Practice of neuroendocrine neoplasms (NENs) of the digestive tract, which comprise a highly diverse group of tumors with a rising incidence, faces multiple biological, diagnostic, and therapeutic... Show morePractice of neuroendocrine neoplasms (NENs) of the digestive tract, which comprise a highly diverse group of tumors with a rising incidence, faces multiple biological, diagnostic, and therapeutic issues. Part of these issues are due to misuse and misinterpretation of the classification and terminology of NENs of the digestive tract, which make it increasingly challenging to evaluate and compare literature. For instance, grade 3 neuroendocrine tumors (NETs) are frequently referred to as neuroendocrine carcinomas (NECs) and vice versa, while NECs are by definition high grade and therefore constitute a separate entity from NETs. Moreover, the term NETs is regularly misused to describe NENs in general, and NETs are frequently referred to as benign, while they should always be considered malignancies as they do have metastatic potential. To prevent misconceptions in future NEN-related research, we reviewed the most recent terminology used to classify NENs of the digestive tract and created an overview that combines the classification of these NENs according to the World Health Organization (WHO) with location- and functionality-based classifications. This overview may help clinicians and researchers in understanding current literature and could serve as a guide in the clinic as well as for writing future studies on NENs of the digestive tract. In this way, we aim for the universal use of terminology, thereby providing an efficient foundation for future NEN-related research. Show less
Arend, B.W.H. van der; Verhagen, I.E.; Leeuwen, M. van; Arend, M.Q.T.P. van der; Casteren, D.S. van; Terwindt, G.M. 2023
BackgroundThere is a need for standardization of the definition of a migraine day for clinical and research purposes. MethodsWe prospectively compared different definitions of a migraine day with E... Show moreBackgroundThere is a need for standardization of the definition of a migraine day for clinical and research purposes. MethodsWe prospectively compared different definitions of a migraine day with E-diary data of n = 1494 patients with migraine. We used a baseline definition based on migraine characteristics with a duration of >= 4 hours OR triptan intake (independently from its effect) OR (visual) aura lasting 5-60 minutes. ResultsOf all migraine days defined by triptan intake only, 66.2% had a duration <4 hours. Adjusting the headache duration criterion to >= 30 minutes led to a decrease in days defined by triptan intake only and resulted in a 5.4% increase in total migraine days (equals 0.45 migraine day increase in monthly migraine days). These additional migraine days had a median duration of 2.5 hours. ConclusionWe propose to define a migraine day as follows: 1) (a) headache duration >= 30 minutes; (b) matching >= 2 of four characteristics: unilateral, pulsating, moderate to severe pain, aggravation by or causing avoidance of routine physical activity; and (c) during headache >= 1 of the following: nausea and/or vomiting, photophobia and phonophobia or 2) (visual) aura duration 5-60 minutes or 3) a day with headache for which acute migraine-specific medication is used irrespective of its effect. Show less
Pulmonary embolism is a serious and potentially life-threatening disease in the acute phase, and may also have a major impact on a patient’s daily life in the long run. The overall aim of this... Show morePulmonary embolism is a serious and potentially life-threatening disease in the acute phase, and may also have a major impact on a patient’s daily life in the long run. The overall aim of this thesis was evaluating important aspects of the post-pulmonary embolism syndrome with an emphasis on early diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) and the associated consequence for patients’ prognosis. Show less
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory loss and declined cognitive functioning. Brain changes in AD involve grey matter atrophy and changes in brain... Show moreAlzheimer’s disease (AD) is a neurodegenerative disease characterized by memory loss and declined cognitive functioning. Brain changes in AD involve grey matter atrophy and changes in brain function. These different brain characteristics can respectively be visualized with structural and functional MRI scans. These MRI modalities have been used for AD classification, but studies typically only include a limited number of features. In this thesis we derived multiple types of features from each MRI modality, and combined those to discriminate AD patients and elderly controls. First, we showed that AD classification accuracy increases when combining multiple types of measures from a single MRI modality. This was shown for structural MRI scans in chapter 2, and for resting state fMRI scans in chapter 3. In chapter 4 we evaluated whether MRI based AD classification models can discriminate AD in a diverse clinical population as well. This worked to some extent, and it worked best using structural MRI scans. In chapter 5 we used baseline multimodal MRI scans from the same diverse clinical population to predict two-year follow-up cognitive decline. Decline was predicted above chance level for the MMSE, but not for six other neuropsychological tests. Show less
Rutgers, J.J.; Banki, T.; Kamp, A. van der; Waterlander, T.J.; Scheijde-Vermeulen, M.A.; Heuvel-Eibrink, M.M. van den; ... ; Krijger, R.R. de 2021
Background Histopathological classification of Wilms tumors determines treatment regimen. Machine learning has been shown to contribute to histopathological classification in various malignancies... Show moreBackground Histopathological classification of Wilms tumors determines treatment regimen. Machine learning has been shown to contribute to histopathological classification in various malignancies but requires large numbers of manually annotated images and thus specific pathological knowledge. This study aimed to assess whether trained, inexperienced observers could contribute to reliable annotation of Wilms tumor components for classification performed by machine learning. Methods Four inexperienced observers (medical students) were trained in histopathology of normal kidneys and Wilms tumors by an experienced observer (pediatric pathologist). Twenty randomly selected scanned Wilms tumor-slides (from n = 1472 slides) were annotated, and annotations were independently classified by both the inexperienced observers and two experienced pediatric pathologists. Agreement between the six observers and for each tissue element was measured using kappa statistics (kappa). Results Pairwise interobserver agreement between all inexperienced and experienced observers was high (range: 0.845-0.950). The interobserver variability for the different histological elements, including all vital tumor components and therapy-related effects, showed high values for all kappa-coefficients (> 0.827). Conclusions Inexperienced observers can be trained to recognize specific histopathological tumor and tissue elements with high interobserver agreement with experienced observers. Nevertheless, supervision by experienced pathologists remains necessary. Results of this study can be used to facilitate more rapid progress for supervised machine learning-based algorithm development in pediatric pathology and beyond. Show less
Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease characterised by the progressive degeneration of the frontal and temporal lobes, which results in behavioural (behavioural... Show moreFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease characterised by the progressive degeneration of the frontal and temporal lobes, which results in behavioural (behavioural variant FTD) and language (primary progressive aphasia) disorders. No effective therapies currently exist to cure FTD or slow disease progression. However, efforts are being made to develop disease modifying treatments, which aim to reverse or inhibit pathological processes leading up to neuronal cell death. Therefore, the ability to diagnose FTD before brain atrophy (i.e., irreversible brain damage) is crucial. Approximately 10–30% of all FTD patients have a familial form, often caused by mutations in the genes MAPT, GRN or a repeat expansion in the gene C9orf72. These families offer the unique opportunity to study mutation carriers in the presymptomatic stage, where early pathological changes may already occur, but subjects are cognitively healthy. In this dissertation, we used multimodal MRI and machine learning to investigate whether MRI biomarkers for FTD have diagnostic value on the single-subject level to detect FTD-related differences in the presymptomatic disease stage. Furthermore, we aimed to advance the combination of resting-state functional MRI data between scanners. Lastly, we studied potential biomarkers for the differentiation between early stages of FTD and Alzheimer’s disease. Show less
Purpose To describe the clinical characteristics and outcome of polypoidal choroidal vasculopathy (PCV), also known as aneurysmal type 1 (sub-retinal pigment epithelium (RPE)) neovascularization,... Show morePurpose To describe the clinical characteristics and outcome of polypoidal choroidal vasculopathy (PCV), also known as aneurysmal type 1 (sub-retinal pigment epithelium (RPE)) neovascularization, in Caucasian patients. Methods Single-centre study in 66 Caucasian patients with a diagnosis of PCV based on optical coherence tomography scan and indocyanine green angiography. Clinical characteristics and multimodal imaging were collected and assessed by an experienced retina specialist. Results This study involved 74 eyes of 66 patients with PCV, with a mean age at onset of 73 years and a female preponderance of 66%. The mean number of polypoidal lesions per eye was 1 (range: 1-5 lesions), out of which 75% was located in the macula and 19% in the peripapillary region. Of the 74 eyes, 37 eyes (50%) had PCV associated with a drusenoidal neovascular age-related macular degeneration (AMD) phenotype (PCV-AMD) and 18 eyes (24%) had PCV associated with non-polypoidal type 1 choroidal neovascularization/branching vascular network (PCV-BVN) without signs of drusenoidal AMD, while 19 eyes (26%) had idiopathic, isolated PCV (iPCV). The mean subfoveal choroidal thickness measured in 22 patients was 245 mu m (range: 71-420 mu m). In 51% of patients, the initially performed therapy showed good anatomical recovery (resolution of intra- and subretinal fluid). Conclusions A spectrum of PCV (aneurysmal type 1/sub-RPE neovascularization) can be seen in Caucasian patients. PCV associated with a drusenoidal neovascular AMD phenotype in Caucasians is phenotypically and presumably pathophysiologically more associated with neovascular AMD (PCV-AMD: type A PCV). However, this may not be the case for patients with PCV with non-polypoidal type 1 choroidal neovascularization or BVN and no signs of drusenoidal AMD (PCV-BVN: type B PCV), and for patients with idiopathic PCV without associated drusen or BVN (iPCV; type C PCV). Most patients have a thin choroid, even when drusen are absent. For the entire patient group, a moderate anatomical recovery was observed after treatment. Show less
Introduction: We recently proposed a scale for assessment of patient-relevant functional limitations following an episode of venous thromboembolism (VTE). Further development of this post-VTE... Show moreIntroduction: We recently proposed a scale for assessment of patient-relevant functional limitations following an episode of venous thromboembolism (VTE). Further development of this post-VTE functional status (PVFS) scale is still needed.Methods: Guided by the input of VTE experts and patients, we refined the PVFS scale and its accompanying manual, and attempted to acquire broad consensus on its use.Results: A Delphi analysis was performed involving 53 international VTE experts with diverse scientific and clinical backgrounds. In this process, the number of scale grades of the originally proposed PVFS scale was reduced and descriptions of the grades were improved. After these changes, a consensus was reached on the number/definitions of the grades, and method/timing of the scale assessment. The relevance and potential impact of the scale was confirmed in three focus groups totaling 18 VTE patients, who suggested additional changes to the manual, but not to the scale itself. Using the improved manual, the.-statistics between PVFS scale self-reporting and its assessment via the structured interview was 0.75 (95%CI 0.58-1.0), and 1.0 (95%CI 0.83-1.0) between independent raters of the recorded interview of 16 focus groups members.Conclusion: We improved the PVFS scale and demonstrated broad consensus on its relevance, optimal grades, and methods of assessing among international VTE experts and patients. The interobserver agreement of scale grade assignment was shown to be good-to-excellent. The PVFS scale may become an important outcome measure of functional impairment for quality of patient care and in future VTE trials. Show less
Nicholson, A.G.; Sauter, J.L.; Nowak, A.K.; Kindler, H.L.; Gill, R.R.; Remy-Jardin, M.; ... ; Galateau-Salle, F. 2020
Introduction: Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where... Show moreIntroduction: Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes.Methods: A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification.Results: Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication; (2) subject to data accrual, malignant mesothelioma in situ could be an additional category; (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken; (4) favorable/unfavorable histologic characteristics should be routinely reported; (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 [BAP1], and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken; (6) other molecular data should be accrued as part of future trials; (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged; (8) ideally, at least three separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging; (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging; (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered; (11) all histologic subtypes should be considered potential candidates for chemotherapy; (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason; (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy; and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome.Conclusions: These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. Show less
Vos, F. de; Schouten, T.M.; Koini, M.; Bouts, M.J.R.J.; Feis, R.A.; Lechner, A.; ... ; Rombouts, S.A.R.B. 2020
Anatomical magnetic resonance imaging (MRI), diffusion MRI and resting state functional MRI (rs-fMRI) have been used for Alzheimer's disease (AD) classification. These scans are typically used to... Show moreAnatomical magnetic resonance imaging (MRI), diffusion MRI and resting state functional MRI (rs-fMRI) have been used for Alzheimer's disease (AD) classification. These scans are typically used to build models for discriminating AD patients from control subjects, but it is not clear if these models can also discriminate AD in diverse clinical populations as found in memory clinics.To study this, we trained MRI-based AD classification models on a single centre data set consisting of AD patients (N = 76) and controls (N = 173), and used these models to assign AD scores to subjective memory complainers (N = 67), mild cognitive impairment (MCI) patients (N = 61), and AD patients (N = 61) from a multi-centre memory clinic data set. The anatomical MRI scans were used to calculate grey matter density, subcortical volumes and cortical thickness, the diffusion MRI scans were used to calculate fractional anisotropy, mean, axial and radial diffusivity, and the rs-fMRI scans were used to calculate functional connectivity between resting state networks and amplitude of low frequency fluctuations. Within the multi-centre memory clinic data set we removed scan site differences prior to applying the models.For all models, on average, the AD patients were assigned the highest AD scores, followed by MCI patients, and later followed by SMC subjects. The anatomical MRI models performed best, and the best performing anatomical MRI measure was grey matter density, separating SMC subjects from MCI patients with an AUC of 0.69, MCI patients from AD patients with an AUC of 0.70, and SMC patients from AD patients with an AUC of 0.86. The diffusion MRI models did not generalise well to the memory clinic data, possibly because of large scan site differences. The functional connectivity model separated SMC subjects and MCI patients relatively good (AUC = 0.66). The multimodal MRI model did not improve upon the anatomical MRI model.In conclusion, we showed that the grey matter density model generalises best to memory clinic subjects. When also considering the fact that grey matter density generally performs well in AD classification studies, this feature is probably the best MRI-based feature for AD diagnosis in clinical practice. Show less
The main objectives of therapeutic trials in venous thromboembolism (VTE) are to prevent recurrent VTE, major bleeding and death. While these outcomes are indeed highly relevant, they are also rare... Show moreThe main objectives of therapeutic trials in venous thromboembolism (VTE) are to prevent recurrent VTE, major bleeding and death. While these outcomes are indeed highly relevant, they are also rare and do not fully capture the overall functional outcome of VTE patients. Importantly, functional limitations after VTE are prevalent after both deep vein thrombosis and pulmonary embolism occurring in up to 50% of patients. These post-VTE syndromes are associated with a decreased quality of life, higher risk of depressive disorders, unemployment and increased utilization of healthcare resources. Because of the major impact of functional limitations on individual patients and society as a whole, development of tools able to capture functional outcomes in clinical trials are urgently needed. We anticipate that a standardized post-VTE functional status scale will aid in demarcating effective and ineffective VTE therapies on functional outcomes in trials with appropriately powered sample sizes, as well as pave the road for value-based healthcare. The scale that we have in mind covers the entire spectrum of functional outcomes ranging from no symptoms to death. Moreover, it focuses on both limitations in usual activity as well as changes in lifestyle. The scale is not meant to replace current diagnostic or prognostic scores for post-VTE syndromes, but to be used as an outcome measure to evaluate the overall consequences of VTE on functional status. This review is a call for action to the VTE community to join forces and support further development of the proposed scale, a process of which we summarize the necessary steps. Show less
Our current mycosis fungoides (MF) and Sezary Syndrome (SS) staging system includes blood-classification from B0-B2 for patch/plaque/tumour or erythroderma based on manual Sezary counts but results... Show moreOur current mycosis fungoides (MF) and Sezary Syndrome (SS) staging system includes blood-classification from B0-B2 for patch/plaque/tumour or erythroderma based on manual Sezary counts but results from our EORTC survey confirm these are rarely performed in patch/plaque/tumour MF, and there is a trend towards using flow cytometry to measure blood-class. Accurately assigning blood-class effects overall stage and the 'global response' used to measure treatment responses in MF/SS and hence impacts management. The EORTC Cutaneous Lymphoma Task Force Committee have reviewed the literature and held a Workshop (June 2017) to agree a definition of blood-class according to flow cytometry.No large study comparing blood-class as defined by Sezary count with flow cytometry has been performed in MF/SS. The definition of blood-class by flow cytometry varies between publications. Low-level blood involvement occurs in patch/plaque/tumour much less than erythroderma (p < 0.001). The prognostic relevance of blood involvement (B1 or B2) in patch/plaque/tumour is not known. Studies have not shown a statistically worse difference in prognosis in erythrodermic MF patients with low-level blood involvement (IIIB) versus those without (IIIA), but Sezary patients who by definition have a leukaemic blood picture (staged IVA1 or higher) have a worse prognosis.For consistency flow, definition for blood-class must be an objective measurement. We propose absolute counts of either CD4thornCD7-or CD4+CD26- where B0<250/mu L, B1 = 250/mu l -<1000/mu L and B2 >= 1000/mu L plus a T-cell blood clone. Fluctuations between B0 and B1 should not be considered in the treatment response criteria until further prognostic information is known. (C) 2018 The Authors. Published by Elsevier Ltd. Show less
Vos, F. de; Koini, M.; Schouten, T.M.; Seiler, S.; Grond, J. van der; Lechner, A.; ... ; Rombouts, S.A.R.B. 2018
Carotid atherosclerosis, a disease in which plaque builds up inside the vessel wall, is a major cause of ischemic stroke. Traditionally, atherosclerosis risk stratification is heavily based on... Show moreCarotid atherosclerosis, a disease in which plaque builds up inside the vessel wall, is a major cause of ischemic stroke. Traditionally, atherosclerosis risk stratification is heavily based on the percentage of stenosis. However, a growing body of evidence suggests that luminal stenosis may not be the only cause of symptoms but the plaque composition may be more likely to impact the disease outcome. High-resolution vessel wall magnetic resonance imaging (VWMRI) is one of the most promising modalities for visualizing and evaluating carotid atherosclerotic plaque. The quantitative assessment of carotid atherosclerotic disease requires vessel wall segmentation and plaque classification, which is generally performed by manual delineations. However, manual contour tracing is labor-intensive, time-consuming and subject to inter-observer and inter-scan variability, which makes manual image analysis impractical for studies where large volume of data needs to be processed. Therefore, the main goal of this thesis is to: 1) develop approaches to automatically, robustly and reproducibly segment the carotid vessel wall and classify the atherosclerotic plaque from multi-spectral VWMRI; 2) validate the developed methods with reference standard; 3) extract the imaging biomarkers that can assist carotid artery disease evaluation. Show less
Boesveld, I.C.; Bruijnzeels, M.A.; Hitzert, M.; Hermus, M.A.A.; Pal-de Bruin, K.M. van der; Akker-van Marle, M.E. van den; ... ; Wiegers, T.A. 2017
