Uncertain Diagnosis Research Articles

Distinguishing hypertensive cardiomyopathy from cardiac amyloidosis in hypertensive patients with heart failure: a CMR study with histological confirmation.

Differentiation of the cause of left ventricular hypertrophy (LVH) is challenging in cases with co-existing hypertension. CMR offers assessment of diffuse myocardial abnormalities via T1 mapping with extracellular volume fraction (ECV) and macroscopic fibrosis via late gadolinium enhancement imaging (LGE). The goal of the study was to understand if CMR parameters can differentiate hypertensive cardiomyopathy (HC) from cardiac amyloidosis (CA) in patients with hypertension and heart failure, using endomyocardial biopsy (EMB) as the gold standard. We retrospectively analyzed patients with hypertension, LVH, and heart failure undergoing EMB due to uncertain diagnosis. CMR parameters including cine, LGE characteristics, T1 mapping, and ECV were analyzed. A total of 34 patients were included (mean age 66.5 ± 10.7 years, 79.4% male). The final EMB-based diagnosis was HC (10, 29%), light chain (AL) CA (7, 21%), and transthyretin (ATTR) CA (17, 50%). There was a significant difference in subendocardial LGE (p = 0.03) and number of AHA segments with subendocardial LGE (p = 0.005). The subendocardial LGE pattern was most common in AL-CA (85.7%) and African American with HC (80%). ECV elevation (≥ 29%) was present in all patients with CA (AL-CA: 57.6 ± 5.2%, ATTR-CA: 59.1 ± 15.3%) and HC (37.3 ± 4.5%). Extensive subendocardial LGE pattern is not pathognomonic for CA but might also be present in African American patients with longstanding or poorly controlled HTN. The ECV elevation in HC with HF might be more significant than previously reported with an overlap of ECV values in HC and CA, particularly in younger African American patients.

Multisite Skin Biopsies vs Cerebrospinal Fluid for Prion Seeding Activity in the Diagnosis of Prion Diseases

Recent studies have revealed that autopsy skin samples from cadavers with prion diseases (PRDs) exhibited a positive prion seeding activity similar to cerebrospinal fluid (CSF). It is worthwhile to validate the findings with a large number of biopsy skin samples and compare the clinical value of prion seeding activity between skin biopsies and concurrent CSF specimens. To compare the prion seeding activity of skin biopsies and CSF samples and to determine the effectiveness of combination of the skin biopsies from multiple sites and numerous dilutions on the diagnosis for various types of PRDs. In the exploratory cohort, patients were enrolled from September 15, 2021, to December 15, 2023, and were followed up every 3 months until April 2024. The confirmatory cohort enrolled patients from December 16, 2023, to June 31, 2024. The exploratory cohort was conducted at a single center, the neurology department at Xuanwu Hospital. The confirmatory cohort was a multicenter study involving 4 hospitals in China. Participants included those diagnosed with probable sporadic Creutzfeldt-Jakob disease or genetically confirmed PRDs. Patients with uncertain diagnoses or those lost to follow-up were excluded. All patients with PRDs underwent skin sampling at 3 sites (the near-ear area, upper arm, lower back, and inner thigh), and a portion of them had CSF samples taken simultaneously. In the confirmatory cohort, a single skin biopsy site and CSF samples were simultaneously collected from a portion of patients with PRDs. The skin and CSF prion seeding activity was assessed using the real-time quaking-induced conversion (RT-QUIC) assay, with rHaPrP90-231, a Syrian hamster recombinant prion protein, as the substrate. In the exploratory cohort, skin samples were tested at dilutions of 10-2 through 10-4. In the confirmatory cohort, skin samples were tested at a dilution of 10-2. A total of four 15-μL wells of CSF were used in the RT-QUIC assay. Correlations between RT-QUIC results from the skin and CSF and the final diagnosis of enrolled patients. In the exploratory cohort, the study included 101 patients (mean [SD] age, 60.9 [10.2] years; 63 female [62.4%]) with PRD and 23 patients (mean [SD] age, 63.4 [9.1] years; 13 female [56.5%]) without PRD. A total of 94 patients had CSF samples taken simultaneously with the skin biopsy samples. In the confirmatory cohort, a single skin biopsy site and CSF sample were taken simultaneously in 43 patients with PRDs. Using an experimental condition of 10-2 dilution, the RT-QUIC positive rates of skin samples from different sites were comparable with those of the CSF (skin: 18 of 26 [69.2%] to 74 of 93 [79.6%] vs CSF: 71 of 94 [75.5%]). When tested at 3 different dilutions, all skin sample positivity rates increased to over 80.0% (79 of 93 for the near-ear area, 21 of 26 for the upper arm, 77 of 92 for the lower back, and 78 of 92 for the inner thigh). Combining samples from skin sites near the ear, inner thigh, and lower back in pairs yielded positivity rates exceeding 92.1% (93 of 101), significantly higher than CSF alone (71 of 94 [75.5%]; P =.002). When all skin sample sites were combined and tested at 3 dilution concentrations for RT-QUIC, the sensitivity reached 95.0% (96 of 101). In the confirmatory cohort, the RT-QUIC positive rate of a single skin biopsy sample was slightly higher than that of the CSF (34 of 43 [79.1%] vs 31 of 43 [72.1%]; P = .45). Results of this diagnostic study suggest that the sensitivity of an RT-QUIC analysis of a combination of 2 or more skin sites was superior to that of CSF in diagnosing PRDs.

Retrospective Investigation of the Utility of Potassium Hydroxide Smear in the Diagnosis and Management of Cutaneous Fungal Infections by Dermatologists

Abstract Background: Superficial cutaneous fungal infections are common dermatologic conditions. A significant proportion do not present with typical clinical findings. However, the 10% potassium hydroxide (KOH) smear, a simple bedside test, is often underused when diagnosing cutaneous fungal infections. Aims: We aimed to evaluate whether KOH smear results altered dermatologists’ diagnosis and management, and the factors that influenced its ability to detect cutaneous fungal infections. Methods: A total of 373 patients with suspected cutaneous fungal infection were identified retrospectively from the dermatology database of inpatient referrals in a Singapore tertiary hospital between 1 January 2017 and 30 June 2020. The dermatologists’ eventual diagnoses, based on their assessment until 2 months post-discharge to allow consideration of KOH smear results and response to treatment, were taken as a gold standard. Statistical analyses evaluated for changes between initial and eventual diagnoses and management relative to the KOH smear. Use of topical steroids, topical and/or systemic antifungals before skin sampling, and whether sampling was done by dermatologically-trained personnel, were assessed for association with KOH smear positivity in eventually diagnosed cases. Results: The percentage of uncertain diagnoses was reduced, and the use of topical antifungal as the sole treatment significantly changed after the KOH smear result was available. The adjusted odds ratio of a positive KOH smear in eventually diagnosed cases was 0.19 when systemic antifungals were used before skin sampling, and 3.03 if sampling was performed by a dermatologically-trained person. Limitations: Limitations of our study include dependence on retrospective medical records which may result in misclassification bias and the limited generalisability of our results to patients managed by non-dermatologists. Conclusions: KOH smear is a useful adjunct in diagnosing and managing cutaneous fungal infections. Clinicians should consider the presence of confounders affecting KOH smears when making an overall clinical diagnosis. Focused training of personnel on skin sample collection may improve the detection rate of KOH smear.

Radiomics and 256-slice-dual-energy CT in the automated diagnosis of mild acute pancreatitis: the innovation of formal methods and high-resolution CT.

Acute pancreatitis (AP) is a common disease, and several scores aim to assess its prognosis. Our study aims to automatically recognize mild AP from computed tomography (CT) images in patients with acute abdominal pain but uncertain diagnosis from clinical and serological data through Radiomic model based on formal methods (FMs). We retrospectively reviewed the CT scans acquired with Dual Source 256-slice CT scanner (Somatom Definition Flash; Siemens Healthineers, Erlangen, Germany) of 80 patients admitted to the radiology unit of Antonio Cardarelli hospital (Naples) with acute abdominal pain. Patients were divided into 2 groups: 40 underwent showed a healthy pancreatic gland, and 40 affected by four different grades (CTSI 0, 1, 2, 3) of mild pancreatitis at CT without clear clinical presentation or biochemical findings. Segmentation was manually performed. Radiologists identified 6 patients with a high expression of diseases (CTSI 3) to formulate a formal property (Rule) to detect AP in the testing set automatically. Once the rule was formulated, and Model Checker classified 70 patients into "healthy" or "unhealthy". The model achieved:accuracy81%, precision 78% and recall81%. Combining FMs results with radiologists agreement, and applying the mode in clinical practice, the global accuracy would have been 100%. Our model was reliable to automatically detect mild AP at primary diagnosis even in uncertain presentation and it will be tested prospectively in clinical practice.

Harnessing uncertainty: A deep mechanistic approach for cautious diagnostic and forecast of Bovine Respiratory Disease

Bovine Respiratory Disease (BRD) is a prevalent infectious disease of respiratory tract in cattle, presenting challenges in accurate diagnosis and forecasting due to the complex interactions of multiple risk factors. Common methods, including mathematical epidemiological models and data-driven approaches such as machine learning models, face limitations such as difficult parameter estimation or the need for data across all potential outcomes, which is challenging given the scarcity and noise in observing BRD processes. In response to these challenges, we introduce a novel approach known as the Bayesian Deep Mechanistic method. This method couples a data-driven model with a mathematical epidemiological model while accounting for uncertainties within the processes. By utilising 265 lung ultrasound videos as sensor data from 163 animals across 9 farms in France, we trained a Bayesian deep learning model to predict the infection status (infected or non-infected) of an entire batch of 12 animals, also providing associated confidence levels. These predictions, coupled with their confidence levels, were used to filter out highly uncertain diagnoses and diffuse uncertainties into the parameterisation of a mathematical epidemiological model to forecast the progression of infected animals. Our findings highlight that considering the confidence levels (or uncertainties) of predictions enhances both the diagnosis and forecasting of BRD. Uncertainty-aware diagnosis reduced errors to 32 %, outperforming traditional automatic diagnosis. Forecast relying on veterinarian diagnoses, considered the most confident, had a 23 % error, whilst forecast taking into account diagnosis uncertainties had a close 27.2 % error. Building upon uncertainty-awareness, our future research could explore integrating multiple types of sensor data, such as video surveillance, audio recordings, and environmental parameters, to provide a comprehensive evaluation of animal health, employing multi-modal methods for processing this diverse data.

Neuroendocrine tumor mimicking a recalcitrant vocal fold granuloma: Appearances can be deceiving.

Posterior glottic lesions resembling granulomas unresponsive to conservative treatment should raise suspicion of a neoplastic condition. Although surgery is rarely recommended for arytenoid granulomas due to their high recurrence rate, histological evaluation is mandatory in cases of uncertain diagnosis. Clinicians should be aware that, although very rare, a laryngeal neuroendocrine tumor occurring in the posterior glottis can mimic the appearance of an idiopathic granuloma, presenting a diagnostic challenge.

A comprehensive scoring system for the diagnosis and staging of adhesive capsulitis: development, application, and implications.

Adhesive capsulitis (AC), often referred to as frozen shoulder, presents a diagnostic challenge due to its insidious onset and progressive nature. The condition is characterized by pain and restricted motion in the shoulder, with a predilection for individuals between 40 and 60years of age. A novel scoring system was developed to enhance the accuracy of diagnosing AC and distinguishing between its stages, aiming to streamline clinical decision-making and treatment planning. A cohort of patients with symptoms suggestive of AC was assessed using the new scoring system, which integrates clinical, radiological, and patient history factors. Parameters included comorbidities like diabetes mellitus, recent immobility, rotator cuff tears, and specific ultrasound findings. Patients were scored and categorized into definitive AC, uncertain diagnosis, or exclusion from AC, with scores > 7, 6-2, and < 2, respectively. The scoring system effectively categorized patients, with those scoring > 7 demonstrating pronounced symptoms and ultrasound changes consistent with Phase 2 AC. Patients with scores between 6 and 2 were classified into uncertain Phase 1 or Phase 3, necessitating further observation. Scores < 2 effectively excluded AC, indicating a need to explore alternative diagnoses. The structured scoring system demonstrated potential as a comprehensive tool for diagnosing AC. By quantitatively assessing a range of contributory factors, it allowed for the stratification of the disease into distinct stages. This system is anticipated to improve early diagnosis and the precision of treatment interventions, although further validation in larger cohorts is warranted. II-III.

Subarachnoid haemorrhage in the emergency department (SHED): a prospective, observational, multicentre cohort study

BackgroundPeople presenting to the ED with acute severe headache often undergo investigation to exclude subarachnoid haemorrhage (SAH). International guidelines propose that brain imaging within 6 hours of headache onset can...

Cutaneous Squamous Cell Carcinoma: From Diagnosis to Follow-Up.

Cutaneous squamous cell carcinoma (SCC) is the second most frequent skin cancer, accounting for approximately 20% of all cutaneous malignancies, and with an increasing incidence due to the progressive increment of the average age of life. The diagnosis is usually firstly suspected based on clinical manifestations; however, dermoscopic features may improve diagnostic sensitivity in cases of an uncertain diagnosis and may guide the biopsy, which should be performed to histopathologically prove the tumor. New diagnostic strategies may improve the sensitivity of the cutaneous SCC, such as reflectance confocal microscopy and line-field confocal optical coherence, for which increasing data have been recently published. Imaging has a central role in the staging of the diseases, while its exact role, as well as the choice of the best techniques, during the follow-up are not fully clarified. The aim of this literature review is to describe diagnostic clinical and instrumental tools of cutaneous SCC, with an insight into the role of imaging in the diagnosis and follow-up of cutaneous SCC.

Application of cell blocks to assist in precise cytological diagnosis of serous effusion

Objective: To investigate the importance of cell block and immunohistochemistry in the accurate diagnosis of serous effusion. Methods: A retrospective study was conducted on 3 124 cases of serous effusion from the Department of Pathology, Beijing Hospital from 2018 to 2022, include 2 213 cases of pleural effusion, 768 cases of peritoneal effusion, 143 cases of pericardial effusion. There were 1 699 males (54.4%) and 1 425 females (45.6%), average age 69 years old. Of which 1 292 cases were prepared with cell blocks and examined with immunohistochemical stain. Results: The percentage of malignant diagnosis increased from 64.9% (839/1 292) to 84.0% (1 086/1 292) after cell block preparation, and 1 086 cases were accurately diagnosed with histological type and/or origin of primary tumor. The undetermined diagnosis of suspected malignancy decreased from 13.3% (172/1 292) to 0.1% (1/1 292) and that of atypical hyperplasia from 18.8% (243/1 292) to 0.4% (5/1 292). The negative result for malignancy rate increased from 3.0% (38/1 292) to 15.5% (200/1 292). The differences highlighted above were statistically significant (Pearson's chi-squared test=12.739, P<0.01). Conclusion: Application of immunohistochemistry based on cell block can significantly improve malignant diagnosis in serous effusion, identify tumor origin and histological type as well as decrease the uncertain diagnosis.

Internal medicine in the 21st century: Back to the future

Healthcare systems face multiple challenges arising from demographic factors (population aging) and epidemiological factors (rise of chronic diseases and patients with multimorbidity) as well as threats to their financial sustainability when maintaining equitable access to medical and technological advances. Current healthcare models, based on specialized medical care, lead to fragmented care that can be harmful to the patient and is inefficient for the system due to the overuse of redundant, low-value medical acts. Internal medicine is the hospital-centered general medical specialty par excellence, providing a comprehensive and holistic vision that is centered on the patient and not on the disease. Internists should be the leading physicians in the hospital setting for complex patients with or those with an uncertain diagnosis. Internists must play a key role, as hospitalists do, in the continued care of acute patients hospitalized for medical or surgical diseases, establishing shared care models in multidisciplinary teams. Likewise, to guarantee continuity of care for chronic patients, internists must establish mechanisms for collaboration with primary care and nursing, participating in the development of new out-of-hospital care models that use the available technological resources. Internal medicine should play a leading role in graduate and postgraduate medical education to promote a holistic vision among medical students and residents in medical subspecialties.

Laboratory data and broncho-alveolar lavage on Covid-19 patients with no intensive care unit admission: Correlation with chest CT features and clinical outcomes.

Broncho-alveolar lavage (BAL) is indicated in cases of uncertain diagnosis but high suspicion of Sars-Cov-2 infection allowing to collect material for microbiological culture to define the presence of coinfection or super-infection. This prospective study investigated the correlation between chest computed tomography (CT) findings, Covid-19 Reporting and Data System score, and clinical outcomes in Coronavirus disease 2019 (Covid-19) patients who underwent BAL with the aim of predicting outcomes such as lung coinfection, respiratory failure, and hospitalization length based on chest CT abnormalities. Study population included 34 patients (range 38-90 years old; 20 males, 14 females) with a positive nucleic acid amplification test for Covid-19 infection, suitable BAL examination, and good quality chest CT scan in the absence of lung cancer history. Pulmonary coinfections were found in 20.6% of patients, predominantly caused by bacteria. Specific correlations were found between right middle lobe involvement and pulmonary co-infections. Severe lung injury (PaO2/FiO2 ratio of 100-200) was associated with substantial involvement of right middle, right upper, and left lower lobes. No significant correlation was found between chest CT findings and inflammatory markers (C-reactive protein, procalcitonin) or hospitalization length of stay. Specific chest CT patterns, especially in right middle lobe, could serve as indicators for the presence of co-infections and disease severity in noncritically ill Covid-19 patients, aiding clinicians in timely interventions and personalized treatment strategies.

Exploring patient experiences of surveillance for pancreatic cystic neoplasms: a qualitative study

BackgroundPancreatic cystic neoplasms (PCN) are considered premalignant conditions to pancreatic adenocarcinoma with varying degrees of cancerous potential. Management for individuals who do not require surgical treatment involves surveillance to assess...

The Usefulness of Intraepithelial Lymphocyte Immunophenotype Testing for the Diagnosis of Coeliac Disease in Clinical Practice.

The diagnosis of coeliac disease (CD) in adults is based on clinical, serological and histological criteria. The inappropriate performance of intestinal biopsies, non-specificity of mild histological lesions and initiation of a gluten-free diet (GFD) before biopsy may hamper the diagnosis. In these situations, determining the intraepithelial lymphogram of the duodenum by flow cytometry (IEL-FC) can be helpful. To describe the clinical scenarios in which the IEL-FC is used and its impact on the diagnosis of CD. All adult patients with suspected CD at three tertiary centres for whom the duodenal histology and IEL-FC were available were identified. Catassi and Fasano's diagnostic criteria and changes to a CD diagnosis after the IEL-FCs were collected. A total of 348 patients were included. The following indications for an IEL-FC formed part of the initial study for CD (38%): negative conventional work-up (32%), already on a GFD before duodenal biopsies (29%) and refractoriness to a GFD (2%). The IEL-FC facilitated a definitive diagnosis in 93% of patients with an uncertain diagnosis who had had a conventional work-up for CD or who were on a GFD before histology. The IEL-FC facilitates the confirmation or rejection of a diagnosis of CD in clinical scenarios in which a conventional work-up may be insufficient.

Quality of heart failure registration in primary care: observations from 1 million electronic health records in the Amsterdam Metropolitan Area.

Proper coding of heart failure (HF) in electronic health records (EHRs) is an important prerequisite for adequate care and research towards this vulnerable patient population. We set out to evaluate the accuracy of registration of HF diagnoses in primary care EHRs. In a routine primary care database covering the Amsterdam Metropolitan Area, we identified all episodes of care with International Classification of Primary Care (ICPC) codes K77 (decompensatio cordis) or K84.03 (cardiomyopathy) up to 31/12/2021. We also performed two text-based searches toidentify HF episodes without an appropriate ICPC-code. Anexpert panel evaluated all ICPC and text matches for congruence between the assigned codes and notes. From a database of 968,433 records we identified 19,106 patients (2.0 %) with a total of 24,011 ICPC-coded HF episodes. Removal of 1,324 episodes found to concern other or uncertain diagnoses and inclusion of 4,582 validated HF episodes identified through text search led to exclusion of 909 (overregistration: 4.8 %) and inclusion of 2,266 additional patients (underregistration: 11.1 %). The inclusion of miscoded HF episodes advanced the first known date of HFdiagnosis in 3.9 % of records, with a median shift of 3.45 years. Episode-level underregistration decreased significantly over time, from 23.8 % in 2006 to 10.0 % in 2021. While there is improvement over time, there are still substantial levels of over- and underregistration ofHF, emphasizing the need for cautious interpretation ofICPC-coded data. The findings contribute to the understanding of HF registration issues in primary care and provide insights for improving registration practices.

I123-FP-CIT (DaTSCAN) SPECT beyond the Most Common Causes of Parkinsonism: A Systematic Review.

As the diagnosis of Parkinson's disease (PD) is fundamentally clinical, the usefulness of ioflupane (123I) single-photon emission computed tomography (SPECT) or DaTSCAN as a diagnostic tool has been a matter of debate for years. The performance of DaTSCAN is generally recommended in the follow-up of patients with a clinically uncertain diagnosis, especially in those with a suspected essential tremor, drug-induced parkinsonism, or vascular parkinsonism. However, there is a dearth of DaTSCAN findings regarding neurodegenerative parkinsonisms besides PD and atypical parkinsonisms. To date, a specific nigrostriatal dopamine uptake pattern that would help differentiate PD from the most frequent atypical parkinsonisms is yet to be described. This fact is further complicated by the possible visualization of abnormalities in the uptake pattern in patients with rarer neurodegenerative parkinsonisms. We aimed to summarize the current literature regarding DaTSCAN findings in patients with rare neurodegenerative parkinsonisms. The PubMed database was systematically screened for studies in English or Spanish up to October 15, 2023, using search terms "DaTSCAN", "ioflupane", "DaT-SPECT", "123I-FP-CIT SPECT", "dopamine transporter imaging", and "[123I] FP-CIT SPECT". Duplicated publications and studies regarding PD, atypical parkinsonisms, dystonia-parkinsonism, essential tremor, and parkinsonism due to non-degenerative causes were excluded. The obtained results were reviewed and summarized, including DaTSCAN findings in fragile X-associated tremor/ataxia syndrome, prion diseases, Huntington's disease, spinocerebellar ataxia, hereditary spastic paraparesis, metabolic disorders, and other diseases (anti-IgLON5 disease, ring chromosome 20 syndrome, chorea-acanthocytosis, and neuronal ceroid lipofuscinosis). This review highlights the need to determine in the future the utility and cost-effectiveness of DaTSCAN, both as a diagnostic and a prognostic tool, in patients with parkinsonian symptoms in rare neurodegenerative diseases.

Hepatocellular Carcinoma Mimicking Focal Nodular Hyperplasia

Focal nodular hyperplasia (FNH) is a common benign liver lesion, mostly solitary, and with no evidence of malignant transformation over time. The diagnosis can usually be made by imaging modalities with distinct features in magnetic resonance imaging (MRI) and computed tomography (CT) scans. We present a case series of three patients with solitary liver tumors which were, based on radiological features, first diagnosed to be large FNH. The patients were sent to our center for second opinion and probable treatment. Indication for resection was given because of nonconclusive radiologic imaging in the first, substantial growth progression in the second and elevated alpha fetoprotein (AFP) in the third case. Histology revealed well to poor differentiated hepatocellular carcinoma (HCC). FNH tends to show a distinct pattern in imaging modalities, but HCC can mimic FNH. The MRI-scan using hepatotropic contrast agent is the most sensitive imaging modality to diagnose FNH. AFP is usually not elevated in FNH. Asymptomatic FNH does not require surgery but a reliable diagnosis is crucial. In case of an un-certain diagnosis surgery should be offered to patients. In cases with a progression in size, an elevated level of AFP should be suspicious. Generally, an over-therapy via surgery should be avoided and follow-ups of a newly diagnosed FNH including measurement of AFP are advisable to detect alterations.

Tips and tricks for a correct interpretation of contrast-enhanced ultrasound.

Although contrast-enhanced ultrasound (CEUS) is a widespread and easily manageable technique, image interpretation errors can occur due to the operator's inexperience and/or lack of knowledge of the frequent pitfalls, which may cause uncertain diagnosis and misdiagnosis. Indeed, knowledge of the basic physical and technical principles of ultrasound is needed both to understand sonographic image findings and to evaluate the potential and limits of the method. Like the B-mode ultrasound, the quality of the CEUS examination is also subject not only to the adequate manual skill of the operator but also to his/her deep knowledge of the technique which improves the quality of the image helping avoid misleading artifacts. In this review, the main parameters influencing a CEUS examination will be described by taking into account the most common errors and pitfalls and their possible solutions.

In vivo PET of synaptic density as potential diagnostic marker for cognitive disorders: prospective comparison with current imaging markers for neuronal dysfunction and relation to symptomatology - study protocol

Background18F-FDG brain PET is clinically used for differential diagnosis in cognitive dysfunction of unclear etiology and for exclusion of a neurodegenerative cause in patients with cognitive impairment in late-life psychiatric disorders. 18F-FDG PET measures regional glucose metabolism, which represents a combination of neuronal/synaptic activity but also astrocytic activity and neuroinflammation. Recently, imaging of synaptic vesicle protein 2 A (SV2A) has become available and was shown to be a proxy of synaptic density. This prospective study will investigate the use of 18F-SynVesT-1 for imaging SV2A and its discriminative power for differential diagnosis in cognitive disorders in a head-to-head comparison to 18F-FDG PET. In addition, simultaneous PET/MR allows an evaluation of contributing factors and the additional value of advanced MRI imaging to FDG/SV2A PET imaging will be investigated. In this work, the study design and protocol are depicted.MethodsIn this prospective, multimodal imaging study, 110 patients with uncertain diagnosis of cognitive impairment who are referred for 18F-FDG PET brain imaging in their diagnostic work-up in a tertiary memory clinic will be recruited. In addition, 40 healthy volunteers (HV) between 18 and 85 years (M/F) will be included. All study participants will undergo simultaneous 18F-SynVesT-1 PET/MR and an extensive neuropsychological evaluation. Amyloid status will be measured by PET using 18FNAV4694, in HV above 50 years of age. Structural T1-weighted and T2-weighted fluid-attenuated inversion recovery MR images, triple-tagging arterial spin labeling (ASL) and resting-state functional MRI (rs-fMRI) will be obtained. The study has been registered on ClinicalTrials.gov (NCT05384353) and is approved by the local Research Ethics Committee.DiscussionThe main endpoint of the study will be the comparison of the diagnostic accuracy between 18F-SynVesT-1 and 18F-FDG PET in cognitive disorders with uncertain etiology and in exclusion of a neurodegenerative cause in patients with cognitive impairment in late-life psychiatric disorders. The strength of the relationship between cognition and imaging data will be assessed, as well as the potential incremental diagnostic value of including MR volumetry, ASL perfusion and rs-fMRI.

Identification of Novel/Rare EWSR1 Fusion Partners in Undifferentiated Mesenchymal Neoplasms.

Recurrent gene fusions (GFs) in translocated sarcomas are recognized as major oncogenic drivers of the disease, as well as diagnostic markers whose identification is necessary for differential diagnosis. EWSR1 is a 'promiscuous' gene that can fuse with many different partner genes, defining different entities among a broad range of mesenchymal neoplasms. Molecular testing of EWSR1 translocation traditionally relies on FISH assays with break-apart probes, which are unable to identify the fusion partner. Therefore, other ancillary molecular diagnostic modalities are being increasingly adopted for accurate classification of these neoplasms. Herein, we report three cases with rare GFs involving EWSR1 in undifferentiated mesenchymal neoplasms with uncertain differential diagnoses, using targeted RNA-seq and confirming with RT-PCR and Sanger sequencing. Two GFs involved hormone nuclear receptors as 3' partners, NR4A2 and RORB, which have not been previously reported. NR4A2 may functionally replace NR4A3, the usual 3' partner in extraskeletal myxoid chondrosarcoma. The third GF, EWSR1::BEND2, has previously been reported in a subtype of astroblastoma and other rare entities, including a single case of a soft-tissue tumor that we discuss in this work. In conclusion, our findings indicate that the catalogue of mesenchymal neoplasm-bearing EWSR1 fusions continues to grow, underscoring the value of using molecular ancillary techniques with higher diagnostic abilities in the routine clinical setting.