Plevier of the Walaeus library in the LUMC for her contribution to the composition of the literature searches for literature inclusion. Abbreviations CAFCancer-associated fibroblastCAMCell adhesion moleculeCath-ECathepsin-ECA19.9Carbohydrate antigen 19.9CDCP1 CUBdomain-containing protein1Ce-CTContrast-enhanced Computed TomographyCEACarcinoembryonic antigen EGFREpidermoid growth factor receptorEpCAMEpithelial cell adhesion moleculeESMOEuropean Society of Medical OncologyFAPFibroblast-activating proteinFAPIFibroblast-activating protein inhibitorFAZAFluoroazomycin arabinosideFDGFluorodeoxyglucoseFGSFluorescence-guided surgery FLTFluorothymidineFMISOFluoromisonidazoleGRP78Glucose-regulating protein-78LAPCLocally-advanced pancreatic cancer mAbMonoclonal antibodyMMPMatrix metalloproteinaseMRIMagnetic resonance imagingNCCNNational Comprehensive Malignancy NetworkNETNeuro endocrine tumorNIRNear infraredNIRFNear infrared fluorescence NPTNormal pancreatic tissueNTNeoadjuvant therapyNTSNeurotensinNTSR-1Neurotensin receptor-1OSOverall survivalPDACPancreatic ductal ACE adenocarcinomaPSMAProstate membrane antigenPETPositron emission tomographyscFvSingle-chain variable fragmentSPECTSingle-photon emission computed tomographySMISmall molecule inhibitorSUVStandardized uptake valueTfR1Transferrin receptor-1TBRTumor-to-background ratioTFTissue FactoruPAUrokinase-type plasminogen activator uPARUrokinase-type plasminogen activator ReceptorVEGFRVascular endothelial growth factor receptorVEGF-AVascular endothelial growth factor AWLIWhite light inspection Appendix A Table A1 Clinical studies evaluating targeted molecular imaging (PET/CTfluorescence Imaging) of PDAC. 0.001)cetuximab-IRDye800CW, monoclonal antibodymAb, chimericNIRF-= 0.05)= 0.05) Fibronec-tin 68Ga-NOTA-ZD2Peptide, linearPET/CTIn vitro/In vivo Preclinical probe construction and target validation in mouse modelSubcutaneous PDAC mouse model br / (BxPC-3, Rucaparib br / Capan-1)After br / 1 hTumor-to-muscle ratio (mouse-1/mouse-2)BxPC-3: 5.4/5.6 br / Pacan-1: 10.0/11.0Proof-of-concept, for in vivo PET/CT-imaging of Fibronectin+ PDAC in Rucaparib mice. several other promising brokers are currently tested preclinically, both with promising results. Their additional diagnostic value and feasibility for future implementation in standard clinical care of PDAC has yet to be established in phase III clinical trials. Abstract Background: Despite recent advances in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC), overall survival remains poor with a 5-12 months cumulative survival of approximately 10%. Neoadjuvant (chemo- and/or radio-) therapy is usually increasingly incorporated in treatment strategies for patients with (borderline) resectable and locally advanced disease. Neoadjuvant therapy aims to improve radical resection rates by reducing tumor mass and (partial) encasement of important vascular structures, as well as eradicating occult micrometastases. Results from recent multicenter clinical trials evaluating this approach demonstrate prolonged survival and increased complete surgical resection rates (R0). Currently, tumor response to neoadjuvant therapy is usually monitored using computed tomography (CT) following the RECIST 1.1 criteria. Accurate assessment of neoadjuvant treatment response and tumor resectability is considered a major challenge, as current conventional imaging modalities provide limited accuracy and specificity for discrimination between necrosis, fibrosis, and remaining vital tumor tissue. As a consequence, resections with tumor-positive margins and subsequent early locoregional tumor recurrences are observed in a substantial number of patients following surgical resection with curative intent. Of these patients, up to 80% are diagnosed with recurrent disease after a median disease-free interval of merely 8 months. These numbers underline the urgent need to improve imaging modalities for more accurate assessment of therapy response and subsequent re-staging of disease, thereby aiming to optimize individual patients treatment strategy. In cases of curative intent resection, additional intra-operative real-time guidance could aid surgeons during complex procedures and potentially reduce the rate of incomplete resections and early (locoregional) tumor recurrences. In recent years intraoperative imaging in cancer has made a shift towards tumor-specific molecular targeting. Several important molecular targets have been identified that show overexpression in PDAC, for example: CA19.9, CEA, EGFR, VEGFR/VEGF-A, uPA/uPAR, and various integrins. Tumor-targeted PET/CT combined with intraoperative fluorescence imaging, could provide useful information for tumor detection and staging, therapy response evaluation with re-staging of disease and intraoperative guidance during surgical resection of PDAC. Methods: Rucaparib A literature search in the PubMed database and (inter)national trial registers was conducted, focusing on studies published over the last 15 years. Data and information of eligible articles regarding PET/CT as well as fluorescence imaging in PDAC were reviewed. Areas covered: This review covers the current strategies, obstacles, challenges, and developments in targeted tumor imaging, focusing on the feasibility and value of PET/CT and fluorescence imaging for integration in the work-up and treatment of PDAC. An overview is usually given of identified targets and their characteristics, as well as the available literature of conducted and ongoing clinical and preclinical trials evaluating PDAC-targeted nuclear and fluorescent tracers. Chaperone protein localized in ERCell-to-cell and cell-to-matrix recognition processes, induction of endoplasmic reticulum stress for cell aging, survival, metastasisCell membrane, pancreatic neoplastic cells (in non-tumor cells located in ER)N/A Diffuse and high expression in PDAC Low expression in precursor lesions Low expression in healthy pancreatic tissue No data available of expression profile in pancreatitis NPT: ?PET/NIRF-tracers, strategies to improve tumor-specific contrast. A dual-labeled PET/NIRF-tracer has the potential to aid in pre-operative PET/CT (re)staging and the consecutive surgery by means of fluorescence guidance using a single systemic administration. Rucaparib Although, careful planning and choice of tracer combination based on half-life is usually important for effectively using dual-labeled tracers. Several dual-labeled PET/NIRF tracers have been described [166,194]. One example is the PDAC-targeted dual-labeled CA19.9 agent that has been evaluated in a preclinical stetting by Houghton et al. (Table A2), which exhibited clear tumor visualization using small-animal PET/CT and NIRF guided resection of subcutaneous tumors in mice..