Objectives: To (1) explore trends of risk of bias (ROB) in prediction research over time following key methodological publications, using the Prediction model Risk Of Bias ASsessment Tool (PROBAST)... Show moreObjectives: To (1) explore trends of risk of bias (ROB) in prediction research over time following key methodological publications, using the Prediction model Risk Of Bias ASsessment Tool (PROBAST) and (2) assess the inter-rater agreement of the PROBAST.Study Design and Setting: PubMed and Web of Science were searched for reviews with extractable PROBAST scores on domain and signaling question (SQ) level. ROB trends were visually correlated with yearly citations of key publications. Inter-rater agreement was asResults: One hundred and thirty nine systematic reviews were included, of which 85 reviews (containing 2,477 single studies) on domain level and 54 reviews (containing 2,458 single studies) on SQ level. High ROB was prevalent, especially in the Analysis domain, and overall trends of ROB remained relatively stable over time. The inter-rater agreement was low, both on domain (Kappa 0.04-0.26) and SQ level (Kappa -0.14 to 0.49). Conclusion: Prediction model studies are at high ROB and time trends in ROB as assessed with the PROBAST remain relatively stable. These results might be explained by key publications having no influence on ROB or recency of key publications. Moreover, the trend may suffer from the low inter-rater agreement and ceiling effect of the PROBAST. The inter-rater agreement could potentially be improved by altering the PROBAST or providing training on how to apply the PROBAST.& COPY; 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Trevisan, M.; Hjemdahl, P.; Clase, C.M.; Jong, Y. de; Evans, M.; Bellocco, R.; ... ; Carrero, J.J. 2023
Rationale & Objective: Direct oral anticoagulants (DOACs) have progressively replaced vitamin K antagonists (VKAs) for stroke prevention in pa-tients with nonvalvular atrial fibrillation (AF).... Show moreRationale & Objective: Direct oral anticoagulants (DOACs) have progressively replaced vitamin K antagonists (VKAs) for stroke prevention in pa-tients with nonvalvular atrial fibrillation (AF). DOACs cause fewer bleeding complications, but their other advantages, particularly related to kid-ney outcomes, remain inconclusive. We studied the risks of chronic kidney disease (CKD) pro-gression and acute kidney injury (AKI) after DOAC and VKA administration for nonvalvular AF.Study Design: Retrospective cohort study. Setting & Participants: Cohort study of Swedish patients enrolled in the Stockholm Creatinine Measurements (SCREAM) project with a diag-nosis of nonvalvular AF during 2011-2018. Exposure: Initiation of DOAC or VKA treatment.Outcome: Primary outcomes were CKD pro-gression (composite of >30% estimated glomer-ular filtration rate [eGFR] decline and kidney failure) and AKI (by diagnosis or KDIGO-defined transient creatinine elevations). Secondary outcomes were death, major bleeding, and the composite of stroke and systemic embolism.Analytical Approach: Propensity score weighted Cox regression was used to balance 50 baseline confounders. Sensitivity analyses included falsification end points, subgroups, and estima-tion of per-protocol effects.Results: We included 32,699 patients (56% initiated DOAC) who were observed for a me-dian of 3.8 years. Their median age was 75 years, 45% were women, and 27% had an eGFR <60 mL/min/1.73 m2. The adjusted HRs for DOAC versus VKA were 0.87 (95% CI, 0.78-0.9 8) for the risk of CKD progression and 0.88 (95% CI, 0.80-0.97) for AKI. HRs were 0.77 (95% CI, 0.67-0.8 9) for major bleeding, 0.93 (95% CI, 0.78-1.11) for the composite of stroke and systemic embolism, and 1.04 (95% CI, 0.95-1.14) for death. The results were similar across subgroups of age, sex, and baseline eGFR when restricting to patients at high risk for thromboembolic events and when censoring follow up at treatment discontinuation or change in type of anticoagulation.Limitations: Missing information on time in ther-apeutic range and treatment dosages.Conclusions: Among patients with nonvalvular AF treated in routine clinical practice compared with VKA use, DOAC use was associated with a lower risk of CKD progression, AKI, and major bleeding but a similar risk of the composite of stroke, systemic embolism, or death. Show less
Endt, V.H.W. van der; Milders, J.; Vries, B.B.L.P. de; Trines, S.A.; Groenwold, R.H.H.; Dekkers, O.M.; ... ; Jong, Y. de 2022
Aims Multiple risk scores to predict ischaemic stroke (IS) in patients with atrial fibrillation (AF) have been developed. This study aims to systematically review these scores, their validations... Show moreAims Multiple risk scores to predict ischaemic stroke (IS) in patients with atrial fibrillation (AF) have been developed. This study aims to systematically review these scores, their validations and updates, assess their methodological quality, and calculate pooled estimates of the predictive performance.Methods and results We searched PubMed and Web of Science for studies developing, validating, or updating risk scores for IS in AF patients. Methodological quality was assessed using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). To assess discrimination, pooled c-statistics were calculated using random-effects meta-analysis. We identified 19 scores, which were validated and updated once or more in 70 and 40 studies, respectively, including 329 validations and 76 updates-nearly all on the CHA(2)DS(2)-VASc and CHADS(2). Pooled c-statistics were calculated among 6 267 728 patients and 359 373 events of IS. For the CHA(2)DS(2)-VASc and CHADS(2), pooled c-statistics were 0.644 [95% confidence interval (CI) 0.635-0.653] and 0.658 (0.644-0.672), respectively. Better discriminatory abilities were found in the newer risk scores, with the modified-CHADS(2) demonstrating the best discrimination [c-statistic 0.715 (0.674-0.754)]. Updates were found for the CHA(2)DS(2)-VASc and CHADS(2) only, showing improved discrimination. Calibration was reasonable but available for only 17 studies. The PROBAST indicated a risk of methodological bias in all studies.Conclusion Nineteen risk scores and 76 updates are available to predict IS in patients with AF. The guideline-endorsed CHA(2)DS(2)-VASc shows inferior discriminative abilities compared with newer scores. Additional external validations and data on calibration are required before considering the newer scores in clinical practice. Show less
Jong, Y. de; Boon, A.E.; Gouw, D.; Gaag, M. van der; Mulder, C.L. 2022
Background: Screening methods for detecting Ultra High Risk status (UHR) or psychosis should be improved, especially in adolescent samples. We therefore tested whether the Child Behavior Checklist ... Show moreBackground: Screening methods for detecting Ultra High Risk status (UHR) or psychosis should be improved, especially in adolescent samples. We therefore tested whether the Child Behavior Checklist (CBCL) and the Youth Self Report (YSR) add value to the Prodromal Questionnaire-16 items version (PQ-16) for detecting UHR status or psychosis. Methods: We included help-seeking adolescents who had completed the PQ-16, YSR, CBCL, and a Comprehensive Assessment of an At Risk Mental States (CAARMS) interview, and used independent samples t-tests and binary logistic regression analyses to determine the scales contributing to the prediction of UHR status or of having reached the psychosis threshold (PT). Cutoff scores were determined using ROC analyses. Results: Our sample comprised 270 help-seeking adolescents (mean age 14.67; SD 1.56, range 12-17); 67.8% were girls and 66.3% were of Dutch origin. The Thought Problems syndrome scales of both the YSR and the CBCL best predicted UHR or PT, and had screening values comparable to the PQ-16. Other syndrome scales did not improve screening values. Although combining measures reduced the number of false negatives, it also increased the number of adolescents to be interviewed. The best choice was to combine the YSR Thought Problems scale and the PQ-16 as a first-step screener. Conclusions: Combining measures improves the detection of UHR or PT in help-seeking adolescents. The Thought Problems subscales of the YSR and CBCL can both be used as a first-step screener in the detection of UHR and/or psychosis. Trial registration Permission was asked according to the rules of the Ethics Committee at Leiden. This study is registered as NL.44180.058.13 Show less
In thrombin generation (TG) assays, regarded as global coagulation tests, contact activation is considered a major problem which can be eliminated by adding Corn Trypsin Inhibitor (CTI). In... Show moreIn thrombin generation (TG) assays, regarded as global coagulation tests, contact activation is considered a major problem which can be eliminated by adding Corn Trypsin Inhibitor (CTI). In previous studies, however, venous thrombosis risk prediction using TG assays did not improve after CTI addition. However, it is unknown whether CTI addition could help to detect subtle but relevant nuances in determinants of TG, making the assay more suitable to detect disturbances in the coagulation system. This study's objective was to assess whether the addition of CTI is associated with a broader contribution of individual coagulation factors to the total amount of thrombin formed in Calibrated Automated Thrombogram (CAT) and Technoclone Thrombin Generation Assay (TGA). Thrombin generation was measured in 326 healthy individuals from THE VTE study at very low tissue factor concentrations, with and without addition of CTI prior to blood sampling. The influence of several coagulation factors on total amount of thrombin formed, i.e. area under the curve (AUC) or endogenous thrombin potential (ETP), was analysed using multiple linear regression with standardisation of all values resulting in Z-scores with 95% confidence intervals (95%CI). Association between coagulation factors and TG changed minimally after addition of CTI. Largest changes after CTI addition were found for following factors: for CAT: free protein S (from 0.00 (95%CI -0.12 to 0.12) to -0.29 (95%CI -0.43 to -0.15)) and protein S (from -0.05 (95%CI -0.18 to 0.08) to -0.21 (95%CI -0.37 to -0.05)); for TGA: antithrombin (from -0.11 (-0.23 to 0.02) to -0.19 (-0.30 to -0.07)), factor VIII (from 0.15 (0.03 to 0.27) to 0.24 (0.13 to 0.36)) and fibrinogen (from 0.12 (-0.01 to 0.26) to 0.19 (0.06 to 0.32)). In conclusion, there is no clear trend towards a broader contribution of coagulation factors in samples handled with CTI compared with those handled without CTI. Show less
Jong, Y. de; Willik, E.M. van der; Milders, J.; Meuleman, Y.; Morton, R.L.; Dekker, F.W.; Diepen, M. van 2021
Rationale & Objective: Explore priorities related to outcomes and barriers of adults with chronic kidney disease (CKD) regarding person centred care and care planning.Study design: Systematic... Show moreRationale & Objective: Explore priorities related to outcomes and barriers of adults with chronic kidney disease (CKD) regarding person centred care and care planning.Study design: Systematic review of qualitative studies.Search Strategy & Sources: In July 2018 six bibliographic databases, and reference lists of included articles were searched for qualitative studies that included adults with CKD stages 1-5, not on dialysis or conservative management, without a previous kidney transplantation.Analytical Approach: Three independent reviewers extracted and inductively coded data using thematic synthesis. Reporting quality was assessed using the COREQ and the review reported according to PRISMA and ENTREQ statements.Results: Forty-six studies involving 1493 participants were eligible. The period after diagnosis of CKD is characterized by feelings of uncertainty, social isolation, financial burden, resentment and fear of the unknown. Patients show interest in ways to return to normality and remain in control of their health in order to avoid further deterioration of kidney function. However, necessary information is often unavailable or incomprehensible. Although patients and healthcare professionals share the predominant interest of whether or not dialysis or transplantation is necessary, patients value many more outcomes that are often unrecognized by their healthcare professionals. We identified 4 themes with 6 subthemes that summarize these findings: 'pursuing normality and control' ('pursuing normality'; 'a search for knowledge'); 'prioritizing outcomes' ('reaching kidney failure'; 'experienced health'; 'social life'; 'work and economic productivity'); 'predicting the future'; and 'realising what matters'. Reporting quality was moderate for most included studies.Limitations: Exclusion of non-English articles.Conclusions: The realisation that patients' priorities do not match those of the healthcare professionals, in combination with the prognostic ambiguity, confirms fatalistic perceptions of not being in control when living with CKD. These insights may contribute to greater understanding of patients' perspectives and a more person-centred approach in healthcare prioritization and care planning within CKD care. Show less
Jong, Y. de; Willik, E.M. van der; Milders, J.; Voorend, C.G.N.; Morton, R.L.; Dekker, F.W.; ... ; Diepen, M. van 2021
Background Reviews of qualitative studies allow for deeper understanding of concepts and findings beyond the single qualitative studies. Concerns on study reporting quality led to the publication... Show moreBackground Reviews of qualitative studies allow for deeper understanding of concepts and findings beyond the single qualitative studies. Concerns on study reporting quality led to the publication of the COREQ-guidelines for qualitative studies in 2007, followed by the ENTREQ-guidelines for qualitative reviews in 2012. The aim of this meta-review is to: 1) investigate the uptake of the COREQ- and ENTREQ- checklists in qualitative reviews; and 2) compare the quality of reporting of the primary qualitative studies included within these reviews prior- and post COREQ-publication. Methods Reviews were searched on 02-Sept-2020 and categorized as (1) COREQ- or (2) ENTREQ-using, (3) using both, or (4) non-COREQ/ENTREQ. Proportions of usage were calculated over time. COREQ-scores of the primary studies included in these reviews were compared prior- and post COREQ-publication using T-test with Bonferroni correction. Results 1.695 qualitative reviews were included (222 COREQ, 369 ENTREQ, 62 both COREQ/ENTREQ and 1.042 non-COREQ/ENTREQ), spanning 12 years (2007-2019) demonstrating an exponential publication rate. The uptake of the ENTREQ in reviews is higher than the COREQ (respectively 28% and 17%), and increases over time. COREQ-scores could be extracted from 139 reviews (including 2.775 appraisals). Reporting quality improved following the COREQ-publication with 13 of the 32 signalling questions showing improvement; the average total score increased from 15.15 to 17.74 (p-value < 0.001). Conclusion The number of qualitative reviews increased exponentially, but the uptake of the COREQ and ENTREQ was modest overall. Primary qualitative studies show a positive trend in reporting quality, which may have been facilitated by the publication of the COREQ. Show less
Jong, Y. de; Ramspek, C.L.; Zoccali, C.; Jager, K.J.; Dekker, F.W.; Diepen, M. van 2021
Over the past few years, a large number of prediction models have been published, often of poor methodological quality. Seemingly objective and straightforward, prediction models provide a risk... Show moreOver the past few years, a large number of prediction models have been published, often of poor methodological quality. Seemingly objective and straightforward, prediction models provide a risk estimate for the outcome of interest, usually based on readily available clinical information. Yet, using models of substandard methodological rigour, especially without external validation, may result in incorrect risk estimates and consequently misclassification. To assess and combat bias in prediction research the prediction model risk of bias assessment tool (PROBAST) was published in 2019. This risk of bias (ROB) tool includes four domains and 20 signalling questions highlighting methodological flaws, and provides guidance in assessing the applicability of the model. In this paper, the PROBAST will be discussed, along with an in-depth review of two commonly encountered pitfalls in prediction modelling that may induce bias: overfitting and composite endpoints. We illustrate the prevalence of potential bias in prediction models with a meta-review of 50 systematic reviews that used the PROBAST to appraise their included studies, thus including 1510 different studies on 2104 prediction models. All domains showed an unclear or high ROB; these results were markedly stable over time, highlighting the urgent need for attention on bias in prediction research. This article aims to do just that by providing (1) the clinician with tools to evaluate the (methodological) quality of a clinical prediction model, (2) the researcher working on a review with methods to appraise the included models, and (3) the researcher developing a model with suggestions to improve model quality. Show less
Jong, Y. de; Fu, E.L.; Diepen, M. van; Trevisan, M.; Szummer, K.; Dekker, F.W.; ... ; Ocak, G. 2021
Aims The increasing prevalence of ischaemic stroke (IS) can partly be explained by the likewise growing number of patients with chronic kidney disease (CKD). Risk scores have been developed to... Show moreAims The increasing prevalence of ischaemic stroke (IS) can partly be explained by the likewise growing number of patients with chronic kidney disease (CKD). Risk scores have been developed to identify high-risk patients, allowing for personalized anticoagulation therapy. However, predictive performance in CKD is unclear. The aim of this study is to validate six commonly used risk scores for IS in atrial fibrillation (AF) patients across the spectrum of kidney function.Methods and results Overall, 36 004 subjects with newly diagnosed AF from SCREAM (Stockholm CREAtinine Measurements), a healthcare utilization cohort of Stockholm residents, were included. Predictive performance of the AFI, CHADS(2), Modified CHADS(2), CHA(2)DS(2)-VASc, ATRIA, and GARFIELD-AF risk scores was evaluated across three strata of kidney function: normal kidney function [estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m(2)], mild CKD (eGFR 30-60 mL/min/1.73 m(2)), and advanced CKD (eGFR <30 mL/min/1.73 m(2)). Predictive performance was assessed by discrimination and calibration. During 1.9 years, 3069 (8.5%) patients suffered an IS. Discrimination was dependent on eGFR: the median c-statistic in normal eGFR was 0.75 (range 0.68-0.78), but decreased to 0.68 (0.58-0.73) and 0.68 (0.55-0.74) for mild and advanced CKD, respectively. Calibration was reasonable and largely independent of eGFR. The Modified CHADS(2) score showed good performance across kidney function strata, both for discrimination [c-statistic: 0.78 (95% confidence interval 0.77-0.79), 0.73 (0.71-0.74) and 0.74 (0.69-0.79), respectively] and calibration.Conclusion In the most clinically relevant stages of CKD, predictive performance of the majority of risk scores was poor, increasing the risk of misclassification and thus of over- or undertreatment. The Modified CHADS2 score performed good and consistently across all kidney function strata, and should therefore be preferred for risk estimation in AF patients. Show less
Chondrosarcomas are malignant cartilage producing tumours, occurring mostly around the age of fifty. Treatment is mainly by surgery, since tumours are relatively resistant toward chemo-and... Show moreChondrosarcomas are malignant cartilage producing tumours, occurring mostly around the age of fifty. Treatment is mainly by surgery, since tumours are relatively resistant toward chemo-and radiotherapy. This means that patients with inoperable disease have no alternative treatment options. In this thesis we describe the use of compound and siRNA screens to identify new targeted treatment options for patients with chondrosarcoma. Using available chondrosarcoma cell lines as a model we investigated apoptotic proteins, kinases and metabolic regulators in a non-biased way to identify most promising hits. In addition the role of individual Bcl-2 family members Bcl-2, Bcl-xl and Bcl-w was investigated. Results reveal a role for Bcl-2 family member Bcl-xl, anti-apoptotic and cell cycle regulator Survivin, cell cycle regulators AURKA, CHK1 and PLK1 and mTOR as important survival proteins in chondrosarcoma. Moreover treatment with Bcl-xl or CHK1 inhibitors could chemo-sensitize a subset of chondrosarcoma cell lines. Furthermore alterations in the Rb1 pathway have been identified as a marker for radio resistance in chondrosarcoma patient samples. Collectively these studies identify several lead targets that might be useful as targeted treatment options for chondrosarcoma patients. Future research should focus more on the therapeutic value of these targets, and translate these pre-clinical findings to clinical practise. Show less
Ramspek, C.L.; Jong, Y. de; Dekker, F.W.; Diepen, M. van 2020
Background. Prediction tools that identify chronic kidney disease (CKD) patients at a high risk of developing kidney failure have the potential for great clinical value, but limited uptake. The aim... Show moreBackground. Prediction tools that identify chronic kidney disease (CKD) patients at a high risk of developing kidney failure have the potential for great clinical value, but limited uptake. The aim of the current study is to systematically review all available models predicting kidney failure in CKD patients, organize empirical evidence on their validity and ultimately provide guidance in the interpretation and uptake of these tools.Methods. PubMed and EMBASE were searched for relevant articles. Titles, abstracts and full-text articles were sequentially screened for inclusion by two independent researchers. Data on study design, model development and performance were extracted. The risk of bias and clinical usefulness were accessed and combined in order to provide recommendations on which models to use.Results. Of 2183 screened studies, a total of 42 studies were included in the current review. Most studies showed high discriminatory capacity and the included predictors had large overlap. Overall, the risk of bias was high. Slightly less than half the studies (48%) presented enough detail for the use of their prediction tool in practice and few models were externally validated.Conclusions. The current systematic review may be used as a tool to select the most appropriate and robust prognostic model for various settings. Although some models showed great potential, many lacked clinical relevance due to being developed in a prevalent patient population with a wide range of disease severity. Future research efforts should focus on external validation and impact assessment in clinically relevant patient populations. Show less
Fu, E.L.; Janse, R.J.; Jong, Y. de; Endt, V.H.W. van der; Milders, J.; Willik, E.M. van der; ... ; Diepen, M. van 2020
Background. Acute kidney injury (AKI) can affect hospitalized patients with coronavirus disease 2019 (COVID-19), with estimates ranging between 0.5% and 40%. We performed a systematic review and... Show moreBackground. Acute kidney injury (AKI) can affect hospitalized patients with coronavirus disease 2019 (COVID-19), with estimates ranging between 0.5% and 40%. We performed a systematic review and meta-analysis of studies reporting incidence, mortality and risk factors for AKI in hospitalized COVID-19 patients.Methods. We systematically searched 11 electronic databases until 29 May 2020 for studies in English reporting original data on AKI and kidney replacement therapy (KRT) in hospitalized COVID-19 patients. Incidences of AKI and KRT and risk ratios for mortality associated with AKI were pooled using generalized linear mixed and random-effects models. Potential risk factors for AKI were assessed using meta-regression. Incidences were stratified by geographic location and disease severity.Results. A total of 3042 articles were identified, of which 142 studies were included, with 49 048 hospitalized COVID-19 patients including 5152 AKI events. The risk of bias of included studies was generally low. The pooled incidence of AKI was 28.6% [95% confidence interval (CI) 19.8-39.5] among hospitalized COVID-19 patients from the USA and Europe (20 studies) and 5.5% (95% CI 4.1-7.4) among patients from China (62 studies), whereas the pooled incidence of KRT was 7.7% (95% CI 5.1-11.4; 18 studies) and 2.2% (95% CI 1.5-3.3; 52 studies), respectively. Among patients admitted to the intensive care unit, the incidence of KRT was 20.6% (95% CI 15.7-26.7; 38 studies). Meta-regression analyses showed that age, male sex, cardiovascular disease, diabetes mellitus, hypertension and chronic kidney disease were associated with the occurrence of AKI; in itself, AKI was associated with an increased risk of mortality, with a pooled risk ratio of 4.6 (95% CI 3.3-6.5).Conclusions. AKI and KRT are common events in hospitalized COVID-19 patients, with estimates varying across geographic locations. Additional studies are needed to better understand the underlying mechanisms and optimal treatment of AKI in these patients. Show less
Jong, Y. de; Ramspek, C.L.; Endt, V.H.W. van der; Rookmaaker, M.B.; Blankestijn, P.J.; Vernooij, R.W.M.; ... ; Diepen, M. van 2020
Chondrosarcomas are malignant cartilage tumors that are relatively resistant towards conventional therapeuticapproaches. Kinase inhibitors have been investigated and shown successful for several... Show moreChondrosarcomas are malignant cartilage tumors that are relatively resistant towards conventional therapeuticapproaches. Kinase inhibitors have been investigated and shown successful for several different cancer types. Inthis study we aimed at identifying kinase inhibitors that inhibit the survival of chondrosarcoma cells and therebyserve as new potential therapeutic strategies to treat chondrosarcoma patients.An siRNA screen targeting 779 different kinases was conducted in JJ012 chondrosarcoma cells in parallelwith a compound screen consisting of 273 kinase inhibitors in JJ012, SW1353 and CH2879 chondrosarcoma celllines. AURKA, CHK1 and PLK1 were identified as most promising targets and validated further in a morecomprehensive panel of chondrosarcoma cell lines. Dose response curves were performed using tyrosine kinaseinhibitors: MK-5108 (AURKA), LY2603618 (CHK1) and Volasertib (PLK1) using viability assays and cell cycleanalysis. Apoptosis was measured at 24 h after treatment using a caspase 3/7 assay. Finally, chondrosarcomapatient samples (N = =34) were used to examine the correlation between AURKA, CHK1 and PLK1 RNAexpression and documented patient survival.Dose dependent decreases in viability were observed in chondrosarcoma cell lines after treatment with MK-5108, LY2603618 and volasertib, with cell lines showing highest sensitivity to PLK1 inhibition. In additionincreased sensitivity to conventional chemotherapy was observed after CHK1 inhibition in a subset of the celllines. Interestingly, whereas AURKA and CHK1 were both expressed in chondrosarcoma patient samples, PLK1expression was found to be low compared to normal cartilage. Analysis of patient samples revealed that highCHK1 RNA expression correlated with a worse overall survival.AURKA, CHK1 and PLK1 are identified as important survival genes in chondrosarcoma cell lines. Althoughfurther research is needed to validate these findings, inhibiting CHK1 seems to be the most promising potentialtherapeutic target for patients with chondrosarcoma. Show less
Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutationsin isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate(D-2-HG). DNA repair... Show moreChondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutationsin isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate(D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP)inhibition occur in IDH mutant glioma and leukemia models. Here we evaluated DNA repairand PARP inhibition, alone or combined with chemo- or radiotherapy, in chondrosarcoma celllines with or without endogenous IDH mutations. Chondrosarcoma cell lines treated with thePARP inhibitor talazoparib were examined for dose–response relationships, as well as underlyingcell death mechanisms and DNA repair functionality. Talazoparib was combined with chemo- orradiotherapy to evaluate potential synergy. Cell lines treated long termwith an inhibitor normalizingD-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparibsensitivity was variable and irrespective of IDH mutation status. All cell lines expressed AtaxiaTelangiectasia Mutated (ATM), but a subset was impaired in poly(ADP-ribosyl)ation (PARylation)capacity, homologous recombination, andO-6-methylguanine-DNAmethyltransferase (MGMT) expression.Talazoparib synergized with temozolomide or radiation, independent of IDH1 mutant inhibition.This study suggests that talazoparib combined with temozolomide or radiation are promisingtherapeutic strategies for chondrosarcoma, irrespective of IDH mutation status. A subset ofchondrosarcomas may be deficient in nonclassical DNA repair pathways, suggesting that PARPinhibitor sensitivity is multifactorial in chondrosarcoma. Show less
Chondrosarcomas are malignant cartilage tumors that are relatively resistant towards conventional therapeutic approaches. Kinase inhibitors have been investigated and shown successful for several... Show moreChondrosarcomas are malignant cartilage tumors that are relatively resistant towards conventional therapeutic approaches. Kinase inhibitors have been investigated and shown successful for several different cancer types. In this study we aimed at identifying kinase inhibitors that inhibit the survival of chondrosarcoma cells and thereby serve as new potential therapeutic strategies to treat chondrosarcoma patients.An siRNA screen targeting 779 different kinases was conducted in JJ012 chondrosarcoma cells in parallel with a compound screen consisting of 273 kinase inhibitors in JJ012, SW1353 and CH2879 chondrosarcoma cell lines. AURKA, CHK1 and PLK1 were identified as most promising targets and validated further in a more comprehensive panel of chondrosarcoma cell lines. Dose response curves were performed using tyrosine kinase inhibitors: MK-5108 (AURKA), LY2603618 (CHK1) and Volasertib (PLK1) using viability assays and cell cycle analysis. Apoptosis was measured at 24 h after treatment using a caspase 3/7 assay. Finally, chondrosarcoma patient samples (N = = 34) were used to examine the correlation between AURKA, CHK1 and PLK1 RNA expression and documented patient survival.Dose dependent decreases in viability were observed in chondrosarcoma cell lines after treatment with MK-5108, LY2603618 and volasertib, with cell lines showing highest sensitivity to PLK1 inhibition. In addition increased sensitivity to conventional chemotherapy was observed after CHK1 inhibition in a subset of the cell lines. Interestingly, whereas AURKA and CHK1 were both expressed in chondrosarcoma patient samples, PLK1 expression was found to be low compared to normal cartilage. Analysis of patient samples revealed that high CHK1 RNA expression correlated with a worse overall survival.AURKA, CHK1 and PLK1 are identified as important survival genes in chondrosarcoma cell lines. Although further research is needed to validate these findings, inhibiting CHK1 seems to be the most promising potential therapeutic target for patients with chondrosarcoma. Show less
Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutations in isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate (D-2-HG). DNA... Show moreChondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutations in isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate (D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibition occur in IDH mutant glioma and leukemia models. Here we evaluated DNA repair and PARP inhibition, alone or combined with chemo- or radiotherapy, in chondrosarcoma cell lines with or without endogenous IDH mutations. Chondrosarcoma cell lines treated with the PARP inhibitor talazoparib were examined for dose-response relationships, as well as underlying cell death mechanisms and DNA repair functionality. Talazoparib was combined with chemo- or radiotherapy to evaluate potential synergy. Cell lines treated long term with an inhibitor normalizing D-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparib sensitivity was variable and irrespective of IDH mutation status. All cell lines expressed Ataxia Telangiectasia Mutated (ATM), but a subset was impaired in poly(ADP-ribosyl)ation (PARylation) capacity, homologous recombination, and O-6-methylguanine-DNA methyltransferase (MGMT) expression. Talazoparib synergized with temozolomide or radiation, independent of IDH1 mutant inhibition. This study suggests that talazoparib combined with temozolomide or radiation are promising therapeutic strategies for chondrosarcoma, irrespective of IDH mutation status. A subset of chondrosarcomas may be deficient in nonclassical DNA repair pathways, suggesting that PARP inhibitor sensitivity is multifactorial in chondrosarcoma. Show less
Jong, Y. de; Ingola, M.; Briaire-de Bruijn, I.H.; Kruisselbrink, A.B.; Venneker, S.; Palubeckaite, I.; ... ; Bovee, J.V.M.G. 2019
