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Contains fulltext : 305495.pdf (Publisher’s version ) (Open Access), Programmed death-ligand 1 (PD-L1) expression is currently used in the clinic to assess eligibility for immune-checkpoint inhibitors via the tumor proportion score (TPS), but its efficacy is limited by high interobserver variability. Multiple papers have presented systems for the automatic quantification of TPS, but none report on the task of determining cell-level PD-L1 expression and often reserve their evaluation to a single PD-L1 monoclonal antibody or clinical center. In this paper, we report on a deep learning algorithm for detecting PD-L1 negative and positive tumor cells at a cellular level and evaluate it on a cell-level reference standard established by six readers on a multi-centric, multi PD-L1 assay dataset. This reference standard also provides for the first time a benchmark for computer vision algorithms. In addition, in line with other papers, we also evaluate our algorithm at slide-level by measuring the agreement between the algorithm and six pathologists on TPS quantification. We find a moderately low interobserver agreement at cell-level level (mean reader-reader F1 score = 0.68) which our algorithm sits slightly under (mean reader-AI F1 score = 0.55), especially for cases from the clinical center not included in the training set. Despite this, we find good AI-pathologist agreement on quantifying TPS compared to the interobserver agreement (mean reader-reader Cohen's kappa = 0.54, 95% CI 0.26-0.81, mean reader-AI kappa = 0.49, 95% CI 0.27-0.72). In conclusion, our deep learning algorithm demonstrates promise in detecting PD-L1 expression at a cellular level and exhibits favorable agreement with pathologists in quantifying the tumor proportion score (TPS). We publicly release our models for use via the Grand-Challenge platform.

Radboud University, 11 mei 2023, Promotores : Herpen, C.M.L. van, Heuvel, M. van den, Heskamp, S. Co-promotor : Aarntzen, E.H.J.G., Contains fulltext : 292271.pdf (Publisher’s version ) (Closed access)

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Radboud University, 27 juni 2022, Promotor : Heuvel, M. van den Co-promotores : Helvoort, H.A.C. van, Jongh, F.H.C. de, Contains fulltext : 250220.pdf (Publisher’s version ) (Closed access)

Radboud University, 18 maart 2022, Promotores : Burger, D.M., Heuvel, M. van den Co-promotores : Heine, R. ter, Derijks, H.J., Contains fulltext : 246882.pdf (Publisher’s version ) (Open Access)

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Radboud University, 17 november 2021, Promotores : Heuvel, M. van den, Wees, P.J. van der Co-promotor : Hul, A.J. van 't, Contains fulltext : 239949.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 237579.pdf (Publisher’s version ) (Open Access)

In deze studie is cognitieve gedragstherapie (CGT) opgesplitst in twee modules, namelijk de gedragsmatige module (GA en RE) en de cognitieve module (CH en PO). Er is een moderatie-analyse uitgevoerd om te kijken of de twee typen modules een verschillend effect hebben voor jongens ten opzichte van meisjes en of het effect verschillend is voor jonge adolescenten ten opzichte van midden en oude adolescenten op de afname van verhoogde depressieve symptomen. Uit de moderatie-analyse bleek dat er geen significant effect was tussen de twee typen modules (X) en geslacht en leeftijd (M). Dit wil zeggen dat de jongens niet meer profiteren van gedragsmatige modules dan meisjes ten opzichte van de cognitieve module op de afname van verhoogde depressieve symptomen. Ook profiteren jonge adolescenten niet meer van de gedragsmatige module dan midden en oude adolescenten ten opzichte van de cognitieve module op de afname van verhoogde depressieve symptomen.

Prevention of depression among adolescents is important, given the prevalence of (sub)clinical depression and its negative consequences. Cognitive behavioral therapy (CBT), consisting of various components such as cognitive restructuring (CR), behavioral activation (BA), problem solving (PS) and relaxation (RE), has proven to be an effective treatment form in the prevention of depression among adolescents, with both specific and non-specific factors playing a role. The present study aimed to investigate the effect of specific factors, namely two CBT components cognitive restructuring and behavioral activation, on a non-specific factor, namely therapeutic alliance. In addition, the role of the non-specific factor (therapeutic alliance) as a mediator, in combination with the specific factors (CBT components) within CBT in the prevention of depression in adolescents was examined. The sample consisted of adolescents with elevated depressive symptoms that were randomly assigned to one of four conditions in which the CBT components were differentially sequenced, with each component consisting of three sessions. The current study focused on condition 1: CR-BA-RE-PS (n = 39) and condition 2: BA-CR-RE-PS (n = 29). No significant difference was found in the level of therapeutic alliance after three sessions of CR and three sessions of BA. Also, no significant differences were found in the change of therapeutic alliance when CR was sequenced before or after BA (followed by RE and PS, resp. condition 1 and 2). At last, no mediating effect of therapeutic alliance on the change of depressive symptoms was found. Possible explanations and suggestions for follow-up research are discussed.

Introductie: Suïcide is wereldwijd de meest voorkomende doodsoorzaak onder jongeren. Zowel depressie als rumineren zijn gerelateerd aan suïcidale gedachten. Cognitieve gedragstherapie (CGT) blijkt effectief in het verminderen van depressieve symptomen en indirect in het verminderen van suïcidale symptomen. Methode: Het huidige onderzoek gebruikt data uit eerder cross-sectioneel onderzoek naar depressieve symptomen bij klinisch depressieve jongeren en jongeren uit de algemene Nederlandse bevolking. Het combineren van de data resulteert in een algemene groep van 685 jongeren en een klinisch depressieve groep van 63 jongeren die werden doorverwezen voor behandeling voor hun depressieve stoornis. Van de klinisch depressieve groep, hebben 35 jongeren vragenlijsten ingevuld voorafgaand en na de CGT behandeling. De vragenlijsten meten depressieve symptomen (CDI-2), rumineren (CERQ) en suïcidale gedachten en gedragingen (SRT). De onderzoeksvragen zijn getoetst met ANOVA’s, gepaarde t-tests en mediatieanalyses in PROCESS. Resultaten: Jongeren uit de klinisch depressieve groep rapporteerden significant meer depressieve symptomen, suïcidale gedachten en suïcide plannen in vergelijking met jongeren uit de algemene Nederlandse bevolking. Daarnaast werd in de klinische depressieve groep een significante afname van zowel depressieve symptomen als suïcidale gedachten na CGT gevonden. Rumineren blijkt geen mediator in de relatie tussen depressieve symptomen en suïcidale gedachten voor CGT en na CGT. Conclusie en discussie: Zowel jongeren uit de algemene Nederlandse bevolking als depressieve jongeren hebben suïcidale gedachten. Vandaar dat het belangrijk is om vroegtijdig suïcidepreventie in te zetten en passende behandeling te bieden, gericht op het voorkomen van suïcidaal gedrag en het verminderen van suïcidale gedachten.

Social media use is more often getting mentioned as an important factor that could influence adolescents’ sleep. Sleep is important for brain development in adolescence, and the lack of sleep has proven to have negative consequences for adolescents. Since earlier scientific literature has shown inconsistent findings on the existence of a relationship between social media use and sleep in adolescents, this study focusses on adding knowledge to the relationship between social media use and sleep in adolescents and includes ‘the fear of missing out’ as a moderator. Based on the existent literature, a negative relationship between social media use and sleep is expected, which can be positively moderated by FOMO. 404 adolescents (mean age was 13.5 years old) and their parents participated in this study. The hypotheses were tested using a regression analysis and a moderation analysis in SPSS-statistics. The results have shown that there was a significant negative relationship between social media use and sleep. Higher levels of social media use were related to lower levels of average sleep per night in adolescents. However, the effect was very small and disappeared when FOMO was added to the model. Furthermore, FOMO did not significantly moderate the relationship between social media use and sleep. Additional research is necessary to determine what other factors possibly contribute to adolescents’ sleeping patterns, since the influence of social media use on sleep wasn’t found to be very robust.

To understand how Cognitive Behavioral Therapy (CBT) can contribute to depression prevention in adolescents and what factors should be taken into account in practice, it is important to distinguish factors that predict the effectiveness of CBT for depression prevention in adolescents. Current research has therefore examined whether age group, gender, school level and ethnicity are predictors for the effectiveness of a whole CBT-prevention program (consisting of 12 sessions), and for the effectiveness of cognitive and behavioral modules separately (all 3 sessions). Depressive symptoms were measured with the Children’s Depression Inventory (CDI-2). The data included data from N = 145 participants and a multiple regression analysis was performed. Results showed that age group, gender, and school level were not significant predictors of the effectiveness of CBT. Ethnicity was found to be a predictor, with depressive symptoms decreasing more in Dutch ethnicity than in non-Dutch ethnicity. With respect to the cognitive modules, no significant differences were found for change in depressive symptoms according to age, gender, and ethnicity. However, school level did provide a significant result, with the effectiveness of the cognitive modules of CBT found to be highest for adolescents with low school levels. For the behavioral modules, none of the variables significantly predicted the effect. The findings provide recommendations for professionals using CBT in the context of depression prevention among adolescents. More research is needed to confirm current results and gain further insight into for whom CBT works.

Subclinical depression is common among adolescents, with prevalence rates ranging from 5 to 29 percent. Cognitive Behavioural Therapy (CBT) has proven to be effective in reducing depressive symptoms in adolescents. CBT consists of multiple components, with cognitive restructuring and problem solving calling upon cognitive abilities that are probably insufficiently developed in younger adolescents. The current study aimed to generate empirical knowledge regarding the effectiveness of cognitive restructuring and problem solving for younger adolescents (11-14 years) and older adolescents (14-19 years). Therefore, we investigated the moderating role of age group on the relative effectiveness of the CBT-components cognitive restructuring and problem solving (both operationalized into a module of three sessions) in indicated depression prevention for adolescents. In addition, a moderated-mediation analysis was conducted to explore whether the effects of the mediators negative cognitive errors and problem solving skills were moderated by age group. A randomized research design with four conditions was used. The sample consisted of 217 adolescents between 11 and 19 years (M=13.8) with elevated depressive symptoms. Results showed that the effectiveness of cognitive restructuring and problem solving on the depressive symptoms of adolescents was not moderated by age group. Also, the mediation effects of negative cognitive errors and problem solving skills did not differ for younger adolescents and older adolescents. Explanations of these results can be found in the limited duration of three sessions and the relatively small sample size. Future research that takes into account the cognitive abilities of adolescents is recommended.

The prevalence of depression in adolescents is estimated to be approximately 7.5% to 11%. Cognitive Behavioral Therapy (CBT) programs have been shown to be the most effective in preventing depression in adolescents. CBT consists of several components, of which cognitive restructuring (CH) and behavioral activation (GA) are most consistent with the original theories of CBT. The aim of this study was to investigate whether depressive symptom severity moderates both the effect of CH and GA and the effect of sequence on reducing depressive symptoms in adolescents. The sample included 102 adolescents. There were two conditions each consisting of two modules of 3 sessions each; CH – GA (n=57) and GA – CH (n=45). Moderator severity was operationalized in two ways, by self-report and clinical interview assessment based on the number of symptoms. The results showed that severity of depressive symptoms is not a moderator for both the effect of the individual modules and the order in which the modules are presented. Current research therefore shows that the severity of the symptoms of adolescents is not relevant for the effect of GA or CH and the order in which these components are presented within indicated prevention. Limitations of this research, recommendations for future research and implications for practice are discussed.

De prevalentie van subklinische depressieve symptomen onder Nederlandse adolescenten wordt tussen de 17 en 21% geschat. Cognitieve Gedragstherapie (CGT) is een veelgebruikte en bewezen effectieve behandelvorm in de preventie van depressie bij adolescenten. Vier veelvoorkomende componenten binnen CGT zijn cognitieve herstructurering (CH), gedragsactivatie (GA), probleem oplossen (PO) en relaxatie (RE). Veel onderzoek richt zich op de effectiviteit van CGT in zijn geheel, maar er is weinig bekend over de effectiviteit van de afzonderlijke componenten en voor wie bepaalde componenten het meest effectief zijn. De componenten CH en GA worden gezien als de klassieke componenten van CGT en worden tevens het vaakst ingezet. Deze studie richtte zich op de moderatie van sekse en comorbide internaliserende en externaliserende problemen in het effect van CH, in vergelijking met GA. De steekproef bestond in totaal uit 116 adolescenten, waarvan 62 adolescenten drie sessies van het component CH (conditie 1) aangeboden kregen en 54 adolescenten drie sessies van het component GA (conditie 2). Uit de resultaten bleek dat het effect van CH niet wordt gemodereerd door sekse. Dit betekent dat het effect van CH op depressieve symptomen niet verschilt voor meisjes of jongens, in vergelijking met GA. Het effect van CH werd tevens niet gemodereerd door internaliserende en externaliserende comorbiditeit, wat betekent dat het niveau van comorbide problematiek niet uitmaakt voor het effect van CH, in vergelijking met GA. Deze kennis over het afzonderlijke component CH draagt bij aan de ontwikkeling van effectieve preventieve interventies. Er worden implicaties voor de praktijk en aanbevelingen voor vervolgonderzoek besproken.

Previous research has shown an association between social media use and body dissatisfaction. However, little is known about the factors that may impact this relation. This study investigates the relation between social media use and body dissatisfaction and explores one potential moderating factor: the role of Instagram use. The sample of this study consisted of 440 participants aged 12 to 19 (mean age 14.9; SD =1.8; 47% girls) from the Netherlands. Results showed that social media use was positively associated with body dissatisfaction, even when controlling for gender. The findings indicate that Instagram use did not moderate the relation between social media use and body dissatisfaction. However, experimental studies are needed to examine the direction of effects of social media use and to explore the influence of Instagram use, while taking into account the online activities on this platform (such as celebrities being followed, the images that are being viewed).

21,4% van de adolescenten (13-17 jaar) in Nederland leidt aan subklinische depressieve symptomen. Deze subklinische depressieve symptomen kunnen leiden tot stress en zijn een belangrijke voorspeller voor een depressieve stoornis. De focus in dit onderzoek lag op deze subklinische depressieve symptomen. Het is belangrijk dat er kennis is over de manier waarop subklinische symptomen geuit kunnen worden zodat ze gesignaleerd kunnen worden en een interventie gestart kan worden. Op deze manier kan een depressie worden voorkomen. Het doel van deze studie was te onderzoeken wat de verschillen in subklinische depressieve symptomen op de totale score en subschalen van de CDI-2 waren wanneer gekeken werd naar leeftijd, sekse, schoolniveau en etniciteit. Hiervoor warden 802 adolescenten geanalyseerd (M leeftijd 14.05, SD=1.84, 28.1% meisjes). De meeste hypothesen werden niet bevestigd, maar de resultaten lieten zien dat er op elk aspect (bijv. leeftijd) wel verschillen waren. Toekomstig onderzoek zal zich meer moeten focussen op individuele behandeling in plaats van een algemeen programma om depressie te herkennen en voorkomen, aangezien elke individu depressie anders kan uiten.

Background; Four components of Cognitive Behavioural Therapy (CBT) and their effectiveness in adolescent depression prevention, were researched in this experimental study, namely cognitive restructuring, problem solving, behavioural activation and relaxation. The components were categorised into categories; think- (cognitive restructuring and problem solving) and act-components (behavioural activation and relaxation). It was investigated whether gender or age would moderate the effectiveness of the think- and act-components. Methods; Each of the components were operationalized into three sessions (Think, Solve, Act and Relax). The sessions Think and Solve (n=102) were later combined, same for the sessions Act and Relax (n=127). In total the sample consisted of 229 Dutch adolescents with elevated depressive symptoms (Mage = 13.8; 56% girls). Through randomization treatment groups were distributed over the conditions. With the Children’s Depression Inventory (CDI-2) two assessments of depressive symptoms were made. Results; Gender or age did not moderate the effect of the think- and act-components on adolescent depression prevention. Discussion; This is the first study on moderation of gender or age, on the effectiveness of think- and act-components of CBT, on adolescent depression prevention. Future research should include longer and more sessions. In addition, the characteristics of the sample should be representative of the population. Furthermore, professionals should not put their focus merely on gender or age, but more specifically on the individual preferences of an adolescent. Keywords; Prevention, adolescence, depression, CBT, moderation, gender, age. Abbreviations; CDI-2:S: Children’s Depression Inventory-2 Short version. STARr: Solve, Think, Act, Relax and repeat.

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Contains fulltext : 229798.pdf (publisher's version ) (Open Access), With the introduction of targeted therapies and immunotherapy, molecular diagnostics gained a more profound role in the management of non-small cell lung cancer (NSCLC). This study aimed to systematically search for studies reporting on the use of liquid biopsies (LB), the correlation between LBs and tissue biopsies, and finally the predictive value in the management of NSCLC. A systematic literature search was performed, including results published after 1 January 2014. Articles studying the predictive value or validity of a LB were included. The search (up to 1 September 2019) retrieved 1704 articles, 1323 articles were excluded after title and abstract screening. Remaining articles were assessed for eligibility by full-text review. After full-text review, 64 articles investigating the predictive value and 78 articles describing the validity were included. The majority of studies investigated the predictive value of LBs in relation to therapies targeting the epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) receptor (n = 38). Of studies describing the validity of a biomarker, 55 articles report on one or more EGFR mutations. Although a variety of blood-based biomarkers are currently under investigation, most studies evaluated the validity of LBs to determine EGFR mutation status and the subsequent targeting of EGFR tyrosine kinase inhibitors based on the mutation status found in LBs of NSCLC patients.

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Contains fulltext : 225028.pdf (publisher's version ) (Open Access), This study aimed to investigate whether changes in progastrin-releasing peptide (ProGRP) levels correlate with treatment response and can be used to optimize clinical management of patients with small-cell lung cancer. Patients with small-cell lung cancer (any stage) receiving chemotherapy were eligible. ProGRP was measured in serum/plasma at baseline and after each chemotherapy cycle using the Elecsys(®) ProGRP assay (Roche Diagnostics). Treatment response was assessed by computed tomography scan. The primary objective was to examine whether changes in ProGRP levels correlated with computed tomography scan results after two cycles of chemotherapy. The prognostic value of ProGRP among patients receiving first-line chemotherapy was also assessed. Overall, 261 patients from six centers were eligible. Among patients with elevated baseline ProGRP (>100 pg/mL), a ProGRP decline after Cycle 2 was associated with nonprogression (area under the curve: 84%; 95% confidence interval: 72.8-95.1; n = 141). ProGRP changes from baseline to end of Cycle 1 were predictive of response, as determined by computed tomography scan 3 weeks later (area under the curve: 87%; 95% confidence interval: 74.1-99.2; n = 137). This was enhanced by repeat measurements, with a 92% area under the curve (95% confidence interval: 85.3-97.8) among patients with ProGRP data after both Cycles 1 and 2 (n = 123); if a patient experienced a ≥25% decline in ProGRP after Cycle 1, and ProGRP remained stable or decreased after Cycle 2, the probability of finding progression on the interim computed tomography scan at the end of Cycle 2 was almost zero (sensitivity: 100%, specificity: 71%). Both ProGRP levels at baseline and at the end of first-line chemotherapy were prognostic; the latter provided a moderately improved hazard ratio of 2.43 (95% confidence interval: 1.33-4.46; n = 110) versus 1.87 (95% confidence interval: 1.04-3.37; n = 216). In summary, for patients with small-cell lung cancer and elevated basel

Contains fulltext : 229841.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 220632.pdf (Publisher’s version ) (Open Access), INTRODUCTION: Pemetrexed is a pharmacotherapeutic cornerstone in the treatment of non-small cell lung cancer. As it is primarily eliminated by renal excretion, adequate renal function is essential to prevent toxic exposure. There is growing evidence for the nephrotoxic potential of pemetrexed, which even becomes a greater issue now combined immuno-chemotherapy prolongs survival. Therefore, the aim of this study was to describe the incidence of nephrotoxicity and related treatment consequences during pemetrexed-based treatment. METHODS: A retrospective cohort study was conducted in the Jeroen Bosch Hospital, Den Bosch, the Netherlands. All patients that received at least 1 cycle of pemetrexed based therapy were included in the dataset. The primary outcome was defined as a >/=25 % reduction in eGFR. Additionally, the treatment consequences of decreased renal function were assessed. Logistic regression was used to identify risk factors for nephrotoxicity during treatment with pemetrexed. RESULTS: Of the 359 patients included in this analysis, 21 % patients had a clinically relevant decline in renal function after treatment and 8.1 % of patients discontinued treatment due to nephrotoxicity. Cumulative dose (>/=10 cycles of pemetrexed based therapy) was identified as a risk factor for the primary outcome measure (adjusted OR 5.66 (CI 1.73-18.54)). CONCLUSION: This study shows that patients on pemetrexed-based treatment are at risk of developing renal impairment. Risk significantly increases with prolonged treatment. Renal impairment is expected to become an even greater issue now that pemetrexed-based immuno-chemotherapy results in longer survival and thus longer treatment duration.

Contains fulltext : 229367.pdf (publisher's version ) (Open Access), BACKGROUND: Oncological computerized clinical decision support systems (CCDSSs) to facilitate workflows of multidisciplinary team meetings (MDTMs) are currently being developed. To successfully implement these CCDSSs in MDTMs, this study aims to: (a) identify barriers and facilitators for implementation for the use case of lung cancer; and (b) provide actionable findings for an implementation strategy. METHODS: The Consolidated Framework for Implementation Science was used to create an interview protocol and to analyze the results. Semi-structured interviews were conducted among various health care professionals involved in MDTMs. The transcripts were analyzed using a thematic analysis following a deductive approach. RESULTS: Twenty-six professionals participated in the interviews. The main facilitators for implementation of the CCDSS were considered to be easy access to well-structured patient data, and the resulting reduction of MDTM preparation time and of duration of MDTMs. Main barriers for adoption were seen in incomplete or non-trustworthy output generated by the system and insufficient adaptability of the system to local and contextual needs. CONCLUSION: Using a CCDSS in lung cancer MDTMs was expected to increase efficiency of workflows. Successful implementation was seen as dependent on the reliability and adaptability of the CCDSS and involvement of key users in the implementation process.

Contains fulltext : 220756.pdf (Publisher’s version ) (Open Access), Programmed cell death ligand 1 (PD-L1) immunohistochemistry is used to determine which patients with advanced non-small-cell lung cancer (NSCLC) respond best to treatment with PD-L1 inhibitors. For each inhibitor, a unique immunohistochemical assay was developed. This systematic review gives an up-to-date insight into the comparability of standardised immunohistochemical assays and laboratory-developed tests (LDTs), focusing specifically on tumour cell (TC) staining and scoring. A systematic search was performed identifying publications that assessed interassay, interobserver and/or interlaboratory concordance of PD-L1 assays and LDTs in tissue of NSCLC patients. Of 4294 publications identified through the systematic search, 27 fulfilled the inclusion criteria and were of sufficient methodological quality. Studies assessing interassay concordance found high agreement between assays 22C3, 28-8 and SP263 and properly validated LDTs, and lower concordance for comparisons involving SP142. A decrease in concordance, however, is seen with use of cut-offs, which hampers interchangeability of PD-L1 immunohistochemistry assays and LDTs. Studies assessing interobserver concordance found high agreement for all assays and LDTs, but lower agreement with use of a 1% cut-off. This may be problematic in clinical practice, as discordance between pathologists at this cut-off may result in some patients being denied valuable treatment options. Finally, five studies assessed interlaboratory concordance and found moderate to high agreement levels for various assays and LDTs. However, to assess the actual existence of interlaboratory variation in PD-L1 testing and PD-L1 positivity in clinical practice, studies using real-world clinical pathology data are needed.

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Item does not contain fulltext, BACKGROUND: Pemetrexed is an antifolate cytostatic drug that targets multiple enzymes involved in folate biosynthesis and is indicated for treatment of non-small-cell lung cancer and malignant pleural mesothelioma. As evidence for an exposure-response/toxicity relationship is accumulating, dose individualization using therapeutic drug monitoring may be a feasible strategy to optimize treatment. The purpose of this study was to develop a simple, sensitive, high-performance liquid chromatography method with UV detection for quantification of pemetrexed levels in human plasma. METHOD: The method involves a simple protein precipitation, followed by ultra-performance liquid chromatography with ultraviolet detection at a wavelength of 254 nm. Pemetrexed was separated using a mobile phase with a linear gradient and a run time of only 7 minutes. RESULTS: The assay has been validated over the concentration range 0.25-500 mg/L of pemetrexed. Accuracy for this assay ranged from -4.50% to 1.78%, and the within- and between-run coefficients of variation were <3.57%. Pemetrexed in plasma was proven to be stable for 8 months at -40 degrees C. CONCLUSIONS: The bioanalytical method we developed proved to be simple, accurate, precise, and fast. This analytical method is successfully in use for therapeutic drug monitoring and will be used for pharmacokinetic studies.

Contains fulltext : 225429.pdf (Publisher’s version ) (Open Access), IMPORTANCE: Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer. OBJECTIVE: To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer. DESIGN, SETTING, AND PARTICIPANTS: This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018. INTERVENTIONS: Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. MAIN OUTCOMES AND MEASURES: The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory. RESULTS: Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17

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Contains fulltext : 218115.pdf (Publisher’s version ) (Open Access), PURPOSE: Pemetrexed is a widely used cytostatic agent with an established exposure-response relationship. Although dosing is based on body surface area (BSA), large interindividual variability in pemetrexed plasma concentrations is observed. Therapeutic drug monitoring (TDM) can be a feasible strategy to reduce variability in specific cases leading to potentially optimized pemetrexed treatment. The aim of this study was to develop a limited sampling schedule (LSS) for the assessment of pemetrexed pharmacokinetics. METHODS: Based on two real-life datasets, several limited sampling designs were evaluated on predicting clearance, using NONMEM, based on mean prediction error (MPE %) and normalized root mean squared error (NRMSE %). The predefined criteria for an acceptable LSS were: a maximum of four sampling time points within 8 h with an MPE and NRMSE

Contains fulltext : 229865.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Phase III studies of checkpoint inhibitors changed the therapeutic landscape for lung cancer. In 2015 the Dutch Society of Chest Physicians (NVALT) introduced a national immunotherapy registry for patients with lung cancer; quality standards for hospitals were implemented. At population level we studied clinical benefit in daily practice and in patients who are underrepresented in phase III trials. MATERIALS AND METHODS: From the initial introduction of checkpoint inhibitors in the Netherlands patients were centrally registered. Educational programs and quality control were provided under supervision of NVALT. The largest immunotherapy providing hospitals were compared to hospitals who provided less checkpoint inhibitors as marker of experience. Patients characteristics, treatment and side effects, response rate and survival were studied. RESULTS: A total of 2676 patients were registered, 2302 with follow up data were evaluated. Between October 2015 and December 2017 a gradual increase from 12 to 30 qualified hospitals showed no major toxicity differences. Toxicity led to a hospital admission rate of 9.1 with an average duration of 10.4 days. Overall tumor response was 21.8 % and median overall survival 12.6 months. Overall survival was not significantly different for patients aged ≥ 75 years, those having brain metastases or selected auto-immune diseases before start checkpoint inhibitors compared to younger patients or those without, respectively. Survival outcomes were worse in patients with PS 2+, non-smokers, and patients who received any palliative radiotherapy (HR 2.1, 95 % CI 1.7-2.7; 1.3, 95 % CI 1.0-1.6 and 1.2, 95 % CI 1.1-1.4, respectively). CONCLUSIONS: Changes in the therapeutic landscape did not lead to major differences in quality of care between hospitals. Elderly patients, those with brain metastases or selected auto-immune disease underrepresented in clinical trials did not do worse on checkpoint inhibitors, except for those with PS 2 +

Negatieve cognities spelen een belangrijke rol bij de etiologie en de instandhouding van depressie. Cognitieve herstructurering (CH) heeft als doel negatieve cognities te veranderen, en is één van de meest toegepaste technieken in effectieve op cognitieve gedragstherapie (CGT) gebaseerde preventieprogramma’s voor depressie. Het is echter onduidelijk of CH de meest effectieve techniek is en op welke manier negatieve cognities een rol spelen bij de werkzaamheid van CGT. De huidige studie heeft onderzocht of CH leidt tot een grotere afname in depressieve symptomen dan andere vaak gebruikte CGT-elementen, en of een verandering in negatieve cognities het verband tussen het CGT-element en een afname in depressieve symptomen medieert. De steekproef bestond uit 220 adolescenten tussen de 10 en 20 jaar welke hebben deelgenomen aan een preventieprogramma voor depressie. Ze werden willekeurig toegewezen aan één van de condities, die elk startte met een ander CGT-element. Dit onderzoek is onderdeel van een longitudinaal onderzoek. De huidige studie richtte zich op behandeluitkomsten na het volgen van één CGT-element, bestaande uit drie sessies. Uit de resultaten blijkt dat cognitieve herstructurering niet onderscheidend is van andere veelgebruikte CGT-elementen; gedragsactivatie, probleem oplossen en relaxatie. Tevens leidde geen enkel CGT-element tot een significante afname in depressieve symptomen. Omdat er geen correlatie is gevonden tussen de variabelen kan er geen uitspraak worden gedaan betreffende een mediërende rol van de verandering in negatieve cognities. Concluderend kan worden gesteld dat het volgen van drie sessies CGT niet leidt tot een afname in depressieve symptomen. Mogelijke verklaringen en implicaties voor vervolgonderzoek worden besproken.

The education level of parents plays a role in their parenting. In studies to this subject, mostly one parenting domain is involved, are mothers the respondents and is the focus on parents of school children. Parenting behaviour is divided into five domains; support, structure, stimulation, negative discipline and positive discipline. The level of education is divided into: high, medium and low. Highly educated parents seem to use more positive parenting, like support, structure, stimulation and positive discipline and less negative parenting, like negative discipline. Research has been done whether the education level of parents of toddlers is related with the five domains support, structure, stimulation, negative discipline and positive discipline. The Comprehensive Early Childhood Parenting Questionnaire is used to question 346 mothers and 342 fathers of children with the age of 18 to 42 months to find their parenting behaviour. The education level is collected with means of a questionnaire asking for the highest finished education. A MANOVA concludes that the domains stucture, negative discipline and positive discipline shows a relation with the education level of fathers. Low educated fathers offer less structure than medium and highly educated fathers and offer more negative discipline than highly educated fathers. Low educated fathers apply less positive discipline than medium educated fathers. No relation is found between the education level of mothers and the parenting domains. This study alos makes clear that fathers are using more structure and negative discipline and mothers are using more support, stimulation and positive discipline compared to fathers.

Currently, only a few studies are known which have researched ACT on adolescents. This longitudinal study explores the effect of ACT on psychological flexibility of adolescents with depressive symptoms, examining whether the use of adaptive and maladaptive cognitive emotion regulation strategies has a mediating effect on this effect. Based on previous research, it was expected that following ‘ACT your way’ would lead to more frequent application of adaptive cognitive emotion regulation strategies and an increase of psychological flexibility and decrease depressive symptoms and the use of maladaptive cognitive emotion regulation strategies. Also, as a harbinger for the mediation analyzes, a coherence was expected between the psychological flexibility during the pre-measurement, psychological flexibility during the post-measurement and the difference score between both the adaptive and maladaptive cognitive emotion regulation strategies during the pre-measurement and post-measurement. The CDI-II, CERQ and AFQ-Y were used to measure the depressive symptoms, cognitive emotion regulation and psychological flexibility of adolescents. These questionnaires were taken by N= 26 adolescents, girls (n= 20, 77%) and boys (n= 6, 23%) within the age of fourteen and 26 years old (M= 18 and SD= 2.83). These results show that the use of adaptive cognitive emotion regulation strategies and the psychological flexibility of adolescents increase and the depressive symptoms and the use of maladaptive cognitive emotion regulation strategies decrease after following ‘ACT your way’. There was only a significant coherence observed between the psychological flexibility during the pre-measurement and the psychological flexibility during the post-measurement. Thus, these results show that ‘ACT your way’ has a positive effect on the psychological flexibility of adolescents with depressive symptoms. Herein, adaptive and maladaptive cognitive emotion regulation strategies appear to have no mediated

In Nederland krijgt 0,4 tot 8,3 procent van de adolescenten te maken met een depressieve stoornis. Cognitieve gedragstherapie (CGT) is een effectieve therapievorm in de preventie van depressieve klachten bij adolescenten. Het element cognitieve herstructurering (CH) wordt het meest ingezet binnen de CGT en vervult een fundamentele rol binnen de therapie. Tot op heden hebben studies zich voornamelijk gericht op de effectiviteit van CGT als geheel waarbij de elementen door elkaar heen werden ingezet. Er is weinig bekend over de werking van CH wanneer dit element geïsoleerd wordt aangeboden. De huidige studie richt zich op het geïsoleerd aanbieden van de CGT elementen, waarbij is onderzocht of het effectiever is om CH vroeg of laat in te zetten gedurende de therapie. Ook is onderzocht of het zinvol is om ouders klachten te laten rapporteren over hun kind, omdat uit de literatuur blijkt dat er nog maar weinig bekend is over of het relevant is om zowel ouders als adolescenten klachten te laten rapporteren. In totaal hebben 233 participanten tussen 12 en 18 jaar met subklinische depressieve symptomen deelgenomen, waarvan 129 in de groep waarin CH vroeg in de therapie (sessie 1-6) werd ingezet en 123 in de groep waarin CH laat (sessie 7-12) werd ingezet. In beide groepen was sprake van een significante afname in depressieve symptomen, waarbij geen verschillen werden gevonden tussen de groepen, wat laat zien dat het niet uit maakt op welk moment CH wordt aangeboden. Er werd geen significant verschil gevonden in de klachtenrapportage tussen adolescenten en hun ouders. Waaruit kan worden geconcludeerd dat het zinvol is om zowel adolescenten als ouders depressieve klachten te laten rapporteren, omdat ouders een extra en betrouwbare bron van informatie zijn in depressiepreventie onderzoek bij adolescenten. Alternatieve verklaringen en aanbevelingen voor vervolgonderzoek en de praktijk worden besproken.

Background: The existing treatment guidelines for depressed young people, namely cognitive behavioral therapy, interpersonal therapy and medication, do not always seem to have sufficient effect. Learning how to use adaptive emotion regulation strategies might be a way to prevent and treat a depression. Acceptance and Commitment Therapy (ACT) contributes to the improvement of these strategies. Aim: This study explores whether there is a positive effect of ACT on the emotion regulation of young people on therefor a mediation effect on their depressive symptoms. In addition, this study examines whether a decrease in the depressive symptoms of young people has a mediation effect on their school experience, the absence and the school results. Method: For this study data was used from the pilot effect study: “ACT your Way”. Participants (n=26) where youngsters aged 14 to 26 years old (M = 18.0, SD = 2.83). All the youngsters have a major depressive mood disorder as main diagnosis. They all have had previous treatment for their depression according to the guidelines (CBT, IPT), from which they have not benefited sufficiently or have fallen back into a depressive disorder (after a symptom-free period of at least two months). A paired t-test was used to compare the pre- and post-measurements and a PROCESS for mediation analysis was used to determine the mediation effect. Results: This study showed that depressed young people report significantly less depressive symptoms after following “ACT your way” and that they make more positive reinterpretation. No difference was found on school experience, absenteeism and school results. Also, no mediating effect of cognitive emotion regulation strategies on depressive symptoms and no mediating effect of depressive symptoms on school experience, absenteeism and school results were found. Conclusion: The results of this study are a first indication that “ACT your way” can contribute to a reduction of depressive symptoms in youngsters. I

Een op vijf adolescenten in Nederland heeft last van depressieve symptomen. Om symptomen te verminderen en verergering te voorkomen, wordt vaak Cognitieve Gedragstherapie (CGT) ingezet. Binnen CGT worden verschillende componenten onderscheiden zoals cognitieve herstructurering (CH), gedragsactivatie (GA), probleemoplossing (PO) en relaxatie (RE). In CGT bestaat geen vaste volgorde waarin deze componenten worden aangeboden. Er is weinig bekend over of de volgorde uitmaakt voor het effect op depressieve symptomen. Uit de literatuur blijkt dat therapie alliantie kan bijdragen aan het verminderen van depressieve symptomen. De huidige studie richt zich op de differentiële effectiviteit van vier verschillende volgorden van componenten: Conditie 1: CH-GA-PO-RE, Conditie 2: GA-CH-RE-PO, Conditie 3: PO-GA-RE-CH en Conditie 4: RE-PO-GA-CH en de mogelijk mediërende rol van therapie alliantie. In totaliteit hebben 233 participanten tussen 12 en 18 jaar met subklinische depressieve symptomen deelgenomen aan de studie. Zij werden gerandomiseerd over de vier condities. In alle condities was sprake van een significante afname in depressieve symptomen, waarbij geen verschillen werden gevonden tussen de condities. De mediatie analyse kon niet worden uitgevoerd, vanwege de afwezigheid van correlaties tussen therapie alliantie en de voor- en nameting van depressieve symptomen. Het volgen van preventieve CGT-training waar de vier componenten aan bod komen leidt tot minder depressieve symptomen. Een betere werkrelatie tussen cliënt en therapeut voorspelde in dit onderzoek geen afname van symptomen. Mogelijke verklaringen en suggesties voor vervolgonderzoek en de praktijk worden besproken.

For the development of prevention and intervention programs, it is important to further understand the development of parental structure. This study investigated whether the relationship between social-emotional behavioral problems in toddlers and maternal structure is mediated by maternal self-efficacy. The sample consisted of 100 mothers (M = 32.91 years, SD = 4.44) with a child between the ages of 24 and 47 months old (M = 34.78 months, SD = 6.86, 48% boys). The degree of maternal structure, maternal self-efficacy and the presence of social-emotional behavioral problems in children were measured using questionnaires completed by the mothers. The results showed an indirect effect between social-emotional problems and maternal structure, with maternal self-efficacy as a mediator. As mothers registered more social-emotional behavioral problems in the child, the lower the maternal self-efficacy. Due to the lower maternal self-efficacy, the structure mothers offered in the upbringing of their children was also found to be lower. It is recommended to conduct longitudinal follow-up research, examining bidirectional relationships to gain more insight into the relationship between the social-emotional behavioral problems in toddlers, parental self-efficacy and structure.

This study examines the importance of relaxation exercises in cognitive behavioral therapy for young people with depression in the Netherlands. Data is collected by analysing 20 depression protocols using a taxonomy regarding: presence or absence of relaxation exercises, different components of relaxation exercises, recipient of the therapy, modality, mode of delivery, the dosage and the place within the treatment in which relaxation exercises start. Thereafter, existing effect studies were compared with the result of the 20 depression protocols and looked at comparison between the use of relaxation exercises and the effectiveness of the protocols. In addition, two cognitive behavioral therapists were interviewed. The results show that 65% of the protocols used relaxation exercises, usually two or more relaxation techniques are used in groups or in combination with parents, a minimum of four and a maximum of seven modalities are used and all except one protocol is given face-to-face treatment, between 8.3% and 27.2% of the total treatment time is spent on relaxation exercises and this is mainly used at the beginning of the treatment. The results indicate insufficient evidence to establish a link between relaxation exercises and the effect of cognitive behavioral therapy. However there are several indicatiosn that are promising and follow-up research is recommended. In particular, the time each protocol spends on relaxation exercises appears to affect the effectiveness of relaxation exercises as an element of cognitive behavioral therapy.