BackgroundIn patients clinically suspected of having pulmonary embolism (PE), physicians often rely on intuitive estimation (“gestalt”) of PE presence. Although shown to be predictive, gestalt is... Show moreBackgroundIn patients clinically suspected of having pulmonary embolism (PE), physicians often rely on intuitive estimation (“gestalt”) of PE presence. Although shown to be predictive, gestalt is criticized for its assumed variation across physicians and lack of standardization.ObjectivesTo assess the diagnostic accuracy of gestalt in the diagnosis of PE and gain insight into its possible variation.MethodsWe performed an individual patient data meta-analysis including patients suspected of having PE. The primary outcome was diagnostic accuracy of gestalt for the diagnosis of PE, quantified as risk ratio (RR) between gestalt and PE based on 2-stage random-effect log-binomial meta-analysis regression as well as gestalts’ sensitivity and specificity. The variability of these measures was explored across different health care settings, publication period, PE prevalence, patient subgroups (sex, heart failure, chronic lung disease, and items of the Wells score other than gestalt), and age.ResultsWe analyzed 20 770 patients suspected of having PE from 16 original studies. The prevalence of PE in patients with and without a positive gestalt was 28.8% vs 9.1%, respectively. The overall RR was 3.02 (95% CI, 2.35-3.87), and the overall sensitivity and specificity were 74% (95% CI, 68%-79%) and 61% (95% CI, 53%-68%), respectively. Although variation was observed across individual studies (I2, 90.63%), the diagnostic accuracy was consistent across all subgroups and health care settings.ConclusionA positive gestalt was associated with a 3-fold increased risk of PE in suspected patients. Although variation was observed across studies, the RR of gestalt was similar across prespecified subgroups and health care settings, exemplifying its diagnostic value for all patients suspected of having PE. Show less
AimsRisk stratification is used for decisions regarding need for imaging in patients with clinically suspected acute pulmonary embolism (PE). The aim was to develop a clinical prediction model that... Show moreAimsRisk stratification is used for decisions regarding need for imaging in patients with clinically suspected acute pulmonary embolism (PE). The aim was to develop a clinical prediction model that provides an individualized, accurate probability estimate for the presence of acute PE in patients with suspected disease based on readily available clinical items and D-dimer concentrations.Methods and resultsAn individual patient data meta-analysis was performed based on sixteen cross-sectional or prospective studies with data from 28 305 adult patients with clinically suspected PE from various clinical settings, including primary care, emergency care, hospitalized and nursing home patients. A multilevel logistic regression model was built and validated including ten a priori defined objective candidate predictors to predict objectively confirmed PE at baseline or venous thromboembolism (VTE) during follow-up of 30 to 90 days. Multiple imputation was used for missing data. Backward elimination was performed with a P-value <0.10. Discrimination (c-statistic with 95% confidence intervals [CI] and prediction intervals [PI]) and calibration (outcome:expected [O:E] ratio and calibration plot) were evaluated based on internal-external cross-validation. The accuracy of the model was subsequently compared with algorithms based on the Wells score and D-dimer testing. The final model included age (in years), sex, previous VTE, recent surgery or immobilization, haemoptysis, cancer, clinical signs of deep vein thrombosis, inpatient status, D-dimer (in µg/L), and an interaction term between age and D-dimer. The pooled c-statistic was 0.87 (95% CI, 0.85–0.89; 95% PI, 0.77–0.93) and overall calibration was very good (pooled O:E ratio, 0.99; 95% CI, 0.87–1.14; 95% PI, 0.55–1.79). The model slightly overestimated VTE probability in the lower range of estimated probabilities. Discrimination of the current model in the validation data sets was better than that of the Wells score combined with a D-dimer threshold based on age (c-statistic 0.73; 95% CI, 0.70–0.75) or structured clinical pretest probability (c-statistic 0.79; 95% CI, 0.76–0.81).ConclusionThe present model provides an absolute, individualized probability of PE presence in a broad population of patients with suspected PE, with very good discrimination and calibration. Its clinical utility needs to be evaluated in a prospective management or impact study. Show less
BackgroundChronic thromboembolic pulmonary hypertension (CTEPH) is considered a complication of pulmonary embolism (PE). However, signs of CTEPH may exist in patients with a first symptomatic PE... Show moreBackgroundChronic thromboembolic pulmonary hypertension (CTEPH) is considered a complication of pulmonary embolism (PE). However, signs of CTEPH may exist in patients with a first symptomatic PE.Research QuestionWhich radiologic findings on CT pulmonary angiography (CTPA) at the time of acute PE could indicate the presence of preexisting CTEPH?Study Design and MethodsThis study included unselected patients with acute PE who were prospectively followed up for 2 years with a structured visit schedule. Two expert radiologists independently assessed patients’ baseline CTPAs for preexisting CTEPH; in case of disagreement, a decision was reached by a 2:1 majority with a third expert radiologist. In addition, the radiologists checked for predefined individual parameters suggesting chronic PE and pulmonary hypertension.ResultsSigns of chronic PE or CTEPH at baseline were identified in 46 of 303 included patients (15%). Intravascular webs, arterial narrowing or retraction, dilated bronchial arteries, and right ventricular hypertrophy were the main drivers of the assessment. Five (1.7%) patients were diagnosed with CTEPH during follow-up. All four patients diagnosed with CTEPH early (83-108 days following acute PE) were found in enriched subgroups based on the experts’ overall assessment or fulfilling a minimum number of the predefined radiologic criteria at baseline. The specificity of preexisting CTEPH diagnosis and the level of radiologists’ agreement improved as the number of required criteria increased.InterpretationSearching for predefined radiologic parameters suggesting preexisting CTEPH at the time of acute PE diagnosis may allow for targeted follow-up strategies and risk-adapted CTEPH screening, thus facilitating earlier CTEPH diagnosis. Show less
Diagnosis of soil-transmitted helminth (STH) and schistosome infections relies largely on conventional microscopy which has limited sensitivity, requires highly trained personnel and is error-prone... Show moreDiagnosis of soil-transmitted helminth (STH) and schistosome infections relies largely on conventional microscopy which has limited sensitivity, requires highly trained personnel and is error-prone. Rapid advances in miniaturization of optical systems, sensors and proces-sors have enhanced research and development of digital and automated microscopes suitable for the detection of these diseases in resource-limited settings. While some studies have reported proof-of-principle results, others have evaluated the performance of working proto-types in field settings. The extensive commercialization of these innovative devices has, how-ever, not yet been achieved. This review provides an overview of recent publications (2010- 2022) on innovative field applicable optical devices which can be used for the diagnosis of STH and schistosome infections. Using an adapted technology readiness level (TRL) scale tak -ing into account the WHO target product profile (TPP) for these diseases, the developmental stages of the devices were ranked to determine the readiness for practical applications in field settings. From the reviewed 18 articles, 19 innovative optical devices were identified and ranked. Almost all of the devices (85%) were ranked with a TRL score below 8 indicating that, most of the devices are not ready for commercialization and field use. The potential lim-itations of these innovative devices were discussed. We believe that the outcome of this review can guide the end-to-end development of automated digital microscopes aligned with the WHO TPP for the diagnosis of STH and schistosome infections in resource-limited settings. Show less
Zande, R.L. van der; Koster, E.S.; Grol, M.; Naber, K.G.; Alidjanov, J.F.; Teichert, M.; Bouvy, M.L. 2022
Aim:This study aimed to provide insight into the congruity of acute cystitis (AC) diagnosis in women, measured both by the Acute Cystitis Symptom Score (ACSS) questionnaire and urine test(s).... Show moreAim:This study aimed to provide insight into the congruity of acute cystitis (AC) diagnosis in women, measured both by the Acute Cystitis Symptom Score (ACSS) questionnaire and urine test(s). Background:The ACSS questionnaire was developed as a self-administering tool for assessing urinary symptoms, quality of life (QoL) and treatment outcomes in healthy, nonpregnant female patients. Methods:This prospective observational cohort study compared AC diagnosis based on the questionnaire with a GP diagnosis based on dipstick/dipslide test(s). ACSS questionnaire form A (typical and differential symptoms, QoL and relevant conditions) was filled in by the patient group, women suspected for AC visiting a GP practice with a urine sample, and the reference group, women visiting a community pharmacy for any medication. Analyses were performed assuming that the GP diagnosis based on urine test(s) was correct. Divergent result(s) of urine test(s) and ACSS questionnaire were analysed for scores of all individual questionnaire domains. Statistical analyses included descriptive statistics and the positive predictive value (PPV) and the negative predictive value (NPV) of the ACSS questionnaire and the urine test(s). Findings:In the patient group, 59 women were included, 38 of whom a GP positively diagnosed for AC. The reference group included 70 women. The PPV of the ACSS questionnaire was 77.3%, and the NPV was 73.3%. Analysis of patient data for divergent results showed that differential symptoms, QoL and relevant conditions explained false-positive and false-negative results. Revised results (most probable diagnosis) based on this analysis showed a PPV and NPV of 88.6% and 73.3% for the ACSS questionnaire and 100% and 76.2% for the urine test(s). For use in primary care, a reduction in false-positive and false-negative results can be achieved by including scores for differential symptoms, QoL and relevant conditions, alongside a total typical symptoms score of 6 or higher. Show less
BackgroundIn multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (PanNETs) have a high prevalence and represent the main cause of death. This study aimed to assess the... Show moreBackgroundIn multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (PanNETs) have a high prevalence and represent the main cause of death. This study aimed to assess the diagnostic accuracy of the currently used conventional pancreatic imaging techniques and the added value of fine needle aspirations (FNAs). MethodsPatients who had at least one imaging study were included from the population-based MEN1 database of the DutchMEN Study Group from 1990 to 2017. Magnetic resonance imaging (MRI), computed tomography (CT), endoscopic ultrasonography (EUS), FNA, and surgical resection specimens were obtained. The first MRI, CT, or EUS was considered as the index test. For a comparison of the diagnostic accuracy of MRI versus CT, patients with their index test taken between 2010 and 2017 were included. The reference standard consisted of surgical histopathology or radiological follow-up. ResultsA total of 413 patients (92.8% of the database) underwent 3,477 imaging studies. The number of imaging studies per patient increased, and a preference for MRI was observed in the last decade. Overall diagnostic accuracy was good with a positive (PPV) and negative predictive value (NPV) of 88.9% (95% confidence interval, 76.0-95.6) and 92.8% (89.4-95.1), respectively, for PanNET in the pancreatic head and 92.0% (85.3-96.0) and 85.3% (80.5-89.1), respectively, in the body/tail. For MRI, PPV and NPV for pancreatic head tumors were 100% (76.1-100) and 87.1% (76.3-93.6) and for CT, 60.0% (22.9-88.4) and 70.4% (51.3-84.3), respectively. For body/tail tumors, PPV and NPV were 91.3% (72.0-98.8) and 87.0% (75.3-93.9), respectively, for MRI and 100% (74.9-100) and 77.8% (54.3-91.5), respectively, for CT. Pathology confirmed a PanNET in 106 out of 110 (96.4%) resection specimens. FNA was performed on 34 lesions in 33 patients and was considered PanNET in 24 [all confirmed PanNET by histology (10) or follow-up (14)], normal/cyst/unrepresentative in 6 (all confirmed PanNET by follow-up), and adenocarcinoma in 4 (2 confirmed and 2 PanNET). Three patients, all older than 60 years, had a final diagnosis of pancreatic adenocarcinoma. ConclusionAs the accuracy for diagnosing MEN1-related PanNET of MRI was higher than that of CT, MRI should be the preferred (non-invasive) imaging modality for PanNET screening/surveillance. The high diagnostic accuracy of pancreatic imaging and the sporadic occurrence of pancreatic adenocarcinoma question the need for routine (EUS-guided) FNA. Show less
Venous thromboembolism (VTE), in particular acute pulmonary embolism (PE), has been shown to be a frequent and potentially fatal complication of coronavirus disease 2019 (COVID-19). In response to... Show moreVenous thromboembolism (VTE), in particular acute pulmonary embolism (PE), has been shown to be a frequent and potentially fatal complication of coronavirus disease 2019 (COVID-19). In response to the observed thrombotic complications, a large number of studies has been devoted to the understanding and management of COVID-19-associated coagulopathy. Notably, only a limited number of mostly retrospective studies has focused on the optimal diagnostic strategy for suspected PE in COVID-19 patients. As in other special populations, the accuracy of diagnostic algorithms for PE-exclusion has been debated in this specific patient subgroup as the specificity of D-dimer assays and clinical decision rules (CDRs) may be lower than normal. From this viewpoint, we discuss the current state-of-the-art diagnostic algorithms for acute PE with a focus on patients with COVID-19 in the perspective of other special patient populations. Furthermore, we summarize current knowledge regarding the natural history of PE resolution with anticoagulant treatment in patients with COVID-19. Show less
For many parasitic diseases, the microscopic examination of clinical samples such as urine and stool still serves as the diagnostic reference standard, primarily because microscopes are accessible... Show moreFor many parasitic diseases, the microscopic examination of clinical samples such as urine and stool still serves as the diagnostic reference standard, primarily because microscopes are accessible and cost-effective. However, conventional microscopy is laborious, requires highly skilled personnel, and is highly subjective. Requirements for skilled operators, coupled with the cost and maintenance needs of the microscopes, which is hardly done in endemic countries, presents grossly limited access to the diagnosis of parasitic diseases in resource-limited settings. The urgent requirement for the management of tropical diseases such as schistosomiasis, which is now focused on elimination, has underscored the critical need for the creation of access to easy-to-use diagnosis for case detection, community mapping, and surveillance. In this paper, we present a low-cost automated digital microscope-the Schistoscope-which is capable of automatic focusing and scanning regions of interest in prepared microscope slides, and automatic detection of Schistosoma haematobium eggs in captured images. The device was developed using widely accessible distributed manufacturing methods and off-the-shelf components to enable local manufacturability and ease of maintenance. For proof of principle, we created a Schistosoma haematobium egg dataset of over 5000 images captured from spiked and clinical urine samples from field settings and demonstrated the automatic detection of Schistosoma haematobium eggs using a trained deep neural network model. The experiments and results presented in this paper collectively illustrate the robustness, stability, and optical performance of the device, making it suitable for use in the monitoring and evaluation of schistosomiasis control programs in endemic settings. Show less
Haimov, D.; Lieberman, S.; Castellvi-Bel, S.; Nielsen, M.; Goldberg, Y. 2022
Simple Summary: Familiarity with nonmalignant features and comorbidities of cancer predisposition syndromes may raise awareness and assist clinicians in the diagnosis and interpretation of... Show moreSimple Summary: Familiarity with nonmalignant features and comorbidities of cancer predisposition syndromes may raise awareness and assist clinicians in the diagnosis and interpretation of molecular test results. Genetic predisposition to colorectal cancer (CRC) should be suspected mainly in young patients, in patients with significant family histories, multiple polyps, mismatch repair-deficient tumors, and in association with malignant or nonmalignant comorbidities. The aim of this review is to describe the main nonmalignant comorbidities associated with selected CRC predisposition syndromes that may serve as valuable diagnostic clues for clinicians and genetic professionals.& nbsp;Genetic diagnosis of affected individuals and predictive testing of their at-risk relatives, combined with intensive cancer surveillance, has an enormous cancer-preventive potential in these families. A lack of awareness may be part of the reason why the underlying germline cause remains unexplained in a large proportion of patients with CRC. Various extracolonic features, mainly dermatologic, ophthalmic, dental, endocrine, vascular, and reproductive manifestations occur in many of the cancer predisposition syndromes associated with CRC and polyposis. Some are mediated via the WNT, TGF-beta, or mTOR pathways. However the pathogenesis of most features is still obscure. Here we review the extracolonic features of the main syndromes, the existing information regarding their prevalence, and the pathways involved in their pathogenesis. This knowledge could be useful for care managers from different professional disciplines, and used to raise awareness, enable diagnosis, and assist in the process of genetic testing and interpretation. Show less
This study aimed to determine the ability of single fiber reflectance (SFR) spectroscopy incorporated in endoscopic ultrasound fine needle biopsy (EUS-FNB) procedures in the pancreas to distinguish... Show moreThis study aimed to determine the ability of single fiber reflectance (SFR) spectroscopy incorporated in endoscopic ultrasound fine needle biopsy (EUS-FNB) procedures in the pancreas to distinguish benign and malignant pancreatic tissue in patient with pancreatic masses suspected for malignancy. Methods: This study was designed as a prospective observational single center study and included consecutive adult patients, who were scheduled for EUS-FNB of a solid pancreatic mass suspected for pancreatic ductal adenocarcinoma (PDAC). In total, seven optical parameters, derived from the absorption acquired spectra, were analyzed: blood volume fraction (BVF), microvascular saturation, average vessel diameter, bilirubin concentration (BIL), Mie amplitude, Mie slope and Rayleigh amplitude. Results: Forty-five patients with a suspicious pancreatic lesion undergoing EUS-FNB were included, of which most of the patients (N=34) were ultimately diagnosed with PDAC. Finally, 27 out of 45 (60.0%) patients were used for the final analysis of the optical parameters. The median (IQR) BVF differed significantly in benign compared to malignant tissue (0.86 [0.30-2.03] and 4.49 [1.28-15.47]; p=0.046). Combining BVF and BIL to a new parameter (Theta) improved the discrimination between PDAC and benign pancreatic tissue (p=0.026). The area under the curve of Theta was 0.84, resulting in a 92.8%, 75.0%, 97.5%, 50.0% and 91.3% sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy for detection of PDAC. Conclusion: Differentiation between PDAC and benign pancreatic tissue using SFR spectroscopy during EUS-FNB procedures is promising. Future work should focus on comparing the diagnostic performance combining SFR spectroscopy with EUS-FNB and EUS-FNB alone. Show less
Zhou, Z.J.; Hooij, A. van; Vervenne, R.; Sombroek, C.C.; Fat, E.T.K.M.; Ottenhoff, T.H.M.; ... ; Geluk, A. 2021
Simple Summary Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is the most lethal infectious disease from a single pathogen for which there is no effective vaccine available. Rhesus... Show moreSimple Summary Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is the most lethal infectious disease from a single pathogen for which there is no effective vaccine available. Rhesus macaques are extremely susceptible to MTB and therefore represent relevant models to study the pathogenesis of TB and assess the potential of TB drugs and vaccines. However, there are no diagnostic tools currently available that allow rapid, user-friendly detection of TB for either TB research purposes or monitoring nonhuman primate colonies. To develop a rapid diagnostic test, we investigated whether low complexity lateral flow assays (LFAs) that we recently developed for rapid and quantitative detection of human serum proteins are applicable to detect and monitor active pulmonary TB in NHPs. We found that serum levels of SAA1, IP-10, and IL-6 detected by LFAs were significantly increased after MTB infection in rhesus macaques. Moreover, levels of these biomarkers correlated with disease severity as determined by pathology scoring and allowed detection of the effect of vaccination and drug treatment in experimentally MTB infected macaques. These UCP-LFAs thus offer a low-cost, convenient, and minimally invasive diagnostic tool that can be used to assess new therapeutic and prophylactic treatment methods in macaques to tackle TB. Nonhuman primates (NHPs) are relevant models to study the pathogenesis of tuberculosis (TB) and evaluate the potential of TB therapies, but rapid tools allowing diagnosis of active pulmonary TB in NHPs are lacking. This study investigates whether low complexity lateral flow assays utilizing upconverting reporter particles (UCP-LFAs) developed for rapid detection of human serum proteins can be applied to detect and monitor active pulmonary TB in NHPs. UCP-LFAs were used to assess serum proteins levels and changes in relation to the MTB challenge dosage, lung pathology, treatment, and disease outcome in experimentally MTB-infected macaques. Serum levels of SAA1, IP-10, and IL-6 showed a significant increase after MTB infection in rhesus macaques and correlated with disease severity as determined by pathology scoring. Moreover, these biomarkers could sensitively detect the reduction of bacterial levels in the lungs of macaques due to BCG vaccination or drug treatment. Quantitative measurements by rapid UCP-LFAs specific for SAA1, IP-10, and IL-6 in serum can be utilized to detect active progressive pulmonary TB in macaques. The UCP-LFAs thus offer a low-cost, convenient, and minimally invasive diagnostic tool that can be applied in studies on TB vaccine and drug development involving macaques. Show less
A. Kawai43, K. Kopeckova44, D. A. Krakorova45, A. Le Cesne46, F. Le Grange1, E. Legius47, A. Leithner48, A. Lopez Pousa49, J. Martin-Broto36, O. Merimsky50, C. Messiou51, A. B. Miah52, O. Mir53, M.... Show moreA. Kawai43, K. Kopeckova44, D. A. Krakorova45, A. Le Cesne46, F. Le Grange1, E. Legius47, A. Leithner48, A. Lopez Pousa49, J. Martin-Broto36, O. Merimsky50, C. Messiou51, A. B. Miah52, O. Mir53, M. Montemurro54, B. Morland55, C. Morosi56, E. Palmerini57, M. A. Pantaleo58, R. Piana59, S. Piperno-Neumann60, P. Reichardt61, P. Rutkowski62, A. A. Safwat63, C. Sangalli64, M. Sbaraglia19, S. Scheipl48, P. Schoffski65, S. Sleijfer66, D. Strauss67, K. Sundby Hall13, A. Trama68, M. Unk69, M. A. J. van de Sande70, W. T. A. van der Graaf66,71, W. J. van Houdt72, T. Frebourg73x, R. Ladenstein41z, P. G. Casali2,74z & Show less
Zhou, Z.J.; Pena, M.; Hooij, A. van; Pierneef, L.; Jong, D. de; Stevenson, R.; ... ; Geluk, A. 2021
Leprosy is an infectious disease caused by Mycobacterium leprae with tropism for skin and peripheral nerves. Incessant transmission in endemic areas is still impeding elimination of leprosy.... Show moreLeprosy is an infectious disease caused by Mycobacterium leprae with tropism for skin and peripheral nerves. Incessant transmission in endemic areas is still impeding elimination of leprosy. Although detection of M. leprae infection remains a challenge in asymptomatic individuals, the presence of antibodies specific for phenolglycolipid-I (PGL-I) correlate with bacterial load. Therefore, serosurveillance utilizing field-friendly tests detecting anti-PGL-I antibodies, can be applied to identify those who may transmit bacteria and to study (reduction of) M. leprae transmission. However, serology based on antibody detection cannot discriminate between past and present M. leprae infection in humans, nor can it detect individuals carrying low bacillary loads. In humans, anti-PGL-I IgM levels are long-lasting and usually detected in more individuals than anti-PGL-I IgG levels. Inherent to the characteristically long incubation time of leprosy, IgM/IgG relations (antibody kinetics) in leprosy patients and infected individuals are not completely clear. To investigate the antibody response directly after infection, we have measured antibody levels by ELISA, in longitudinal samples of experimentally M. leprae infected, susceptible nine-banded armadillos (Dasypus novemcinctus). In addition, we assessed the user- and field-friendly, low-cost lateral flow assay (LFA) utilizing upconverting reporter particles (UCP), developed for quantitative detection of human anti-PGL-I IgM (UCP-LFA), to detect treatment- or vaccination-induced changes in viable bacterial load. Our results show that serum levels of anti-PGL-I IgM, and to a lesser extent IgG, significantly increase soon after experimental M. leprae infection in armadillos. In view of leprosy phenotypes in armadillos, this animal model can provide useful insight into antibody kinetics in early infection in the various spectral forms of human leprosy. The UCP-LFA for quantitative detection of anti-PGL-I IgM allows monitoring the efficacy of vaccination and rifampin-treatment in the armadillo leprosy model, thereby providing a convenient tool to evaluate the effects of drugs and vaccines and new diagnostics. Show less
Delemarre, E.M.; Hoorn, L. van; Bossink, A.W.J.; Drylewicz, J.; Joosten, S.A.; Ottenhoff, T.H.M.; ... ; Nierkens, S. 2021
IntroductionThere is an urgent medical need to differentiate active tuberculosis (ATB) from latent tuberculosis infection (LTBI) and prevent undertreatment and overtreatment. The aim of this study... Show moreIntroductionThere is an urgent medical need to differentiate active tuberculosis (ATB) from latent tuberculosis infection (LTBI) and prevent undertreatment and overtreatment. The aim of this study was to identify biomarker profiles that may support the differentiation between ATB and LTBI and to validate these signatures.Materials and MethodsThe discovery cohort included adult individuals classified in four groups: ATB (n = 20), LTBI without prophylaxis (untreated LTBI; n = 20), LTBI after completion of prophylaxis (treated LTBI; n = 20), and healthy controls (HC; n = 20). Their sera were analyzed for 40 cytokines/chemokines and activity of adenosine deaminase (ADA) isozymes. A prediction model was designed to differentiate ATB from untreated LTBI using sparse partial least squares (sPLS) and logistic regression analyses. Serum samples of two independent cohorts (national and international) were used for validation.ResultssPLS regression analyses identified C-C motif chemokine ligand 1 (CCL1), C-reactive protein (CRP), C-X-C motif chemokine ligand 10 (CXCL10), and vascular endothelial growth factor (VEGF) as the most discriminating biomarkers. These markers and ADA(2) activity were significantly increased in ATB compared to untreated LTBI (p <= 0.007). Combining CCL1, CXCL10, VEGF, and ADA2 activity yielded a sensitivity and specificity of 95% and 90%, respectively, in differentiating ATB from untreated LTBI. These findings were confirmed in the validation cohort including remotely acquired untreated LTBI participants.ConclusionThe biomarker signature of CCL1, CXCL10, VEGF, and ADA2 activity provides a promising tool for differentiating patients with ATB from non-treated LTBI individuals. Show less
Early diagnosis of pediatric cancer is key for adequate patient management and improved outcome. Although multiparameter flow cytometry (MFC) has proven of great utility in the diagnosis and... Show moreEarly diagnosis of pediatric cancer is key for adequate patient management and improved outcome. Although multiparameter flow cytometry (MFC) has proven of great utility in the diagnosis and classification of hematologic malignancies, its application to non-hematopoietic pediatric tumors remains limited. Here we designed and prospectively validated a new single eight-color antibody combination-solid tumor orientation tube, STOT-for diagnostic screening of pediatric cancer by MFC. A total of 476 samples (139 tumor mass, 138 bone marrow, 86 lymph node, 58 peripheral blood, and 55 other body fluid samples) from 296 patients with diagnostic suspicion of pediatric cancer were analyzed by MFC vs. conventional diagnostic procedures. STOT was designed after several design-test-evaluate-redesign cycles based on a large panel of monoclonal antibody combinations tested on 301 samples. In its final version, STOT consists of a single 8-color/12-marker antibody combination (CD99-CD8/(nu)myogenin/CD4-EpCAM/CD56/GD2/(sm)CD3-CD19/(cy)CD3-CD271/CD45). Prospective validation of STOT in 149 samples showed concordant results with the patient WHO/ICCC-3 diagnosis in 138/149 cases (92.6%). These included: 63/63 (100%) reactive/disease-free samples, 43/44 (98%) malignant and 4/4 (100%) benign non-hematopoietic tumors together with 28/38 (74%) leukemia/lymphoma cases; the only exception was Hodgkin lymphoma that required additional markers to be stained.& nbsp;In addition, STOT allowed accurate discrimination among the four most common subtypes of malignant CD45(-) CD56(++) non-hematopoietic solid tumors: 13/13 (GD2(++) (nu)myogenin(-) CD271(-/+) (nu)MyoD1(-) CD99(-) EpCAM(-)) neuroblastoma samples, 5/5 (GD2(-) (nu)myogenin(++) CD271(++) (nu)MyoD1(++) CD99(-/+) EpCAM(-)) rhabdomyosarcomas, 2/2 (GD2(-/+) (nu)myogenin(-) CD271(+) (nu)MyoD1(-) CD99(+) EpCAM(-)) Ewing sarcoma family of tumors, and 7/7 (GD2(-) (nu)myogenin(-) CD271(+) (nu)MyoD1(-) CD99(-) EpCAM(+)) Wilms tumors. In summary, here we designed and validated a new standardized antibody combination and MFC assay for diagnostic screening of pediatric solid tumors that might contribute to fast and accurate diagnostic orientation and classification of pediatric cancer in routine clinical practice. Show less
Dronkers, C.E.A.; Hulle, T. van der; Gal, G. le; Kyrle, P.A.; Huisman, M.V.; Cannegieter, S.C.; Klok, F.A. 2021
Accumulating studies on COVID-19 patients report high incidences of thrombotic complications, but guidance on the best diagnostic approach for suspected pulmonary embolism (PE) in COVID-19 patients... Show moreAccumulating studies on COVID-19 patients report high incidences of thrombotic complications, but guidance on the best diagnostic approach for suspected pulmonary embolism (PE) in COVID-19 patients is lacking. Diagnosing PE in these patients is challenging as signs and symptoms of PE and COVID-19 show wide overlap, D-dimer levels are often elevated in the absence of thrombosis and computed tomography pulmonary angiography (CTPA) may be unfeasible in the case of severe renal impairment and/or hemodynamic instability. This narrative review discusses available literature and guidelines on current diagnostic algorithms for suspected PE in special patient populations, in particular COVID-19. A special focus is on reviewing the literature aimed at identifying symptoms with a high suspicion for PE and on the diagnostic performance of diagnostic algorithms for suspected PE in the setting of COVID-19. Based on available literature, the index of suspicion for PE should be high in the case of unexplained abrupt worsening of respiratory status, typical symptoms of deep-vein thrombosis and/or acute unexplained right ventricular dysfunction. Despite the lack of prospective diagnostic management studies, we propose to adhere to current diagnostic algorithms applying assessment of pretest probability and D-dimer testing as available evidence suggests that these might be considered safe. Preferably, algorithms using adjusted D-dimer thresholds are recommended as it likely improves the yield of the clinical decision rule/D-dimer combination. Show less
Background Compression ultrasonography (CUS) is the first-line imaging test for diagnosing upper extremity deep vein thrombosis (UEDVT), but often yields inconclusive test results. Contrast... Show moreBackground Compression ultrasonography (CUS) is the first-line imaging test for diagnosing upper extremity deep vein thrombosis (UEDVT), but often yields inconclusive test results. Contrast venography is still considered the diagnostic standard but is an invasive technique.Objectives We aimed to determine the diagnostic accuracy of magnetic resonance noncontrast thrombus imaging (MR-NCTI) for the diagnosis of UEDVT.Methods In this international multicenter diagnostic study, we prospectively included patients with clinically suspected UEDVT who were managed according to a diagnostic algorithm that included a clinical decision rule (CDR), D-dimer test, and diagnostic imaging. UEDVT was confirmed by CUS or (computed tomography [CT]) venography. UEDVT was excluded by (1) an unlikely CDR and normal D-dimer, (2) a normal serial CUS or (3) a normal (CT) venography. Within 48 h after the final diagnosis was established, patients underwent MR-NCTI. MR-NCTI images were assessed post hoc by two independent radiologists unaware of the presence or absence of UEDVT. The sensitivity, specificity, and interobserver agreement of MR-NCTI for UEDVT were determined.Results Magnetic resonance noncontrast thrombus imaging demonstrated UEDVT in 28 of 30 patients with UEDVT and was normal in all 30 patients where UEDVT was ruled out, yielding a sensitivity of 93% (95% CI 78-99) and specificity of 100% (95% CI 88-100). The interobserver agreement of MR-NCTI had a kappa value of 0.83 (95% CI 0.69-0.97).Conclusions Magnetic resonance noncontrast thrombus imaging is an accurate and reproducible method for diagnosing UEDVT. Clinical outcome studies should determine whether MR-NCTI can replace venography as the second-line imaging test in case of inconclusive CUS. Show less
Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade... Show moreEpithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication. Show less
