Purpose The aim of this study was to evaluate whether the addition of brain CT imaging data to a model incorporating clinical risk factors improves prediction of ischemic stroke recurrence over 5... Show morePurpose The aim of this study was to evaluate whether the addition of brain CT imaging data to a model incorporating clinical risk factors improves prediction of ischemic stroke recurrence over 5 years of follow-up. Methods A total of 638 patients with ischemic stroke from three centers were selected from the Dutch acute stroke study (DUST). CT-derived candidate predictors included findings on non-contrast CT, CT perfusion, and CT angiography. Five-year follow-up data were extracted from medical records. We developed a multivariable Cox regression model containing clinical predictors and an extended model including CT-derived predictors by applying backward elimination. We calculated net reclassification improvement and integrated discrimination improvement indices. Discrimination was evaluated with the optimism-corrected c-statistic and calibration with a calibration plot. Results During 5 years of follow-up, 56 patients (9%) had a recurrence. The c-statistic of the clinical model, which contained male sex, history of hyperlipidemia, and history of stroke or transient ischemic attack, was 0.61. Compared with the clinical model, the extended model, which contained previous cerebral infarcts on non-contrast CT and Alberta Stroke Program Early CT score greater than 7 on mean transit time maps derived from CT perfusion, had higher discriminative performance (c-statistic 0.65,P= 0.01). Inclusion of these CT variables led to a significant improvement in reclassification measures, by using the net reclassification improvement and integrated discrimination improvement indices. Conclusion Data from CT imaging significantly improved the discriminatory performance and reclassification in predicting ischemic stroke recurrence beyond a model incorporating clinical risk factors only. Show less
This thesis comprises immunophenotypic and molecular studies in several types of cutaneous lymphomas. These studies provide a better definition of the clinicopathologic entities and provide... Show moreThis thesis comprises immunophenotypic and molecular studies in several types of cutaneous lymphomas. These studies provide a better definition of the clinicopathologic entities and provide adjunctive diagnostic markers that may aid in diagnosis of these patients in routine diagnostics, including TOX expression in cutaneous T-cell lymphomas and MYC expression and MYC rearrangements in cutaneous B-cell lymphomas (CBCLs). Also, the results demonstrate that adverse prognostic factors in systemic lymphomas are not directly transferrable to cutaneous lymphoma patients, including TP63 rearrangements in primary cutaneous CD30+ lymphoproliferative disorders and double hit status in CBCL, underlining the importance of a separate classification system for cutaneous lymphomas. Finally, these studies may have consequences for the management and treatment of patients with cutaneous lymphomas, because of the identification of recurrent molecular alterations that could provide attractive targets for novel therapeutics, including MYD88 and CD79B mutations in patients with intravascular large B-cell lymphomas. Show less
Background and objectives The histopathologic classification for ANCA-associated GN distinguishes four classes on the basis of patterns of injury. In the original validation study, these classes... Show moreBackground and objectives The histopathologic classification for ANCA-associated GN distinguishes four classes on the basis of patterns of injury. In the original validation study, these classes were ordered by severity of kidney function loss as follows: focal, crescentic, mixed, and sclerotic. Subsequent validation studies disagreed on outcomes in the crescentic and mixed classes. This study, driven by the original investigators, provides several analyses in order to determine the current position of the histopathologic classification of ANCA-associated GN.Design, setting, participants, & measurements Avalidation study was performed with newly collected data from 145 patients from ten centers worldwide, including an analysis of interobserver agreement on the histopathologic evaluation of the kidney biopsies. This study also included a meta-analysis on previous validation studies and a validation of the recently proposed ANCA kidney risk score.Results The validation study showed that kidney failure at 10-year follow-up was significantly different between the histopathologic classes (P < 0.001). Kidney failure at 10-year follow-up was 14% in the crescentic class versus 20% in the mixed class (P=0.98). In themeta-analysis, no significant difference in kidney failure was also observed when crescentic class was compared with mixed class (relative risk, 1.15; 95% confidence interval, 0.94 to 1.41). When we applied the ANCA kidney risk score to our cohort, kidney survival at 3 years was 100%, 96%, and 77% in the low-, medium-, andhigh-risk groups, respectively (P<0.001). These survival percentages are higher compared with the percentages in the original study.Conclusions The crescentic and mixed classes seem to have a similar prognosis, also after adjusting for differences in patient populations, treatment, and interobserver agreement. However, at this stage, we are not inclined to merge the crescentic and mixed classes because the reported confidence intervals do not exclude important differences in prognosis and because an important histopathologic distinction would be lost. Show less
Abou, R.; Goedemans, L.; Bijl, P. van der; Fortuni, F.; Prihadi, E.A.; Mertens, B.; ... ; Delgado, V. 2020
Background: Left ventricular (LV) mechanical dispersion (LVMD), measured with speckle-tracking echocardiography (STE) after ST-segment elevationmyocardial infarction (STEMI), has been proposed as a... Show moreBackground: Left ventricular (LV) mechanical dispersion (LVMD), measured with speckle-tracking echocardiography (STE) after ST-segment elevationmyocardial infarction (STEMI), has been proposed as a measurement of regional heterogeneity of myocardial contraction and may reflect changes in the myocardial structure (e.g., fibrosis or edema). Further insight into this parameter may aid in the risk stratification of STEMI patients.Methods: A total of 1,000 STEMI patients (77% male, 60 +/- 12 years) treated with primary percutaneous coronary intervention were retrospectively analyzed. The LVMD was assessed with two-dimensional STE within 48 hours following the index infarction. Patients were followed for the occurrence of all-cause mortality.Results: After a median follow-up of 117 months, 229 (23%) patients died. Nonsurvivors showed worse LV ejection fraction (43% +/- 10% vs 48% +/- 9%; P <.001) and global longitudinal strain (-12.0% +/- 3.5% vs -14.2% +/- 3.5%; P =.001) and prolonged LVMD (63 [interquartile range, 50-85] msec vs 52 [interquartile range, 42-63] msec; P <.001) compared with survivors. Increasing age, systolic blood pressure, and heart rate at discharge as well as diabetes mellitus, anterior STEMI, TIMI flow < 2, less usage of angiotensin converter enzyme inhibitors or angiotensin receptor blockers, and impaired LV global longitudinal strain were independently associated with more prolonged LVMD. On multivariable analysis, prolonged LVMD was independently associated with increased risk of all-cause mortality (hazard ratio = 1.012; 95% CI, 1.005-1.018; P =.001) and had incremental value for all-cause mortality over clinical and echocardiographic parameters.Conclusions: In contemporary STEMI patients, prolonged LVMD was associated with various clinical and echocardiographic parameters. Prolonged LVMD was associated with worse long-term outcome. Show less
Mes, S.W.; Velden, F.H.P. van; Peltenburg, B.; Peeters, C.F.W.; Beest, D.E. te; Wiel, M.A. van de; ... ; Graaf, P. de 2020
Objectives Head and neck squamous cell carcinoma (HNSCC) shows a remarkable heterogeneity between tumors, which may be captured by a variety of quantitative features extracted from diagnostic... Show moreObjectives Head and neck squamous cell carcinoma (HNSCC) shows a remarkable heterogeneity between tumors, which may be captured by a variety of quantitative features extracted from diagnostic images, termed radiomics. The aim of this study was to develop and validate MRI-based radiomic prognostic models in oral and oropharyngeal cancer. Materials and Methods Native T1-weighted images of four independent, retrospective (2005-2013), patient cohorts (n = 102, n = 76, n = 89, and n = 56) were used to delineate primary tumors, and to extract 545 quantitative features from. Subsequently, redundancy filtering and factor analysis were performed to handle collinearity in the data. Next, radiomic prognostic models were trained and validated to predict overall survival (OS) and relapse-free survival (RFS). Radiomic features were compared to and combined with prognostic models based on standard clinical parameters. Performance was assessed by integrated area under the curve (iAUC). Results In oral cancer, the radiomic model showed an iAUC of 0.69 (OS) and 0.70 (RFS) in the validation cohort, whereas the iAUC in the oropharyngeal cancer validation cohort was 0.71 (OS) and 0.74 (RFS). By integration of radiomic and clinical variables, the most accurate models were defined (iAUC oral cavity, 0.72 (OS) and 0.74 (RFS); iAUC oropharynx, 0.81 (OS) and 0.78 (RFS)), and these combined models outperformed prognostic models based on standard clinical variables only (p < 0.001). Conclusions MRI radiomics is feasible in HNSCC despite the known variability in MRI vendors and acquisition protocols, and radiomic features added information to prognostic models based on clinical parameters. Show less
Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury.Study Design and Setting: We... Show moreObjective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury.Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale <13, n = 1,554). Both calibration (calibration slope/intercept) and discrimination (area under the curve) was quantified.Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study.Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations. (C) 2020 The Authors. Published by Elsevier Inc. Show less
Munter, L. de; Polinder, S.; Haagsma, J.A.; Kruithof, N.; Ree, C.L.P. van de; Steyerberg, E.W.; Jongh, M. de 2020
Objective: To describe the prevalence and prognostic factors of symptoms of anxiety and depression and posttraumatic stress symptoms (PTSS) after injury in the clinical trauma population.Design:... Show moreObjective: To describe the prevalence and prognostic factors of symptoms of anxiety and depression and posttraumatic stress symptoms (PTSS) after injury in the clinical trauma population.Design: Multicenter, prospective, observational cohort study.Setting: Ten hospitals in Noord-Brabant, The Netherlands.Participants: Four thousand two hundred thirty-nine adult patients (N=4239) admitted due to injury between August 2015 and December 2016.Interventions: Patients were asked to complete a questionnaire at 1 week and at 1, 3, 6, and 12 months after injury.Main Outcome Measures: The Hospital Anxiety and Depression Scale was used to assess anxiety and depressive symptoms and the Impact of Event Scale was used to assess PTSS.Results: The prevalence of symptoms of anxiety and depression decreased from 10% and 12%, respectively, at 1 week after injury to 7% and 7% at 12 months after injury. Acute traumatic stress symptoms were present in 13% at 1 week and PTSS was prevalent in 10% of the participants at 12 months after injury. Strong prognostic factors for poor psychological outcome in multivariable logistic mixed models were preinjury frailty, psychological complaints and nonworking status preinjury, female sex, low educational level, and accident category (ie, traffic accident, work-related accident, or accidents at home compared to sport injuries).Conclusions: Psychological distress is a common health problem during the first year after injury. Important prognostic factors for psychological distress include psychological complaints before injury and frailty. Early recognition of psychological problems after injury could facilitate discussion between caregivers and patients and improve recovery. (C) 2019 by the American Congress of Rehabilitation Medicine Show less
Bijl, P. van der; Abou, R.; Goedemans, L.; Gersh, B.J.; Holmes, D.R.; Marsan, N.A.; ... ; Bax, J.J. 2020
Aims Left ventricular (LV) remodelling after ST-segment elevation myocardial infarction (STEMI) worsens outcome. The effect of sex on LV post-infarct remodelling is unknown. We therefore... Show moreAims Left ventricular (LV) remodelling after ST-segment elevation myocardial infarction (STEMI) worsens outcome. The effect of sex on LV post-infarct remodelling is unknown. We therefore investigated the sex distribution and long-term prognosis of LV post-infarct remodelling after STEMI in the contemporary era of primary percutaneous coronary intervention (PCI) and optimal pharmacotherapy.Methods and results Data were obtained from an ongoing primary PCI STEMI registry. LV remodelling was defined as >= 20% increase in LV end-diastolic volume at either 3, 6, or 12 months post-infarct, and LV remodelling impact on outcome was evaluated with a log-rank test. A total population of 1995 STEMI patients were analysed (mean age 60 +/- 12 years): 1527 (77%) men and 468 (23%) women. The mean age of male patients was 60 +/- 11 versus 63 +/- 13 years for women (P < 0.001). A total of 953 (48%) patients experienced LV remodelling in the first 12 months of follow-up, and it was equally frequent amongst men (n = 729, 48%) and women (n = 224, 48%). After a median follow-up of 94 (interquartile range 69-119) months, 225 patients died: 171 (11%) men and 54 (12%) women. No survival difference was seen between remodellers and non-remodellers in the male (P = 0.113) and female (P = 0.920) groups.Conclusion LV post-infarct remodelling incidence, as well as long-term survival of LV remodellers and non-remodellers, was similar in men and women who were treated with primary PCI and optimal pharmacotherapy post-STEMI. Show less
Purpose The tumour microenvironment in older patients is subject to changes. The tumour-stroma ratio (TSR) was evaluated in order to estimate the amount of intra-tumoural stroma and to evaluate the... Show morePurpose The tumour microenvironment in older patients is subject to changes. The tumour-stroma ratio (TSR) was evaluated in order to estimate the amount of intra-tumoural stroma and to evaluate the prognostic value of the TSR in older patients with breast cancer (>= 70 years). Methods Two retrospective cohorts, the FOCUS study (N = 619) and the Nottingham Breast Cancer series (N = 1793), were used for assessment of the TSR on haematoxylin and eosin stained tissue slides. Results The intra-tumoural stroma increases with age in the FOCUS study and the Nottingham Breast Cancer series (B 0.031, 95% CI 0.006-0.057, p = 0.016 and B 0.034, 95% CI 0.015-0.054, p < 0.001, respectively). Fifty-one per cent of the patients from the Nottingham Breast Cancer series < 40 years had a stroma-high tumour compared to 73% of the patients of >= 90 years from the FOCUS study. The TSR did not validate as an independent prognostic parameter in patients >= 70 years. Conclusions The intra-tumoural stroma increases with age. This might be the result of an activated tumour microenvironment. The TSR did not validate as an independent prognostic parameter in patients >= 70 years in contrast to young women with breast cancer as published previously. Show less
Introduction: Optimized treatment of primary rectal cancer might have influenced treatment characteristics and outcome of locally recurrent rectal cancer (LRRC). Subgroup analysis of the Dutch TME... Show moreIntroduction: Optimized treatment of primary rectal cancer might have influenced treatment characteristics and outcome of locally recurrent rectal cancer (LRRC). Subgroup analysis of the Dutch TME trial showed that preoperative radiotherapy (PRT) for the primary tumour was an independent poor prognostic factor after diagnosis of LRRC. This cross-sectional population study aimed to evaluate treatment and overall survival (OS) of LRRC patients, stratified for prior preoperative radiotherapy (PRT) and intention of treatment of LRRC.Methods: All patients developing LRRC were selected from a collaborative Snapshot study on 2095 surgically treated rectal cancer patients from 71 Dutch hospitals in the year 2011. Cox proportional hazard analysis was performed to determine predictors for OS.Results: A total of 107 LRRC patients (5.1%) were included, of whom 88 (82%) underwent PRT for their primary tumour. LRRC was treated with initial curative intent in 31 patients (29%), with eventual resection in 20 patients (19%). Median OS was 22 and 8 months after curative and palliative intent treatment, respectively (p < 0.001). Initial CRM positivity and palliative intent treatment were associated with worse OS after LRRC, while prior PRT was not.Conclusions: This cross-sectional study revealed that rectal cancer patients, who underwent curative resection in the Netherlands in 2011 and subsequently developed local recurrence, were amenable for again curative intent treatment in 29%, with a corresponding median survival of 22 months. Prior PRT was not significantly associated with survival after diagnosis of LRRC. (C) 2019 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Show less
Wynants, L.; Smeden, M. van; McLernon, D.J.; Timmerman, D.; Steyerberg, E.W.; Calster, B. van; Topic Grp Evaluating Diagnosti 2019
Background: Right ventricular (RV) systolic function in patients admitted with ST-segment elevation myocardial infarction (STEMI) with chronic obstructive pulmonary disease (COPD) and its impact on... Show moreBackground: Right ventricular (RV) systolic function in patients admitted with ST-segment elevation myocardial infarction (STEMI) with chronic obstructive pulmonary disease (COPD) and its impact on prognosis have not been characterized. The present study aims to compare the prevalence of RV systolic dysfunction in COPD versus non-COPD patients with STEMI and evaluate the prognostic implications.Methods: One hundred seventeen STEMI patients with COPD with transthoracic echocardiography performed within 48 hours of admission were retrospectively selected. Matched on age, gender, and infarct size (determined by cardiac biomarkers and left ventricular ejection fraction [LVEF]), 207 non-COPD patients were selected. RV dysfunction was defined based on tricuspid annular plane systolic excursion <17 mm (TAPSE), tricuspid annular systolic velocity <6 cm/s (S'), RV fractional area change <35% (FAC), and RV longitudinal free wall strain (FWSL) measured with speckle-tracking echocardiography >-20%. Patients were followed for the occurrence of all-cause mortality.Results: RV assessment was feasible in 112 COPD and 199 non-COPD patients (mean age, 69 +/- 10; 74% male; mean, LVEF 47% +/- 8%). Patients with COPD had significantly lower RV FAC (38% +/- 11% vs 40% +/- 9%; P = .04), equal TAPSE and S' (17.9 +/- 3.7 vs 18.1 +/- 3.8 mm, P = .72; and 8.4 +/- 2.2 vs 8.5 +/- 2.2 cm/sec, P = .605, respectively) and more impaired RV FWSL (-21.1% +/- 6.6% vs -23.4% +/- 6.5%, P = .005), compared with patients without COPD. RV dysfunction was more prevalent in patients with COPD, particularly when assessed with RV FWSL (46% vs 32%; P = .021). During a median followup of 30 (interquartile range 1.5-44) months, 49 patients died (16%). Multivariate models stratified for COPD status showed that RV FWS >-20% was independently associated with 5-year all-cause mortality (hazard ratio, 2.05; 95% CI, 1.12-3.76; P = .020), after adjusting for age, diabetes, peak troponin level, and LVEF. Interestingly, RV FAC < 35%, S'< 6 cm/sec, and TAPSE < 17 mm were not independently associated with survival.Conclusion: In a STEMI population with relatively preserved LVEF, COPD patients had significantly worse RV FWSL compared with patients without COPD. Moreover, RV FWSL > -20% was independently associated with worse survival. In contrast, conventional parameters were not associated with survival. Show less
Objective. There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS)... Show moreObjective. There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT.Methods. We established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS).Results. 877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5-65) and 28 months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0.55 (95% CI, 0.45-0.66; P < 0.001) and 0.65 (95% CI 0.50-0.85, P = 0.002) respectively; no heterogeneity was identified (PFS: Q = 6.42, P = 0.698, I2 = 0.0%; OS: Q = 6.89, P = 0 648, I2 = 0.0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0.027).Conclusions. CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design. (C) 2019 The Authors. Published by Elsevier Inc. Show less
Ventricular-arterial coupling (VAC) plays a major role in the physiology of cardiac and aortic mechanics, as well as in the pathophysiology of cardiac disease. VAC assessment possesses independent... Show moreVentricular-arterial coupling (VAC) plays a major role in the physiology of cardiac and aortic mechanics, as well as in the pathophysiology of cardiac disease. VAC assessment possesses independent diagnostic and prognostic value and may be used to refine riskstratification and monitor therapeutic interventions. Traditionally, VAC is assessed by the non-invasive measurement of the ratio of arterial (Ea) to ventricular end-systolic elastance (Ees). With disease progression, both Ea and Ees may become abnormal and the Ea/Ees ratio may approximate its normal values. Therefore, the measurement of each component of this ratio or of novel more sensitive markers of myocardial (e.g. global longitudinal strain) and arterial function (e.g. pulse wave velocity) may better characterize VAC. In valvular heart disease, systemic arterial compliance and valvulo-arterial impedance have an established diagnostic and prognostic value and may monitor the effects of valve replacement on vascular and cardiac function. Treatment guided to improve VAC through improvement of both or each one of its components may delay incidence of heart failure and possibly improve prognosis in heart failure. In this consensus document, we describe the pathophysiology, the methods of assessment as well as the clinical implications of VAC in cardiac diseases and heart failure. Finally, we focus on interventions that may improve VAC and thus modify prognosis. Show less
Fernandez, J.; Prado, V.; Trebicka, J.; Amoros, A.; Gustot, T.; Wiest, R.; ... ; European Fdn Study Chronic Liver 2019
