Metastases remain the leading cause of cancer-related death worldwide. Therefore, improving the treatment efficacy against such tumors is essential to enhance patient survival. AU-011 (belzupacap... Show moreMetastases remain the leading cause of cancer-related death worldwide. Therefore, improving the treatment efficacy against such tumors is essential to enhance patient survival. AU-011 (belzupacap sarotalocan) is a new virus-like drug conjugate which is currently in clinical development for the treatment of small choroidal melanoma and high-risk indeterminate lesions in the eye. Upon light activation, AU-011 induces rapid necrotic cell death which is pro-inflammatory and pro-immunogenic, resulting in an anti-tumor immune response. As AU-011 is known to induce systemic anti-tumor immune responses, we investigated whether this combination therapy would also be effective against distant, untreated tumors, as a model for treating local and distant tumors by abscopal immune effects. We compared the efficacy of combining AU-011 with several different checkpoint blockade antibodies to identify optimal treatment regimens in an in vivo tumor model. We show that AU-011 induces immunogenic cell death through the release and exposure of damage-associated molecular patterns (DAMPs), resulting in the maturation of dendritic cells in vitro. Furthermore, we show that AU-011 accumulates in MC38 tumors over time and that ICI enhances the efficacy of AU-011 against established tumors in mice, resulting in complete responses for specific combinations in all treated animals bearing a single MC38 tumor. Finally, we show that AU-011 and anti-PD-L1/anti-LAG-3 antibody treatment was an optimal combination in an abscopal model, inducing complete responses in approximately 75% of animals. Our data show the feasibility of combining AU-011 with PD-L1 and LAG-3 antibodies for the treatment of primary and distant tumors. Show less
Kroese, T.E.; Laarhoven, H.W.M. van; Schoppman, S.F.; Deseynde, P.R.A.J.; Cutsem, E. van; Haustermans, K.; ... ; Rossum, P.S.N. van 2023
Background: Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about... Show moreBackground: Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesopha-gogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophago-gastric cancer. Methods: In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Del-phi study. The consensus finding process consisted of a starting meeting, 2 online Delphi ques-tionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%-75%) or consensus (>75%). Results: A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with meta-static oesophagogastric cancer limited to 1 organ with <3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without pro-gression at restaging after systemic therapy (consensus). For patients with synchronous or me-tachronous OMD with a disease-free interval <2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment fol-lowed by restaging was considered as treatment (fair agreement). Conclusion: The OMEC project has resulted in a multidisciplinary European consensus state -ment for the definition, diagnosis and treatment of oligometastatic oesophagogastric adeno-carcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials. 2023 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
Jong, E. de; Quint, K.D.; Ghalbzouri, A. el; Verdijk, R.M.; Goeman, J.J.; Heidt, S.; ... ; Bavinck, J.N.B. 2023
Background: Solid organ-transplant recipients (SOTR) have an increased risk of cutaneous squamous-cell carcinoma (cSCC), metastasis and death from cSCC. In immunocompetent patients with mucosal SCC... Show moreBackground: Solid organ-transplant recipients (SOTR) have an increased risk of cutaneous squamous-cell carcinoma (cSCC), metastasis and death from cSCC. In immunocompetent patients with mucosal SCC, downregulation of HLA class I is associated with poor prognosis. Since the degree of HLA expression on tumor cells could play a role in immunogenicity and pathophysiology of cSCC metastasis, we hypothesized that decreased HLA expression is associated with an increased risk of metastasis.Methods: We compared HLA expression between primary metastasized cSCCs, their metastases, and nonmetastasized cSCCs from the same patients. Samples were stained for HLA-A, HLA-B/-C and quantified by calculating the difference in immunoreactivity score (IRS) of the primary cSCC compared with all nonmetastasized cSCCs. Results: The mean IRS score for HLA-B/C expression was 2.07 point higher in metastasized compared to nonmetastasized cSCCs (p = 0.065, 95 % CI -0.18-4.32). 83.3 % of the primary metastasized cSCCs had an IRS score of 4 or higher, compared to 42.9 % in non-metastasized cSCCs. Moderately to poorly differentiated cSCCs had more HLA class I expression compared to well-differentiated cSCCs. Conclusion: Contrary to immunocompetent patients, HLA-B/C expression tends to be upregulated in metastasized cSCC compared to non-metastasized cSCC in SOTR, suggesting that different tumor escape mechanisms play a role in SOTR compared to immunocompetent patients. Show less
Sluimer, L.M.; Bullock, E.; Rätze, M.A.K.; Enserink, L.; Overbeeke, C.; Hornsveld, M.; ... ; Tavares, S. 2023
High expression of the non-receptor tyrosine kinase FER is an independent prognostic factor that correlates with poor survival in breast cancer patients. To investigate whether the kinase activity... Show moreHigh expression of the non-receptor tyrosine kinase FER is an independent prognostic factor that correlates with poor survival in breast cancer patients. To investigate whether the kinase activity of FER is essential for its oncogenic properties, we developed an ATP analogue-sensitive knock-in allele (FERASKI). Specific FER kinase inhibition in MDA-MB-231 cells reduces migration and invasion, as well as metastasis when xenografted into a mouse model of breast cancer. Using the FERASKI system, we identified Ski family transcriptional corepressor 1 (SKOR1) as a direct FER kinase substrate. SKOR1 loss phenocopies FER inhibition, leading to impaired proliferation, migration and invasion, and inhibition of breast cancer growth and metastasis formation in mice. We show that SKOR1 Y234, a candidate FER phosphorylation site, is essential for FER-dependent tumor progression. Finally, our work suggests that the SKOR1 Y234 residue promotes Smad2/3 signaling through SKOR1 binding to Smad3. Our study thus identifies SKOR1 as a mediator of FER-dependent progression of high-risk breast cancers. Show less
Local coagulation activation has been shown to impact both primary tumor growth and metastasis in mice. It is well known that components of the blood clotting cascade such as tissue factor and... Show moreLocal coagulation activation has been shown to impact both primary tumor growth and metastasis in mice. It is well known that components of the blood clotting cascade such as tissue factor and thrombin play a role in tumor progression by activating cellular receptors and local formation of fibrin. However, whether venous thromboembolism (VTE) or a hypercoagulable state has a direct impact on cancer progression is unknown. Here we have combined an orthotopic murine breast cancer model, using female Nod-SCID mice, with siRNA-mediated silencing of antithrombin (siAT) leading to the induction of a systemic hypercoagulable state. We show that, compared to control siRNA-treated (not experiencing a hypercoagulable state) tumor-bearing mice, siAT treated tumor-bearing mice do not show enhanced tumor growth nor enhanced metastasis. We conclude that, in this murine model for hypercoagulability, induction of a hypercoagulable state does not contribute to breast cancer progression. Show less
Piaggio, F.; Croce, M.; Reggiani, F.; Monti, P.; Bernardi, C.; Ambrosio, M.; ... ; Amaro, A. 2022
Background and aim of the study: Mutations in the G alpha-genes GNAQ and GNA11 are found in 85-90% of uveal melanomas (UM). Aim of the study is to understand whether the mutations in both genes... Show moreBackground and aim of the study: Mutations in the G alpha-genes GNAQ and GNA11 are found in 85-90% of uveal melanomas (UM). Aim of the study is to understand whether the mutations in both genes differentially affect tumor characteristics and outcome and if so, to identify potential mechanisms. Methods: We analyzed the association between GNAQ and GNA11 mutations with disease specific survival, gene expression profiles, and cytogenetic alterations in 219 UMs. We used tandem-affinity-purification, mass spectrometry and immunoprecipitation to identify protein interaction partners of the two G-proteins and analyzed their impact on DNA-methylation. Results: GNA11 mutation was associated with: i) an increased frequency of loss of BRCA1- associated protein 1 (BAP1) expression (p = 0.0005), ii) monosomy of chromosome 3 (p < 0.001), iii) amplification of chr8q (p = 0.038), iv) the combination of the latter two (p = 0.0002), and inversely with v) chr6p gain (p = 0.003). Our analysis also showed a shorter disease-specific survival of GNA11-mutated cases as compared to those carrying a GNAQ mutation (HR = 1.97 [95%CI 1.12-3.46], p = 0.02). GNAQ and GNA11 encoded G-proteins have different protein interaction partners. Specifically, the Tet Methylcytosine Dioxygenase 2 (TET2), a protein that is involved in DNA demethylation, physically interacts with the GNAQ protein but not with GNA11, as confirmed by immunoprecipitation analyses. High risk UM cases show a clearly different DNA-methylation pattern, suggesting that a different regulation of DNA methylation by the two G-proteins might convey a different risk of progression. Conclusions: GNA11 mutated uveal melanoma has worse prognosis and is associated with high risk cytogenetic, mutational and molecular tumor characteristics that might be determined at least in part by differential DNA-methylation. (C) 2022 Elsevier Ltd. All rights reserved. Show less
Background: In patients with active cancer and atrial fibrillation (AF) anticoagulation, thrombotic and bleeding risk still entail uncertainty.Aim: We explored the results of an international... Show moreBackground: In patients with active cancer and atrial fibrillation (AF) anticoagulation, thrombotic and bleeding risk still entail uncertainty.Aim: We explored the results of an international survey examining the knowledge and behaviours of a large group of physicians.Methods and results: A web-based survey was completed by 960 physicians (82.4% cardiologists, 75.5% from Europe). Among the currently available anticoagulants for stroke prevention in patients with active cancer, direct oral anticoagulants (DOACs) were preferred by 62.6%, with lower values for low molecular weight heparin (LMWH) (24.1%) and for warfarin (only 7.3%). About 46% of respondents considered that DOACs should be used in all types of cancers except in non-operable gastrointestinal cancers. The lack of controlled studies on bleeding risk (33.5% of respondents) and the risk of drug interactions (31.5%) were perceived as problematic issues associated with use of anticoagulants in cancer. The decision on anticoagulation involved a cardiologist in 27.8% of cases, a cardiologist and an oncologist in 41.1%, and a team approach in 21.6%. The patient also was involved in decision-making, according to similar to 60% of the respondents. For risk stratification, use of CHA2DS2-VASc and HAS-BLED scores was considered appropriate, although not specifically validated in cancer patients, by 66.7% and 56.4%, respectively.Conclusion: This survey highlights that management of anticoagulation in patients with AF and active cancer is challenging, with substantial heterogeneity in therapeutic choices. Direct oral anticoagulants seems having an emerging role but still the use of LMWH remains substantial, despite the absence of long-term data on thromboprophylaxis in AF. Show less
Acem, I.; Verhoef, C.; Rueten-Budde, A.J.; Grunhagen, D.J.; Houdt, W.J. van; Sande, M.A.J. van de; PERSARC Study Grp 2020
Purpose: No studies extensively compared the young adults (YA, 18-39 years), middle-aged (40-69 years), and elderly (>70 years) population with primary high-grade extremity soft tissue sarcoma ... Show morePurpose: No studies extensively compared the young adults (YA, 18-39 years), middle-aged (40-69 years), and elderly (>70 years) population with primary high-grade extremity soft tissue sarcoma (eSTS). This study aimed to determine whether the known effect of age on overall survival (OS) and disease progression can be explained by differences in tumour characteristics and treatment protocol among the YA, middle-aged and elderly population in patients with primary high-grade eSTS treated with curative intent.Methods: In this retrospective multicentre study, inclusion criteria were patients with primary high-grade eSTS of 18 years and older, surgically treated with curative intent between 2000 and 2016. Cox proportional hazard models and a multistate model were used to determine the association of age on OS and disease progression.Results: A total of 6260 patients were included in this study. YA presented more often after 'whoops'-surgery or for reresection due to residual disease, and with more deep-seated tumours. Elderly patients presented more often with grade III and larger (>10 cm) tumours. After adjustment for the imbalance in tumour and treatment characteristics the hazard ratio for OS of the middle-aged population is 1.47 (95% confidence interval [CI]: 1.23-1.76) and 3.13 (95% CI: 2.59-3.78) in the elderly population, compared with YA.Discussion: The effect of age on OS could only partially be explained by the imbalance in the tumour characteristics and treatment variables. The threefold higher risk of elderly could, at least partially, be explained by a higher other-cause mortality. The results might also be explained by a different tumour behaviour or suboptimal treatment in elderly compared with the younger population. (C) 2020 The Authors. Published by Elsevier Ltd. Show less
Todd, G.M.; Gao, Z.C.; Hyvonen, M.; Brazil, D.P.; Dijke, P. ten 2020
Bone morphogenetic proteins (BMPs) are multifunctional secreted cytokines that act in a highly context-dependent manner. BMP action extends beyond the induction of cartilage and bone formation, to... Show moreBone morphogenetic proteins (BMPs) are multifunctional secreted cytokines that act in a highly context-dependent manner. BMP action extends beyond the induction of cartilage and bone formation, to encompass pivotal roles in controlling tissue and organ homeostasis during development and adulthood. BMPs signal via plasma membrane type I and type II serine/threonine kinase receptors and intracellular SMAD transcriptional effectors. Exquisite temporospatial control of BMP/SMAD signalling and crosstalk with other cellular cues is achieved by a series of positive and negative regulators at each step in the BMP/SMAD pathway. The interaction of BMP ligand with its receptors is carefully controlled by a diverse set of secreted antagonists that bind BMPs and block their interaction with their cognate BMP receptors. Perturbations in this BMP/BMP antagonist balance are implicated in a range of developmental disorders and diseases, including cancer. Here, we provide an overview of the structure and function of secreted BMP antagonists, and summarize recent novel insights into their role in cancer progression and bone metastasis. Gremlin1 (GREM1) is a highly studied BMP antagonist, and we will focus on this molecule in particular and its role in cancer. The therapeutic potential of pharmacological inhibitors for secreted BMP antagonists for cancer and other human diseases will also be discussed. Show less
Background Extracellular vesicles (EVs) have shown great potential for targeted therapy, as they have a natural ability to pass through biological barriers and, depending on their origin, can... Show moreBackground Extracellular vesicles (EVs) have shown great potential for targeted therapy, as they have a natural ability to pass through biological barriers and, depending on their origin, can preferentially accumulate at defined sites, including tumors. Analyzing the potential of EVs to target specific cells remains challenging, considering the unspecific binding of lipophilic tracers to other proteins, the limitations of fluorescence for deep tissue imaging and the effect of external labeling strategies on their natural tropism. In this work, we determined the cell-type specific tropism of B16F10-EVs towards cancer cell and metastatic tumors by using fluorescence analysis and quantitative gold labeling measurements. Surface functionalization of plasmonic gold nanoparticles was used to promote indirect labeling of EVs without affecting size distribution, polydispersity, surface charge, protein markers, cell uptake or in vivo biodistribution. Double-labeled EVs with gold and fluorescent dyes were injected into animals developing metastatic lung nodules and analyzed by fluorescence/computer tomography imaging, quantitative neutron activation analysis and gold-enhanced optical microscopy. Results We determined that B16F10 cells preferentially take up their own EVs, when compared with colon adenocarcinoma, macrophage and kidney cell-derived EVs. In addition, we were able to detect the preferential accumulation of B16F10 EVs in small metastatic tumors located in lungs when compared with the rest of the organs, as well as their precise distribution between tumor vessels, alveolus and tumor nodules by histological analysis. Finally, we observed that tumor EVs can be used as effective vectors to increase gold nanoparticle delivery towards metastatic nodules. Conclusions Our findings provide a valuable tool to study the distribution and interaction of EVs in mice and a novel strategy to improve the targeting of gold nanoparticles to cancer cells and metastatic nodules by using the natural properties of malignant EVs. Show less
Depreitere, B.; Ricciardi, F.; Arts, M.; Balabaud, L.; Bunger, C.; Buchowski, J.M.; ... ; Choi, D. 2020
Background The benefits of surgery for symptomatic spinal metastases have been demonstrated, largely based on series of patients undergoing debulking and instrumentation operations. However, as... Show moreBackground The benefits of surgery for symptomatic spinal metastases have been demonstrated, largely based on series of patients undergoing debulking and instrumentation operations. However, as cancer treatments improve and overall survival lengths increase, the incidence of recurrent spinal cord compression after debulking may increase. The aim of the current paper is to document the postoperative evolution of neurological function, pain, and quality of life following debulking and instrumentation in the Global Spine Tumor Study Group (GSTSG) database. Methods The GSTSG database is a prospective multicenter data repository of consecutive patients that underwent surgery for a symptomatic spinal metastasis. For the present analysis, patients were selected from the database that underwent decompressive debulking surgery with instrumentation. Preoperative tumor type, Tomita and Tokuhashi scores, EQ-5D, Frankel, Karnofsky, and postoperative complications, survival, EQ-5D, Frankel, Karnofsky, and pain numeric rating scores (NRS) at 3, 6, 12, and 24 months were analyzed. Results A total of 914 patients underwent decompressive debulking surgery with instrumentation and had documented follow-up until death or until 2 years post surgery. Median preoperative Karnofsky performance index was 70. A total of 656 patients (71.8%) had visceral metastases and 490 (53.6%) had extraspinal bone metastases. Tomita scores were evenly distributed above (49.1%) and below or equal to 5 (50.9%), and Tokuhashi scores almost evenly distributed below or equal to 8 (46.3%) and above 8 (53.7%). Overall, 12-month survival after surgery was 56.3%. The surgery resulted in EQ-5D health status improvement and NRS pain reduction that was maintained throughout follow-up. Frankel scores improved at first follow-up in 25.0% of patients, but by 12 months neurological deterioration was observed in 18.8%. Conclusion We found that palliative debulking and instrumentation surgeries were performed throughout all Tomita and Tokuhashi categories. These surgeries reduced pain scores and improved quality of life up to 2 years after surgery. After initial improvement, a proportion of patients experienced neurological deterioration by 1 year, but the majority of patients remained stable. Show less
Verschoor, A.J.; Speetjens, F.M.; Dijkstra, P.D.S.; Fiocco, M.; Sande, M.A.J. van de; Bovee, J.V.M.G.; Gelderblom, H. 2019
Introduction Metastatic spinal cancer is a common condition that may lead to spinal instability, pain and paralysis. In the 1980s, surgery was discouraged because results showed worse neurological... Show moreIntroduction Metastatic spinal cancer is a common condition that may lead to spinal instability, pain and paralysis. In the 1980s, surgery was discouraged because results showed worse neurological outcomes and pain compared with radiotherapy alone. However, with the advent of modern imaging and spinal stabilisation techniques, the role of surgery has regained centre stage, though few studies have assessed quality of life and functional outcomes after surgery. Objective We investigated whether surgery provides sustained improvement in quality of life and pain relief for patients with symptomatic spinal metastases by analysing the largest reported surgical series of patients with epidural spinal metastases. Methods A prospective cohort study of 922 consecutive patients with spinal metastases who underwent surgery, from the Global Spine Tumour Study Group database. Pre- and post-operative EQ-5D quality of life, visual analogue pain score, Karnofsky physical functioning score, complication rates and survival were recorded. Results Quality of life (EQ-5D), VAS pain score and Karnofsky physical functioning score improved rapidly after surgery and these improvements were sustained in those patients who survived up to 2 years after surgery. In specialised spine centres, the technical intra-operative complication rate of surgery was low, however almost a quarter of patients experienced post-operative systemic adverse events. Conclusion Surgical treatment for spinal metastases produces rapid pain relief, maintains ambulation and improves good quality of life. However, as a group, patients with cancer are vulnerable to post-operative systemic complications, hence the importance of appropriate patient selection. Show less
