Towards new therapeutic strategies in chondrosarcoma

This thesis presents the identification of new targets for therapeutic treatment of chondrosarcoma, tumours that are highly insensitive to conventional chemo- and radiation thearapy. A relatively new array technique to identify active kinases in chondrosarcoma cell cultures was used, which identified Src inhibitor dasatinib as a potential target in chondrosarcoma treatment. Subsequently, growth of the majority of chondrosarcoma cell cultures was inhibited by dasatinib. In addition to dasatinib, CDK inhibitor Flavoperidol, Aurorakinase inhibitor AZD1152 and AKT inhibitor Enzastaurin were identified as candidates for therapeutic intervention in chondrosarcomas. Moreover, the use of selective COX-2 inhibition was evaluated preclinically. In vitro, chondrosarcoma cell viability was inhibited by celecoxib, a selective COX-2 inhibitor. Also in a grade II and III chondrosarcoma xenograft mouse model an anti- tumourigenic effect of celecoxib was found, since tumor size was negatively correlated to celecoxib serum levels. The results described in this thesis have led to a better understanding of molecular events that are important in the growth of conventional chondrosarcoma. In addition, new targets were identified, which are expected to lead to the implementation of new therapy modalities for patients that have inoperable or metastatic chondrosarcoma.The work presented in this thesis was financially supported by Netherlands Organisation for Scientific Research (908-02-018) and Eurobonet (018814)UBL - phd migration 201

COX-2 expression in chondrosarcoma: A role for celecoxib treatment?

Chondrosarcomas are resistant to conventional chemo- and radiotherapy. A subset of chondrosarcomas arises secondarily in the benign tumour syndromes enchondromatosis (EC) and multiple osteochondromas (MO), and prevention of tumour development would greatly improve prognosis. We therefore investigated the effect of selective COX-2 inhibition on chondrosarcoma growth. COX-2 expression was studied in central- and peripheral cartilaginous tumours. The effect of COX-2 inhibition was assessed in four high-grade chondrosarcoma cell lines using celecoxib and NS-398 treatment. COX-2 activity (prostaglandin E-2 (PGE(2)) ELISA) and cell viability were measured. The (prophylactic) effect of celecoxib on chondrosarcoma growth in vivo was studied for 8 weeks using a xenograft model of cell line CH2879 in immunoincompetent nude mice. High COX-2 protein expression was mainly found in solitary peripheral chondrosarcoma and in enchondromatosis-related central chondrosarcoma, which was confirmed by qPCR. After 72 h of celecoxib treatment, a significant decrease in cell viability was observed in three chondrosarcoma cell lines. in vivo, celecoxib initially slowed tumour growth in chondrosarcoma xenografts; however, after prolonged treatment relapsed tumour growth was observed. Tumour volume was negatively associated with celecoxib serum levels, and seemed smaller in the high-dose prophylactic treatment group. We confirmed the expression of COX-2 in 65% of chondrosarcomas, and COX-2 inhibition by celecoxib diminished cell viability in vitro. The initial response and the decrease in tumour volume with increased celecoxib serum levels in vivo supported a role for celecoxib, although relapsed tumour growth after 6 weeks was worrisome. Also the role of high-dose prophylactic celecoxib in preventing the development of benign and malignant cartilage tumours in EC and MO patients deserves further investigation. (C) 2009 Elsevier Ltd. All rights reserved.Molecular tumour pathology - and tumour genetic

T-VEC for stage IIIB-IVM1a melanoma achieves high rates of complete and durable responses and is associated with tumor load: a clinical prediction model

Background Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous and nodal melanoma lesions in stage IIIB-IVM1a patients. This study set out to identify prognostic factors for achieving a complete response that can be used to optimize patient selection for T-VEC monotherapy. Methods Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2020-01 with a follow-up time > 6 months, were included. Data were collected on baseline characteristics, responses and adverse events (AEs). Uni- and multivariable analyses were conducted, and a prediction model was developed to identify prognostic factors associated with CR. Results A total of 93 patients were included with a median age of 69 years, median follow-up time was 16.6 months. As best response, 58 patients (62%) had a CR, and the overall response rate was 79%. The durable response rate (objective response lasting > 6 months) was 51%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, prior treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving CR. The prediction model includes the predictors tumor size, type of metastases and number of lesions. Conclusions This study shows that intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.Analysis and support of clinical decision makin

Multimodality treatment of undifferentiated pleomorphic soft tissue sarcoma of the extremity (eUPS) in the elderly

Introduction: This subgroup analysis of undifferentiated pleomorphic soft tissue sarcoma of the extremity (eUPS) from the PERSARC collaborative group aimed to achieve a more personalized multimodality treatment approach for primary eUPS in elderly patients.Material and methods: A multicenter retrospective study including primary high-grade eUPS surgically treated with curative intent between 2000 and 2016. Overall survival (OS), local recurrence (LR) and distant metastasis (DM) curves were calculated by Kaplan Meier analysis. Cox proportional hazard models were used to determine the effect of radiotherapy.Results: From a total of 2511 patients with extremity soft tissue sarcoma (eSTS) of the PERSARC study collaborative; 703 patients with eUPS were included in this study. In elderly patients with eUPS 5-year OS, LR and DM were 35.4 (95%CI 29.3-42.8), 17.7 (95%CI 12.7-22.6) and 24.6 (95%CI 19.1-30.1). eUPS was significantly less treated with radiotherapy compared with other eSTS, especially in elderly patients. Patients with R1-R2 margins treated with radiotherapy had about half the risk of developing LR compared with patients treated without radiotherapy (HR = 0.454, p = 0.033).Conclusion: Elderly patients with eUPS were less often treated with radiotherapy and showed higher LR. Nowadays, given an increasing life expectancy in elderly patients, multimodality treatment should be considered. (C) 2021 The Authors. Published by Elsevier Ltd.Orthopaedics, Trauma Surgery and Rehabilitatio

Multimodality treatment of undifferentiated pleomorphic soft tissue sarcoma of the extremity (eUPS) in the elderly

Introduction: This subgroup analysis of undifferentiated pleomorphic soft tissue sarcoma of the extremity (eUPS) from the PERSARC collaborative group aimed to achieve a more personalized multimodality treatment approach for primary eUPS in elderly patients.Material and methods: A multicenter retrospective study including primary high-grade eUPS surgically treated with curative intent between 2000 and 2016. Overall survival (OS), local recurrence (LR) and distant metastasis (DM) curves were calculated by Kaplan Meier analysis. Cox proportional hazard models were used to determine the effect of radiotherapy.Results: From a total of 2511 patients with extremity soft tissue sarcoma (eSTS) of the PERSARC study collaborative; 703 patients with eUPS were included in this study. In elderly patients with eUPS 5-year OS, LR and DM were 35.4 (95%CI 29.3-42.8), 17.7 (95%CI 12.7-22.6) and 24.6 (95%CI 19.1-30.1). eUPS was significantly less treated with radiotherapy compared with other eSTS, especially in elderly patients. Patients with R1-R2 margins treated with radiotherapy had about half the risk of developing LR compared with patients treated without radiotherapy (HR = 0.454, p = 0.033).Conclusion: Elderly patients with eUPS were less often treated with radiotherapy and showed higher LR. Nowadays, given an increasing life expectancy in elderly patients, multimodality treatment should be considered. (C) 2021 The Authors. Published by Elsevier Ltd

Intraoperative Near-Infrared Fluorescence Imaging with Indocyanine Green for Identification of Gastrointestinal Stromal Tumors (GISTs), a Feasibility Study

Simple Summary Surgical resection plays a pivotal role in the treatment of GIST patients. The current study aims to explore the use of near-infrared fluorescence imaging to optimize the intraoperative tumor identification of GISTs. For this purpose, the potential and limitations of the widely used, and non-specific, tracer indocyanine green were assessed in a multicenter study including 10 patients. Our results show that GISTs typically have similar fluorescence intensity to the surrounding tissue, within several minutes after the intravenous administration of indocyanine green. These findings justify future research into specific fluorescent tracers for GISTs, and set a reference for future intraoperative imaging trials. Background: Optimal intraoperative tumor identification of gastrointestinal stromal tumors (GISTs) is important for the quality of surgical resections. This study aims to assess the potential of near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG) to improve intraoperative tumor identification. Methods: Ten GIST patients, planned to undergo resection, were included. During surgery, 10 mg of ICG was intravenously administered, and NIRF imaging was performed at 5, 10, and 15 min after the injection. The tumor fluorescence intensity was visually assessed, and tumor-to-background ratios (TBRs) were calculated for exophytic lesions. Results: Eleven GIST lesions were imaged. The fluorescence intensity of the tumor was visually synchronous and similar to the background in five lesions. In one lesion, the tumor fluorescence was more intense than in the surrounding tissue. Almost no fluorescence was observed in both the tumor and healthy peritoneal tissue in two patients with GIST lesions adjacent to the liver. In three GISTs without exophytic growth, no fluorescence of the tumor was observed. The median TBRs at 5, 10, and 15 min were 1.0 (0.4-1.2), 1.0 (0.5-1.9), and 0.9 (0.7-1.2), respectively. Conclusion: GISTs typically show similar fluorescence intensity to the surrounding tissue in NIRF imaging after intraoperative ICG administration. Therefore, intraoperatively administered ICG is currently not applicable for adequate tumor identification, and further research should focus on the development of tumor-specific fluorescent tracers for GISTs.Surgical oncolog

Intraoperative Near-Infrared Fluorescence Imaging with Indocyanine Green for Identification of Gastrointestinal Stromal Tumors (GISTs), a Feasibility Study

Simple Summary Surgical resection plays a pivotal role in the treatment of GIST patients. The current study aims to explore the use of near-infrared fluorescence imaging to optimize the intraoperative tumor identification of GISTs. For this purpose, the potential and limitations of the widely used, and non-specific, tracer indocyanine green were assessed in a multicenter study including 10 patients. Our results show that GISTs typically have similar fluorescence intensity to the surrounding tissue, within several minutes after the intravenous administration of indocyanine green. These findings justify future research into specific fluorescent tracers for GISTs, and set a reference for future intraoperative imaging trials. Background: Optimal intraoperative tumor identification of gastrointestinal stromal tumors (GISTs) is important for the quality of surgical resections. This study aims to assess the potential of near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG) to improve intraoperative tumor identification. Methods: Ten GIST patients, planned to undergo resection, were included. During surgery, 10 mg of ICG was intravenously administered, and NIRF imaging was performed at 5, 10, and 15 min after the injection. The tumor fluorescence intensity was visually assessed, and tumor-to-background ratios (TBRs) were calculated for exophytic lesions. Results: Eleven GIST lesions were imaged. The fluorescence intensity of the tumor was visually synchronous and similar to the background in five lesions. In one lesion, the tumor fluorescence was more intense than in the surrounding tissue. Almost no fluorescence was observed in both the tumor and healthy peritoneal tissue in two patients with GIST lesions adjacent to the liver. In three GISTs without exophytic growth, no fluorescence of the tumor was observed. The median TBRs at 5, 10, and 15 min were 1.0 (0.4-1.2), 1.0 (0.5-1.9), and 0.9 (0.7-1.2), respectively. Conclusion: GISTs typically show similar fluorescence intensity to the surrounding tissue in NIRF imaging after intraoperative ICG administration. Therefore, intraoperatively administered ICG is currently not applicable for adequate tumor identification, and further research should focus on the development of tumor-specific fluorescent tracers for GISTs