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
Kalisvaart, G.M.; Berghe, T. van den; Grootjans, W.; Lejoly, M.; Huysse, W.C.J.; Bovée, J.V.M.G.; ... ; Bloem, J.L. 2023
ObjectiveTo identify which dynamic contrast-enhanced (DCE-)MRI features best predict histological response to neoadjuvant chemotherapy in patients with an osteosarcoma.MethodsPatients with... Show moreObjectiveTo identify which dynamic contrast-enhanced (DCE-)MRI features best predict histological response to neoadjuvant chemotherapy in patients with an osteosarcoma.MethodsPatients with osteosarcoma who underwent DCE-MRI before and after neoadjuvant chemotherapy prior to resection were retrospectively included at two different centers. Data from the center with the larger cohort (training cohort) was used to identify which method for region-of-interest selection (whole slab or focal area method) and which change in DCE-MRI features (time to enhancement, wash-in rate, maximum relative enhancement and area under the curve) gave the most accurate prediction of histological response. Models were created using logistic regression and cross-validated. The most accurate model was then externally validated using data from the other center (test cohort).ResultsFifty-five (27 poor response) and 30 (19 poor response) patients were included in training and test cohorts, respectively. Intraclass correlation coefficient of relative DCE-MRI features ranged 0.81–0.97 with the whole slab and 0.57–0.85 with the focal area segmentation method. Poor histological response was best predicted with the whole slab segmentation method using a single feature threshold, relative wash-in rate <2.3. Mean accuracy was 0.85 (95%CI: 0.75–0.95), and area under the receiver operating characteristic curve (AUC-index) was 0.93 (95%CI: 0.86–1.00). In external validation, accuracy and AUC-index were 0.80 and 0.80.ConclusionIn this study, a relative wash-in rate of <2.3 determined with the whole slab segmentation method predicted histological response to neoadjuvant chemotherapy in osteosarcoma. Consistent performance was observed in an external test cohort. Show less
Background: Patients with osteosarcoma (OS) and Ewing sarcoma (ES) are considered to have a high venous thromboembolism (VTE) risk, although the exact incidence and prognostic impact are under... Show moreBackground: Patients with osteosarcoma (OS) and Ewing sarcoma (ES) are considered to have a high venous thromboembolism (VTE) risk, although the exact incidence and prognostic impact are under-researched in general as well as in relevant age groups. Aims: To study the impact of VTE and major bleeding (MB) in OS and ES patients, subdivided in children, Ad-olescents Young Adults (AYAs; aged 18-39) and older adults. Methods: Retrospective single-center chart review in 519 OS and 165 ES patients treated between 1980 and 2018. Patients were followed from sarcoma diagnosis until an outcome of interest (VTE, MB) or death occurred. Cu-mulative incidences were estimated with death as competing risk. Cox models were used to determine prognostic impact. Results: Five-year cumulative incidences of VTE were 12 % (95%CI 9.1-15) for OS and 6.7 % (95%CI 3.5-11) for ES patients, mostly happening in patients >= 18 years; the most frequent VTE presentation was catheter-related upper-extremity thrombosis (OS: 18/65, ES: 7/11). Five-year cumulative incidences for MB were 5.8 % (95% CI 4.0-8.1) in OS and 5.4 % (95%CI 2.5-9.8) in ES patients. 192 OS and 77 ES AYAs were included, who faced similar VTE and MB incidences as older adults. In OS, VTE and MB were both associated with mortality (adjusted HRs 2.0 [95%CI 1.4-2.9] and 2.4 [95%CI 1.4-4.0], respectively), whereas in ES this association was only present for MB (aHR 3.4 [95%CI 1.2-9.6]). Conclusions: VTE is a frequent complication in adult OS and to a lesser extent in ES patients, while the rate of MB was comparably high in both sarcoma types. 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
Neo(adjuvant) systemic treatment regimens containing anthracyclines such as doxorubicin cause a significant risk of heart failure. These regimens are one of the corner stones of osteosarcoma... Show moreNeo(adjuvant) systemic treatment regimens containing anthracyclines such as doxorubicin cause a significant risk of heart failure. These regimens are one of the corner stones of osteosarcoma treatment, and therefore several guidelines are in place to steer cardiotoxicity monitoring through baseline risk stratification and cardiac surveillance during and after completion of cancer therapy. Importantly, baseline risk stratification modules are dependent on age, prior cardiovascular disease and cardiovascular risk factors. Because the majority of osteosarcoma patients are below 30 years of age these criteria rarely apply and most patients are assigned to low or medium risk categories, whereas cardiovascular complications have profound impact on morbidity and mortality in this young population. Therefore, cardiac surveillance is very important in this group for timely detection of cardiotoxicity. Moreover, when severe cardiotoxicity that requires advanced heart failure treatment occurs, a cancer diagnosis has significant implications on treatment options, i.e. mechanical circulatory support and heart transplantation. These challenges are presented in this case of a patient without clinical risk factors admitted with cardiogenic shock requiring advanced heart failure treatment within 1 month after completion of doxorubicin containing chemotherapy for the treatment of high grade osteosarcoma. Show less
This thesis describes the generation of cell-of-origin based models, using mesenchymal stem cells, to further elucidate the underlying mechanism of molecular alterations of the bone-forming tumours... Show moreThis thesis describes the generation of cell-of-origin based models, using mesenchymal stem cells, to further elucidate the underlying mechanism of molecular alterations of the bone-forming tumours osteoid osteoma, osteoblastoma and osteosarcoma. Furthermore, we describe the identification of novel treatment options for osteosarcoma using 2D and 3D in vitro models. Show less
Time-varying covariates are of great interest in clinical research since they represent dynamic patterns which reflect disease progression. In cancer studies biomarkers values change as functions... Show moreTime-varying covariates are of great interest in clinical research since they represent dynamic patterns which reflect disease progression. In cancer studies biomarkers values change as functions of time and chemotherapy treatment is modified by delaying a course or reducing the dose intensity, according to patient's toxicity levels. In this work, a Functional covariate Cox Model (FunCM) to study the association between time-varying processes and a time-to-event outcome is proposed. FunCM first exploits functional data analysis techniques to represent time-varying processes in terms of functional data. Then, information related to the evolution of the functions over time is incorporated into functional regression models for survival data through functional principal component analysis. FunCM is compared to a standard time-varying covariate Cox model, commonly used despite its limiting assumptions that covariate values are constant in time and measured without errors. Data from MRC BO06/EORTC 80931 randomised controlled trial for treatment of osteosarcoma are analysed. Time-varying covariates related to alkaline phosphatase levels, white blood cell counts and chemotherapy dose during treatment are investigated. The proposed method allows to detect differences between patients with different biomarkers and treatment evolutions, and to include this information in the survival model. These aspects are seldom addressed in the literature and could provide new insights into the clinical research. Show less
The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory... Show moreThe phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS. Show less
Spreafico, M.; Ieva, F.; Arlati, F.; Capello, F.; Fatone, F.; Fedeli, F.; ... ; Fiocco, M. 2021
Objectives This study aims at exploring and quantifying multiple types of adverse events (AEs) experienced by patients during cancer treatment. A novel longitudinal score to evaluate the Multiple... Show moreObjectives This study aims at exploring and quantifying multiple types of adverse events (AEs) experienced by patients during cancer treatment. A novel longitudinal score to evaluate the Multiple Overall Toxicity (MOTox) burden is proposed. The MOTox approach investigates the personalised evolution of high overall toxicity (high-MOTox) during the treatment.Design Retrospective analysis of the MRC-BO06/EORTC-80931 randomised controlled trial for osteosarcoma.Setting International multicentre population-based study.Participants A total of 377 patients with resectable high-grade osteosarcoma, who completed treatment within 180 days after randomisation without abnormal dosages (+25% higher than planned).Interventions Patients were randomised to six cycles of conventional versus dose-intense regimens of doxorubicin and cisplatin. Non-haematological toxicity data were collected prospectively and graded according to the Common Terminology Criteria for Adverse Events (CTCAE).Main outcome measures The MOTox score described the overall toxicity burden in terms of multiple toxic AEs, maximum-severity episode and cycle time-dimension. Evolution of high-MOTox was assessed through multivariable models, that investigated the impact of personalised characteristics (eg, achieved chemotherapy dose, previous AEs or biochemical factors) cycle-by-cycle.Results A cycle-by-cycle analysis identifies different evolutions of MOTox levels during treatment, detecting differences in patients' health. Mean MOTox values and percentages of patients with high-MOTox decreased cycle-by-cycle from 2.626 to 1.953 and from 57.8% to 36.6%, respectively. High-MOTox conditions during previous cycles were prognostic risk factors for a new occurrence (ORs range from 1.522 to 4.439), showing that patient's history of toxicities played an important role in the evolution of overall toxicity burden during therapy. Conventional regimen may be preferred to dose-intense in terms of AEs at cycles 2-3 (p<0.05).Conclusions The novel longitudinal method developed can be applied to any cancer studies with CTCAE-graded toxicity data. After validation in other studies, the MOTox approach may lead to improvements in healthcare assessment and treatment planning. Show less
This thesis describes several retrospective studies in mesenchymal tumours. Sarcomas are the malignant variant and are very rare with an incidence of approximately 1000 patients per year in the... Show moreThis thesis describes several retrospective studies in mesenchymal tumours. Sarcomas are the malignant variant and are very rare with an incidence of approximately 1000 patients per year in the Netherlands divided over more than 50 subtypes. It is essential to use the available patient data as much as possible.Due to its rarity, all stages of sarcomas are usually grouped in one study. This thesis shows that patients with distant metastatic disease have a worse prognosis compared to patients with locally advanced disease. To improve the prognosis of sarcoma patients, maintenance treatment after first line doxorubicin treatment is currently considered. However, we show that only 33% of the patients qualifies for maintenance treatment. Patients that qualify for maintenance treatment have a significantly better prognosis than all doxorubicin treated sarcoma patients.Further, this thesis describes several rare side effects and treatment for this side effect of treatment in mesenchymal tumours and it reports the incidences of giant cell tumours of bone and gastro-intestinal stromal tumours . It also studies the outcomes of non-surgical treatment options for desmoid-type fibromatosis. Last, the outcomes of ifosfamide treatment as second line treatment for osteosarcoma are reported. Show less
In clinical research, associating dynamic time-varying covariates (e.g. biomarkers or drug assumption) with an event-time outcome represents a challenging task that could be tackled exploiting... Show moreIn clinical research, associating dynamic time-varying covariates (e.g. biomarkers or drug assumption) with an event-time outcome represents a challenging task that could be tackled exploiting Functional Data Analysis (FDA). In particular, FDA techniques can be used to represent dynamic time-varying covariates in terms of functions, which can be plugged into a Cox-type regression model to investigate the effect on survival outcomes. Data from MRC BO06/EORTC 80931 randomised controlled trial for treatment of osteosarcoma were analysed. Time-varying covariates related to alkaline phosphatase levels and chemotherapy dose during treatment were considered. 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
Bone tumours are difficult to diagnose and treat, as they are rare and over 60 different subtypes are recognised. The emergence of next-generation sequencing has partly elucidated the molecular... Show moreBone tumours are difficult to diagnose and treat, as they are rare and over 60 different subtypes are recognised. The emergence of next-generation sequencing has partly elucidated the molecular mechanisms behind these tumours, including the group of bone forming tumours (osteoma, osteoid osteoma, osteoblastoma and osteosarcoma). Increased knowledge on the molecular mechanism could help to identify novel diagnostic markers and/or treatment options. Osteoid osteoma and osteoblastoma are bone forming tumours without malignant potential that have overlapping morphology. They were recently shown to carry FOS and-to a lesser extent-FOSB rearrangements suggesting that these tumours are closely related. The presence of these rearrangements could help discriminate these entities from other lesions with woven bone deposition. Osteosarcoma is a malignant bone forming tumour for which different histological subtypes are recognised. High-grade osteosarcoma is the prototype of a complex karyotype tumour, and extensive research exploring its molecular background has identified phenomena like chromothripsis and kataegis and some recurrent alterations. Due to lack of specificity, this has not led to a valuable novel diagnostic marker so far. Nevertheless, these studies have also pointed towards potential targetable drivers of which the therapeutic merit remains to be further explored. 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
Smeland, S.; Bielack, S.S.; Whelan, J.; Bernstein, M.; Hogendoorn, P.; Krailo, M.D.; ... ; Marina, N. 2019
Background: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of... Show moreBackground: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials.Methods: Patients eligible for EURAMOS-1 were aged <= 40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients.Results: For all registered patients at a median follow-up of 54 months (interquartile range: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57-61%) and 54% (95% CI: 52-56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] Z2.34, 95% CI: 1.95-2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38-2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10-2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33-0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52-0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77-81%) and 71% (95% CI: 68-73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome.Conclusions: In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution-or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider. (C) 2018 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
Thesis explored potential new therapeutic strategies by identifying cellular pathways that are essential for chondrosarcoma and osteosarcoma cell survival. Although clinical trials with IGF1R... Show moreThesis explored potential new therapeutic strategies by identifying cellular pathways that are essential for chondrosarcoma and osteosarcoma cell survival. Although clinical trials with IGF1R inhibitors have disappointing results in osteosarcoma, this thesis strengthens the view that the IGF pathway can be an effective target for osteosarcoma therapy if an appropriate selection of patients is treated with IGF1R/IR dual inhibitors. When optimized clinical trials targeting the IGF pathway will be performed in the future, chondrosarcoma patients should not be recruited, as there is limited preclinical rationale for the efficacy of IGF1R targeting agents in chondrosarcoma. We identified two promising pathways that can be used to target chondrosarcoma; the NAD+ synthesis pathway and glutaminolysis. Our results suggest that chondrosarcoma patients should be included in future studies with drugs that interfere in these pathways, regardless of their IDH1/2 mutation status. Show less
