Overview and future perspectives on tumor-targeted positron emission tomography and fluorescence imaging of pancreatic cancer in the era of neoadjuvant therapy

Simple Summary Patients diagnosed with pancreatic cancer have a poor prognosis at time of diagnosis, with a 5-year survival rate of merely 10%. The only treatment with curative intent is surgical resection of the tumor and adjacent tumor-containing lymph nodes. To improve surgical outcome and survival, additional (imaging) tools are needed that support complete surgical tumor resection. Firstly, more accurate monitoring of tumor response to neoadjuvant treatment and subsequent determination of resectability is needed. Secondly, an imaging tool is needed for intraoperative guidance allowing accurate identification, delineation, and complete resection of the tumor and suspected lymph nodes. Therefore, both tumor-targeted PET/CT before surgery and real time fluorescence-guidance during surgery could be helpful to improve patient outcome. This review focusses on literature considering tumor-targeted PET/CT and near-infrared fluorescence (NIRF) imaging. Several tumor-targeted agents are under clinical evaluation, and several other promising agents 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. Background: Despite recent advances in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC), overall survival remains poor with a 5-year cumulative survival of approximately 10%. Neoadjuvant (chemo- and/or radio-) therapy is 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 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 patient's 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 valuable information for tumor detection and staging, therapy response evaluation with re-staging of disease and intraoperative guidance during surgical resection of PDAC. Methods: 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 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.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Visceral adipose tissue is a better predictor than BMI in the alternative Fistula Risk Score in patients undergoing pancreatoduodenectomy

Background: Muscle attenuation (MA) and visceral adipose tissue (VAT) have not yet been included in the currently used alternative Fistula Risk Score (a-FRS). The aim of this study was to examine the added value of these parameters as predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) in the a-FRS after pancreatoduodenectomy compared to Body Mass Index (BMI). Methods: A single center retrospective cohort study was performed in patients who underwent pancreatoduodenectomy between 2009 and 2018. The a-FRS model was reproduced, MA and VAT were both combined and separately added to the model instead of BMI using logistic regression analysis. Model discrimination was assessed by ROC-curves. Results: In total, 329 patients were included of which 55 (16.7%) developed CR-POPF. The a-FRS model showed an AUC of 0.74 (95%CI: 0.68-0.80). In this model, BMI was not significantly associated with CR-POPF (p = 0.16). The MA + VAT model showed an AUC of 0.81 (95%CI: 0.75-0.86). VAT was significantly associated with CR-POPF (per cm2, OR: 1.01; 95%CI: 1.00-1.01; p < 0.001). The AUC of the MA + VAT model differed significantly from the AUC of the a-FRS model (p = 0.001). Conclusion: Visceral adipose tissue is of added value in the a-FRS compared to BMI in predicting CRPOPF in patients undergoing pancreatoduodenectomy

Intraoperative Near-Infrared Fluorescence Imaging of Multiple Pancreatic Neuroendocrine Tumors: A Case Report

Surgical oncolog

High Systemic Immune Inflammation Index Is Associated With Low Skeletal Muscle Quantity in Resectable Pancreatic Ductal Adenocarcinoma

Background and AimsFailing immune surveillance in pancreatic ductal adenocarcinoma (PDAC) is related to poor prognosis. PDAC is also characterized by its substantial alterations to patients' body composition. Therefore, we investigated associations between the host systemic immune inflammation response and body composition in patients with resected PDAC. MethodsPatients who underwent a pancreatectomy for PDAC between 2004 and 2016 in two tertiary referral centers were included. Skeletal muscle mass quantity and muscle attenuation, as well as subcutaneous and visceral adipose tissue at the time of diagnosis, were determined by CT imaging measured transversely at the third lumbar vertebra level. Baseline clinicopathological characteristics, laboratory values including the systemic immune inflammation index (SIII), postoperative, and survival outcomes were collected. ResultsA total of 415 patients were included, and low skeletal muscle mass quantity was found in 273 (65.7%) patients. Of the body composition indices, only low skeletal muscle mass quantity was independently associated with a high (>= 900) SIII (OR 7.37, 95% CI 2.31-23.5, p=0.001). The SIII was independently associated with disease-free survival (HR 1.86, 95% CI 1.12-3.04), and cancer-specific survival (HR 2.21, 95% CI 1.33-3.67). None of the body composition indices were associated with survival outcomes. ConclusionThis study showed a strong association between preoperative low skeletal muscle mass quantity and elevated host systemic immune inflammation in patients with resected PDAC. Understanding how systemic inflammation may contribute to changes in body composition or whether reversing these changes may affect the host systemic immune inflammation response could expose new therapeutic possibilities for improving patients' survival outcomes

High Systemic Immune Inflammation Index Is Associated With Low Skeletal Muscle Quantity in Resectable Pancreatic Ductal Adenocarcinoma

Background and AimsFailing immune surveillance in pancreatic ductal adenocarcinoma (PDAC) is related to poor prognosis. PDAC is also characterized by its substantial alterations to patients' body composition. Therefore, we investigated associations between the host systemic immune inflammation response and body composition in patients with resected PDAC. MethodsPatients who underwent a pancreatectomy for PDAC between 2004 and 2016 in two tertiary referral centers were included. Skeletal muscle mass quantity and muscle attenuation, as well as subcutaneous and visceral adipose tissue at the time of diagnosis, were determined by CT imaging measured transversely at the third lumbar vertebra level. Baseline clinicopathological characteristics, laboratory values including the systemic immune inflammation index (SIII), postoperative, and survival outcomes were collected. ResultsA total of 415 patients were included, and low skeletal muscle mass quantity was found in 273 (65.7%) patients. Of the body composition indices, only low skeletal muscle mass quantity was independently associated with a high (>= 900) SIII (OR 7.37, 95% CI 2.31-23.5, p=0.001). The SIII was independently associated with disease-free survival (HR 1.86, 95% CI 1.12-3.04), and cancer-specific survival (HR 2.21, 95% CI 1.33-3.67). None of the body composition indices were associated with survival outcomes. ConclusionThis study showed a strong association between preoperative low skeletal muscle mass quantity and elevated host systemic immune inflammation in patients with resected PDAC. Understanding how systemic inflammation may contribute to changes in body composition or whether reversing these changes may affect the host systemic immune inflammation response could expose new therapeutic possibilities for improving patients' survival outcomes.Surgical oncolog