Background: Fear of cancer recurrence (FCR) is one of the greatest problems with which cancer survivors have to deal. High levels of FCR are characterized by intrusive thoughts about cancer-related... Show moreBackground: Fear of cancer recurrence (FCR) is one of the greatest problems with which cancer survivors have to deal. High levels of FCR are characterized by intrusive thoughts about cancer-related events and re-experiencing these events, avoidance of reminders of cancer, and hypervigilance, similar to post-traumatic stress disorder (PTSD). Eye movement desensitization and reprocessing (EMDR) therapy focuses on these images and memories. It is effective in reducing PTSD and may be effective in reducing high levels of FCR. Objective: The aim of the present study is to investigate the effectiveness of EMDR for severe FCR in breast and colorectal cancer survivors. Method: A multiple-baseline single-case experimental design (n = 8) was used. Daily repeated measurements for FCR were taken during the baseline phase and treatment phase, post-treatment, and at the 3 month follow-up. Participants answered the Cancer Worry Scale (CWS) and the Fear of Cancer Recurrence Inventory, Dutch version (FCRI-NL) five times, i.e. at the start and at the end of each phase (baseline, treatment, post-treatment, and follow-up). The study was prospectively registered at clinicaltrials.gov (NL8223). Results: Visual analysis and effect size calculation by Tau-U were executed for the daily questionnaire on FCR. The weighted average Tau-U score was .63 (p < .01) for baseline versus post-treatment, indicating large change, and .53 (p < .01) between baseline and follow-up, indicating moderate change. The scores on the CWS and FCRI-NL-SF decreased significantly from baseline to follow-up. Conclusion: The results seem promising for EMDR therapy as a potentially effective treatment for FCR. Further research is recommended. Show less
Meer, D.J. van der; Zevenbergen, S.; Vlooswijk, C.; Bijlsma, R.M.; Kaal, S.E.J.; Kerst, J.M.; ... ; Husson, O. 2023
Background: Adolescent and young adult cancer survivors (AYAs, aged 18-39 years at first diagnosis) have a higher second cancer risk. Accelerated aging is hypothesized as underlying mechanism and... Show moreBackground: Adolescent and young adult cancer survivors (AYAs, aged 18-39 years at first diagnosis) have a higher second cancer risk. Accelerated aging is hypothesized as underlying mechanism and has been described clinically by 6 indicators; fatigue, low quality of sleep, low mood, lack of motivation, subjective memory complaints, and poor exercise tolerance. Using patient-reported outcomes, we aimed to identify clusters of accelerated aging among AYA cancer survivors and to investigate their association with second cancer development.Patients and Methods: Patient, tumor, and treatment data were obtained from the Netherlands Cancer Registry. Patient-reported clinical indicators and second cancer data were obtained from the SURVivors (5-20 years) of cancer in AYAs (SURVAYA) questionnaire study between 1999 and 2015. Latent class and multivariable logistic regression analyses were performed.Results: In total, n = 3734 AYA survivors with known second cancer status (n = 278 [7.4%] second cancers) were included. Four latent clusters were identified and named based on their clinical indicator features; (1) high accelerated aging (31.3%), (2) intermediate accelerated aging without poor exercise tolerance (15.1%), (3) intermediate accelerated aging without lack of motivation (27.4%), and (4) low accelerated aging (26.2%). AYAs in the high accelerated aging cluster were more likely to have second cancer (odds ratio: 1.6; 95% CI, 1.1-2.3) compared to the low accelerated aging cluster.Conclusion: AYAs with a higher burden of accelerated aging were more likely to develop a second cancer. Validation of the clinical indicators and how to best capture them is needed to improve (early) detection of AYAs at high risk of developing second cancer. Show less
Kruiswijk, A.A.; Sande, M.A.J. van de; Haas, R.L.; Marle, E.M.V.; Engelhardt, E.G.; Mheen, P.M. van de; ... ; VALUE-PERSARC Res Group 2023
Introduction Current treatment decision-making in high-grade soft-tissue sarcoma (STS) care is not informed by individualised risks for different treatment options and patients’ preferences. Risk... Show moreIntroduction Current treatment decision-making in high-grade soft-tissue sarcoma (STS) care is not informed by individualised risks for different treatment options and patients’ preferences. Risk prediction tools may provide patients and professionals insight in personalised risks and benefits for different treatment options and thereby potentially increase patients’ knowledge and reduce decisional conflict. The VALUE-PERSARC study aims to assess the (cost-)effectiveness of a personalised risk assessment tool (PERSARC) to increase patients’ knowledge about risks and benefits of treatment options and to reduce decisional conflict in comparison with usual care in high-grade extremity STS patients.Methods The VALUE-PERSARC study is a parallel cluster randomised control trial that aims to include at least 120 primarily diagnosed high-grade extremity STS patients in 6 Dutch hospitals. Eligible patients (≥18 years) are those without a treatment plan and treated with curative intent. Patients with sarcoma subtypes or treatment options not mentioned in PERSARC are unable to participate. Hospitals will be randomised between usual care (control) or care with the use of PERSARC (intervention). In the intervention condition, PERSARC will be used by STS professionals in multidisciplinary tumour boards to guide treatment advice and in patient consultations, where the oncological/orthopaedic surgeon informs the patient about his/her diagnosis and discusses benefits and harms of all relevant treatment options. The primary outcomes are patients’ knowledge about risks and benefits of treatment options and decisional conflict (Decisional Conflict Scale) 1 week after the treatment decision has been made. Secondary outcomes will be evaluated using questionnaires, 1 week and 3, 6 and 12 months after the treatment decision. Data will be analysed following an intention-to-treat approach using a linear mixed model and taking into account clustering of patients within hospitals. Show less
Giraud, E.L.; Brake, L.M.H. te; Hombergh, E.C.A. van den; Desar, I.M.E.; Kweekel, D.M.; Erp, N.P. van 2023
Aims: With the rising number of oral targeted oncolytics and growing awareness of the benefits of therapeutic drug monitoring (TDM) within the field of oncology, it is expected that the requests... Show moreAims: With the rising number of oral targeted oncolytics and growing awareness of the benefits of therapeutic drug monitoring (TDM) within the field of oncology, it is expected that the requests for quantifying concentrations of these drugs will increase. It is important to (cross-)validate available assays and ensure its quality, as results may lead to altered dosing recommendations. Therefore, we aimed to evaluate the performance of laboratories measuring concentrations of targeted oral oncolytics in a one-time international quality control (QC) programme.Methods: Participating laboratories received a set of plasma samples containing low, medium and high concentrations of imatinib, sunitinib, desethylsunitinib, pazopanib, cabozantinib, olaparib, enzalutamide, desmethy lenzalutamide and abiraterone, with the request to report their results back within five weeks after shipment. Accuracy was defined acceptable if measurements where within 85%-115% from the weighed-in reference concentrations. Besides descriptive statistics, an exploratory ANOVA was performed.Results: Seventeen laboratories from six countries reported 243 results. Overall, 80.7% of all measurements were within the predefined range of acceptable accuracy. Laboratories performed best in quantifying imatinib and poorest in quantifying desethylsunitinib (median absolute inaccuracy respectively 4.0% (interquartile range (IQR) 1.8%-6.5%) and 15.5% (IQR 8.8%-34.9%)). The poorest performance of desethylsunitinib might be caused by using the stable-isotope-labelled sunitinib instead of desethylsunitinib as an internal standard, or due to the light-induced cis(Z)/trans(E) isomerization of (desethyl)sunitinib. Overall, drug substance and performing laboratory seemed to influence the absolute inaccuracy (F = 16.4; p < 0.001 and F = 35.5; p < 0.001, respectively).Conclusion: Considering this is the first evaluation of an international QC programme for oral targeted oncolytics, an impressive high percentage of measurements were within the predefined range of accuracy. Cross-validation of assays that are used for dose optimization of oncolytics will secure the performance and will protect patients from incorrect advices. Show less
PURPOSE. The virus-like drug conjugate belzupacap sarotalocan (AU-011), currently under clinical investigation for first-line treatment of primary uveal melanoma (UM), shows enhanced tumor... Show morePURPOSE. The virus-like drug conjugate belzupacap sarotalocan (AU-011), currently under clinical investigation for first-line treatment of primary uveal melanoma (UM), shows enhanced tumor specificity by targeting heparan sulfate proteoglycans (HSPG). Such a treatment may potentially lead to systemic immune responses. We studied the potential of AU-011 treatment to induce immunogenic cell death as the first step to induce systemic immunity. METHODS. We determined binding and uptake of AU-011 in ten primary and metastatic UM cell lines. The subcellular location of AU-011 was assessed by fluorescence microscopy. Following light activation (wavelength 690 nm) of AU-011, the half-maximal effective concentration (EC50) of AU-011 treatment and exposure of damage-associated molecu-lar patterns (DAMPs) were assessed using flow cytometry. DAMPs were measured by RNAseq. RESULTS. Fluorescence microscopy revealed most of the AU-011 was present in the cyto-plasm. AU-011 binding and uptake by UM cells increased over time, with a lower uptake in BAP1-negative than in BAP1-positive cell lines. AU-011 activation induced cell death across all UM cell lines with EC50 values at picomolar concentrations. The AU-011 concen-tration and total light dose (J/cm2) were the most important parameters for the observed cytotoxicity. Finally, light-activated AU-011 induced exposure of DAMPs calreticulin (CRT) and HSP90. CRT exposure by light-activated AU-011 as well as CRT RNA exposure were lower in BAP1-negative compared to BAP1-positive UM cell lines. CONCLUSIONS. AU-011 treatment at low picomolar range induces immunogenic cell death in all 10 UM cell lines. The in vitro cytotoxicity was accompanied by exposure of DAMPs (HSP90 and CRT), suggesting AU-011 may contribute to the development of systemic immunity and be a suitable candidate for combination with immunotherapy in vivo. AU -011 treatment was more effective against BAP1-positive cell lines, with a lower EC50 and CRT Show less
Uveal melanoma (UM) is a rare malignant cancer of the eye, with up to 50% of patients dying from metastasis, for which no effective treatment is available. Due to the rarity of the disease, there... Show moreUveal melanoma (UM) is a rare malignant cancer of the eye, with up to 50% of patients dying from metastasis, for which no effective treatment is available. Due to the rarity of the disease, there is a great need to harness the limited material available from primary tumors and metastases for advanced research and preclinical drug screening. We established a platform to isolate, preserve, and transiently recover viable tissues, followed by the generation of spheroid cultures derived from primary UM. All assessed tumor-derived samples formed spheroids in culture within 24 h and stained positive for melanocyte-specific markers, indicating the retention of their melanocytic origin. These short-lived spheroids were only maintained for the duration of the experiment (7 days) or re-established from frozen tumor tissue acquired from the same patient. Intravenous injection of fluorescently labeled UM cells derived from these spheroids into zebrafish yielded a reproducible metastatic phenotype and recapitulated molecular features of the disseminating UM. This approach allowed for the experimental replications required for reliable drug screening (at least 2 individual biological experiments, with n > 20). Drug treatments with navitoclax and everolimus validated the zebrafish patient-derived model as a versatile preclinical tool for screening anti-UM drugs and as a preclinical platform to predict personalized drug responses. Show less
Soeteman, M.; Kappen, T.H.; Engelen, M. van; Marcelis, M.; Kilsdonk, E.; Heuvel-Eibrink, M.M. van den; ... ; Wosten-van Asperen, R.M. 2022
Background Hospitalized pediatric oncology patients are at risk of severe clinical deterioration. Yet Pediatric Early Warning System (PEWS) scores have not been prospectively validated in these... Show moreBackground Hospitalized pediatric oncology patients are at risk of severe clinical deterioration. Yet Pediatric Early Warning System (PEWS) scores have not been prospectively validated in these patients. We aimed to determine the predictive performance of the modified BedsidePEWS score for unplanned pediatric intensive care unit (PICU) admission and cardiopulmonary resuscitation (CPR) in this patient population. Methods We performed a prospective cohort study in an 80-bed pediatric oncology hospital in the Netherlands, where care has been nationally centralized. All hospitalized pediatric oncology patients aged 0-18 years were eligible for inclusion. A Cox proportional hazard model was estimated to study the association between BedsidePEWS score and unplanned PICU admissions or CPR. The predictive performance of the model was internally validated by bootstrapping. Results A total of 1137 patients were included. During the study, 103 patients experienced 127 unplanned PICU admissions and three CPRs. The hazard ratio for unplanned PICU admission or CPR was 1.65 (95% confidence interval [CI]: 1.59-1.72) for each point increase in the modified BedsidePEWS score. The discriminative ability was moderate (D-index close to 0 and a C-index of 0.83 [95% CI: 0.79-0.90]). Positive and negative predictive values of modified BedsidePEWS score at the widely used cutoff of 8, at which escalation of care is required, were 1.4% and 99.9%, respectively. Conclusion The modified BedsidePEWS score is significantly associated with requirement of PICU transfer or CPR. In pediatric oncology patients, this PEWS score may aid in clinical decision-making for timing of PICU transfer. Show less
Background: Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are... Show moreBackground: Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are still dosed using a one-size-fits-all approach. Consequently, individuals have a high probability to be either underexposed or overexposed, potentially leading to suboptimal outcomes. Therapeutic drug monitoring, which is personalized dosing based on measured systemic drug concentrations, could address these problems.Patients and methods: Patients were enrolled in this prospective multicenter study (www.trialregister.nl; NL6695) if they started treatment with one of the 24 participating oral targeted therapies. Primary outcome was to halve the proportion of underexposed patients, compared with historical data. PK sampling was carried out after 4, 8 and 12 weeks, and every 12 weeks thereafter. In case of Cmin below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drugedrug interactions, concomitant intake with food, splitting intake moments or dose increments).Results: In total, 600 patients were included of whom 426 patients are assessable for the primary outcome and 552 patients had >= 1 PK sample(s) available and were therefore assessable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third PK measurement by 39.0% (95% confidence interval 28.0% to 49.0%) compared with historical data. At the third PK measurement, 110 out of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had >= 1 PK sample(s) below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were carried out, which were successful in 113 out of 152 assessable patients (74.3%).Conclusions: Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably. Show less
Aim: Traditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new... Show moreAim: Traditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new opportunities for studies in healthy volunteers, which are conducted faster and are less susceptible to confounders. Aim of this study was to investigate to what extent this approach is utilized and whether pharmacodynamic endpoints are evaluated in these early phase trials. We conducted a comprehensive review of clinical trials with healthy volunteers using immunotherapies potentially relevant for oncology. Methods: Literature searches according to PRISMA guidelines and after registration in PROSPERO were conducted in PubMed, Embase, Web of Science and Cochrane databases with the cut-off date 20 October 2020, using search terms of relevant targets in immuno-oncology. Articles describing clinical trials with immunotherapeutics in healthy volunteers with a mechanism relevant for oncology were included. "Immunotherapeutic " was defined as compounds exhibiting effects through immunological targets. Data including study design and endpoints were extracted, with specific attention to pharmacodynamic endpoints and safety. Results: In total, we found 38 relevant immunotherapeutic compounds tested in HVs, with 86% of studies investigating safety, 82% investigating the pharmacokinetics (PK) and 57% including at least one pharmacodynamic (PD) endpoint. Most of the observed adverse events (AEs) were Grade 1 and 2, consisting mostly of gastrointestinal, cutaneous and flu-like symptoms. Severe AEs were leukopenia, asthenia, syncope, headache, flu-like reaction and liver enzymes increase. PD endpoints investigated comprised of cytokines, immune and inflammatory biomarkers, cell counts, phenotyping circulating immune cells and ex vivo challenge assays. Discussion: Healthy volunteer studies with immuno-oncology compounds have been performed, although not to a large extent. The integration of healthy volunteers in well-designed proof-of-mechanism oriented drug development programs has advantages and could be pursued more in the future, since integrative clinical trial protocols may facilitate early dose selection and prevent cancer patients to be exposed to non-therapeutic dosing regimens. Show less
Microphthalmia-associated transcription factor (MITF) is an important regulator of melanogenesis and melanocyte development. Although it has been studied extensively in cutaneous melanoma, the role... Show moreMicrophthalmia-associated transcription factor (MITF) is an important regulator of melanogenesis and melanocyte development. Although it has been studied extensively in cutaneous melanoma, the role of MITF in uveal melanoma (UM) has not been explored in much detail. We review the literature about the role of MITF in normal melanocytes, in cutaneous melanoma, and in UM. In normal melanocytes, MITF regulates melanocyte development, melanin synthesis, and melanocyte survival. The expression profile and the behaviour of MITF-expressing cells suggest that MITF promotes local proliferation and inhibits invasion, inflammation, and epithelial-to-mesenchymal (EMT) transition. Loss of MITF expression leads to increased invasion and inflammation and is more prevalent in malignant cells. Cutaneous melanoma cells switch between MITF-high and MITF-low states in different phases of tumour development. In UM, MITF loss is associated with loss of BAP1 protein expression, which is a marker of poor prognosis. These data indicate a dual role for MITF in benign and malignant melanocytic cells. Show less
Fisher, F.L.; Najafabadi, A.H.Z.; Meer, P.B. van der; Boele, F.W.; Peerdeman, S.M.; Peul, W.C.; ... ; Furth, W.R. van 2022
OBJECTIVE Patients with skull base meningioma (SBM) often require complex surgery around critical neurovascular structures, placing them at high risk of poor health-related quality of life (HRQOL)... Show moreOBJECTIVE Patients with skull base meningioma (SBM) often require complex surgery around critical neurovascular structures, placing them at high risk of poor health-related quality of life (HRQOL) and possibly neurocognitive dysfunction. As the survival of meningioma patients is near normal, long-term neurocognitive and HRQOL outcomes are important to evaluate, including evaluation of the impact of specific tumor location and treatment modalities on these outcomes. METHODS In this multicenter cross-sectional study including patients 5 years or more after their last tumor intervention, Short-Form Health Survey (SF-36) and European Organisation for Research and Treatment of Cancer (EORTC) QLQ-BN20 questionnaires were used to assess generic and disease-specific HRQOL. Neurocognitive functioning was assessed with standardized neuropsychological assessment. SBM patient assessments were compared with those of 1) informal caregivers of SBM patients who served as controls and 2) convexity meningioma patients. In addition, the authors compared anterior/middle SBM patients with posterior SBM patients and anterior/middle and posterior SBM patients separately with controls. Multivariable and propensity score regression analyses were performed to correct for possible confounders. RESULTS Patients with SBM (n = 89) with a median follow-up of 9 years after the last intervention did not significantly differ from controls (n = 65) or convexity meningioma patients (n = 84) on generic HRQOL assessment. Statistically significantly but not clinically relevantly better disease-specific HRQOL was found for SBM patients compared with convexity meningioma patients. Anterior/middle SBM patients (n = 62) had significantly and clinically relevantly better HRQOL in SF-36 and EORTC QLQ-BN20 scores than posterior SBM patients (n = 27): physical role functioning (corrected difference 17.1, 95% CI 0.2-34.0), motor dysfunction (-10.1, 95% CI -17.5 to -2.7), communication deficit (-14.2, 95% CI -22.7 to -5.6), and weakness in both legs (-10.1, 95% CI -18.8 to -1.5). SBM patients whose primary treatment was radiotherapy had lower HRQOL scores compared with SBM patients who underwent surgery on two domains: bodily pain (-33.0, 95% CI -55.2 to -10.9) and vitality (-18.9. 95% CI -33.7 to -4.1). Tumor location and treatment modality did not result in significant differences in neurocognitive functioning, although 44% of SBM patients had deficits in at least one domain. CONCLUSIONS In the long term, SBM patients do not experience significantly more sequelae in HRQOL and neurocognitive functioning than do controls or patients with convexity meningioma. Patients with posterior SBM had poorer HRQOL than anterior/middle SBM patients, and primary treatment with radiotherapy was associated with worse HRQOL. Neurocognitive functioning was not affected by tumor location or treatment modality. Show less
Background Shared decision-making (SDM) is often considered the ideal for decision-making in oncology. Views of specific groups such as ethnic minorities have seldom been considered in its... Show moreBackground Shared decision-making (SDM) is often considered the ideal for decision-making in oncology. Views of specific groups such as ethnic minorities have seldom been considered in its development. Aim In this study we seek to assess in oncology if there is a need for adaptation of the current SDM model to ethnic minorities and to formulate possible adjustments. Design This study is embedded in empirical bioethics, an interdisciplinary approach integrating empirical data with ethical reasoning to formulate normative conclusions regarding a practice. For the empirical social scientific part, a cross-sectional qualitative study will be conducted; for the ethical reflection the Reflective Equilibrium will be used to develop a coherent view on the application of SDM among ethnic minorities in oncology. Method Semi-structured interviews combined with visual methods (timelines and relational maps) will be held with healthcare professionals (HCPs), ethnic minority patients, and their relatives to identify values steering the behavior of these actors in SDM. In addition, focus groups (FGs) will be held with ethnic minority community members to identify value structures at the group level. Respondents will be recruited through organizations with access to ethnic minorities and collaborating hospitals. Data will be analyzed using a reflexive thematic analysis through the lens of Schwartz's value theory. The results of the empirical phase will be included in the RE to formulate possible adjustments of the SDM model, if needed. Discussion The integration of empirical data with ethical reflection is an innovative method in decision-making. This method enables a systematic and profound assessment of the need for adaptation of SDM and the formulation of theoretically and empirically based suggestions for adaptations of the model. Findings of this study may enrich the SDM model. Show less
Background: Screening glioma patients regularly for possible mood disorders may facilitate early identification and referral of patients at risk. This study evaluated if the EORTC QLQ-C30 Emotional... Show moreBackground: Screening glioma patients regularly for possible mood disorders may facilitate early identification and referral of patients at risk. This study evaluated if the EORTC QLQ-C30 Emotional Functioning (EF) scale could be used as an initial screening measure to identify patients possibly having a mood disorder. Methods: EORTC QLQ-C30 EF and Hospital Anxiety and Depression Scale (HADS) scores were collected as part of a study assessing the impact of timing of patient-reported outcome assessments on actual health-related quality of life outcomes (N = 99). Spearman correlations and Mann-Whitney U tests were used to determine the association between the EF and HADS (sub)scales. Receiver Operating Characteristic analyses were performed to determine optimal cut-off EF scores to identify patients possibly having a mood disorder (i.e. HADS subscale score >= 8 points). Results: EF and HADS (sub)scales correlated moderately (HADS-A: r = -0.65; HADS-D: r = -0.52). Significant EF score differences were found between patients with HADS >= 8 versus <8 points (HADS-A: mean difference (MD) = 32 and HADS-D: MD = 23). The EF scale had excellent (HADS-A; AUC = 0.88) and borderline excellent (HADS-D; AUC = 0.78) distinguishing capabilities. A statistically optimal (EF score <80) and a most inclusive (sensitivity of 100%, corresponding to an EF score <97) EF cut-off score correctly identified 88.0% and 96.0% of patients with a possible mood disorder, respectively. Conclusion: EORTC QLQ-C30 EF scale seems to be an appropriate screening measure to identify glioma patients possibly having a mood disorder in need of further assessment. Show less
Simple Summary We hypothesize that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, may play a role in tumor development in uveal melanoma.... Show moreSimple Summary We hypothesize that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, may play a role in tumor development in uveal melanoma. We determined the expression of these cytokines in both uveal melanoma tissue as well as in aqueous humor, which provides a unique combination of data. We observed that ANG-2, in contrast to ANG-1, showed more expression in high-risk tumors and was associated with the development of metastases. Its presence in aqueous humor correlated with expression in tumor tissue. Knowledge about the expression of these cytokines may help to identify targets for personalized treatment. Uveal melanoma (UM) metastasize haematogeneously, and tumor blood vessel density is an important prognostic factor. We hypothesized that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, might play a role in tumor development and metastatic behavior. mRNA levels of ANG-1 and ANG-2 were determined in 64 tumors using an Illumina HT-12 v4 mRNA chip and compared to clinical, pathologic, and genetic tumor parameters. Tissue expression was also determined by immunohistochemistry (IHC). Samples of aqueous humor were collected from 83 UM-containing enucleated eyes and protein levels that were determined in a multiplex proximity extension assay. High tissue gene expression of ANG-2, but not of ANG-1, was associated with high tumor thickness, high largest basal diameter, involvement of the ciliary body, and with UM-related death (ANG-2 mRNA p < 0.001; ANG-2 aqueous protein p < 0.001). The presence of the ANG-2 protein in aqueous humor correlated with its mRNA expression in the tumor (r = 0.309, p = 0.03). IHC showed that ANG-2 was expressed in macrophages as well as tumor cells. The presence of ANG-2 in the tumor and in aqueous humor, especially in high-risk tumors, make ANG-2 a potential targetable cytokine in uveal melanoma. Show less
Simple Summary Uveal melanoma (UM) is a rare ocular malignancy that often gives rise to metastases. Tumours with an inflammatory phenotype have an especially bad prognosis. As an increased HLA... Show moreSimple Summary Uveal melanoma (UM) is a rare ocular malignancy that often gives rise to metastases. Tumours with an inflammatory phenotype have an especially bad prognosis. As an increased HLA expression and the presence of tumour-infiltrating lymphocytes and macrophages may be regulated by miRNAs, we set out to investigate whether any miRNAs are associated with inflammatory parameters in this malignancy. Some miRNAs were increased in UM with a high HLA expression and high T cell numbers, while others were decreased, showing two opposing patterns; however, both patterns were related to the tumour's chromosome 3/BAP1 status. We conclude that specific miRNAs are related to the inflammatory phenotype and that these are differentially expressed between disomy 3/BAP1-positive versus monosomy 3/BAP1-negative UM. MicroRNAs are known to play a role in the regulation of inflammation. As a high HLA Class I expression is associated with a bad prognosis in UM, we set out to determine whether any miRNAs were related to a high HLA Class I expression and inflammation. We also determined whether such miRNAs were related to the UM's genetic status. The expression of 125 miRNAs was determined in 64 primary UM from Leiden. Similarly, the mRNA expression of HLA-A, HLA-B, TAP1, BAP1, and immune cell markers was obtained. Expression levels of 24 of the 125 miRNAs correlated with expression of at least three out of four HLA Class I probes. Four miRNAs showed a positive correlation with HLA expression and infiltration with leukocytes, 20 a negative pattern. In the first group, high miRNA levels correlated with chromosome 3 loss/reduced BAP1 mRNA expression, in the second group low miRNA levels. The positive associations between miRNA-22 and miRNA-155 with HLA Class I were confirmed in the TCGA study and Rotterdam cohort, and with TAP1 in the Rotterdam data set; the negative associations between miRNA-125b2 and miRNA-211 and HLA-A, TAP1, and CD4 were confirmed in the Rotterdam set. We demonstrate two patterns: miRNAs can either be related to a high or a low HLA Class I/TAP1 expression and the presence of infiltrating lymphocytes and macrophages. However, both patterns were associated with chromosome 3/BAP1 status, which suggests a role for BAP1 loss in the regulation of HLA expression and inflammation in UM through miRNAs. Show less
Purpose Solutions to improve the implementation of shared decision making (SDM) in oncology often focus on the consultation, with limited effects. In this study, we used a service design... Show morePurpose Solutions to improve the implementation of shared decision making (SDM) in oncology often focus on the consultation, with limited effects. In this study, we used a service design perspective on the care path of locally advanced pancreatic cancer (LAPC). We aimed to understand how experiences of patients, their significant others, and medical professionals over the entire care path accumulate to support their ability to participate in SDM. Participants and methods We used qualitative interviews including design research techniques with 13 patients, 13 significant others, and 11 healthcare professionals, involved in the diagnosis or treatment of LAPC. The topic list was based on the literature and an auto-ethnography of the illness trajectory by a caregiver who is also a service design researcher. We conducted a thematic content analysis to identify themes influencing the ability to participate in SDM. Results We found four interconnected themes: (1) Decision making is an ongoing and unpredictable process with many decision moments, often unannounced. The unpredictability of the disease course, tumor response to treatment, and consequences of choices on the quality of life complicate decision making; (2) Division of roles, tasks, and collaboration among professionals and between professionals and patients and/or their significant others is often unclear to patients and their significant others; (3) It involves "work" for patients and their significant others to obtain and understand information; (4) In "their disease journey," patients are confronted with unexpected energy drains and energy boosts, that influence their level of empowerment to participate in SDM. Conclusion The service design perspective uncovered how the stage for SDM is often set outside the consultation, which might explain the limited effect currently seen of interventions focusing on consultation itself. Our findings serve as a starting point for (re)designing care paths to improve the implementation of SDM in oncology. Show less
OBJECTIVE Decision-making for intracranial tumor surgery requires balancing the oncological benefit against the risk for resection-related impairment. Risk estimates are commonly based on... Show moreOBJECTIVE Decision-making for intracranial tumor surgery requires balancing the oncological benefit against the risk for resection-related impairment. Risk estimates are commonly based on subjective experience and generalized num-bers from the literature, but even experienced surgeons overestimate functional outcome after surgery. Today, there is no reliable and objective way to preoperatively predict an individual patient's risk of experiencing any functional impair-ment. METHODS The authors developed a prediction model for functional impairment at 3 to 6 months after microsurgical resection, defined as a decrease in Karnofsky Performance Status of >= 10 points. Two prospective registries in Swit- zerland and Italy were used for development. External validation was performed in 7 cohorts from Sweden, Norway, Germany, Austria, and the Netherlands. Age, sex, prior surgery, tumor histology and maximum diameter, expected major brain vessel or cranial nerve manipulation, resection in eloquent areas and the posterior fossa, and surgical approach were recorded. Discrimination and calibration metrics were evaluated. RESULTS In the development (2437 patients, 48.2% male; mean age +/- SD: 55 +/- 15 years) and external validation (2427 patients, 42.4% male; mean age +/- SD: 58 +/- 13 years) cohorts, functional impairment rates were 21.5% and 28.5%, respectively. In the development cohort, area under the curve (AUC) values of 0.72 (95% CI 0.69-0.74) were observed. In the pooled external validation cohort, the AUC was 0.72 (95% CI 0.69-0.74), confirming generalizability. Calibration plots indicated fair calibration in both cohorts. The tool has been incorporated into a web-based application available at https://neurosurgery.shinyapps.io/impairment/. CONCLUSIONS Functional impairment after intracranial tumor surgery remains extraordinarily difficult to predict, al- though machine learning can help quantify risk. This externally validated prediction tool can serve as the basis for case by-case discussions and risk-to-benefit estimation of surgical treatment in the individual patient. Show less
Introduction: Uncertainty is omnipresent in cancer care, including the ambiguity of diagnostic tests, efficacy and side effects of treatments, and/or patients' long-term prognosis. During second... Show moreIntroduction: Uncertainty is omnipresent in cancer care, including the ambiguity of diagnostic tests, efficacy and side effects of treatments, and/or patients' long-term prognosis. During second opinion consultations, uncertainty may be particularly tangible: doubts and uncertainty may drive patients to seek more information and request a second opinion, whereas the second opinion in turn may also affect patients' level of uncertainty. Providers are tasked to clearly discuss all of these uncertainties with patients who may feel overwhelmed by it. The aim of this study was to explore how oncologists communicate about uncertainty during second opinion consultations in medical oncology.Methods: We performed a secondary qualitative analysis of audio-recorded consultations collected in a prospective study among cancer patients (N = 69) who sought a second opinion in medical oncology. We purposively selected 12 audio-recorded second opinion consultations. Any communication about uncertainty by the oncologist was double coded by two researchers and an inductive analytic approach was chosen to allow for novel insights to arise.Results: Seven approaches in which oncologists conveyed or addressed uncertainty were identified: (1) specifying the degree of uncertainty, (2) explaining reasons of uncertainty, (3) providing personalized estimates of uncertainty to patients, (4) downplaying or magnifying uncertainty, (5) reducing or counterbalancing uncertainty, and (6) providing support to facilitate patients in coping with uncertainty. Moreover, oncologists varied in their (7) choice of words/language to convey uncertainty (i.e., "I" vs. "we"; level of explicitness).Discussion: This study identified various approaches of how oncologists communicated uncertain issues during second opinion consultations. These different approaches could affect patients' perception of uncertainty, emotions provoked by it, and possibly even patients' behavior. For example, by minimizing uncertainty, oncologists may (un)consciously steer patients toward specific medical decisions). Future research is needed to examine how these different ways of communicating about uncertainty affect patients. This could also facilitate a discussion about the desirability of certain communication strategies. Eventually, practical and evidence-based guidance needs to be developed for clinicians to optimally inform patients about uncertain issues and support patients in dealing with these. Show less
Overbeek, K.A.; Rodriguez Girondo, M.D.M.; Wagner, A.; Stoep, N. van der; Akker, P.C. van den; Oosterwijk, J.C.; ... ; Potjer, T.P. 2021
BackgroundPathogenic variants in the CDKN2A gene are generally associated with the development of melanoma and pancreatic ductal adenocarcinoma (PDAC), but specific genotype-phenotype correlations... Show moreBackgroundPathogenic variants in the CDKN2A gene are generally associated with the development of melanoma and pancreatic ductal adenocarcinoma (PDAC), but specific genotype-phenotype correlations might exist and the extent of PDAC risk is not well established for many variants.MethodsUsing the Dutch national familial melanoma database, we identified all families with a pathogenic CDKN2A variant and investigated the occurrence of PDAC within these families. We also estimated the standardised incidence ratio and lifetime PDAC risk for carriers of a highly prevalent variant in these families.ResultsWe identified 172 families in which 649 individuals carried 15 different pathogenic variants. The most prevalent variant was the founder mutation c.225_243del (p16-Leiden, 484 proven carriers). Second most prevalent was c.67G>C (55 proven carriers). PDAC developed in 95 of 163 families (58%, including 373 of 629 proven carriers) harbouring a variant with an effect on the p16INK4a protein, whereas PDAC did not occur in the 9 families (20 proven carriers) with a variant affecting only p14ARF. In the c.67G>C families, PDAC occurred in 12 of the 251 (5%) persons at risk. The standardised incidence ratio was 19.1 (95% CI 8.3 to 33.6) and the cumulative PDAC incidence at age 75 years (lifetime risk) was 19% (95% CI 7.5% to 30.1%).ConclusionsOur results support the notion that pathogenic CDKN2A variants affecting the p16INK4a protein, including c.67G>C, are associated with increased PDAC risk and carriers of such variants should be offered pancreatic cancer surveillance. There is no clinical evidence that impairment of only the p14ARF protein leads to an increased PDAC risk. Show less
Brouwer, N.J.; Konstantinou, E.K.; Gragoudas, E.S.; Marinkovic, M.; Luyten, G.P.M.; Kim, I.K.; ... ; Vavvas, D.G. 2021
PURPOSE. The purpose of this study was to determine whether YAP/TAZ activation in uveal melanoma (UM) and the susceptibility of melanoma cell lines to YAP/TAZ inhibition by verteporfin (VP) is... Show morePURPOSE. The purpose of this study was to determine whether YAP/TAZ activation in uveal melanoma (UM) and the susceptibility of melanoma cell lines to YAP/TAZ inhibition by verteporfin (VP) is related to the tumor's genetic background.METHODS. Characteristics of 144 patients with enucleated UM were analyzed together with mRNA expression levels of YAP/TAZ-related genes (80 patients from the The Cancer Genome Atlas [TCGA] project and 64 patients from Leiden, The Netherlands). VP was administered to cell lines 92.1, OMM1, Mel270, XMP46, and MM28 (UM), CRMM1 and CRMM2 (conjunctival melanoma), and OCM3 (cutaneous melanoma). Viability, growth speed, and expression of YAP1-related proteins were assessed.RESULTS. In TCGA data, high expression of YAP1 and WWTR1 correlated with the presence of monosomy 3 (P = 0.009 and P < 0.001, respectively) and BAP1-loss (P = 0.003 and P = 0.001, respectively) in the primary UM; metastasis development correlated with higher expression of YAP1 (P = 0.05) and WWTR1 (P = 0.003). In Leiden data, downstream transcription factor TEAD4 was increased in cases with M3/BAP1-loss (P = 0.002 and P = 0.006) and related to metastasis (P = 0.004). UM cell lines 92.1, OMM1, and Mel270 (GNAQ/11-mutation, BAP1-positive) and the fast-growing cell line OCM3 (BRAF-mutation) showed decreased proliferation after exposure to VP. Two slow-growing UM cell lines XMP46 and MM28 (GNAQ/11-mutation, BAP1-negative) were not sensitive to VP, and neither were the two conjunctival melanoma cell lines (BRAF/NRAS-mutation).CONCLUSIONS. High risk UM showed an increased expression of YAP/TAZ-related genes. Although most UM cell lines responded in vitro to VP, BAP1-negative and conjunctival melanoma cell lines did not. Not only the mutational background, but also cell growth rate is an important predictor of response to YAP/TAZ inhibition by VP. Show less
