Diagnostic Yield In Patients Research Articles

Rapid Whole-Genome Sequencing in Acutely Ill Children: A Single Pediatric Center Experience

AbstractThe aim of this study was to describe the turnaround time, diagnostic yield, and clinical impact of rapid whole-genomic sequencing (rWGS). We conducted a prospective observational study in acutely ill children (0–21 years) with an undiagnosed, potentially genetic abnormality in a children's hospital. A phenotype-prioritized analysis approach for rWGS was utilized. The turnaround times, diagnostic yield, number of genes detected, inheritance pattern, zygosity, and the clinical impact of positive or negative tests were analyzed. Out of a total of 109 children, 92 abnormal (pathogenic or likely pathogenic) gene variants were detected in 60 (55%) patients. There were 45 neonates, 35 infants, and 29 children. The admission location was 49.5, 34.9, and 15.6% in the pediatric intensive care unit (PICU), neonatal intensive care unit (NICU), and cardiac intensive care unit (CICU), respectively. The median (interquartile range [IQR]) times for the return of preliminary and final results were 3 (2–5) and 10 (6–14) days, respectively. With ultra-rapid processing, the median time to final results was shorter (5 [3–7] vs. 12 [7.75–15] days). Neurologic issues were the most common underlying admission diagnoses. The diagnostic yield for a causative gene was 47.7%. The diagnostic yield was not different based on age group or location of admission but higher in metabolic issues (78.6 vs. 43.2%; odds ratio [OR]: 4.8; 95% confidence interval [CI]: 1.3–18.4). There was a change in clinical management in 39.4%. In acutely ill children with undiagnosed conditions and with clinical suspicion of a genetic disorder, rWGS detected gene variants in 55% with a diagnostic yield of 47.7% and resulted in a change in the management in 39.4%. The diagnostic yield in patients with metabolic conditions was the highest.

Dobutamine Stress Echocardiography in Low-Gradient Aortic Stenosis

Guidelines recommend the use of dobutamine stress echocardiography (DSE) in patients with low-gradient aortic stenosis (AS) and left ventricular ejection fraction (LVEF)<50%. However, a paucity of DSE data exists when LVEF >35%. To examine the diagnostic accuracy of DSE in patients with low-gradient AS with a wide range of LVEF and to examine the interaction between the diagnostic accuracy of DSE and LVEF. Patients with mean gradient <40mm Hg, aortic valve area <1.0cm2, and stroke volume index ≤35mL/m2 undergoing DSE and cardiac computer tomography (C-CT) were identified from 3 prospectively collected patient cohorts and stratified according to LVEF: LVEF<35%, LVEF 35% to 50%, and LVEF>50%. Dobutamine stress echocardiography and C-CT were performed on patients with low-gradient AS. Severe AS was defined as aortic valve calcification score ≥2,000 arbitrary units (AU) among men and ≥1,200 AU for women on C-CT. Of 221 patients included in the study, 78 (35%) presented with LVEF <35%, 67 (30%) with LVEF 35% to 50%, and 76 (34%) with LVEF >50%. Mean-gradient and aortic valve peak velocity during DSE showed significant diagnostic heterogeneity between LVEF groups, being most precise when LVEF <35% (both areas under the curve [AUC]=0.90), albeit with optimal thresholds of 30mm Hg and 377cm/sec and a limited diagnostic yield in patients with LVEF ≥35% (AUC=0.67 and 0.66 in LVEF 35% to 50% and AUC=0.65 and 0.60 in LVEF ≥50%). Using guideline thresholds led to a sensitivity/specificity of 49%/84% for all patients with LVEF <50%. While DSE is safe and leads to an increase in stroke volume in patients with low-gradient AS regardless of LVEF, the association between DSE gradients and AS severity assessed by C-CT demonstrates important heterogeneity depending on LVEF, with the highest accuracy in patients with LVEF <35%.

Clinician-Driven Reanalysis of Exome Sequencing Data From Patients With Inherited Retinal Diseases

Despite advances in next-generation sequencing (NGS), a significant proportion of patients with inherited retinal disease (IRD) remain undiagnosed after initial genetic testing. Exome sequencing (ES) reanalysis in the clinical setting has been suggested as one method for improving diagnosis of IRD. To investigate the association of clinician-led reanalysis of ES data, which incorporates updated clinical information and comprehensive bioinformatic analysis, with the diagnostic yield in a cohort of patients with IRDs in Korea. This was a multicenter prospective cohort study involving 264 unrelated patients with IRDs, conducted in Korea between March 2018 and February 2020. Comprehensive ophthalmologic examinations and ES analyses were performed, and ES data were reanalyzed by an IRD specialist for single nucleotide variants, copy number variants, mobile element insertions, and mitochondrial variants. Data were analyzed from March to July 2023. Diagnostic rate of conventional bioinformatic analysis and clinician-driven ES reanalysis. A total of 264 participants (151 [57.2%] male; mean [SD] age at genetic testing, 33.6 [18.9] years) were enrolled, including 129 patients (48.9%) with retinitis pigmentosa and 26 patients (9.8%) with Stargardt disease or macular dystrophy. Initial bioinformatic analysis diagnosed 166 patients (62.9%). Clinician-driven reanalysis identified the molecular cause of diseases in an additional 22 patients, corresponding to an 8.3-percentage point increase in diagnostic rate. Key factors associated with new molecular diagnoses included clinical phenotype updates (4 patients) and detection of previously overlooked variation, such as structural variants (9 patients), mitochondrial variants (3 patients), filtered or not captured variants (4 patients), and noncanonical splicing variants (2 patients). Among the 22 patients, variants in 7 patients (31.8%) were observed in the initial analysis but not reported to patients, while those in the remaining 15 patients (68.2%) were newly detected by the ES reanalysis. In this cohort study, clinician-centered reanalysis of ES data was associated with improved molecular diagnostic yields in patients with IRD. This approach is important for uncovering missed genetic causes of retinal disease.

Assessing the effectiveness and safety of transbronchial lung cryobiopsy utilizing a flexible bronchoscope with an endobronchial blocker in diffuse parenchymal lung lesions.

Transbronchial lung cryobiopsy (TBLC) with flexible bronchoscope represents an encouraging modality to obtain a larger size specimen without crush artifact, and a higher diagnostic yield in patients with diffuse parenchymal lung lesions/diseases as compared to conventional transbronchial lung biopsy, and fewer complications as opposed to surgical lung biopsy. Artificial airway is preferred as it provides better airway protection in cases of severe bleeding. Although various researchers have published data on different modalities, the data is not sufficient to standardize a single technique. This study describes the procedural technique, safety, and yield of TBLC using a flexible bronchoscope with an endobronchial blocker. We performed a retrospective analysis of 100 consecutive patients who underwent TBLC using flexible bronchoscopy from May 2018 to June 2022. TBLC samples were obtained under moderate sedation without the use of artificial airway or fluoroscopy. Among the 100 patients, the majority were male (63%). The mean age of the enrolled patients was 44.43±15.92 years. The predominant diagnoses in our study were hypersensitivity pneumonitis (27%), followed by sarcoidosis (12%) and tuberculosis (10%). We obtained alveolated lung tissue in 90 out of 100 cases with a median biopsy size of 5 mm (in greatest dimension, interquartile range 5-4 mm), resulting in a specific histopathological diagnosis in 82 cases. The most frequent complications were bleeding and pneumothorax (13%). Mild bleeding occurred in 58% of the patients, and moderate bleeding occurred in 20% of the patients. There was no episode of severe/life-threatening bleeding. None of the patients required intensive care unit admission or endotracheal intubation. In conclusion, the use of TBLC through flexible bronchoscopy with an endobronchial blocker emerges as a minimally invasive, secure, time-efficient, and readily reproducible technique. Significantly, this procedure can be seamlessly executed in the bronchoscopy suite, eliminating the requirement for an artificial airway or general anesthesia.

Robotic-assisted Navigation Bronchoscopy: A Meta-Analysis of Diagnostic Yield and Complications.

Robotic-assisted navigation bronchoscopy (RANB) is a novel method to biopsy lung nodules, with initial reports demonstrating excellent accuracy. We aimed to evaluate pooled estimates of diagnostic yields and complication rates with RANB by performing a meta-analysis of the available literature. We searched 3 databases, including PubMed, EmBase, and Web of Science. The resulting abstracts were reviewed by 2 investigators. Analyses were performed using random effects models, and diagnostic yield and complication rates were estimated after the Freeman-Tukey transformation. A total of 23 articles, comprising 1409 patients and 1541 nodules, were included in the final analysis. Mean ages ranged from 63.2 to 69.3 years. The average size of the nodules ranged between 5.9 and 25.0mm. Most patients (54.0% to 92.0%) had a current or prior smoking history in studies that reported them (n=8). The pooled diagnostic yield was 81.9% (12 studies, 838 nodules, 95% CI: 83.4%-91.0%), and the pooled sensitivity for malignancy was 87.6% (8 studies, 699 nodules, 95% CI: 81.3%-89.5%). The pooled incidence of pneumothorax rates was 0.60% (95% CI: 0.11%-1.35%). The pooled incidence of major bleeding was <0.01%. Diagnostic yield for patients with pulmonary nodules undergoing RANB is high, though may be impacted by the prevalence of malignancy, participant selection, and publication bias. Complication rates, including pneumothoraces and bleeding rates, appear low across all studies. If RANB is available, clinicians should consider utilizing this platform to biopsy pulmonary nodules.

Prospective evaluation of NGS-based sequencing in epilepsy patients: results of seven NASGE-associated diagnostic laboratories.

Epilepsy is one of the most common and disabling neurological disorders. It is highly prevalent in children with neurodevelopmental delay and syndromic diseases. However, epilepsy can also be the only disease-determining symptom. The exact molecular diagnosis is essential to determine prognosis, comorbidity, and probability of recurrence, and to inform therapeutic decisions. Here, we describe a prospective cohort study of patients with epilepsy evaluated in seven diagnostic outpatient centers in Germany. Over a period of 2 months, 07/2022 through 08/2022, 304 patients (317 returned result) with seizure-related human phenotype ontology (HPO) were analyzed. Evaluated data included molecular results, phenotype (syndromic and non-syndromic), and sequencing methods. Single exome sequencing (SE) was applied in half of all patients, followed by panel (P) testing (36%) and trio exome sequencing (TE) (14%). Overall, a pathogenic variant (PV) (ACMG cl. 4/5) was identified in 22%; furthermore, a significant number of patients (12%) carried a reported clinically meaningful variant of unknown significance (VUS). The average diagnostic yield in patients ≤ 12 y was higher compared to patients >12 y cf. Figure 2B vs. Figure 3B. This effect was more pronounced in cases, where TE was applied in patients ≤ 12 vs. >12 y [PV (PV + VUS): patients ≤ 12 y: 35% (47%), patients > 12 y: 20% (40%)]. The highest diagnostic yield was achieved by TE in syndromic patients within the age group ≤ 12 y (ACMG classes 4/5 40%). In addition, TE vs. SE had a tendency to result in less VUS in patients ≤ 12 y [SE: 19% (22/117) VUS; TE: 17% (6/36) VUS] but not in patients >12 y [SE: 19% (8/42) VUS; TE: 20% (2/10) VUS]. Finally, diagnostic findings in patients with syndromic vs. non-syndromic symptoms revealed a significant overlap of frequent causes of monogenic epilepsies, including SCN1A, CACNA1A, and SETD1B, confirming the heterogeneity of the associated conditions. In patients with seizures-regardless of the detailed phenotype-a monogenic cause can be frequently identified, often implying a possible change in therapeutic action (36.7% (37/109) of PV/VUS variants); this justifies early and broad application of genetic testing. Our data suggest that the diagnostic yield is highest in exome or trio-exome-based testing, resulting in a molecular diagnosis within 3 weeks, with profound implications for therapeutic strategies and for counseling families and patients regarding prognosis and recurrence risk.

Timing of cardiac magnetic resonance and diagnostic yield in patients with myocardial infarction with nonobstructive coronary arteries

Introduction and objectivesThe present study sought to establish the diagnostic yield of cardiovascular magnetic resonance (CMR) in a large cohort of patients admitted with myocardial infarction (MI) with nonobstructive coronary artery disease (MINOCA) based on the timing of referral to CMR. MethodsConsecutive patients referred to CMR from January 2009 to February 2022 with a working diagnosis of MINOCA were retrospectively evaluated. Cine, T2-weighted, early, and late gadolinium-enhanced images were acquired and analyzed. The frequency of the underlying diagnosis and the association between timing of CMR and relative frequency of each diagnosis were assessed. ResultsWe included 207 patients (median age 50 years, 60% men). Final diagnosis after CMR was achieved in 91% of the patients (myocarditis in 45%, MI in 20%, tako-tsubo cardiomyopathy in 19%, and other cardiomyopathies in 7%). The performance of CMR within 7 days of admission with MINOCA (median, 5 days; 117 patients) allowed a higher diagnostic yield compared with CMR performed later (median, 10 days; 88 patients) (96% vs 86%, P=.02). Although myocarditis was the most frequent diagnosis in both groups according to time to CMR, its frequency was higher among patients with a CMR performed within the first 7 days (53% vs 35%, P=.02). The frequency of other underlying diagnoses was not influenced by CMR timing. ConclusionsCMR led to an underlying diagnosis of MINOCA in 91% of patients and its diagnostic yield increased to 96% when CMR was performed within 7 days of admission. The most frequent diagnosis was myocarditis..

Multi-vessel Coronary Function Testing increases diagnostic yield in INOCA

Abstract Background Coronary vasomotor disorders (CVDs), comprising endotypes of coronary spasm and/or microcirculatory impairment, are common amongst patients with ischaemia and no obstructive coronary arteries (INOCA). Invasive coronary function testing (CFT) is the gold standard for diagnosing CVDs [1]. Most institutions recommend only testing the left coronary circulation focusing on the left anterior descending (LAD) artery as it typically subtends the largest myocardial territory [2]. Current practice is based on consensus, and it is unknown whether testing multiple coronary territories will increase diagnostic yield. Purpose To evaluate the diagnostic yield of multi-vessel, compared to single-vessel CFT in patients with INOCA. Methods Multi-vessel CFT was systematically performed in patients with suspected CVD. Vasoreactivity testing was performed through acetylcholine provocation in the left (20-200mcg) and right (20-80mcg) coronary artery. Incremental doses were manually injected via a guiding catheter over 20 seconds. A pressure-temperature sensor guidewire was used for coronary physiology assessment in all three epicardial vessels (figure 1). Microvascular or vasospastic angina was diagnosed according to previously published international consensus. Results A total of 50 patients (57.5+/-12.8years with 60% females) and 147 vessels were included from 2 tertiary referral institutions. Compared to single-vessel CFT, multi-vessel testing resulted in more patients diagnosed with coronary vasomotor dysfunction (80% vs 62%, p = &amp;lt;0.0001), vasospastic angina (50% vs 38%, p = 0.04) and microvascular angina (58% vs 38%, p = 0.004) (figure 2). Epicardial vasospasm (n=25) predominated in the left coronary system (n = 19), though isolated right coronary spasm was noted in 20.7% (n=6).Over half the patients (n=28) had coronary microvascular dysfunction (CMD), 50% had 1-vessel CMD, 35.7% had 2-vessel CMD, 14.3% had 3-vessel CMD. CMD was observed at a similar rate in the territories supplied by all three major coronary vessels (LAD = 36%, LCX = 28%, RCA = 28%, p = 0.648). Conclusion Multi-vessel CFT resulted in an increased diagnostic yield in patients with INOCA when compared to single-vessel testing. The results of this study suggest that multi-vessel CFT has a role in the management of patients with INOCA.Multi-vessel CFT algorithmDiagnostic yield of multi-vessel CFT

Video-EEG in the first 24 hours after the first unprovoked seizure in patients with normal neurological examination and head CT scan

Purpose: to determine the yield of Video-Electroencephalogram (VEEG) in the first 24 h in patients with a first unprovoked seizure and normal neurological examination, laboratory findings, and cranial CT scans. Methods: we analyzed retrospectively the yield of VEEG performed in these patients in the emergency department. All the patients were subsequently seen in the Epilepsy Clinic, and the epilepsy diagnosis was confirmed. Results: we included 19 patients who met the inclusion criteria; all of them underwent VEEG with the 10–20 system within the first 24 h after the seizure. The duration of the recordings averaged at 108.53 min and may or may not have included intermittent photic stimulation and sleep recording; 74% of the recordings were abnormal, with 26% being normal. Among the abnormal cases, epileptogenic activity was found in 47% and seizures in 26% of the patients; because both findings could be present in the same VEEG, 63% of all the VEEG showed epileptogenic alterations or seizures. The VEEG anomalies were recorded before the 20th minute (standard VEEG duration) in 58% of patients who exhibited epileptogenic activity and/or seizures, and after the 20th minute in 42%. Conclusion: conducting approximately 100-minute VEEGs within the first 24 h after a first unprovoked seizure can enhance the diagnostic yield in patients with epilepsy. However, the study has the limitations of its sample size and retrospective nature.

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients.

Familial dilated cardiomyopathy (DCM) causes heart failure and may lead to heart transplantation. DCM is typically a monogenic disorder with autosomal dominant inheritance. Currently disease-causing variants have been reported in over 60 genes that encode proteins in sarcomeres, nuclear lamina, desmosomes, cytoskeleton, and mitochondria. Over half of the patients undergoing comprehensive genetic testing are left without a molecular diagnosis even when patient selection follows strict DCM criteria. This study was a retrospective review of patients referred for genetic testing at Blueprint Genetics due to suspected inherited DCM. Next generation sequencing panels included 23-316 genes associated with cardiomyopathies and other monogenic cardiac diseases. Variants were considered diagnostic if classified as pathogenic (P) or likely pathogenic (LP). Of the 2,088 patients 514 (24.6%) obtained a molecular diagnosis; 534 LP/P variants were observed across 45 genes, 2.7% (14/514) had two diagnostic variants in dominant genes. Nine copy number variants were identified: two multigene and seven intragenic. Diagnostic variants were observed most often in TTN (45.3%), DSP (6.7%), LMNA (6.7%), and MYH7 (5.2%). Clinical characteristics independently associated with molecular diagnosis were: a lower age at diagnosis, family history of DCM, paroxysmal atrial fibrillation, absence of left bundle branch block, and the presence of an implantable cardioverter-defibrillator. Panel testing provides good diagnostic yield in patients with clinically suspected DCM. Causative variants were identified in 45 genes. In minority, two diagnostic variants were observed in dominant genes. Our results support the use of genetic panels in clinical settings in DCM patients with suspected genetic etiology.

Targeted gene panel provides advantages over whole-exome sequencing for diagnosing obesity and diabetes mellitus.

A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause. Here, we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes. We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing (WES) data available for 146 of these patients. The coverage of targeted gene panel sequencing was significantly higher than that of WES. The diagnostic yield in patients sequenced by the panel was 32.9% with subsequent WES leading to three additional diagnoses with two novel genes. In total, 178 variants in 83 genes were detected in 146 patients by targeted sequencing. Three of the 178 variants were missed by WES, although the WES-only approach had a similar diagnostic yield. For the 335 samples only receiving targeted sequencing, the diagnostic yield was 32.2%. In conclusion, taking into account the lower costs, shorter turnaround time, and higher quality of data, targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES. Therefore, this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.

Genetic diagnosis of kidney disease by whole exome sequencing and its clinical application.

The genetic spectrum of genetic kidney diseases (GKD) and the application of genetic diagnoses to patient care were assessed by whole exome sequencing (WES) of the DNA of 172 pediatric or adult patients with various kidney diseases. WES diagnosed genetic diseases in 63 (36.6%) patients. The diagnostic yields in patients with glomerulopathy were 33.8% (25/74 pts) due to variants in 10 genes, 58.8% (20/34) in patients with tubulointerstitial disease due to variants in 18 genes, 33.3% (15/45) in patients with cystic disease/ciliopathy due to variants in 10 genes, 18.2% (2/11) in patients with congenital anomalies of the kidneys and urinary tract (CAKUT) due to variants in two genes, and 12.5% (1/8) in patients with end stage kidney disease (ESKD). The diagnosis rate was high in patients aged <1-6 years (46-50.0%), and low in patients aged ≥40 years (9.1%). Renal phenotype was reclassified in 10 (15.9%) of 63 patients and clinical management altered in 10 (15.9%) of 63 patients after genetic diagnosis. In conclusion, these findings demonstrated the diagnostic utility of WES and its effective clinical application in patients, with various kinds of kidney diseases, across the different age groups.

Small Bowel Capsule Endoscopy: Experience from a single large tertiary care centre.

Background and study aims Capsule endoscopy (CE) has transformed examination of the small bowel (SB), once considered a dark continent. The present study aimed to describe the indications, diagnostic yield, practical issues and complications of CE in one of the largest tertiary center in India. Patients and methods This retrospective analysis from a prospectively maintained database, conducted from January 2013 to June 2021 included 1155 CEs performed during this period. Patient medical records were reviewed for indications, results, and complications of CE. Results A total of 1154 patients (809 males and 345 females), mean age 53 years (range 6-87 years), one capsule got stuck in the esophagus, were included in the study. Active SB bleeding had no effect on SB transit time (324.7±161 minutes, n = 137 patients with active bleed vs 310.6±166.9 minutes, n = 1017 patients without active bleed; P = 0.35). The indication and diagnostic yield (DY) of CE were potential overt SB bleed (68.6% & 43.9%), potential occult SB bleed (8.2% and 40%), chronic diarrhea (7.9% and 28.4%), abdominal pain (6.5% and 21.3%), anemia (5.9% and 57.9%), and suspected/known case of Crohn's disease (2.3% & 56.5%) respectively. The DY for patients with age ≥60 years was similar to those with age < 60 years (61.9% vs. 51.8% respectively; P = 0.4). 21 patients (1.8%) had capsule retention of which six (0.5%) had to be referred for surgery. Conclusions CE is a safe and effective investigation with ever increasing range of indications. Potential SB bleed remains the most common indication for CE with high detection rate.

COVID-19 Associated Mucormycosis

Abstract This case series explores Covid-19 associated Mucormycosis (CAM), its risk factors, clinical features and outcomes from a tertiary centre in Maharashtra, India, during the second wave of COVID-19. Methods: A retrospective, observational case series of 104 consecutive patients admitted to the hospital at various stages of complications of CAM, during the second wave of the COVID-19 pandemic (Jan’21-Apr’21). The diagnosis was confirmed using Potassium hydroxide wet mount (KOH), histopathology, fungal culture, and Cone-Beam Computed Tomography(CBCT). Results: There were 81% men, mean age of 49 ± 12.4 years, and all patients had a history of corticosteroids usage, 82% had a prior diagnosis of diabetes mellitus (DM) and the rest were newly diagnosed. Diagnosis of mucormycosis was confirmed on 2 modalities in 71%; KOH and histopathology in 31 (30%), and fungal culture with KOH and histopathology together detected 25 (24%). 9% were diagnosed exclusively with CBCT. Patients with prior DM had higher morbidity OR 8.30 [95% CI: 2.12, 32.5; p=0.002] and mortality OR 13.23 [95% CI: 1.67, 104.7; p=0.014] than non-DM patients. Mortality was higher in patients with rhino + orbital involvement than patients with rhino + maxillary involvement [OR 8.37 [95% CI: 1.52, 46.09; p=0.014]. Conclusion: Diabetes remained the highest risk factor for the development of CAM in patients with COVID-19 on corticosteroids, with high mortality and morbidity. Timely medical and surgical interventions and multi-disciplinary approaches could potentially reduce mucormycosis-associated mortality. Among the diagnostic modalities, detection using CBCT may increase the diagnostic yield in patients not detected in other modalities.

Is Bone Marrow Aspiration and Biopsy of Clinical Importance in the Initial Staging of Extraskeletal Ewing Sarcoma?

Extraskeletal Ewing sarcoma are rare tumors within the Ewing sarcoma family. Initial staging studies for extraskeletal Ewing sarcoma historically have included imaging and bone marrow aspiration and biopsy (BMAB). However, recent studies on Ewing sarcoma of bone have questioned the utility of BMAB in the initial staging of patients, but no studies of which we are aware have evaluated the role of BMAB in extraskeletal Ewing sarcoma. We suspected that BMAB was of low diagnostic yield in patients with extraskeletal Ewing sarcoma and exposed patients to potential morbidity without an impact on their clinical course. Is BMAB a useful test in the staging of extraskeletal Ewing sarcoma? Between January 1996 and December 2021, our institution evaluated 109 patients with a listed diagnosis of extraskeletal Ewing sarcoma. Those patients were retrospectively reviewed for this study. Of those, we considered patients with biopsy-confirmed diagnosis of extraskeletal Ewing sarcoma. Biopsy was performed based on institutional protocols, with all diagnoses assigned by a board-certified pathologist. Based on that criteria, 96% (105 of 109) were eligible. An additional 18% (20 of 109) were excluded because records of their initial diagnostic and staging workup were not available. This left 78% (85 of 109) for analysis. Of those, 52% (44 of 85) were male. The average age was 32 ± 16 years. Primary tumor locations included extremities in 26% (22 of 85), paraspinal in 20% (17 of 85), chest in 19% (16 of 85), retroperitoneum in 13% (11 of 85), intraabdominal in 12% (10 of 85), intrapelvic in 7% (6 of 85), and head or neck in 4% (3 of 85). Initial diagnostic and staging information, including the use of PET-CT, bone scan, CT chest, and BMAB, was collected. Metastatic disease at the time of presentation or during follow-up was noted. The utility of BMAB was determined by the rate of positive tests in those undergoing BMAB during the initial staging process. Descriptive statistical analysis was sufficient to address the study question, and therefore no comparative statistics were performed. BMAB was obtained during the initial staging process in 64% (54 of 85) of patients. This BMAB was negative in all 54 patients, including those with known metastatic disease. Diagnosing metastatic disease in extraskeletal Ewing sarcoma is important as the presence of metastases at diagnosis adversely affects prognosis. The routine use of BMAB in the staging process of extraskeletal Ewing sarcoma is of low diagnostic yield. BMAB is unlikely to diagnose metastatic involvement even in patients with known metastases to bone. We do not have enough data to suggest whether other modalities, such as PET-CT, might be more useful. Similar studies should be pursued to determine the utility of the remainder of staging modalities in patients with extraskeletal Ewing sarcoma to elucidate the most efficient and effective staging protocol. Level III, diagnostic study.

Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing.

Rare neurodevelopmental disorders, including inherited white matter disorders or leukodystrophies, often present a diagnostic challenge on a genetic level given the large number of causal genes associated with a range of disease subtypes. This study aims to demonstrate the challenges and lessons learned in the genetic investigations of leukodystrophies through presentation of a series of cases solved using exome or genome sequencing. Each of the six patients had a leukodystrophy associated with hypomyelination or delayed myelination on MRI, and inconclusive clinical diagnostic genetic testing results. We performed next generation sequencing (case-based exome or genome sequencing) to further investigate the genetic cause of disease. Following different lines of investigation, molecular diagnoses were obtained for each case, with patients harboring pathogenic variants in a range of genes including TMEM106B, GJA1, AGA, POLR3A, and TUBB4A. We describe the lessons learned in reaching the genetic diagnosis, including the importance of (a) utilizing proper multi-gene panels in clinical testing, (b) assessing the reliability of biochemical assays in supporting diagnoses, and (c) understanding the limitations of exome sequencing methods in regard to CNV detection and region coverage in GC-rich areas. This study illustrates the importance of applying a collaborative diagnostic approach by combining detailed phenotyping data and metabolic results from the clinical environment with advanced next generation sequencing analysis techniques from the research environment to increase the diagnostic yield in patients with genetically unresolved leukodystrophies.

A118 BALLOON-ASSISTED ENTEROSCOPY TIMING INCREASES DIAGNOSTIC YIELD IN PATIENTS WITH OVERT OBSCURE GASTROINTESTINAL BLEEDING: A RETROSPECTIVE STUDY

Abstract Background Obscure gastrointestinal bleeding (OGIB) is defined as bleeding from an unknown etiology despite initial investigations with upper endoscopy and colonoscopy, of which 75-80% is attributed to a small bowel (SB) source. OGIB poses a significant diagnostic and therapeutic challenge, resulting in high morbidity and mortality with increased utilization of health care resources. Balloon-assisted enteroscopy (BAE) is a useful procedure for the evaluation and management of small bowel bleeding, with reported diagnostic and therapeutic rates up to 87% and 80%, respectively. Purpose This retrospective study aims to evaluate the diagnostic and therapeutic yields in a large cohort of adult patients presenting with different subtypes of OGIB who have undergone BAE, as well as to assess for association between various patient and disease factors, and clinical outcomes. Method We performed a retrospective review of 1057 cases of BAE at a large quaternary referral centre between 2016 to 2021 and 158 OGIB cases were identified. Sex, age, and, preprocedural variables including indication, time from video capsule endoscopy (VCE) to BAE and subclassification of SB bleed were collected. Endoscopic modality, findings, and therapeutic interventions were used to calculate diagnostic and therapeutic yields. The association between the timing of BAE relative to VCE and clinical outcomes including rebleeding rate, diagnostics and therapeutic yields were assessed. Bleeding free-survival was estimated using Kaplan-Meier function. All data analyses were performed with SPSS. Result(s) The overall diagnostic yield of BAE was 74%. Patients with active overt bleeding were found to have a statistically significant higher yield compared to those with inactive overt bleeding (94% vs 67%, P= 0.03). The therapeutic yield was 51%, with a significantly higher rate of injection therapy and hemoclip placement in those with active overt bleeding compared to those with inactive overt and occult bleeding (P&amp;lt; 0.001). BAE performed within 72 hours of overt GI bleeding was found to have a statistically significant higher diagnostic yield when compared to procedures performed after 72 hours (94% vs 67%, p =0.05). Univariable analysis revealed higher diagnostic yield in patients requiring transfusion within the past 12 months (P= 0.02) Finally, rebleeding-free survival in all patients at 1 year and 5 years was 98% and 68%, respectively. Image Conclusion(s) Balloon-assisted enteroscopy continues to be an effective diagnostic and therapeutic modality for the investigation of obscure gastrointestinal bleeding. Our retrospective study shows a higher diagnostic yield in those presenting with active overt GI bleed as well as those who underwent BAE within 72 hours of overt GI bleeding. Furthermore, patients who required transfusion within the past 12 months are more likely to have a positive BAE finding. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Gene panel analysis of 119 index patients with suspected periodic paralysis in Japan.

Genetic factors are recognized as the major reason for patients with periodic paralysis. The goal of this study was to determine the genetic causes of periodic paralysis in Japan. We obtained a Japanese nationwide case series of 119 index patients (108 men and 11 women) clinically suspected of periodic paralysis, and a gene panel analysis, targeting CACNA1S, SCN4A, and KCNJ2 genes, was conducted. From 34 cases, 25 pathogenic/likely pathogenic/unknown significance variants were detected in CACNA1S (nine cases), SCN4A (19 cases), or KCNJ2 (six cases), generating a molecular diagnostic rate of 28.6%. In total, seven variants have yet been found linked to periodic paralysis previously. The diagnostic yield of patients with hypokalemic and hyperkalemic periodic paralyzes was 26.2 (17/65) and 32.7% (17/52), respectively. A considerably higher yield was procured from patients with than without positive family history (18/25 vs. 16/94), onset age ≤20 years (24/57 vs. 9/59), or recurrent paralytic attacks (31/94 vs. 3/25). The low molecular diagnostic rate and specific genetic proportion of the present study highlight the etiological complexity of patients with periodic paralysis in Japan.

Diagnostic yield of pipelle biopsy in detection of endometrial carcinoma in patients with abnormal uterine bleeding

Introduction: Endometrial carcinoma is the type of cancer of the female genital tract that occurs most frequently. Pipelle is an excellent method for screening and diagnostic purposes and has a high degree of sensitivity and specificity for the detection of endometrial carcinoma. Objective: To determine the diagnostic yield of pipelle biopsy in detection of endometrial carcinoma in patients with abnormal uterine bleeding. Methodology: The current cross-sectional (Descriptive) study was carried out at the Department of Obstetrics &amp; Gynecology in Khyber Teaching Hospital, Peshawar. The study duration was one years from December 2021 to December 2022. From all of the women who fulfilled the inclusion criteria, biopsy were performed on an outpatient basis. Performa developed for this study was used to record all the data. SPSS version 17.0 was used to input the data and evaluate the results. Results: A total of 107 women presenting with abnormal uterine bleeding were included in the study. Average age of the patients was 54.52 years with standard deviation of ±8.16. The Diagnostic yield in patients with abnormal uterine bleeding was observed in 99(92.52%). Conclusion: Our research shows that pipelle is a good device for diagnosing carcinoma in patients with abnormal uterine bleeding.

Performance of D-Dimers in Patients with Prior History of Venous Thromboembolism Based on Anticoagulation Status

Background: D-dimers frequently stay elevated in patients with prior history of venous thromboembolism (VTE). Moreover, D-dimers seem to have lower diagnostic yield in patients presenting with a suspicion of recurrent VTE and it is not clear how D-dimers perform in patients on anticoagulation. Aim: To evaluate the performance of D-dimers in patients with a history of VTE based on anticoagulation status. Methods: The PREDICTORS study is an international prospective multicenter observational cohort study of outpatients with suspected VTE recurrence. The aim is to improve the performance of diagnostic strategies in patients with a suspicion of recurrent VTE. Pre-test clinical probability was assessed, and D-dimers were performed based on local clinical practices. Negative D-dimers were determined based on the manufacturer's threshold for every commercial assay used in each center. Recurrent VTE events (defined as proximal deep venous thrombosis or segmental or more proximal pulmonary embolism) at enrollment and during the 3-month follow-up were assessed and all suspected recurrent events were independently adjudicated. Results: D-dimer measurements were used in the diagnostic management of 482 patients, of which, 168 patients were on anticoagulation and 314 were not on anticoagulation. At enrollment, the prevalence of recurrent VTE was 29.9% (144/482). Moreover, at the index suspicion, 35.1% (169/482) had negative D-dimers. Amongst patients on anticoagulation, 4/90 (4.4%; 95%CI 1.2%-11.0%) and 21/78 (26.9%) had recurrent VTE at enrollment in patients with negative and positive D-dimers, respectively. During follow-up, no recurrent VTE occurred in patients with negative D-dimers. Amongst patients without anticoagulation, 2/79 (2.5%; 95%CI 0.3%-8.9%) and 117/235 (49.8%) had recurrent VTE at enrollment in patients with negative and positive D-dimers, respectively. One recurrent VTE occurred during follow-up amongst patients with initial negative D-dimers (1.3%; 95%CI 0.0-7.0%). Conclusion: In patients presenting with a suspected recurrent VTE, the prevalence of VTE was high, including in patients receiving anticoagulant therapy. Prevalence of VTE based on D-dimers positivity was comparable between patients on anticoagulation and patients without anticoagulation. False negative rate of D-dimers appears to be higher in patients with a suspicion of recurrent VTE than in patients with a suspected first thromboembolic event. Further studies are needed to assess if a change in the D-dimers cut-off could improve diagnostic yield.