PurposeResection of pediatric osteosarcoma in the extremities with soft tissue involvement presents surgical challenges due to difficult visualization and palpation of the tumor. Therefore, an... Show morePurposeResection of pediatric osteosarcoma in the extremities with soft tissue involvement presents surgical challenges due to difficult visualization and palpation of the tumor. Therefore, an adequate image-guided surgery (IGS) system is required for more accurate tumor resection. The use of a 3D model in combination with intraoperative tracked ultrasound (iUS) may enhance surgical decision making. This study evaluates the clinical feasibility of iUS as a surgical tool using a porcine cadaver model.MethodsFirst, a 3D model of the porcine lower limb was created based on preoperative scans. Second, the bone surface of the tibia was automatically detected with an iUS by a sweep on the skin. The bone surface of the preoperative 3D model was then matched with the bone surface detected by the iUS. Ten artificial targets were used to calculate the target registration error (TRE). Intraoperative performance of iUS IGS was evaluated by six pediatric surgeons and two pediatric oncologic orthopedists. Finally, user experience was assessed with a post-procedural questionnaire.ResultsEight registration procedures were performed with a mean TRE of 6.78 +/- 1.33 mm. The surgeons agreed about the willingness for clinical implementation in their current clinical practice. They mentioned the additional clinical value of iUS in combination with the 3D model for the localization of the soft tissue components of the tumor. The concept of the proposed IGS system is considered feasible by the clinical panel, but the large TRE and degree of automation need to be addressed in further work.ConclusionThe participating pediatric surgeons and orthopedists were convinced of the clinical value of the interaction between the iUS and the 3D model. Further research is required to improve the surgical accuracy and degree of automation of iUS-based registration systems for the surgical management of pediatric osteosarcoma. Show less
BackgroundLocal treatment is a crucial element in the standard of care for Ewing sarcoma (EWS). While systemic treatment is improved in randomised clinical trials, local treatment modalities are... Show moreBackgroundLocal treatment is a crucial element in the standard of care for Ewing sarcoma (EWS). While systemic treatment is improved in randomised clinical trials, local treatment modalities are discussed controversially. We analysed the association between local therapy and event-free survival (EFS), overall survival (OS), and local recurrence (LR) in prospectively collected data of patients with localised EWS.Patients and methodsWe analysed data from the international Ewing 2008 study registered between 2009 and 2019 in 117 centres. After induction chemotherapy, patients received surgery, radiotherapy, or a combination thereof. We performed Cox regression, conducted propensity score-weighted sensitivity analysis, and performed subgroup analyses. Hazard ratios (HRs) and 95% confidence intervals are reported.ResultsWe included 863 patients with localised EWS (surgery alone: 331, combination therapy: 358, definitive radiotherapy: 174). In patients treated with combination therapy compared to surgery alone, EFS HR was 0.84 (0.57–1.24; p = 0.38), OS HR was 0.84 (0.57–1.23; p = 0.41), and LR HR was 0.58 (0.26–1.31; p = 0.19). Hazards of any event were increased in patients treated with definitive radiotherapy compared to surgery only, HR 1.53 (1.02–2.31; p = 0.04). Patients with poor responses to chemotherapy benefitted from combination therapy over definitive surgery with an EFS HR 0.49 (0.27–0.89; p = 0.02). Patients with pelvic tumours benefitted from combination therapy over surgery only regarding LR, HR 0.12 (0.02–0.72; p = 0.02).ConclusionPatients with poor responses to chemotherapy benefitted from radiotherapy added to surgery. In the whole group, radiotherapy alone as opposed to surgery alone increased the hazards of any event. Show less
Jeremiasse, B.; Rijs, Z.; Angoelal, K.R.; Hiemcke-Jiwa, L.S.; Boed, E.A. de; Kuppen, P.J.K.; ... ; Steeg, A.F.W. van der 2023
Simple Summary The only cure for children with Ewing sarcoma (ES) is surgery. Unfortunately, surgeons are often not able to differentiate healthy from malignant tissue. Fluorescent imaging during... Show moreSimple Summary The only cure for children with Ewing sarcoma (ES) is surgery. Unfortunately, surgeons are often not able to differentiate healthy from malignant tissue. Fluorescent imaging during the operation will facilitate recognition of malignant cells, but unfortunately there are no ES specific tracers available yet. We searched for proteins on ES cells that could be used as a target against which specific tracers could be developed. The most promising proteins, CD99, CD117, and GD2, were found in paraffin-embedded tissue samples collected from ES patients. Tracers against CD99 and CD117, consisting of monoclonal antibodies attached with a fluorescent dye, showed positive signals on cultured ES cells. In a proof-of-concept study, these tracers were topically applied on fresh ES tissue, showing a signal in the tumor. Our results indicate the applicability for fluorescence-guided surgery of ES-based tracers, but these data have to be confirmed in a larger cohort of pediatric ES patients. Fluorescence-guided surgery (FGS), based on fluorescent tracers binding to tumor-specific biomarkers, could assist surgeons to achieve complete tumor resections. This study evaluated potential biomarkers for FGS in pediatric Ewing sarcoma (ES). Immunohistochemistry (IHC) was performed to assess CD99, CXCR4, CD117, NPY-R-Y1, and IGF-1R expression in ES biopsies and resection specimens. LINGO-1 and GD2 evaluation did not work on the acquired tissue. Based on the immunoreactive scores, anti-CD99 and anti-CD117 were evaluated for binding specificity using flow cytometry and immunofluorescence microscopy. Anti-GD2, a tracer in the developmental phase, was also tested. These three tracers were topically applied to a freshly resected ES tumor and adjacent healthy tissue. IHC demonstrated moderate/strong CD99 and CD117 expression in ES tumor samples, while adjacent healthy tissue had limited expression. Flow cytometry and immunofluorescence microscopy confirmed high CD99 expression, along with low/moderate CD117 and low GD2 expression, in ES cell lines. Topical anti-CD99 and anti-GD2 application on ES tumor showed fluorescence, while anti-CD117 did not show fluorescence for this patient. In conclusion, CD99-targeting tracers hold promise for FGS of ES. CD117 and GD2 tracers could be potential alternatives. The next step towards development of ES-specific FGS tracers could be ex vivo topical application experiments on a large cohort of ES patients. Show less
Aim: Follow-up strategies for high-grade bone sarcomas have been optimized to facilitate early detection of local recurrence and distant metastasis. The ideology is that early detection enables... Show moreAim: Follow-up strategies for high-grade bone sarcomas have been optimized to facilitate early detection of local recurrence and distant metastasis. The ideology is that early detection enables early treatment presuming better survival. However, the clinical value for each individual patient remains questionable. This study aims to evaluate oncological events after initial treatment in order to assess current follow-up strategies for high-grade bone sarcomas in the Netherlands.Patients and Methods: A retrospective cohort study was conducted based on a national registry. All cases were retrieved from the Netherlands Cancer Registry. Our study consisted of 393 patients treated between 2007 and 2011 with complete follow-up data. Baseline characteristics were analysed for all entities. Local recurrence and distant metastasis was analysed along with overall survival for high-grade chondrosarcoma, high-grade osteo-sarcoma, Ewing sarcoma and chordoma.Results: Median follow-up was 8,3 years for high-grade chondrosarcoma, 4,9 for high-grade osteosarcoma, 3,8 for Ewing sarcoma and 7,5 for chordoma. Median time to local recurrence and distant metastasis was 1,2 years for high-grade osteosarcoma and 1,5 years for Ewing sarcoma. For high-grade osteosarcoma with localized disease at presentation, 0.09 new distant metastatic events per patient per year were seen after five years of follow-up with 11,1 patients needed to follow-up for any event. Five-year overall survival was 60,0% for high-grade chon-drosarcoma, 50,0% for high-grade osteosarcoma, 45,3% for Ewing sarcoma and 71,4% for chordoma.Conclusions: This nationwide study shows a plateau in local recurrences and distant metastatic events after four years of treatment for patients with high-grade osteosarcoma and Ewing sarcoma. Due to a lack of reliable ev-idence however, we were not able to provide additional guidance on follow-up intervals and duration. Collab-orative research with larger groups is needed in order to provide a solid scientific recommendation for follow-up in the heterogenous patient population with bone sarcoma. Show less
Rijs, Z.; Jeremiasse, B.; Shifai, N.; Gelderblom, H.; Sier, C.F.M.; Vahrmeijer, A.L.; ... ; Sande, M.A.J. van de 2021
Sarcomas are a rare heterogeneous group of malignant neoplasms of mesenchymal origin which represent approximately 13% of all cancers in pediatric patients. The most prevalent pediatric bone... Show moreSarcomas are a rare heterogeneous group of malignant neoplasms of mesenchymal origin which represent approximately 13% of all cancers in pediatric patients. The most prevalent pediatric bone sarcomas are osteosarcoma (OS) and Ewing sarcoma (ES). Rhabdomyosarcoma (RMS) is the most frequently occurring pediatric soft tissue sarcoma. The median age of OS and ES is approximately 17 years, so this disease is also commonly seen in adults while non-pleiomorphic RMS is rare in the adult population. The mainstay of all treatment regimens is multimodal treatment containing chemotherapy, surgical resection, and sometimes (neo)adjuvant radiotherapy. A clear resection margin improves both local control and overall survival and should be the goal during surgery with a curative intent. Real-time intraoperative fluorescence-guided imaging could facilitate complete resections by visualizing tumor tissue during surgery. This review evaluates whether non-targeted and targeted fluorescence-guided surgery (FGS) could be beneficial for pediatric OS, ES, and RMS patients. Necessities for clinical implementation, current literature, and the positive as well as negative aspects of non-targeted FGS using the NIR dye Indocyanine Green (ICG) were evaluated. In addition, we provide an overview of targets that could potentially be used for FGS in OS, ES, and RMS. Then, due to the time- and cost-efficient translational perspective, we elaborate on the use of antibody-based tracers as well as their disadvantages and alternatives. Finally, we conclude with recommendations for the experiments needed before FGS can be implemented for pediatric OS, ES, and RMS patients. Show less
This thesis describes the effects of shortterm fasting on chemotherapy outcome in patients with breast cancer and the IGF-1 and insulin pathway as a target for cancer therapy and as a biomarker for... Show moreThis thesis describes the effects of shortterm fasting on chemotherapy outcome in patients with breast cancer and the IGF-1 and insulin pathway as a target for cancer therapy and as a biomarker for chemotherapy outcome.Preclinical research is evaluated, which shows that short-term fasting during chemotherapy is effective. The effects of short-term fasting in humans is not evident yet. Although the first small clinical studies of short-term fasting as adjunct to chemotherapy are promising in terms of decreased toxicity and enhanced efficacy, the exact mechanism and effects are not established yet. More studies and a longer follow-up are needed to prove this.Insulin-like growth factor 1 (IGF-1) and insulin are members of the IGF-1 pathway, which is involved in cell growth and proliferation. The effects of the IGF-1 pathway on chemotherapy outcome and the pathway itself as target for cancer therapy are described. The disappointing results of clinical studies of IGF-1R inhibitors may be caused by the complexity of the IGF-1R pathway. Lowering both insulin and IGF-1, perhaps with a short-term fasting intervention, serves as a possible target in cancer therapy. Show less
Gerrand, C.; Bate, J.; Seddon, B.; Dirksen, U.; Randall, R.L.; Sande, M. van de; ... ; Whelan, J. 2020
Background The local treatment of Ewing sarcoma of bone involves surgery, radiotherapy or both. The selection of treatment depends on the anatomical extent of the tumour, the effectiveness of the... Show moreBackground The local treatment of Ewing sarcoma of bone involves surgery, radiotherapy or both. The selection of treatment depends on the anatomical extent of the tumour, the effectiveness of the proposed treatment, its morbidity, and the expectation of cure. However, not only are there variations in the approach to local treatment between individual patients, but also between treatment centres and countries. Our aim was to explore variation in practice and develop consensus statements about local treatment. Methods A three stage modified Delphi technique was used with international collaborators. This involved an expert panel to identify areas of controversy, an online survey of international collaborators and a consensus meeting in London, UK in June 2017. In the consensus meeting, teams of clinicians discussed the local management of selected cases and their responses were collected with electronic voting. Results Areas of greater or less consensus were identified. The lack of evidence underpinning different approaches was noted and areas for collaborative research became apparent. Conclusion This has demonstrated that there is an international consensus around many aspects of the local treatment of Ewing sarcoma of bone, including the use of specialist MultiDisciplinary Team (MDT) meetings with access to all appropriate treatments. However, considerable variation remains including the use of different staging investigations, decision making, definitions of response, and radiotherapy doses and timing. Further collaborative work should be undertaken to determine the impact of these variations in order to define best practice. Show less
Simple SummaryThe insulin-like growth factor-1 receptor (IGF1R) is a receptor commonly overexpressed and overactivated in a variety of cancers, including Ewing sarcoma, and promotes cell growth and... Show moreSimple SummaryThe insulin-like growth factor-1 receptor (IGF1R) is a receptor commonly overexpressed and overactivated in a variety of cancers, including Ewing sarcoma, and promotes cell growth and survival. After promising results with targeting and inhibiting the receptor in vitro, multiple different IGF1R targeting compounds have been clinically tried but showed limited efficacy. Here we discuss several possible resistance mechanisms which could explain why IGF1R targeting fails in the clinic and discuss possible ways to overcome these resistances.Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor. Show less
One of the main questions in Ewing sarcoma treatment is to identify low-risk patients that can be treated with less intensive treatment so that toxicity and the occurrence of long-term adverse... Show moreOne of the main questions in Ewing sarcoma treatment is to identify low-risk patients that can be treated with less intensive treatment so that toxicity and the occurrence of long-term adverse effects can be limited while still maintaining high cure rates or to identify those patients for whom treatment is expected to have limited benefit. Furthermore, to identify high-risk patients in which treatment needs to be intensified to improve outcome. Selection of risk groups and adjusted treatment allows for early decision making, will help to improve future outcomes and assists in clinical trial design. Additionally, treatment of Ewing sarcoma is multimodal and surgery, if feasible, is crucial for curative management. However, accurate detection and localization of tumor boundaries, especially in anatomical complex locations such as the pelvic is challenging. Inadequate surgical margins lead to a higher risk of local recurrence which has major impact on oncological outcome. Developments in intra-operative imaging, like CT-based navigation systems and near infrared (NIR)fluorescence guided surgery (FGS) make accurate defining and localization of surgical margins possible. They represent a whole new field of precision medicine and provide new treatment options for patients, thereby improving function outcome and healthcare quality. Show less
Objective To determine the level of discrepancy between magnetic resonance imaging (MRI) and F-18-FDG PET-CT in detecting osseous metastases in patients with Ewing sarcoma. Methods Twenty patients... Show moreObjective To determine the level of discrepancy between magnetic resonance imaging (MRI) and F-18-FDG PET-CT in detecting osseous metastases in patients with Ewing sarcoma. Methods Twenty patients with histopathologically confirmed Ewing sarcoma between 2000 and 2017 who underwent F-18-FDG PET-CT and MRI within a 4-week range were included. Each imaging modality was evaluated by a separate observer. Reference diagnosis of each lesion was based on histopathology or consensus of an expert panel using all available data, including at least 6 months' follow-up. Sensitivity, specificity, and predictive values were determined. Osseous lesions were analyzed on a patient and a lesion basis. Factors possibly related to false-negative findings were evaluated using Pearson's Chi-squared or Fisher's exact test. Results A total of 112 osseous lesions were diagnosed in 13 patients, 107 malignant and 5 benign. Seven patients showed no metastases on either F-18-FDG PET-CT or MRI. Forty-one skeletal metastases (39%) detected with MRI did not show increased F-18-FDG uptake on F-18-FDG PET-CT (false-negative). Lesion-based sensitivities and specificities were 62% (95%CI 52-71%) and 100% (48-100%) for F-18-FDG PET-CT; and 99% (97-100%) and 100% (48-100%) for MRI respectively. Bone lesions were more likely to be false-negative on F-18-FDG PET-CT if hematopoietic bone marrow extension was widespread and active (p = 0.001), during or after (neo)-adjuvant treatment (p = 0.001) or when the lesion was smaller than 10 mm (p < 0.001). Conclusion Although no definite conclusions can be drawn from this small retrospective study, it shows that caution is needed when using F-18-FDG PET-CT for diagnosing skeletal metastases in Ewing sarcoma. Poor contrast between metastases and active hematopoietic bone marrow, chemotherapeutic treatment, and/or small size significantly decrease the diagnostic yield of F-18-FDG PET-CT, but not of MRI. Show less
Ewing and chondrosaroma are two forms of primary bone cancer. The few clinical studies that are published in recent decades show disappointing results. With a 5 year survival of 10% for inoperable... Show moreEwing and chondrosaroma are two forms of primary bone cancer. The few clinical studies that are published in recent decades show disappointing results. With a 5 year survival of 10% for inoperable Ewing sarcoma and 2% for inoperable chondrosarcoma patients the outcome is poor. If a patient has not responded to standard treatment, they are often treated with combinations based on expert opinion of the treating physician. These treatment combinations have not been investigated in studies because of the small patient numbers which makes starting a study very difficult and time-consuming. One combination is of the chemotherapeutic agents etoposide with carboplatin or cisplatin. Analysis of the survival data of patients treated with these combinations shows that they are comparable to other standard treatment options. New non-chemotherapy treatment options are currently being investigated. Examples are the IGF-1R and PARP route. The current knowledge of both routes shows that disregulation causes malignant transformation and / or disease progression. Inhibition of these routes is therefore a possible treatment. In clinical studies, the results are not positive for all patients. This is due to incorrect patient selection and not being tested in combination with already used treatments. Show less
Aims: Chondrosarcoma, osteosarcoma and Ewing sarcoma form the majority of malignant primary tumours of bone. High-grade bone sarcomas require intensive treatment due to their rapid and invasive... Show moreAims: Chondrosarcoma, osteosarcoma and Ewing sarcoma form the majority of malignant primary tumours of bone. High-grade bone sarcomas require intensive treatment due to their rapid and invasive growth pattern and metastasising capabilities. This nationwide study covers overall incidence, treatment and survival patterns of bone sarcomas in a 15-year period (2000-2014) in the total population of the Netherlands.Patients and methods: Data for this study were derived from the Netherlands Cancer Registry, which receives primary notification from the national pathology database. Classification and categorisation was based on the ICD-O-3 classification and the WHO classification 2013 applied according to our clinicopathological expertise. Overall incidence over the 15-year-period was calculated as a rate per 100,000 person-years (using the European Standardised Rate, ESR). Survival was analysed with Kaplan-Meier curves and Cox proportional hazards regression.Results: Incidence for high-grade chondrosarcoma (n = 429) was estimated at 0.15 per 100,000 ESR, and 5-year overall survival at 65.9% (95% confidence interval (CI): 61.0%-70.4%). Incidence for high-grade central osteosarcoma (n = 605) was estimated at 0.25 per 100,000 ESR and 5-year survival at 53.9% (95% CI: 49.7%-58.0%). Ewing sarcoma incidence (n = 334) was estimated at 0.15 per 100,000 ESR and 5-year survival at 59.3% (95% CI: 53.5%-64.6%). For high-grade central osteosarcoma, treatment at a bone tumour centre was associated with better survival (HR 0.593).Conclusions: This study provides comprehensive incidence estimates for all the main primary bone sarcomas over a 15-year time period in a Northern European country with little migration. Centralisation of bone sarcoma care improves the clinical outcome in osteosarcoma. Show less
Ewing sarcoma is an aggressive primary malignant bone tumor with high degree of tumor vascularization and is the second most common sarcoma of bone in children and young adults. Patients... Show more Ewing sarcoma is an aggressive primary malignant bone tumor with high degree of tumor vascularization and is the second most common sarcoma of bone in children and young adults. Patients with disseminated disease at diagnosis or early relapse have a poor prognosis. To identify novel therapies and biomarkers for these patients we focused on the chemokines and chemokine receptors in Ewing sarcoma cells and their role its tumor microenvironment. CCL21 CXCL14, CXCR7 and the ratio between CXCR4-1 and CXCR4-2 have been identified as candidate prognostic markers, CCL21 immunotherapy as potential therapy and CXCR4 as potential therapeutic target in EWS. In addition, the presented peptide-based life cell imaging methods improve the ability to study CXCR4 cell membrane expression and dynamics qualitatively and quantitatively. This approach might be helpful for the measurement of anti-CXCR4 therapy efficacy. This work identified specific the chemokine signaling pathways that can be used to target Ewing sarcoma and its tumor microenvironment. Show less
Kovar, H.; Amatruda, J.; Brunet, E.; Burdach, S.; Cidre-Aranaz, F.; Alava, E. de; ... ; Delattre, O. 2016
Ewing sarcoma (ES) is a special type of bone cancer, first described by Dr. James Ewing in his paper __Diffusive endothelioma of bone__. Today Ewing sarcoma represents the second most common bone... Show moreEwing sarcoma (ES) is a special type of bone cancer, first described by Dr. James Ewing in his paper __Diffusive endothelioma of bone__. Today Ewing sarcoma represents the second most common bone cancer among adolescents and young adults. Contrary to the positive achievement in treatment of localized tumors, the long-term (5-years) survival for Ewing sarcoma patients with metastasis, however, remain below the 30% mark. In this thesis a report on experimental work aiming for a better understanding of the mechanisms underlying Ewing sarcoma metastasis is presented. Two distinct mechanisms are investigated: (1) a biochemical approach in which the initial steps in the CXCR4 signaling cascade are followed, and (2) a biophysical approach in which the guidance of Ewing sarcoma metastasis by the stiffness of their microenvironment is demonstrated. The results presented in this thesis provide deeper insights into the mechanisms controlling signaling of the chemokine receptor CXCR4 and into the role of the micro-environment in Ewing sarcoma cells behavior.Through various experimental approaches it was shown that both biochemical and biophysical guidance control how Ewing sarcoma develops into its distinct metastatic phenotype. Show less
