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Purpose: To evaluate the feasibility of CT perfusion performed during routine multiphase contrast-enhanced CT on a 160 mm wide-coverage 256-slice scanner in patients with pancreatic ductal adenocarcinoma (PDAC). Methods: Fifty-seven patients had a CT perfusion acquisition during their routine multiphase CT. Perfusion was performed 5 to 42.5 s (15 passes at 2.5 s intervals) after intravenous contrast administration (4.2–5 ml/s), followed by pancreatic parenchymal and portal venous phases for clinical interpretation. Perfusion maps were generated and blood flow (BF), blood volume (BV), and permeability surface area product (PS) for tumor and uninvolved pancreas were calculated using deconvolution algorithms and compared to existing similar publications. Radiation dose information was recorded and size-specific dose estimate (SSDE) was calculated using body dimensions. Results: Diagnostic quality of standard images was unaffected by performing the perfusion acquisition. Average tumor center BF was 20.8 ± 12.1 ml/100 g/min, BV 2.5 ± 2.1 ml/100 g and PS 15.5 ± 39.4 ml/100 g/min. Average pancreas BF was 90.8 ± 50.2 ml/100 g/min, BV 11.9 ± 4.3 ml/100 g and PS 33.6 ± 27.7 ml/100 g/min. For the perfusion acquisition, mean SSDE was 57 ± 11 mGy, CTDIvol 43 ± 6 mGy and DLP 685 ± 100 mGy-cm. Conclusion: Adding a perfusion CT acquisition to standard pancreatic CT protocol is feasible using a wide-detector 256-slice CT scanner and adds quantitative information while maintaining diagnostic quality of the standard of care examination. This novel protocol adds no time or cost to the examination and yields perfusion parameters that are comparable to existing literature using a separate dedicated perfusion protocol. [ABSTRACT FROM AUTHOR]

Simple Summary: Glycogen synthase kinase-3 beta is a protein kinase implicated in the promotion and development of various cancers, including pancreatic cancer. In cell culture and animal studies, drugs targeting the inhibition of this protein show treatment potential in pancreatic cancer. Studies show targeting this protein for treatment may overcome resistance to conventional chemotherapy in pancreatic tumors. Early-stage clinical trials are currently studying small molecule inhibitors targeting glycogen synthase kinase-3 beta and interim results show favorable results. Recent studies also suggest that targeting this protein will create synergy with immunotherapy, such as checkpoint inhibitors. Future studies should aim to study new combination treatments involving glycogen synthase kinase-3 beta targeting drugs with chemotherapy and immunotherapy in pancreatic cancer. Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease that is rarely cured, despite many recent successes with immunotherapy for other malignancies. As the human disease is heavily infiltrated by effector T cells, we postulated that accurately modeling the PDA immune microenvironment would allow us to study mechanisms of immunosuppression that could be overcome for therapeutic benefit. Using viable precision-cut slices from fresh PDA, we developed an organotypic culture system for this purpose. We confirmed that cultured slices maintain their baseline morphology, surface area, and microenvironment after at least 6 d in culture, and demonstrated slice survival by MTT assay and by immunohistochemistry staining with Ki-67 and cleaved-Caspase-3 antibodies. Immune cells, including T cells (CD3+, CD8+, and FOXP3+) and macrophages (CD68+, CD163+and HLA-DR+), as well as stromal myofibroblasts (αSMA+) were present throughout the culture period. Global profiling of the PDA proteome before and after 6 d slice culture indicated that the majority of the immunological proteins identified remain stable during the culture process. Cytotoxic effects of drug treatment (staurosporine, STS and cycloheximide, CHX) on PDA slices culture confirmed that this system can be used to assess functional response and cell survival following drug treatment in both a treatment time- and dose-dependent manner. Using multicolor immunofluorescence, we stained live slices for both cancer cells (EpCAM+) and immune cells (CD11b+and CD8+). Finally, we confirmed that autologous CFSE-labeled splenocytes readily migrate into co-cultured tumor slices. Thus, our present study demonstrates the potential to use tumor slice cultures to study the immune microenvironment of PDA. [ABSTRACT FROM PUBLISHER]