Circulating isomiRs May Be Superior Biomarkers Compared to Their Corresponding miRNAs: A Pilot Biomarker Study of Using isomiR-Ome to Detect Coronary Calcium-Based Cardiovascular Risk in Patients with NAFLD.

Circulating miRNAs are increasingly being considered as biomarkers in various medical contexts, but the value of analyzing isomiRs (isoforms of canonical miRNA sequences) has not frequently been assessed. Here we hypothesize that an in-depth analysis of the full circulating miRNA landscape could identify specific isomiRs that are stronger biomarkers, compared to their corresponding miRNA, for identifying increased CV risk in patients with non-alcoholic fatty liver disease (NAFLD)-a clinical unmet need. Plasma miRNAs were sequenced with next-generation sequencing (NGS). Liver fat content was measured with magnetic-resonance spectrometry (MRS); CV risk was determined, beyond using traditional biomarkers, by a CT-based measurement of coronary artery calcium (CAC) score and the calculation of a CAC score-based CV-risk percentile (CAC-CV%). This pilot study included n = 13 patients, age > 45 years, with an MRS-measured liver fat content of ≥5% (wt/wt), and free of overt CVD. NGS identified 1103 miRNAs and 404,022 different isomiRs, of which 280 (25%) and 1418 (0.35%), respectively, passed an abundance threshold. Eighteen (sixteen/two) circulating miRNAs correlated positively/negatively, respectively, with CAC-CV%, nine of which also significantly discriminated between high/low CV risk through ROC-AUC analysis. IsomiR-ome analyses uncovered 67 isomiRs highly correlated (R ≥ 0.55) with CAC-CV%. Specific isomiRs of miRNAs 101-3p, 144-3p, 421, and 484 exhibited stronger associations with CAC-CV% compared to their corresponding miRNA. Additionally, while miRNAs 140-3p, 223-3p, 30e-5p, and 342-3p did not correlate with CAC-CV%, specific isomiRs with altered seed sequences exhibited a strong correlation with coronary atherosclerosis burden. Their predicted isomiRs-specific targets were uniquely enriched (compared to their canonical miRNA sequence) in CV Disease (CVD)-related pathways. Two of the isomiRs exhibited discriminative ROC-AUC, and another two showed a correlation with reverse cholesterol transport from cholesterol-loaded macrophages to ApoB-depleted plasma. In summary, we propose a pipeline for exploring circulating isomiR-ome as an approach to uncover novel and strong CVD biomarkers.

Molecularly Confirmed Female Donor-Transmitted Lobular Breast Cancer to Male following Renal Transplantation.

INTRODUCTION: Lobular breast cancer represents 10%-15% of breast cancers in women but is virtually nonexistent in men, related to the typical absence of the anatomic breast lobule structure in male breast tissue. We describe donor-transmitted metastatic lobular carcinoma to a male after kidney transplantation. Determining whether a post-transplant cancer is transplant associated, donor transmitted, or donor derived is significant for treatment, prognosis, and possibly management of other organ recipients. CASE REPORT: A 74-year-old Caucasian male presented to the emergency department with lower abdominal pain and macro-hematuria. Past medical history included two renal transplantations. Computed tomography identified a 4-5-cm space-occupying lesion in the native left kidney. A left native nephrectomy was performed. Histology pathologic examination demonstrated lobular (as opposed to ductal) breast carcinoma. Fluorescent in situ hybridization probes to identify X- and Y-chromosomes showed tumor cells with an XX genotype, whereas the surrounding host cells were of XY genotype. These findings confirmed the female-sex origin (donor) of the tumor within the XY native male (current patient) tissues. DISCUSSION/CONCLUSION: Due to discordance between the donor and recipient sex, fluorescent in situ hybridization as a molecular technique correctly identified the origin of an individual's cancer in the post-transplant setting. The metastatic breast cancer behaved more indolently than usually seen. Expanded criteria donors (ECD) are those who cannot donate under standard criteria for organ transplantation; expanded criteria widen the potential organ donor pool at the expense of increased risk for post-transplant complications (e.g., graft failure, the transmission of malignancy). The case provides a potential area of future research into considering allowing ECDs with a distant history of cancer with very low transmission risk when the biochemical environment of the recipient would, in the unlikely event of transmission, induce the tumor to pursue an indolent clinical course.

Treatment Modality and Second Primary Tumors of the Head and Neck.

INTRODUCTION: Second primary tumors (SPTs) in head and neck cancer are thought to occur from premalignant lesions that are present at the time of the primary tumor diagnosis. The association of the modality used to treat the primary lesion with SPT occurrence is not clear. OBJECTIVE: The aim of the study was to assess the incidence of SPTs in patients with head and neck malignancies, according to treatment modality. METHODS: We conducted a retrospective cohort study. All patients who were treated at Soroka Medical Center between 2000 and 2013 for a head and neck squamous cell carcinoma were assessed. Data analysis included tumor site of the primary and second primary and treatment modality of the primary tumor. In addition, demographics as well as habits were recorded as well. RESULTS: Of the 184 patients included in the cohort, SPT developed in 31 patients (17%) with a median time to diagnosis of 4.3 years. Smoking was reported in 74% of those with SPT and 78% of those without. The most common site for SPT was the lungs, with 13 cases, 42% of the total SPTs. Among patients who developed an SPT, for 12 of those with an index tumor in the oral cavity or oro-hypopharynx, 8 (67%) developed an SPT in the same location; for 18 of those with an index tumor in the larynx, 11 (61%) developed a SPT in the lungs and bronchi (p = 0.001). On multivariate analysis, the treatment modality used was not found to be associated with the occurrence of SPTs and the radiotherapy showed no protective or harmful effect (HR 0.64 p = 0.24). CONCLUSION: Treatment modality used for head and neck cancer does not seem to be associated with the occurrence of SPTs.

Blood-Brain Barrier Leakage: A New Biomarker in Transient Ischemic Attacks.

Background and Purpose- The diagnosis of transient ischemic attack is challenging. Evidence of acute ischemia on MRI diffusion-weighted imaging is highly variable and confirmed in only about one-third of patients. This study investigated the significance of blood-brain barrier dysfunction (BBBD) mapping in patients with transient neurological deficits, as a diagnostic and prognostic biomarker required for risk stratification and stroke prevention. Methods- We used dynamic contrast-enhanced MRI to quantitatively map BBBD in a prospective cohort study of 57 patients diagnosed with transient ischemic attack/minor stroke and 50 healthy controls. Results- Brain volume with BBBD was significantly higher in patients compared with controls ( P=0.002). BBBD localization corresponded with the clinical presentation in 41 patients (72%) and was more extensive in patients with acute infarct on diffusion-weighted imaging ( P=0.05). Patients who developed new stroke during follow-up had a significantly greater BBBD at the initial presentation ( P=0.03) with a risk ratio of 5.35 for recurrent stroke. Conclusions- This is the first description of the extent and localization of BBBD in patients with transient ischemic attack/minor stroke. We propose BBBD mapping as a valuable tool for detection of subtle brain ischemia and a promising predictive biomarker required for risk stratification and stroke prevention.

Uncommon Detection of Leiomyoma in the Penile Corpus Spongiosum Using FDG PET/CT: A Case Report.

ABSTRACT: Primary tumors of the penile corpus spongiosum are rare. Hereby we describe the scintigraphic findings of a case of penile leiomyoma within the corpus spongiosum tissue, which was incidentally detected on FDG PET/CT. The benign neoplasm was growing in close proximity to the urethra showing increased focal FDG uptake on sequential PET/CT studies. Subsequently, the patient experienced obstructive urinary symptoms, and the tumor was resected. We concluded that the possibility of neoplasm should be kept in mind while evaluating a patient with persistent focal penile FDG uptake, which may be the first and only manifestation of the disease.

Clinical and Radiological Characteristics of Non-Obese Female Patients with Idiopathic Intracranial Hypertension.

While the typical patient with idiopathic intracranial hypertension (IIH) is an obese female of childbearing age, there are unique patient populations, such as non-obese females, that have not been well studied. Characterizing this subpopulation may increase awareness our of it, which may prevent underdiagnosis and improve our understanding of IIH's underlying pathophysiology. We retrospectively reviewed electronic medical records and compared the clinical and radiological characteristics of non-obese (BMI < 30) and obese (BMI > 30) female patients with IIH. Two hundred and forty-six patients (age 32.3 ± 10) met our inclusion criteria. The non-obese patients (n = 59, 24%) were significantly younger than the obese patients (29.4 ± 9.9 vs. 33.2 ± 10.2, p = 0.004) and had higher rates of severe papilledema (Friesen 4-5; 25.4% vs. 11.8%, p = 0.019), scleral flattening (62.7% vs. 36.9%, p = 0.008), and optic nerve dural ectasia (78.0% vs. 55.6%, p = 0.044). Non-obese patients also had a tendency to have a higher lumbar puncture opening pressure (368 ± 92.7 vs. 344 ± 76.4, p = 0.062). Non-obese patients were three times more likely to present with a combination of scleral flattening and optic nerve dural ectasia (OR = 3.00, CI: 1.57-5.72, χ2 = 11.63, α < 0.001). Overall, non-obese females with IIH were found to have a more fulminant presentation, typified by higher rates of severe papilledema and radiological findings typical for IIH.

The impact of interactive clinically-based learning on the performance of medical students in radiology.

Objectives: The purpose of this study is to evaluate the effectiveness of changing the teaching method in the radiology course at a medical school from lecture-based learning to clinically case-based learning using interactive methods, with the aim to improve undergraduate radiology education and students' diagnostic abilities. Methods: During the 2018-2019 academic year, we compared the achievements of medical students in the radiology course. Teaching in the first year was primarily conducted through conventional lectures (traditional course; TC), while in the following year, a case-based teaching approach along with an interactive web application called "Nearpod" (clinically-oriented course; COC) was employed to motivate student participation. The student knowledge assessments were composed of identical post-test questions, which included five images of common diagnoses. The results were compared using Pearson's Chi-Square test or Fisher Exact Test. Results: There were 72 students who answered the post-test in the first year and 55 students responded in the second year. Post-test student achievements following the methodological changes were significantly higher as compared with the control group in the total grade (65.1 ± 21.5 vs. 40.8 ± 19.1, p < 0.001). An improvement in the identification rates of all assessed cases was noticed, with the most prominent improvement in pneumothorax recognition (4.2% vs. 61.8%, p < 0.001). Conclusion: Teaching radiology using clinical case-based teaching methods combined with web-based interactive applications like Nearpod results in significant improvements in identifying key imaging pathologies when compared to traditional teaching methods. This approach has the potential to enhance radiology learning and better prepare students for their future roles as clinicians.

Improved first-pass effect in acute stroke thrombectomy using Solitaire-X compared to Solitaire-FR.

Background: In acute ischemic stroke (AIS), successful endovascular thrombectomy (EVT) of large vessel occlusion (LVO) necessitates the most suited device. Solitaire-X has longer and larger diameter pusher wires than Solitaire-FR.As the role of a larger pusher-wire diameter is uncertain, we aim to compare procedural, clinical, and radiological outcomes for AIS patients undergoing EVT using either type of Solitaire device. Procedures were performed using the Solumbra technique, which combines a large-bore aspiration catheter with a stentriever. The primary outcome was to compare rates of successful first-pass recanalization (defined as TICI 2b/3 score). The secondary objectives were procedural (rates of successful recanalization), clinical (post-procedural NIHSS and days of hospitalization), and radiological (post-procedural ASPECT score and hemorrhagic transformation) outcome measures. Design: Consecutive AIS patients undergoing EVT for LVO were recruited into a prospective multicenter database at our academic center. We have used Solitaire-FR until October 2020 and Solitaire-X ever since. We retrospectively analyzed our prospective consecutive registry. Included in our analysis are patients undergoing EVT using Solitaire only; patients with tandem lesions or underlying stenosis requiring emergent stenting during the procedure were excluded. The cohort of patients treated with Solitaire-X was compared with a cohort consisting of the most recent consecutive cases undergoing EVT with the Solitaire-FR. Results: A total of 182 (71.9 ± 14, 61% male patients) AIS patients were included in the analysis with both groups (n = 91 each) sharing similar demographic characteristics, premorbid conditions, and stroke characteristics (time from symptom-onset, NIHSS, ASPECTS, occlusion site, and rates of intravenous-tPA treatment). The Solitaire-X group had a higher rate of first-pass recanalization (65.9% vs. 50.5%, p = 0.049). On 24-h post-procedural head-CT, the Solitaire-X group had higher ASPECT scores (6.51 ± 2.9 vs. 5.49 ± 3.4, p = 0.042) and lower post-procedural average bleeding volumes (0.67 ± 2.1 vs. 1.20 ± 3.4 mL, p = 0.041). The Solitaire-X group had shorter duration of hospitalization (16.6 ± 13.1 days vs. 25.1 ± 23.2, p = 0.033). On multivariate analysis, using Solitaire-X was the sole independent predictor of first-pass recanalization (OR 2.17, 95% CI 1.12-4.26, p = 0.023). Conclusion: In our study, the use of the Stentriever-X with a larger pusher-wire diameter was associated with a higher likelihood of first-pass effect and improved procedural, clinical, and radiological outcomes in AIS patients.

Emergent cerebral venous stenting: A valid treatment option for fulminant idiopathic intracranial hypertension.

BACKGROUND: Fulminant idiopathic intracranial hypertension (FIIH) is characterized by rapid, severe, progressive vision loss and often treated surgically. Cerebral transverse venous stenting (CTVS) is efficacious in IIH patients, but emergent CTVS in FIIH is rarely reported. We present our experience with emergent CTVS in patients with FIIH. METHODS: Since 01/2019, an institutional protocol allowed emergent CTVS in FIIH patients with bilateral transverse sinus stenosis and gradient pressure > 15 on digital subtraction angiography (DSA). We retrospectively analyzed a prospective registry of all IIH patients with details of neurological and neuro-ophthalmological assessments before and after treatment, and subjective assessments of headache and tinnitus were made pre-and post-procedure. RESULTS: 259 IIH patients, including 49 who underwent CTVS, were registered. Among them, five female patients met inclusion criteria for FIIH and underwent emergent CTVS. FIIH patients were younger (18.8 ± 1.64 vs 27.7 ± 4.85, p < 0.01), mean BMI was lower (30.8 ± 10.57 vs 34.6 ± 4.3, p < 0.01), and lumbar puncture opening pressure higher (454 ± vs 361 ± 99.4, p < 0.01) than that of IIH patients. They presented with acute visual loss, severe headache, papilledema, significant bilateral transverse sinus stenosis on CT-venography, and mean dominant side gradient pressure of 26.4 ± 6.2 on DSA. CTVS was performed without significant complications, resulting in remarkable improvement in headache, optical coherence tomography, and visual fields within 1 week. At 1-year follow-up (four patients) and 6-month follow-up (1 patient), there was complete resolution of papilledema and headache, and marked improvement in visual acuity. CONCLUSIONS: In these patients, emergent-CTVS was a safe and effective treatment option for FIIH. Further evaluation is warranted.

Pleural hemangioma: A case report and review of the literature.

A middle-aged female with history of multinodular goiter, Hashimoto disease, and chronic vitamin B12 deficiency presented with palpitations and subsequent exertional dyspnea. Initial radiographic analysis suggested mediastinal cavernous hemangioma, but biopsy showed features consistent with pleural hemangioma. Pleural hemangioma should be considered among the differential diagnoses for recurrent unilateral pleural effusion. Pleural hemangioma should be distinguished from other more common entities including the similarly benign pulmonary hemangioma and the more aggressive pleural hemangioendothelioma.

Müllerian duct cyst: Case report with updates in cellular origin, corresponding immunohistochemistry, and contrast to prostatic utricle cyst.

A 20-year-old male presented to the emergency department with lower abdominal pain, urinary retention, and constipation. Computed tomography (CT) revealed a large cyst on the posterior aspect of the prostate gland; he was ultimately diagnosed with a Müllerian duct cyst (MDC). Although much has been written on the radiologic diagnosis of such cysts, there is a paucity of recent literature concerning the pathological diagnosis. While older studies debated the Müllerian origin of a midline cyst abutting the poster prostate, we believe that with the advent of monoclonal PAX8 (which was positive in this lesion) and monoclonal PAX2 (which was negative), we have strong evidence that the present cyst is indeed of Müllerian origin. Further, there is debate in the literature as to whether MDC is synonymous or distinct from prostatic utricle cyst. We present an interdisciplinary analysis as to the merits and weaknesses of both sides of the debate and how data gathered from the current case could be used in a future, larger study to arrive at a more definitive conclusion.

Distorted Optic Nerve Portends Neurological Complications in Infants With External Hydrocephalus.

Background: Benign external hydrocephalus (BEH) is defined by rapid increase in head circumference in infancy, with neuroimaging evidence of enlarged cerebrospinal fluid (CSF) spaces. BEH was postulated to predispose to subdural hematoma, neurocognitive impairments, and autism. There is currently no consensus on BEH diagnostic criteria and no biomarkers to predict neurological sequalae. Methods: MRI-based quantitative approach was used for measurement of potential imaging markers related to external hydrocephalus and their association with neurological outcomes. We scanned 23 infants diagnosed with BEH and 11 age-similar controls. Using anatomical measurements from a large sample of healthy infants (n = 150), Z-scores were calculated to classify subject's CSF spaces as enlarged (≥1.96SD of mean values) or normal. Results: Subjects with abnormally enlarged CSF spaces had a significantly wider and longer ON (p = 0.017 and p = 0.020, respectively), and a significantly less tortuous ON (p = 0.006). ON deformity demonstrated a high diagnostic accuracy for abnormally enlarged frontal subarachnoid space (AUC = 0.826) and interhemispheric fissure (AUC = 0.833). No significant association found between enlarged CSF spaces and neurological complications (OR = 0.330, 95%CI 0.070-1.553, p = 0.161). However, cluster analysis identified a distinct subgroup of children (23/34, 67.6%) with enlarged CSF spaces and a wider, longer and less tortuous ON, to have an increased risk for neurological complications (RR = 7.28, 95%CI 1.07-49.40). Discussion: This is the first report on the association between external hydrocephalus, ON deformity and neurological complications. Our findings challenge the current view of external hydrocephalus as a benign condition. ON deformity is a potential auxiliary marker for risk stratification in patients with enlarged CSF spaces.

Paroxysmal slow cortical activity in Alzheimer's disease and epilepsy is associated with blood-brain barrier dysfunction.

A growing body of evidence shows that epileptic activity is frequent but often undiagnosed in patients with Alzheimer's disease (AD) and has major therapeutic implications. Here, we analyzed electroencephalogram (EEG) data from patients with AD and found an EEG signature of transient slowing of the cortical network that we termed paroxysmal slow wave events (PSWEs). The occurrence per minute of the PSWEs was correlated with level of cognitive impairment. Interictal (between seizures) PSWEs were also found in patients with epilepsy, localized to cortical regions displaying blood-brain barrier (BBB) dysfunction, and in three rodent models with BBB pathology: aged mice, young 5x familial AD model, and status epilepticus-induced epilepsy in young rats. To investigate the potential causative role of BBB dysfunction in network modifications underlying PSWEs, we infused the serum protein albumin directly into the cerebral ventricles of naïve young rats. Infusion of albumin, but not artificial cerebrospinal fluid control, resulted in high incidence of PSWEs. Our results identify PSWEs as an EEG manifestation of nonconvulsive seizures in patients with AD and suggest BBB pathology as an underlying mechanism and as a promising therapeutic target.

Diagnosing necrotic meningioma: a distinctive imaging pattern in diffusion MRI and MR spectroscopy.

The differential diagnosis of necrotic meningiomas includes brain abscess and malignant neoplasms. We report and discuss hereby the work-up of two patients diagnosed with necrotic meningioma using diffusion-weighted imaging, magnetic resonance spectroscopy, resective surgery, and histopathology. The purpose of the present article is to add to the scant literature on the use of advanced imaging modalities in the routine investigation of brain lesions and their utility in arriving at the final diagnosis.