Möglichkeiten des kontrastverstärkten Ultraschalls (CEUS) in radiologischen Anwendungsgebieten

Der CEUS wird heutzutage zur interdisziplinären Klärung einer Vielzahl unter-schiedlichster Fragestellungen verwendet. Im Rahmen dieser Dissertationsar-beit sollte die Rolle des CEUS zur Beurteilung von 1.) Nierenläsionen der Ka-tegorie Bosniak 3 und 2.) abdominellen Veränderungen während der Schwangerschaft untersucht werden. Zwischen 01/2010 und 04/2020 wurden im Rahmen der ersten retrospektiven Studie bei 49/476 CEUS-Untersuchungen Bosniak 3 Läsionen detektiert, von denen 29 Läsionen nach (partieller) Nephrektomie mit dem entsprechenden histopathologischen Korrelat als diagnostische Referenz verglichen wurden. Folgende NCC-Subtypen mit absteigender Reihenfolge lagen den malignen Tumoren zugrunde: klarzelliges NCC, papilläres NCC, gemischtes NCC, chromophobes NCC und multilokulär zystisches NCC. Unter den benignen Läsionen fanden sich: epitheliale (hämorrhagische) Zyste, renales Onkozy-tom, papilläres renales Adenom, zystisches Hamartom und adultes zystisches Nephrom. In unserem Patientenkollektiv konnte eine Malignitätsrate von 66% unter Bosniak 3 Nierenläsionen festgestellt werden, welche damit etwas höher liegt als in bisher publizierten Studien. Selektionsbias sowie die exzellente diagnostische Genauigkeit des CEUS sind mögliche Erklärungen hierfür. Un-sere Resultate zeigten zudem, dass es sonomorphologische Überlappungen zwischen benignen und malignen Nierenläsionen gibt, die eine nicht-invasive Differenzierung herausfordernd, teilweise sogar – wie die Studienlage zeigt auch mittels CT bzw. MRT – bislang unmöglich macht. Die Resultate dieser Arbeit verdeutlichen die hohe diagnostische Performanz des CEUS, der bis-lang von den führenden urologischen Gesellschaften - neben der CT und MRT - nicht als primäres bildgebendes Instrument zur Beurteilung von Nieren-läsionen empfohlen wird. Für die zweite retrospektive Studie wurden fünf schwangere Patientinnen, im Durchschnitt in der 21. Schwangerschaftswoche, eingeschlossen, die zwi-schen 06/2020 – 10/2020 eine CEUS-Untersuchung zur Abklärung abdomi-neller Fragestellungen erhielten. In keiner der CEUS-Untersuchungen konn-ten weder fetale noch maternale Nebenwirkungen bzw. Komplikationen regis-triert werden. Ebenfalls ließ sich in keiner der CEUS-Untersuchungen eine fetale Kontrastierung zeigen, was sich mit den Erkenntnissen voriger Studien deckt, dass die rein intravaskulären Mikrobläschen im Rahmen des CEUS die Blut-Plazenta-Schranke nicht passieren. Der CEUS konnte in dieser Studie bei allen untersuchten schwangeren Patientinnen entscheidend zur Diagno-sestellung der jeweilig abzuklärenden abdominellen Veränderung beitragen. Es fanden sich: renales Angiomyolipom, pyelonephritische Veränderungen unter Ausschluss einer Abszessformation, nekrotisches Uterusmyom, Gallen-blasenpolyp und eine Thrombosierung der Vena mesenterica superior mit marginaler Restperfusion. Die Erkenntnisse der Studie betonen die sichere Anwendbarkeit sowie die diagnostische Rolle des CEUS während der Schwangerschaft. Bislang gibt es keine offiziellen Empfehlungen der führen-den Gesellschaften zur Anwendung des CEUS während der Schwanger-schaft. In Zusammenschau mit weiteren aktuellen Studien, die die Rolle des CEUS in der Schwangerschaft untersuchten, stellt der CEUS somit ein vielver-sprechendes diagnostisches Instrument dar, welches wertvolle Zusatzinforma-tionen beisteuern und dadurch die klinische Entscheidungsfindung sowie das therapeutische Patientenmanagement in der Schwangerschaft bestimmen kann. Trotz der vielen Vorteile des CEUS – unmittelbare Anwendbarkeit und Wie-derholbarkeit, nicht-ionisierend, exzellentes Sicherheitsprofil, Kosteneffizienz, sehr hohe räumliche und zeitliche Auflösung in Echtzeit – und der vielverspre-chenden wissenschaftlichen Erkenntnisse seit seiner Einführung, bleibt bis heute eine flächendecke Versorgung mit dem CEUS in Deutschland aus. Die beiden vorliegenden Arbeiten der kumulativen Dissertation betonen das hohe diagnostische Potential des CEUS, hier insbesondere in der interdisziplinären Zusammenarbeit zwischen der Radiologie, der Urologie sowie der Gynäkolo-gie/Reproduktionsmedizin.Up to date, CEUS is being interdisciplinarily applied for investigating a pletho-ra of different medical conditions. The intention of the present doctoral thesis was to evaluate the role of CEUS for assessing 1.) Bosniak 3 renal lesions, and 2.) abdominal conditions during pregnancy. Between 01/2010 – 04/2020 Bosniak 3 renal lesions could be detected during 49/476 CEUS examinations. In total, 29 patients underwent (partial) nephrec-tomy, sonomorphology was then correlated with corresponding histopatholo-gy. The following subtypes of renal cell carcinoma (RCC) with decreasing fre-quencies could be revealed: clear cell RCC, papillary RCC, mixed RCC, chromophobe RCC, multilocular cystic RCC. Among benign tumor entities were: epithelial (hemorrhagic) cyst, renal oncocytoma, papillary renal adeno-ma, cystic hamartoma, and adult cystic nephroma. The malignancy rate of the investigated Bosniak 3 renal lesions accounted for 66%, which is higher than previously described in the literature. Selection bias and the excellent diag-nostic accuracy of CEUS are possible explanations. Moreover, our results show sonomorphological overlapping between benign and malignant renal lesions, thus rendering non-invasive diagnostic challenging, or partially– as previous studies already showed when using CT and MRI – even unfeasible. The results of this study emphasize the high diagnostic performance of CEUS. Still, CEUS is not being recommended as primary imaging modality to assess renal lesions – in addition to CT and MRI - by the leading urology societies. Five pregnant patients were examined by using CEUS between 06/2020 – 10/2020 at a mean gestational week of 21 due to different abdominal condi-tions. No fetal nor maternal adverse effects were registered in any of the CEUS examinations. Furthermore, no fetal contrast enhancement could be detected in none of the CEUS examinations, which goes in line with results from previ-ous studies, indicating that microbubbles in the context of CEUS do not cross the blood-placental barrier. In each of the five cases, CEUS significantly con-tributed to the diagnostic workup of the corresponding abdominal condition, and facilitated the evaluation of: renal angiomyolipoma, exclusion of a renal abscess during pyelonephritis, necrotic uterine fibroid, polyp of the gallblad-der, and thrombosis of the superior mesenteric vein with detection of marginal perfusion. The findings of the retrospective study again demonstrate the safe and pivotal role of CEUS during pregnancy. Up to now, CEUS is not officially being recommended by the leading societies of ultrasound and gynecolo-gy/obstetrics. In line with recent studies which investigated the application of CEUS during pregnancy, CEUS depicts a promising diagnostic tool which may provide further relevant information and thus may facilitate clinical decision making and patient management during pregnancy. Despite the critical benefits of CEUS – immediate accessibility and repeatabil-ity, non-ionizing, excellent safety profile, cost-effectiveness, high spatial and temporal resolutions, real-time approach – and the promising results from clin-ical trials since its introduction, CEUS still is not utilized in a widespread man-ner in Germany. Both presented studies of the cumulative dissertation under-score the high diagnostic potential of using CEUS, particularly within the inter-disciplinary collaboration between radiology, urology and gynecolo-gy/obstetrics

Therapeutic Outcome of MR-Guided High-Intensity Focused Ultrasound (MR-HIFU) in Solitary versus Multiple Uterine Fibroids

MR-guided high-intensity focused ultrasound (MR-HIFU) is an effective method for treating symptomatic uterine fibroids, especially solitary lesions. The aim of our study was to compare the clinical and morphological outcomes of patients who underwent MR-HIFU due to solitary fibroid (SF) or multiple fibroids (MFs) in a prospective clinical trial. We prospectively included 21 consecutive patients with SF (10) and MF (11) eligible for MR-guided HIFU. The morphological data were assessed using mint Lesion (TM) for MRI. The clinical data were determined using the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire before and 6 months after treatment. Unpaired and paired Wilcoxon-test and t-tests were applied, and Pearson's coefficient was used for correlation analysis. A p-value of 0.05 was considered statistically significant. The volume of treated fibroids significantly decreased in both the SF (mean baseline: 118.6 cm(3);mean 6-month follow-up: 64.6 cm(3)) and MF (107.2 cm(3);55.1 cm(3)) groups. The UFS-QOL showed clinical symptoms significantly improved for patients in both the SF and MF groups regarding concern, activities, energy/mood, and control. The short-term outcome for the treatment of symptomatic fibroids in myomatous uterus by MR-guided HIFU is clinically similar to that of solitary fibroids

Evaluation of patients with respiratory infections during the first pandemic wave in Germany: characteristics of COVID-19 versus non-COVID-19 patients

BACKGROUND Characteristics of COVID-19 patients have mainly been reported within confirmed COVID-19 cohorts. By analyzing patients with respiratory infections in the emergency department during the first pandemic wave, we aim to assess differences in the characteristics of COVID-19 vs. Non-COVID-19 patients. This is particularly important regarding the second COVID-19 wave and the approaching influenza season. METHODS We prospectively included 219 patients with suspected COVID-19 who received radiological imaging and RT-PCR for SARS-CoV-2. Demographic, clinical and laboratory parameters as well as RT-PCR results were used for subgroup analysis. Imaging data were reassessed using the following scoring system: 0 - not typical, 1 - possible, 2 - highly suspicious for COVID-19. RESULTS COVID-19 was diagnosed in 72 (32,9%) patients. In three of them (4,2%) the initial RT-PCR was negative while initial CT scan revealed pneumonic findings. 111 (50,7%) patients, 61 of them (55,0%) COVID-19 positive, had evidence of pneumonia. Patients with COVID-19 pneumonia showed higher body temperature (37,7~± 0,1 vs. 37,1~± 0,1 °C; p = 0.0001) and LDH values (386,3~± 27,1 vs. 310,4~± 17,5 U/l; p = 0.012) as well as lower leukocytes (7,6~± 0,5 vs. 10,1~± 0,6G/l; p = 0.0003) than patients with other pneumonia. Among abnormal CT findings in COVID-19 patients, 57 (93,4%) were evaluated as highly suspicious or possible for COVID-19. In patients with negative RT-PCR and pneumonia, another third was evaluated as highly suspicious or possible for COVID-19 (14 out of 50; 28,0%). The sensitivity in the detection of patients requiring isolation was higher with initial chest CT than with initial RT-PCR (90,4% vs. 79,5%). CONCLUSIONS COVID-19 patients show typical clinical, laboratory and imaging parameters which enable a sensitive detection of patients who demand isolation measures due to COVID-19

Clinically focused multi-cohort benchmarking as a tool for external validation of artificial intelligence algorithm performance in basic chest radiography analysis

Artificial intelligence (AI) algorithms evaluating [supine] chest radiographs ([S]CXRs) have remarkably increased in number recently. Since training and validation are often performed on subsets of the same overall dataset, external validation is mandatory to reproduce results and reveal potential training errors. We applied a multicohort benchmarking to the publicly accessible (S)CXR analyzing AI algorithm CheXNet, comprising three clinically relevant study cohorts which differ in patient positioning ([S]CXRs), the applied reference standards (CT-/[S]CXR-based) and the possibility to also compare algorithm classification with different medical experts’ reading performance. The study cohorts include [1] a cohort, characterized by 563 CXRs acquired in the emergency unit that were evaluated by 9 readers (radiologists and non-radiologists) in terms of 4 common pathologies, [2] a collection of 6,248 SCXRs annotated by radiologists in terms of pneumothorax presence, its size and presence of inserted thoracic tube material which allowed for subgroup and confounding bias analysis and [3] a cohort consisting of 166 patients with SCXRs that were evaluated by radiologists for underlying causes of basal lung opacities, all of those cases having been correlated to a timely acquired computed tomography scan (SCXR and CT within < 90 min). CheXNet non-significantly exceeded the radiology resident (RR) consensus in the detection of suspicious lung nodules (cohort [1], AUC AI/RR: 0.851/0.839, p = 0.793) and the radiological readers in the detection of basal pneumonia (cohort [3], AUC AI/reader consensus: 0.825/0.782, p = 0.390) and basal pleural effusion (cohort [3], AUC AI/reader consensus: 0.762/0.710, p = 0.336) in SCXR, partly with AUC values higher than originally published (“Nodule”: 0.780, “Infiltration”: 0.735, “Effusion”: 0.864). The classifier “Infiltration” turned out to be very dependent on patient positioning (best in CXR, worst in SCXR). The pneumothorax SCXR cohort [2] revealed poor algorithm performance in CXRs without inserted thoracic material and in the detection of small pneumothoraces, which can be explained by a known systematic confounding error in the algorithm training process. The benefit of clinically relevant external validation is demonstrated by the differences in algorithm performance as compared to the original publication. Our multi-cohort benchmarking finally enables the consideration of confounders, different reference standards and patient positioning as well as the AI performance comparison with differentially qualified medical readers

A novel potent tumour promoter aberrantly overexpressed in most human cancers

The complexity and heterogeneity of tumours have hindered efforts to identify commonalities among different cancers. Furthermore, because we have limited information on the prevalence and nature of ubiquitous molecular events that occur in neoplasms, it is unfeasible to implement molecular-targeted cancer screening and prevention. Here, we found that the FEAT protein is overexpressed in most human cancers, but weakly expressed in normal tissues including the testis, brain, and liver. Transgenic mice that ectopically expressed FEAT in the thymus, spleen, liver, and lung spontaneously developed invasive malignant lymphoma (48%, 19/40) and lung-metastasizing liver cancer (hepatocellular carcinoma) (35%, 14/40) that models human hepatocarcinogenesis, indicating the FEAT protein potently drives tumorigenesis in vivo. Gene expression profiling suggested that FEAT drives receptor tyrosine kinase and hedgehog signalling pathways. These findings demonstrate that integrated efforts to identify FEAT-like ubiquitous oncoproteins are useful and may provide promising approaches for cost-effective cancer screening and prevention

Neuromatch Academy: a 3-week, online summer school in computational neuroscience

Neuromatch Academy (https://academy.neuromatch.io; (van Viegen et al., 2021)) was designed as an online summer school to cover the basics of computational neuroscience in three weeks. The materials cover dominant and emerging computational neuroscience tools, how they complement one another, and specifically focus on how they can help us to better understand how the brain functions. An original component of the materials is its focus on modeling choices, i.e. how do we choose the right approach, how do we build models, and how can we evaluate models to determine if they provide real (meaningful) insight. This meta-modeling component of the instructional materials asks what questions can be answered by different techniques, and how to apply them meaningfully to get insight about brain function

Particles, air quality, policy and health

The diversity of ambient particle size and chemical composition considerably complicates pinpointing the specific causal associations between exposure to particles and adverse human health effects, the contribution of different sources to ambient particles at different locations, and the consequent formulation of policy action to most cost-effectively reduce harm caused by airborne particles. Nevertheless, the coupling of increasingly sophisticated measurements and models of particle composition and epidemiology continue to demonstrate associations between particle components and sources (and at lower concentrations) and a wide range of adverse health outcomes. This article reviews the current approaches to source apportionment of ambient particles and the latest evidence for their health effects, and describes the current metrics, policies and legislation for the protection of public health from ambient particles. A particular focus is placed on particles in the ultrafine fraction. The review concludes with an extended evaluation of emerging challenges and future requirements in methods, metrics and policy for understanding and abating adverse health outcomes from ambient particles

Genome-wide Association Study of Borderline Personality Disorder Reveals Genetic Overlap with Bipolar Disorder, Major Depression and Schizophrenia

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies