with survival. RESULTS Of 2162 (34%) adjuvant RT and 4155 (66%) noRT patients, 1509 adjuvant RT and 1509 noRT patients remained in the cohort after matching. The rates of node-negative disease (N0), node-positive disease (N+), and unknown node status (Nx) were 39%, 51%, and 10%, respectively. After matching, adjuvant RT was associated with improved survival (median, 29.3 vs 26.8 months; P < .001), which remained after multivariable adjustment (HR, 0.86; 95% CI, 0.80-0.93; P < .001). Multivariable interaction analyses showed this benefit was seen irrespective of nodal status (N0: HR, 0.77; 95% CI, 0.66-0.89; P < .001; N+: HR, 0.79; 95% CI, 0.71-0.89; P < .001) and margin status (R0: HR, 0.58; 95% CI, 0.50-0.67; P < .001; R1: HR, 0.87; 95% CI, 0.78-0.96; P = .007). Stratified analyses by nodal and margin status demonstrated consistent results. CONCLUSIONS Adjuvant RT after dCCA resection was associated with a survival benefit in patients, even in patients with margin- or node-negative resections. Adjuvant RT should be considered routinely irrespective of margin and nodal status after resection for dCCA. LAY SUMMARY Adjuvant radiotherapy after resection of distal cholangiocarcinoma was associated with a survival benefit in patients, even in patients with margin-negative or node-negative resections. Adjuvant radiotherapy should be considered routinely irrespective of margin and nodal status after resection of distal cholangiocarcinoma

Bmi1 enhances tumorigenicity and cancer stem cell function in pancreatic adenocarcinoma.

Bmi1 is an integral component of the Polycomb Repressive Complex 1 (PRC1) and is involved in the pathogenesis of multiple cancers. It also plays a key role in the functioning of endogenous stem cells and cancer stem cells. Previous work implicated a role for cancer stem cells in the pathogenesis of pancreatic cancer. We hypothesized that Bmi1 plays an integral role in enhancing pancreatic tumorigenicity and the function of cancer stem cells in pancreatic ductal adenocarcinoma.We measured endogenous Bmi1 levels in primary human pancreatic ductal adenocarcinomas, pancreatic intraepithelial neoplasias (PanINs) and normal pancreas by immunohistochemistry and Western blotting. The function of Bmi1 in pancreatic cancer was assessed by alteration of Bmi1 expression in several cell model systems by measuring cell proliferation, cell apoptosis, in vitro invasion, chemotherapy resistance, and in vivo growth and metastasis in an orthotopic model of pancreatic cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human pancreatic cancer xenografts after Bmi1 silencing.Bmi1 was overexpressed in human PanINs, pancreatic cancers, and in several pancreatic cancer cell lines. Overexpression of Bmi1 in MiaPaCa2 cells resulted in increased proliferation, in vitro invasion, larger in vivo tumors, more metastases, and gemcitabine resistance while opposite results were seen when Bmi1 was silenced in Panc-1 cells. Bmi1 was overexpressed in the cancer stem cell compartment of primary human pancreatic cancer xenografts. Pancreatic tumorspheres also demonstrated high levels of Bmi1. Silencing of Bmi1 inhibited secondary and tertiary tumorsphere formation, decreased primary pancreatic xenograft growth, and lowered the proportion of cancer stem cells in the xenograft tissue.Our results implicate Bmi1 in the invasiveness and growth of pancreatic cancer and demonstrate its key role in the regulation of pancreatic cancer stem cells

The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer.

BackgroundPancreatic cancer stem cells (CSCs) represent a small subpopulation of pancreatic cancer cells that have the capacity to initiate and propagate tumor formation. However, the mechanisms by which pancreatic CSCs are maintained are not well understood or characterized.MethodsExpression of Notch receptors, ligands, and Notch signaling target genes was quantitated in the CSC and non-CSC populations from 8 primary human pancreatic xenografts. A gamma secretase inhibitor (GSI) that inhibits the Notch pathway and a shRNA targeting the Notch target gene Hes1 were used to assess the role of the Notch pathway in CSC population maintenance and pancreatic tumor growth.ResultsNotch pathway components were found to be upregulated in pancreatic CSCs. Inhibition of the Notch pathway using either a gamma secretase inhibitor or Hes1 shRNA in pancreatic cancer cells reduced the percentage of CSCs and tumorsphere formation. Conversely, activation of the Notch pathway with an exogenous Notch peptide ligand increased the percentage of CSCs as well as tumorsphere formation. In vivo treatment of orthotopic pancreatic tumors in NOD/SCID mice with GSI blocked tumor growth and reduced the CSC population.ConclusionThe Notch signaling pathway is important in maintaining the pancreatic CSC population and is a potential therapeutic target in pancreatic cancer