BackgroundPatients diagnosed with haematologic malignancies (HMs) have a higher risk of developing subsequent solid tumours, such as melanoma. Patients with HM were mostly excluded from clinical...Show moreBackgroundPatients diagnosed with haematologic malignancies (HMs) have a higher risk of developing subsequent solid tumours, such as melanoma. Patients with HM were mostly excluded from clinical trials but potentially derive less benefit from immune checkpoint inhibitors (ICIs) due to disease- or treatment-related T- or B-cell dysfunction.MethodsAll advanced melanoma patients treated with anti-PD-1-based treatment or targeted therapy between 2015 and 2021 were included from the prospective nationwide Dutch Melanoma Treatment Registry. Progression-free survival (PFS) and melanoma-specific survival (MSS) were analysed for patients with HM (HM+) and without HM (HM−). A cox model was used to account for confounders associated with PFS and MSS.ResultsIn total, 4638 advanced melanoma patients received first-line anti-PD-1 monotherapy (n = 1763), ipilimumab-nivolumab (n = 800), or BRAF(/MEK) inhibitors (n = 2075). Concurrent HMs were present for 46 anti-PD1-treated patients, 11 ipilimumab-nivolumab-treated patients and 43 BRAF(/MEK)-inhibitor-treated patients. In anti-PD-1-treated patients, the median PFS was 2.8 months for HM+ and 9.9 months for HM− (p = 0.01). MSS was 41.2 months for HM+ and 58.1 months for HM− (p = 0.00086). In multivariable analysis, the presence of an HM was significantly associated with higher risk of melanoma progression (HRadj 1.62; 95% confidence interval [95% CI] 1.15–2.29; p = 0.006) and melanoma-related death (HRadj 1.74; 95% CI 1.09–2.78; p = 0.020). Median PFS and MSS for first-line BRAF(/MEK-) inhibitor-treated HM+ and HM− patients were not significantly different.ConclusionsPatients with HM and advanced melanoma show significantly worse melanoma-related outcomes when treated with ICI, but not targeted therapy, compared to patients without HM. Clinicians should be aware of potentially altered effectiveness of ICI in patients with active HM. Show less
Background: Recent reports suggest the limited efficacy of immune checkpoints inhibitors in advanced acral melanoma (AM). This study aims to investigate the clinical outcomes of immune checkpoint... Show moreBackground: Recent reports suggest the limited efficacy of immune checkpoints inhibitors in advanced acral melanoma (AM). This study aims to investigate the clinical outcomes of immune checkpoint inhibitors in patients with stage III and IV AM and compare them to cutaneous melanoma (CM). Methods: We included patients with advanced AM and CM treated with first-line anti -programmed cell death (PD)-1 monotherapy or ipilimumab-nivolumab registered in the prospective nationwide Dutch Melanoma Treatment Registry. Objective response rates, progression free survival (PFS) and overall survival (OS) were calculated. A Cox proportional hazard model was used to assess the prognostic factors with PFS and OS. Results: In total, 2058 patients (88 AM and 1970 CM) with advanced melanoma were included. First-line objective response rates were 34% for AM versus 54% for CM in the advanced anti-PD-1 cohort and 33% for AM versus 53% for CM in the advanced ipilimumab-nivolumab cohort. The Median PFS was significantly shorter for anti-PD-1 treated AM patients (3.1 months; 95%CI: 2.8-5.6) than patients with CM (10.1 months; 95%CI: 8.5-12.2) (P < 0.001). In patients with advanced melanoma, AM was significantly associated with a higher risk of progression (HRadj 1.63; 95%CI: 1.26-2.11 ; P < 0.001) and death (HRadj 1.54; 95%CI: 1.15-2.06; P Z 0.004) than CM. Conclusions: This study shows lower effectiveness of anti-PD-1 monotherapy and ipilimumab-nivolumab in AM, with lower response rates, PFS and OS than CM. This group of patients should be prioritised in the development of alternative treatment strategies. 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Aim: In the registration trial, cabozantinib exposure >= 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic... Show moreAim: In the registration trial, cabozantinib exposure >= 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic renal cell cancer (mRCC). Because patients in routine care often differ from patients in clinical trials, we explored the cabozantinib exposure-response relationship in patients with mRCC treated in routine care. Methods: Cabozantinib trough concentrations (C-min) were collected and average exposure was calculated per individual. Exposure-response analyses were performed using the earlier identified target of C-min > 750 ng/mL and median C-min. In addition, the effect of dose reductions on response was explored. PFS was used as measure of response. Results: In total, 59 patients were included:10% were classified as favourable, 61% as intermediate and 29% as poor IMDC risk group, respectively. Median number of prior treatment lines was 2 (0-5). Starting dose was 60 mg in 46%, 40 mg in 42% and 20 mg in 12% of patients. Dose reductions were needed in 58% of patients. Median C-min was 572 ng/mL (IQR: 496-701). Only 17% of patients had an average C-min >= 750 ng/mL. Median PFS was 52 weeks (95% CI: 40-64). No improved PFS was observed for patients with C-min >= 750 ng/mL or >= 572 ng/ml. A longer PFS was observed for patients with a dose reduction vs. those without (65 vs. 31 weeks, p = .001). After incorporating known covariates (IMDC risk group and prior treatment lines (< 2 vs. >= 2)) in the multivariable analysis, the need for dose reduction remained significantly associated with improved PFS (HR 0.32, 95% CI:0.14-0.70, p = .004). Conclusion: In these explorative analyses, no clear relationship between increased cabozantinib exposure and improved PFS was observed. Average cabozantinib exposure was below the previously proposed target in 83% of patients. Future studies should focus on validating the cabozantinib exposure required for long term efficacy. Show less
The causes of involvement in terrorism continue to be subject to a rich academic debate. In several recent contributions, Lorne Dawson, professor of new religious movements, has argued that... Show moreThe causes of involvement in terrorism continue to be subject to a rich academic debate. In several recent contributions, Lorne Dawson, professor of new religious movements, has argued that terrorism researchers too often downplay the role of religious convictions. In setting out his arguments, Dawson has repeatedly referred to some of my own work as an example of this practice. In this article, I respond to Dawson’s criticism in order to show that it does not accurately represent the views that my co-authors and I have put forward. Rather than dismiss the role of ideology, I have argued the need for its contextualization. Extremist beliefs certainly play an important role in motivating and justifying terrorist violence. But they are not sufficient as explanations for such violence because most people who hold extremist views will never act on them. Secondly, even fanatical adherents of extremist beliefs tend to be motivated by more than their convictions alone. Finally, the different degrees of ideological commitment found among terrorists further underline the need to remain critical of the explanatory power of extremist beliefs alone. Show less
The objectives of this thesis, aimed to reduce overtreatment of ductal carcinoma in situ (DCIS) of the breast, were : 1) to evaluate the risk of underestimation after a diagnosis of DCIS and the... Show moreThe objectives of this thesis, aimed to reduce overtreatment of ductal carcinoma in situ (DCIS) of the breast, were : 1) to evaluate the risk of underestimation after a diagnosis of DCIS and the interrater reliability in the histopathological classification of DCIS, important conditions in order to safely adopt an active surveillance strategy for low-risk DCIS, 2) to investigate associations of clinicopathological factors with the risk of developing ipsilateral invasive breast cancer after treatment of DCIS and 3) to analyze the extent of response of DCIS, adjacent to HER2-positive breast cancer, to neoadjuvant systemic therapy and to investigate associations of clinicopathological factors with DCIS response.We have taken significant steps on the road towards conquering overtreatment of DCIS: by having identified several clinicopathological prognostic factors in pure DCIS, by providing reassuring evidence regarding underestimation in the context of active surveillance, by stressing the need for improvement of interrater reliability in histopathological classification, and by showing that the presence of DCIS adjacent to HER2-positive breast cancer should not preclude the option of breast conserving surgery. Show less
Mullens, W.; Auricchio, A.; Martens, P.; Witte, K.; Cowie, M.R.; Delgado, V.; ... ; Leclercq, C. 2020
Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction and leads to improved quality of life, reductions in heart failure... Show moreCardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction and leads to improved quality of life, reductions in heart failure hospitalization rates and all-cause mortality. Nevertheless, up to two-thirds of eligible patients are not referred for CRT. Furthermore, post-implantation follow-up is often fragmented and suboptimal, hampering the potential maximal treatment effect. This joint position statement from three European Society of Cardiology Associations, Heart Failure Association (HFA), European Heart Rhythm Association (EHRA) and European Association of Cardiovascular Imaging (EACVI), focuses on optimized implementation of CRT. We offer theoretical and practical strategies to achieve more comprehensive CRT referral and post-procedural care by focusing on four actionable domains: (i) overcoming CRT under-utilization, (ii) better understanding of pre-implant characteristics, (iii) abandoning the term 'non-response' and replacing this by the concept of disease modification, and (iv) implementing a dedicated post-implant CRT care pathway. Show less
Hebbrecht, K.; Stuivenga, M.; Birkenhager, T.; Mast, R.C. van der; Sabbe, B.; Giltay, E.J. 2020
Background:Although differences in symptom profiles and outcome between depressive patients with an underlying major depressive disorder (MDD) and bipolar depression (BD) have been reported,... Show moreBackground:Although differences in symptom profiles and outcome between depressive patients with an underlying major depressive disorder (MDD) and bipolar depression (BD) have been reported, studies with sequential short-interval assessments in a real-life inpatient setting are scarce.Objectives:To examine potential differences in symptom profile and course of depressive symptomatology in depressive inpatients with underlying MDD and BD.Methods:A cohort of 276 consecutive inpatients with MDD (n= 224) or BD (n= 52) was followed during their hospitalization using routine outcome monitoring (ROM), which included a structured diagnostic interview at baseline (Mini-International Neuropsychiatric Interview Plus [MINI-Plus]) and repeated 17-item Hamilton Depression Rating Scale every 2 weeks. MDD and BD were compared regarding their symptom profiles and time to response and remission. Furthermore, the concordance between the MINI-Plus and clinical diagnosis was analyzed.Results:Patients were on average 52 and 47 years old in the MDD and BD group, respectively, and 66 versus 64% were female. Compared to patients with BD, patients with MDD scored higher on weight loss (p= 0.02), whereas the BD group showed a higher long-term likelihood of response (hazard ratio = 1.93, 95% confidence interval 1.16-3.20,pfor interaction with time = 0.04). Although the same association was seen for remission, the interaction with time was not significant (p= 0.48). Efficiency between the MINI-Plus and clinical diagnosis of BD was high (0.90), suggesting that the MINI-Plus is an adequate ROM diagnostic tool.Conclusions:In routine clinical inpatient care, minor differences in the symptom profile and the course of depressive symptomatology may be helpful in distinguishing MDD and BD, particularly when using sequential ROM assessments. Show less
In the latest twenty years we have witnessed an exponential proliferation of international commissions of inquiry mandated to investigate serious violations of international law. However, the... Show moreIn the latest twenty years we have witnessed an exponential proliferation of international commissions of inquiry mandated to investigate serious violations of international law. However, the inquiry tool has been originally institutionalised at the beginning of the 20th century as mean of preventive diplomacy aimed at stating the facts for dispute settlement purposes. Since then inquiries have significantly evolved into mechanisms that denounce and shed light on serious violations of international law in order to provoke a response by the international community. What are the underlying causes of this new role and of the recent surge of inquiry commissions? Should commissions of inquiry be viewed as merely fact-finders or as law-applicable/adjudication bodies? Should their tasks be confined to finding the facts or may they perform more dynamic and political roles such as raising alert and provoking reactions? What (arguably) should be the role of commissions of inquiry in the criminal accountability process? These and other questions are the core of this academic contribution which, through a comprehensive analysis of the work and practice of commissions of inquiry, aims to shed more light on a topic that has increasingly become the focus of intense debate among academics, practitioners and international decision-makers. Show less
Garderet, L.; D'Souza, A.; Jacobs, P.; Biezen, A. van; Schonland, S.; Kroeger, N.; ... ; Hari, P. 2017
This thesis studies Venetian painting in its golden age, the sixteenth century, from an unconventional, anthropological point of view. Paintings of masters like Titian are demonstrated to have... Show moreThis thesis studies Venetian painting in its golden age, the sixteenth century, from an unconventional, anthropological point of view. Paintings of masters like Titian are demonstrated to have had social lives. Together with human beings they were embedded in social networks in which humans and paintings interacted; this happened to such an extent that paintings indeed became person-like. These interactions could take many forms; examples that are analysed include the miraculous image that is believed to supernaturally heal the faithful; images that suffer from violence (iconoclasm); and the veneration of female portraits that became substitutes for their absent sitters. Making use of a wide variety of sources, such as chronicles, letters, poetry, treatises, and legal documents, this study argues that the remarkable agency of these paintings was the result of a highly complex interplay of forces; religious, political, social, cultural and artistic factors all carried weight. One of its major conclusions is that the role of the artist, the one who physically produced the work, was relatively unimportant for the way these paintings functioned. Using a framework that is both anthropologically and historically informed, this thesis offers a new model for the study of pre-modern European art that is less biased by conceptions of art in the modern West. Show less
This thesis concerns the vibrational properties of different classical disordered condensed matter systems. In the first part we focus on materials that exhibit a rigidity transition as their... Show moreThis thesis concerns the vibrational properties of different classical disordered condensed matter systems. In the first part we focus on materials that exhibit a rigidity transition as their density is increased. By introducing a new method into the field, we were able to look into the localization behavior of vibrational modes of jammed packings of soft spherical particles, both in the localized regime where the localization length is much less and in the regime where it is grater than the linear system size. We also analyze the nature of vibrational modes of jammed packings of soft elliptical particles, where we uncover the change of the structure of the spectrum, compared to the simplest model of sphere packings, due to the rotational degrees of freedom of the particles. In the second part of this thesis we explore the localization properties of collective modes and response to uniform driving of bubble clouds. We find that the response is often very different from that of a typical mode because the frequency response of each mode is sufficiently wide that many modes are excited when the cloud is driven by an ultrasound. Show less
