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
Ma, J.; Sanchez Duffhues, G.; Caradec, J.; Benderitter, P.; Hoflack, J.; Dijke, P. ten 2022
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
Souri, Z.; Jochemsen, A.G.; Versluis, M.; Wierenga, A.P.A.; Nemati, F.; Velden, P.A. van der; ... ; Jager, M.J. 2020
Simple SummaryChemotherapy and immunotherapy are both used to treat malignancies. The immunotherapy of cancer often involves T cells, which recognise the antigens presented in HLA molecules. Uveal... Show moreSimple SummaryChemotherapy and immunotherapy are both used to treat malignancies. The immunotherapy of cancer often involves T cells, which recognise the antigens presented in HLA molecules. Uveal melanoma (UM) is an intraocular malignancy, which often gives rise to metastases. We determined whether high-risk tumours expressed the target of two drugs, histone deacetylase (HDAC) inhibitor Quisinostat and Tazemetostat, an inhibitor of Enhancer of zeste homologue 2 (EZH2). We observed that especially high-risk UM tumours (monosomy 3, gain of 8q, loss of BAP1) expressed several HDACs, and showed a high HLA Class I expression. We further tested whether these drugs influenced HLA Class I expression on three UM cell lines. The drug Quisinostat led to an upregulation of HLA protein and mRNA levels in three UM cell lines, while Tazemetostat had little effect. We concluded that the use of drugs that influence epigenetic regulators may impact immunotherapy approaches.The treatment of uveal melanoma (UM) metastases or adjuvant treatment may imply immunological approaches or chemotherapy. It is to date unknown how epigenetic modifiers affect the expression of immunologically relevant targets, such as the HLA Class I antigens, in UM. We investigated the expression of HDACs and the histone methyl transferase EZH2 in a set of 64 UMs, using an Illumina HT12V4 array, and determined whether a histone deacetylase (HDAC) inhibitor and EZH2 inhibitor modified the expression of HLA Class I on three UM cell lines. Several HDACs (HDAC1, HDAC3, HDAC4, and HDAC8) showed an increased expression in high-risk UM, and were correlated with an increased HLA expression. HDAC11 had the opposite expression pattern. While in vitro tests showed that Tazemetostat did not influence cell growth, Quisinostat decreased cell survival. In the three tested cell lines, Quisinostat increased HLA Class I expression at the protein and mRNA level, while Tazemetostat did not have an effect on the cell surface HLA Class I levels. Combination therapy mostly followed the Quisinostat results. Our findings indicate that epigenetic drugs (in this case an HDAC inhibitor) may influence the expression of immunologically relevant cell surface molecules in UM, demonstrating that these drugs potentially influence immunotherapy. Show less
Bloem, J.L.; Vriens, D.; Krol, A.D.G.; Ozdemir, M.; Sande, M.A.J. van de; Gelderblom, H.; ... ; Noebauer-Huhmann, I.M. 2020
Knowledge of imaging findings related to therapy administered to patients with sarcoma is pivotal in selecting appropriate care for these patients. Imaging studies are performed as surveillance in... Show moreKnowledge of imaging findings related to therapy administered to patients with sarcoma is pivotal in selecting appropriate care for these patients. Imaging studies are performed as surveillance in asymptomatic patients or because symptoms, including anxiety, develop. In addition to detection of recurrent disease and assessment of response to therapy, diagnosis of conditions related to therapy that may or may not need treatment has a marked positive impact on quality of life. The purpose of this review is to assist radiologists, nuclear physicians, and others clinicians involved in the diagnosis and treatment of these patients in recognizing imaging findings related to therapy and not to activity of the previously treated sarcoma. Imaging findings are time dependent and often specific in relation to therapy given. Show less
Bloem, J.L.; Vriens, D.; Krol, A.D.G.; Ozdemir, M.; Sande, M.A.J. van de; Gelderblom, H.; ... ; Noebauer-Huhmann, I.M. 2020
Knowledge of imaging findings related to therapy administered to patients with sarcoma is pivotal in selecting appropriate care for these patients. Imaging studies are performed as surveillance in... Show moreKnowledge of imaging findings related to therapy administered to patients with sarcoma is pivotal in selecting appropriate care for these patients. Imaging studies are performed as surveillance in asymptomatic patients or because symptoms, including anxiety, develop. In addition to detection of recurrent disease and assessment of response to therapy, diagnosis of conditions related to therapy that may or may not need treatment has a marked positive impact on quality of life. The purpose of this review is to assist radiologists, nuclear physicians, and others clinicians involved in the diagnosis and treatment of these patients in recognizing imaging findings related to therapy and not to activity of the previously treated sarcoma. Imaging findings are time dependent and often specific in relation to therapy given. Show less
Uveal melanoma (UM) is a global disease which especially occurs in elderly people. Its incidence varies widely between populations, with the highest incidence among Caucasians, and a South-to-North... Show moreUveal melanoma (UM) is a global disease which especially occurs in elderly people. Its incidence varies widely between populations, with the highest incidence among Caucasians, and a South-to-North increase in Europe. As northern Europeans often have blond hair and light eyes, we wondered whether iris colour may be a predisposing factor for UM and if so, why. We compared the distribution of iris colour between Dutch UM patients and healthy Dutch controls, using data from the Rotterdam Study (RS), and reviewed the literature regarding iris colour. We describe molecular mechanisms that might explain the observed associations. When comparing a group of Dutch UM patients with controls, we observed that individuals from Caucasian ancestry with a green/hazel iris colour (Odds Ratio (OR) = 3.64, 95% Confidence Interval (CI) 2.57-5.14) and individuals with a blue/grey iris colour (OR = 1.38, 95% CI 1.04-1.82) had a significantly higher crude risk of UM than those with brown eyes. According to the literature, this may be due to a difference in the function of pheomelanin (associated with a light iris colour) and eumelanin (associated with a brown iris colour). The combination of light-induced stress and aging may affect pheomelanin-carrying melanocytes in a different way than eumelanin-carrying melanocytes, increasing the risk of developing a malignancy. Show less
Objective This study aimed to assess psychological functioning, quality of life, and regret about screening after a positive fecal immunochemical test (FIT) and subsequent colonoscopy, and to... Show moreObjective This study aimed to assess psychological functioning, quality of life, and regret about screening after a positive fecal immunochemical test (FIT) and subsequent colonoscopy, and to evaluate changes over time.Methods This is a prospective cohort study. Individuals aged 55 to 75 with a positive FIT that were referred for colonoscopy between July 2017 and November 2018, were invited to complete questionnaires related to psychological distress and health-related quality of life at three predefined time points: before colonoscopy, after histopathology result notification, and after 6 months. Four questionnaires were used: the Psychological Consequences Questionnaire (PCQ), the six-item Cancer Worry Scale (CWS), the Decision Regret Scale (DRS), and the 36-item Short-Form (SF-36).Results A total of 1066 participants out of 2151 eligible individuals were included. Patients with cancer showed a significant increase in psychological dysfunction (P = .01) and cancer worry (P = .008) after colonoscopy result notification, and a decline to pre-colonoscopy measurements after 6 months. In the no-cancer groups, psychological dysfunction and cancer worry significantly decreased over time (P < .05) but there was no ongoing decline. After 6 months, 17% of participants with no cancer experienced high level of cancer worry (CWS >= 10). Yet, only 5% reported high level of regret about screening participation (DRS > 25). A good global quality of life was reported in participants with no cancer.Conclusion Some psychological distress remains up to 6 months after colonoscopy in participants who tested false-positive in the Dutch bowel cancer screening program. Show less
