Earlier detection of pancreatic cancer is necessary to improve its poor prognosis. Currently, screening of the general population is not feasible due to the relatively low lifetime risk. However,... Show moreEarlier detection of pancreatic cancer is necessary to improve its poor prognosis. Currently, screening of the general population is not feasible due to the relatively low lifetime risk. However, up to one in ten cases occur in individuals with a strong family history of germline mutation carriers, known as high-risk individuals (HRIs). For these HRIs, pancreatic cancer surveillance in expert centers is recommended. The first part of this thesis focuses on evaluating the effectiveness of pancreatic cancer surveillance in carriers of a germline CD2KNA/p16 mutation who have a very high lifetime risk of developing pancreatic cancer. The second part focuses on various aspects to improve pancreatic cancer surveillance programs, including the study of biomarkers, risk stratification, and assessment of psychosocial aspects. Finally, attention is given to the identification of individuals at increased risk from the general population. Show less
This thesis consists of two sections. In Section I, (pre)clinical research investigating novel targets for pre- and intraoperative molecular imaging of pancreatic cancer are discussed. In Section... Show moreThis thesis consists of two sections. In Section I, (pre)clinical research investigating novel targets for pre- and intraoperative molecular imaging of pancreatic cancer are discussed. In Section II, various studies are described which lay the groundwork for further investigation into response monitoring and prediction in rectal cancer using various imaging modalities. Show less
Bergonzini, C.; Gregori, A.; Hagens, T.M.S.; Noord, V.E. van der; Water, B. van de; Zweemer, A.J.M.; ... ; Danen, E.H.J. 2024
BACKGROUND\nMETHODS\nRESULTS\nCONCLUSION\nPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and the chemotherapies such as gemcitabine/nab-paclitaxel are confronted... Show moreBACKGROUND\nMETHODS\nRESULTS\nCONCLUSION\nPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and the chemotherapies such as gemcitabine/nab-paclitaxel are confronted with intrinsic or acquired resistance. The aim of this study was to investigate mechanisms underlying paclitaxel resistance in PDAC and explore strategies to overcome it.\nThree paclitaxel (PR) and gemcitabine resistant (GR) PDAC models were established. Transcriptomics and proteomics were used to identify conserved mechanisms of drug resistance. Genetic and pharmacological approaches were used to overcome paclitaxel resistance.\nUpregulation of ABCB1 through locus amplification was identified as a conserved feature unique to PR cells. ABCB1 was not affected in any of the GR models and no cross resistance was observed. The ABCB1 inhibitor verapamil or siRNA-mediated ABCB1 depletion sensitized PR cells to paclitaxel and prevented efflux of ABCB1 substrates in all models. ABCB1 expression was associated with a trend towards shorter survival in patients who had received gemcitabine/nab-paclitaxel treatment. A pharmacological screen identified known and novel kinase inhibitors that attenuate efflux of ABCB1 substrates and sensitize PR PDAC cells to paclitaxel.\nUpregulation of ABCB1 through locus amplification represents a novel, conserved mechanism of PDAC paclitaxel resistance. Kinase inhibitors identified in this study can be further (pre) clinically explored as therapeutic strategies to overcome paclitaxel resistance in PDAC. Show less
Pancreatic cancer is an aggressive cancer associated with a poor prognosis as a large proportion of these patients have locally advanced disease or metastases at the time of diagnosis. Currently... Show morePancreatic cancer is an aggressive cancer associated with a poor prognosis as a large proportion of these patients have locally advanced disease or metastases at the time of diagnosis. Currently onlypatients with localized pancreatic tumors can undergo surgery, which is the cornerstone in thetreatment of pancreatic cancer, whether or not preceded by neoadjuvant (chemo/radio)therapy. To establish the diagnosis, imaging techniques are used, tumor tissue must be obtained, and certain tumor markers can be determined in the blood. During surgery, the tumor must be removed in its entirety to prevent early recurrence. This thesis describes the potential role of tumor markers, which can be determined in the blood, and several experimental optical imaging techniques applied to pancreatic cancer. Show less
BackgroundSurgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic... Show moreBackgroundSurgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach.MethodsThis multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and & LE; 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m(2), leucovorin 400 mg/m(2), irinotecan 150 mg/m(2) at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m(2)). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized.DiscussionThe multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. Show less
Background: The necessity of the staging laparoscopy in patients with pancreatic cancer is still debated. The objective of this study was to assess the yield of staging laparoscopy for detecting... Show moreBackground: The necessity of the staging laparoscopy in patients with pancreatic cancer is still debated. The objective of this study was to assess the yield of staging laparoscopy for detecting occult metastases in patients with resectable or borderline resectable pancreatic cancer.Method: This was a post-hoc analysis of the randomized controlled PREOPANC trial in which patients with resectable or borderline resectable pancreatic cancer were randomized between preoperative chemoradiotherapy or immediate surgery. Patients assigned to preoperative treatment underwent a staging laparoscopy prior to preoperative treatment according to protocol, to avoid unnecessary che-moradiotherapy in patients with occult metastatic disease.Results: Of the 246 included patients, 7 did not undergo surgery. A staging laparoscopy was performed in 133 patients (55.6%) and explorative laparotomy in 106 patients (4 4.4%). At staging laparoscopy, occult metastases were detected in 13 patients (9.8%); 12 liver metastases and 1 peritoneal metastasis. At direct explorative laparotomy, occult metastases were found in 9 patients (8.5%); 6 with liver metastases, 1 with peritoneal metastases, and 2 with metastases at multiple sites. One patient had peritoneal metastases at exploration after a negative staging laparoscopy. Patients with occult metastases were more likely to receive palliative chemotherapy if found with staging laparoscopy compared to laparotomy (76.9% vs. 30.0%, p 1/4 0.040).Conclusions: Staging laparoscopy detected occult metastases in about 10% of patients with resectable or borderline resectable pancreatic cancer. These patients were more likely to receive palliative systemic chemotherapy compared to patients in whom occult metastases were detected with laparotomy. A staging laparoscopy is recommended before planned resection.(c) 2022 Published by Elsevier Ltd. Show less
Jong, T.L. de; Koopman, D.; Worp, C.A.J. van der; Stevens, H.; Vuijk, F.A.; Vahrmeijer, A.L.; ... ; Patijn, G.A. 2023
Background: We studied the added value of digital FDG-PET/CT in disease staging and restaging compared to the standard work-up with contrast enhanced CT (ceCT) and CA19-9 in patients with... Show moreBackground: We studied the added value of digital FDG-PET/CT in disease staging and restaging compared to the standard work-up with contrast enhanced CT (ceCT) and CA19-9 in patients with resectable or borderline resectable pancreatic cancer who received neo-adjuvant therapy. Primary endpoints were tumor response compared to ceCT and CA19.9 as well as the ability to detect distant metastatic disease.Methods: 35 patients were included in this dual-center prospective study. FDG-PET using digital photon counting technology combined with CT scans were acquired before (T1) and after neo-adjuvant therapy (T2). Patients were staged and restaged based on standard protocol with ceCT and CA 19.9, while all PET/CT scans were stored securely and not included in clinical decision making. After the pancreatic resection, an expert team retro-spectively assessed the CT tumor diameter, CA19-9, tumor FDG-uptake, and appearance of metastatic disease of all patients for both time points.Results: CA19-9 levels, CT tumor diameter, and tumor FDG-uptake on PET significantly decreased from T1 to T2 (p = 0.017, p = 0.001, and p < 0.0001). The change in FDG-uptake values showed a strong positive correlation with the change in CT tumor diameter and change in CA19-9 (R = 0.75 and R = 0.73, respectively). In addition, small-volume liver lesions were detected on digital PET/CT in 5/35 patients (14%), 4 of which were pathology confirmed at laparotomy. Only one of these five cases was detected on baseline staging ceCT (3%). Conclusion: We found that adding digital PET/CT strengthens restaging after neo-adjuvant therapy based on the observed strong correlation with ceCT tumor diameter and Ca19.9. Also, digital PET/CT was found to detect occult metastatic disease not visualized on ceCT, that would have resulted in altered disease staging and ther-apeutic strategy in a substantial proportion of patients. Show less
Gregori, A.; Bergonzini, C.; Capula, M.; Mantini, G.; Khojasteh-Leylakoohi, F.; Comandatore, A.; ... ; Giovannetti, E. 2023
Immunotherapy is a highly promising treatment option for cancer. At present, only a small proportion of cancer patients benefits from immunotherapeutic interventions. There is an unmet need to... Show moreImmunotherapy is a highly promising treatment option for cancer. At present, only a small proportion of cancer patients benefits from immunotherapeutic interventions. There is an unmet need to understand which factors determine a patient’s response to immunotherapy as well as to develop novel immunotherapeutic approaches that address shortcomings of current immunotherapies.In this thesis, we have performed an unprecedented characterization of immune cell subsets participating in anti-tumor responses in colorectal cancer and pancreatic ductal adenocarcinoma with different single-cell technologies. Most cancer immunology research studied the role of cytotoxic T cells in both cancer types, while a comprehensive analysis of both innate and adaptive components of cancer immunity was largely lacking. With such an approach, we demonstrated an important involvement of understudied unconventional (γδ T cells) and innate (innate lymphoid cells (ILCs)) immune effector cells in anti-tumor immunity. These immune subsets displayed cytotoxic activity and showed potential for therapeutic exploitation. Further studies will focus on their functional characterization and potential reconversion into a therapeutic agent.This thesis resulted from the collaboration between research groups led by Noel de Miranda (Pathology, LUMC) and Frits Koning (Immunology, LUMC), and underscores the relevance of applying single-cell technologies for the study of complex biological systems. Show less
Lau, S.P.; Land, F.R. van 't; Burg, S.H. van der; Homs, M.Y.V.; Lolkema, M.P.; Aerts, J.G.J.V.; Eijck, C.H.J. van 2022
Introduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy... Show moreIntroduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy may complement our current treatment strategies. We previously demonstrated that the combination of an allogeneic tumour-lysate dendritic cell (DC) vaccine with an anti-CD40 agonistic antibody resulted in robust antitumour responses with survival benefit in a murine PDAC model. In the Rotterdam PancrEAtic Cancer Vaccination-2 trial, we aim to translate our findings into patients. This study will determine the safety of DC/anti-CD40 agonistic antibody combination treatment, and treatment-induced tumour-specific immunological responses. Methods and analysis In this open-label, single-centre (Erasmus Univsersity Medical Center, Rotterdam, Netherlands), single-arm, phase I dose finding study, adult patients with metastatic pancreatic cancer with progressive disease after FOLFIRINOX chemotherapy will receive monocyte-derived DCs loaded with an allogeneic tumour lysate in conjunction with a CD40 agonistic antibody. This combination-immunotherapy regimen will be administered three times every 2 weeks, and booster treatments will be given after 3 and 6 months following the third injection. A minimum of 12 and a maximum of 18 patients will be included. The primary endpoint is safety and tolerability of the combination immunotherapy. To determine the maximum tolerated dose, DCs will be given at a fixed dosage and anti-CD40 agonist in a traditional 3+3 dose-escalation design. Secondary endpoints include radiographic response according to the RECIST (V.1.1) and iRECIST criteria, and the detection of antitumour specific immune responses. Ethics and dissemination The Central Committee on Research Involving Human Subjects (CCMO; NL76592.000.21) and the Medical Ethics Committee (METC; MEC-2021-0566) of the Erasmus M.C. University Medical Center Rotterdam approved the conduct of the trial. Written informed consent will be required for all participants. The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Show less
Lau, S.P.; Land, F.R. van 't; Burg, S.H. van der; Homs, M.Y.V.; Lolkema, M.P.; Aerts, J.G.J.V.; Eijck, C.H.J. van 2022
Introduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy... Show moreIntroduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy may complement our current treatment strategies. We previously demonstrated that the combination of an allogeneic tumour-lysate dendritic cell (DC) vaccine with an anti-CD40 agonistic antibody resulted in robust antitumour responses with survival benefit in a murine PDAC model. In the Rotterdam PancrEAtic Cancer Vaccination-2 trial, we aim to translate our findings into patients. This study will determine the safety of DC/anti-CD40 agonistic antibody combination treatment, and treatment-induced tumour-specific immunological responses.Methods and analysis In this open-label, single-centre (Erasmus Univsersity Medical Center, Rotterdam, Netherlands), single-arm, phase I dose finding study, adult patients with metastatic pancreatic cancer with progressive disease after FOLFIRINOX chemotherapy will receive monocyte-derived DCs loaded with an allogeneic tumour lysate in conjunction with a CD40 agonistic antibody. This combination-immunotherapy regimen will be administered three times every 2 weeks, and booster treatments will be given after 3 and 6 months following the third injection. A minimum of 12 and a maximum of 18 patients will be included. The primary endpoint is safety and tolerability of the combination immunotherapy. To determine the maximum tolerated dose, DCs will be given at a fixed dosage and anti-CD40 agonist in a traditional 3+3 dose-escalation design. Secondary endpoints include radiographic response according to the RECIST (V.1.1) and iRECIST criteria, and the detection of antitumour specific immune responses.Ethics and dissemination The Central Committee on Research Involving Human Subjects (CCMO; NL76592.000.21) and the Medical Ethics Committee (METC; MEC-2021-0566) of the Erasmus M.C. University Medical Center Rotterdam approved the conduct of the trial. Written informed consent will be required for all participants. The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Show less
Levink, I.J.M.; Klatte, D.C.F.; Hanna Sawires, R.G.; Vreeker, G.C.M.; Ibrahim, I.S.; Burgt, Y.E.M. van der; ... ; Mesker, W.E. 2022
Background: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities... Show moreBackground: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals. Methods: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature. Results: 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri-and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans).The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%. Conclusion: Serum N-glycan monitoring may support early detection in a pancreas surveillance program.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Lau, S.P.; Klaase, L.; Vink, M.; Dumas, J.; Bezemer, K.; Krimpen, A. van; ... ; Eijck, C.H.J. van 2022
Background: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor prognosis even after curative resection. Responses to immunotherapy are rare and related to inadequate T-cell priming.... Show moreBackground: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor prognosis even after curative resection. Responses to immunotherapy are rare and related to inadequate T-cell priming. We previously demonstrated the potency of allogeneic lysatedendritic cell (DC) vaccination in a preclinical model. Here we translate this concept to patients.Methods: In this phase I study, patients with resected PDAC were included when they demonstrated no radiologic signs of recurrence after standard-of-care treatment. Allogeneic tumour lysate-loaded autologous monocyte-derived DCs were injected at weeks 0, 2, 4 and at months 3 and 6. Objectives are feasibility, safety and immunogenicity of allogeneic tumour-DCs. The presence of tumour antigens shared between the vaccine and patient tumours was investigated. Immunological analyses were performed on peripheral blood, skin and tumour.Results: Ten patients were included. DC production and administration were successful. All patients experienced a grade 1 injection-site and infusion-related reaction. Two patients experienced a grade 2 fever and 1 patient experienced a grade 3 dyspnoea. No vaccine-related serious adverse events were observed. Shared tumour antigens were found between the vaccine and patient tumours. All evaluated patients displayed a vaccine-induced response indicated by increased frequencies of Ki67+ and activated PD-1+ circulating T-cells. In addition, treatment-induced T-c ell reactivity to autologous tumour of study patients was detected. Seven out of ten patients have not experienced disease recurrence or progression at a median follow-up of 25 months (15-32 months).Conclusion: Allogeneic tumour lysate-DC treatment is feasible, safe and induces immune reactivity to PDAC expressed antigens. 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Part I - Hepatic perfusion for the treatment of unresectable liver metastasesBecause the majority of metastasized uveal melanoma (UM) patients have unresectable liver only metastases, locoregional... Show morePart I - Hepatic perfusion for the treatment of unresectable liver metastasesBecause the majority of metastasized uveal melanoma (UM) patients have unresectable liver only metastases, locoregional therapy was developed. In this thesis percutaneous hepatic perfusion (PHP) is described as a treatment for these patients. During this procedure, the chemotherapeutic agent is infused in the hepatic artery and thereby delivered to the liver and metastases directly. Via a veno-venous filtration system, the chemotherapeutic agent is filtered before it reaches the systemic circulation. In this thesis a clinical study was described treating 20 UM patients with metastases confined to the liver with PHP. It was concluded that the results PHP outbalanced the (minimal) toxicity for patients with uveal melanoma metastases.Part II - Tailored care for patients with pancreatic cancerThe poor prognosis of pancreatic cancer did not change much over the last decades, despite the improvements in treatment modalities. Previous studies have reported variations in incidence and mortality in pancreatic cancer between countries worldwide and European countries. A collaboration was initiated across Europe to compare patterns of care and identify best practices for pancreatic cancer care. A core dataset was identified to identificate differences in age, gender, incidence, tumour stage and differences in treatment strategies. To identify any differences in treatment and/or survival of elderly patients with pancreatic cancer, a comparison was performed of data on geriatric pancreatic cancer care and survival with data from the Netherlands and a special ‘Senior Adult Oncology Program’. Show less
Introduction: Pancreatic cancer is associated with a high risk of venous thromboembolism (VTE). However, comprehensive data on incidence, timing and relevant determinants of VTE in this particular... Show moreIntroduction: Pancreatic cancer is associated with a high risk of venous thromboembolism (VTE). However, comprehensive data on incidence, timing and relevant determinants of VTE in this particular population are scarce. Current study assesses incidence, timing and predictors of VTE in pancreatic cancer through different phases of disease. Methods: All pancreatic cancer patients treated in our tertiary referral center between 2013 through 2017 were studied. Occurrence of VTE was evaluated from diagnosis through end of follow-up or death. Relevant de-terminants of VTE were identified in logistic regression models. Hazard ratios were calculated to evaluate impact of VTE on overall survival. Results: In total, 361 patients were followed for a median period of 43 months; 64 were diagnosed with VTE (18%). Most were tumor related thrombosis (59%), incidental (75%) and occurred after anti-cancer treatment had been stopped (80%), only 1.6% occurred during remission phase. Stage IV pancreatic cancer was a predictor for VTE (hazard ratio (HR) 2.46, 95% confidence interval (CI) 0.9-6.8). Biliary drainage (HR 0.52, 95%CI 0.28-0.98) and tumor resection (HR 0.45, 95%CI 0.45-1.83) were protective factors. VTE was not associated with worse survival (HR 1.3; 95% CI 0.97-1.74). Conclusions: VTE in pancreatic cancer is disease-stage dependent, with 80% occurring in advanced phases of disease when patients no longer receive active treatment. We speculate that this is the main reason for the absence of a survival effect of VTE in our cohort. These practice-based findings should be taken into account when considering wide-spread introduction of primary thromboprophylaxis in patients with pancreatic cancer. Show less
Baart, V.M.; Manen, L. van; Bhairosingh, S.S.; Vuijk, F.A.; Iamele, L.; Jonge, H. de; ... ; Sier, C.F.M. 2021
Purpose Radical resection is paramount for curative oncological surgery. Fluorescence-guided surgery (FGS) aids in intraoperative identification of tumor-positive resection margins. This study aims... Show morePurpose Radical resection is paramount for curative oncological surgery. Fluorescence-guided surgery (FGS) aids in intraoperative identification of tumor-positive resection margins. This study aims to assess the feasibility of urokinase plasminogen activator receptor (uPAR) targeting antibody fragments for FGS in a direct comparison with their parent IgG in various relevant in vivo models. Procedures Humanized anti-uPAR monoclonal antibody MNPR-101 (uIgG) was proteolytically digested into F(ab')2 and Fab fragments named uFab2 and uFab. Surface plasmon resonance (SPR) and cell assays were used to determine in vitro binding before and after fluorescent labeling with IRDye800CW. Mice bearing subcutaneous HT-29 human colonic cancer cells were imaged serially for up to 120 h after fluorescent tracer administration. Imaging characteristics and ex vivo organ biodistribution were further compared in orthotopic pancreatic ductal adenocarcinoma (BxPc-3-luc2), head-and-neck squamous cell carcinoma (OSC-19-luc2-GFP), and peritoneal carcinomatosis (HT29-luc2) models using the clinical Artemis fluorescence imaging system. Results Unconjugated and conjugated uIgG, uFab2, and uFab specifically recognized uPAR in the nanomolar range as determined by SPR and cell assays. Subcutaneous tumors were clearly identifiable with tumor-to-background ratios (TBRs) > 2 after 72 h for uIgG-800F and 24 h for uFab2-800F and uFab-800F. For the latter two, mean fluorescence intensities (MFIs) dipped below predetermined threshold after 72 h and 36 h, respectively. Tumors were easily identified in the orthotopic models with uIgG-800F consistently having the highest MFIs and uFab2-800F and uFab-800F having similar values. In biodistribution studies, kidney and liver fluorescence approached tumor fluorescence after uIgG-800F administration and surpassed tumor fluorescence after uFab2-800F or uFab-800F administration, resulting in interference in the abdominal orthotopic mouse models. Conclusions In a side-by-side comparison, FGS with uPAR-targeting antibody fragments compared with the parent IgG resulted in earlier tumor visualization at the expense of peak fluorescence intensity. Show less
Introduction: Whereas neoadjuvant chemo(radio)therapy is increasingly used in pancreatic cancer, it is currently not recommended for other periampullary (non-pancreatic) cancers. This has important... Show moreIntroduction: Whereas neoadjuvant chemo(radio)therapy is increasingly used in pancreatic cancer, it is currently not recommended for other periampullary (non-pancreatic) cancers. This has important implications for the relevance of the preoperative diagnosis for pancreatoduodenectomy. This retrospective multicentre cohort study aimed to determine the frequency of clinically relevant misdiagnoses in patients undergoing pancreatoduodenectomy for pancreatic or other periampullary cancer. Methods: Data from all consecutive patients who underwent a pancreatoduodenectomy between 2014 and 2018 were obtained from the prospective Dutch Pancreatic Cancer Audit. The preoperative diagnosis as concluded by the multidisciplinary team (MDT) meeting was compared with the final postoperative diagnosis at pathology to determine the rate of clinically relevant misdiagnosis (defined as missed pancreatic cancer or incorrect diagnosis of pancreatic cancer). Results: In total, 1244 patients underwent pancreatoduodenectomy of whom 203 (16%) had a clinically relevant misdiagnosis preoperatively. Of all patients with a final diagnosis of pancreatic cancer, 13% (87/ 679) were preoperatively misdiagnosed as distal cholangiocarcinoma (n = 41, 6.0%), ampullary cancer (n = 27, 4.0%) duodenal cancer (n = 16, 2.4%), or other (n = 3, 0.4%). Of all patients with a final diagnosis of periampullary (non-pancreatic) cancer, 21% (116/565) were preoperatively incorrectly diagnosed as pancreatic cancer. Accuracy of preoperative diagnosis was 84% for pancreatic cancer, 71% for distal cholangiocarcinoma, 73% for ampullary cancer and 73% for duodenal cancer. A prediction model for the preoperative likelihood of pancreatic cancer (versus other periampullary cancer) prior to pancreatoduodenectomy demonstrated an AUC of 0.88. Discussion: This retrospective multicentre cohort study showed that 16% of patients have a clinically relevant misdiagnosis that could result in either missing the opportunity of neoadjuvant chemotherapy in patients with pancreatic cancer or inappropriate administration of neoadjuvant chemotherapy in patients with non-pancreatic periampullary cancer. A preoperative prediction model is available on www.pancreascalculator.com. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Background: high recurrence rates of up to 75% within 2 years in pancreatic ductal adenocarcinoma (PDAC) patients resected for cure indicate a high medical need for clinical prediction tools and... Show moreBackground: high recurrence rates of up to 75% within 2 years in pancreatic ductal adenocarcinoma (PDAC) patients resected for cure indicate a high medical need for clinical prediction tools and patient specific treat-ment approaches. Addition of the EGFR inhibitor erlotinib to adjuvant chemotherapy failed to improve out-come but its efficacy in some patients warrants predictors of responsiveness.Patients and Methods: we analysed tumour samples from 293 R0-resected patients from the randomized, multicentre phase III CONKO-005 trial (gemcitabine +/- erlotinib) with targeted sequencing, copy number, and RNA expression analyses.Findings: a total of 1086 mutations and 4157 copy-number aberrations (CNAs) with a mean of 17.9 /tumour were identified. Main pathways affected by genetic aberrations were the MAPK-pathway (99%), cell cycle control (92%), TGFb signalling (77%), chromatin remodelling (71%), and the PI3K/AKT pathway (65%). Based on genetic signatures extracted with non-negative matrix factorization we could define five patient clusters, which differed in mutation patterns, gene expression profiles, and survival. In multivariable Cox regression analysis, SMAD4 aberrations were identified as a negative prognostic marker in the gemcitabine arm, an effect that was counteracted when treated with erlotinib (DFS: HR=1.59, p = 0.016, and OS: HR = 1.67, p = 0.014). Integration of differential gene expression analysis established SMAD4 alterations with low MAPK9 expression (n = 91) as a predictive biomarker for longer DFS (HR=0.49; test for interaction, p = 0.02) and OS (HR = 0.32; test for interaction, p = 0.001).Interpretation: this study identified five biologically distinct patient clusters with different actionable lesions and unravelled a previously unappreciated association of SMAD4 alteration status with erlotinib effective-ness. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that SMAD4 status might guide addition of erlotinib treatment in early-stage PDAC patients. (C) 2021 The Author(s). Published by Elsevier B.V. Show less
Background: Fluorescence-guided surgery can provide surgeons with an imaging tool for real-time intraoperative tumor detection. SGM-101, an anti-CEA antibody labelled with a fluorescent dye, is a... Show moreBackground: Fluorescence-guided surgery can provide surgeons with an imaging tool for real-time intraoperative tumor detection. SGM-101, an anti-CEA antibody labelled with a fluorescent dye, is a tumor-specific imaging agent that can aid in improving detection and complete resection for CEA-positive tumors. In this study, the performance of SGM-101 for the detection of colorectal and pancreatic liver metastases was investigated.Methods: In this open-label, non-randomized, single-arm pilot study, patients were included with liver metastases from colorectal origin and intraoperatively detected liver metastases from pancreatic origin (during planned pancreatic surgery). SGM-101 was administered two to four days before the scheduled surgery as a single intravenous injection. Intraoperative fluorescence imaging was performed using the Quest Spectrum (R) imaging system. The performance of SGM-101 was assessed by measuring the intraoperative fluorescence signal and comparing this to histopathology.Results: A total of 19 lesions were found in 11 patients, which were all suspected as malignant in white light and subsequent fluorescence inspection. Seventeen lesions were malignant with a mean tumor-tobackground ratio of 1.7. The remaining two lesions were false-positives as proven by histology.Conclusion: CEA-targeted fluorescence-guided intraoperative tumor detection with SGM-101 is feasible for the detection of colorectal and pancreatic liver metastases. (C) 2020 Published by Elsevier Ltd. Show less
Strijker, M.; Veldhuisen, E. van; Geest, L.G. van der; Busch, O.R.; Bijlsma, M.F.; Mohammad, N.H.; ... ; Dutch Pancreatic Canc Grp 2021
BackgroundIdentification of metastatic pancreatic cancer (mPC) patients with the worst prognosis could help to tailor therapy. We evaluated readily available biomarkers for the prediction of 90-day... Show moreBackgroundIdentification of metastatic pancreatic cancer (mPC) patients with the worst prognosis could help to tailor therapy. We evaluated readily available biomarkers for the prediction of 90-day mortality in a nationwide cohort of mPC patients.MethodsPatients with synchronous mPC were included from the Netherlands Cancer Registry (2015-2017). Baseline CA19-9, albumin, CRP, LDH, CRP/albumin ratio, and (modified) Glasgow Prognostic Score ((m)GPS composed of albumin and CRP) were evaluated. Multivariable logistic regression analyses were performed to identify predictors of 90-day mortality. Prognostic value per predictor was quantified by Nagelkerke's partial R-2.ResultsOverall, 4248 patients were included. Median overall survival was 2.2 months and 90-day mortality was 59.4% (n = 1629). All biomarkers predicted 90-day mortality in univariable analysis, and remained statistically significant after adjustment for clinically relevant factors and all other biomarkers (all p < 0.001). The prognostic value of the biomarkers combined was similar to WHO performance status. Patients who received chemotherapy had better outcomes than those who did not, regardless of biomarker levels.ConclusionsIn mPC patients, albumin, CA19-9, CRP, LDH, CRP/albumin ratio, and (m)GPS are prognostic for poor survival. Biomarkers did not predict response to chemotherapy. These readily available biomarkers can be used to better inform patients and to stratify in clinical trials. Show less
