Significant Interobserver Variability Research Articles

Evaluation of the Simpson's Method to Determine Left Ventricular Ejection Fraction Using the Transgastric Two-Chamber View.

Left ventricular chamber size and functional assessment by transesophageal echocardiography can be difficult if visualization is poor in the mid-esophageal views. However, the accuracy of using the Simpson's method in the transgastric 2-chamber (TG2C) as an alternative approach has not been assessed. The Simpson's method was performed by 2 independent reviewers using midesophageal 2-chamber (ME2C) and TG2C views. Echocardiographic images were retrieved retrospectively for 49 adult cardiac surgical patients. Two-way random effects intraclass correlation coefficients demonstrated no significant interobserver variability. Linear mixed effects models showed no significant differences in ME2C and TG2C measurements with regard to EDV (P=.4407), ESV (P=.5113), or EF (P=.0610).Compared to the ME2C view, the TG2C view had better image quality of the LV walls (image quality score median [interquartile range]: 2.00 [.00] vs 1.00 [1.00]; P<.0001), but worse image quality of the mitral annulus (1.00 [1.00] vs 2.00 [.00]; P<.0001) and LV apex (.00 [1.00] vs 2.00 [1.00]; P<.0001). This study suggests the Simpson's method can be applied to the TG2C view as an alternative to the standard midesophageal method to estimate chamber volumes and EF.

POS-772 SHEAR WAVE BASED ELASTOGRAPHY POINT QUALIFICATION IN THE EVALUATION OF RENAL PARENCHYMA STIFFNESS IN KIDNEY TRANSPLANT RECIPIENTS UNDERGOING GRAFT BIOPSY

Shear wave elastography (SWE) is an ultrasound technique that measures tissue stiffness non-invasively. In SWE, a real-time short-duration acoustic push pulse generates shear waves travelling perpendicular to the main US beam. Renal biopsy remains the gold standard in assessing rejection and chronicity in kidney transplantation. However, biopsy remains imperfect, with limitations and inherent risks, including sampling errors, allograft trauma with multiple needle pass attempts, and significant interobserver variation in interpreting biopsy samples among pathologists.

Interobserver variability among experienced electrocardiogram readers to diagnose acute thrombotic coronary occlusion in patients with out of hospital cardiac arrest: Impact of metabolic milieu and angiographic culprit

ObjectivesWe sought to evaluate interobserver concordance among experienced electrocardiogram (ECG) readers in predicting acute thrombotic coronary occlusion (ATCO) in the context of abnormal metabolic milieu (AMM) following resuscitated out of hospital cardiac arrest (OHCA). MethodsOHCA patients with initial shockable rhythm who underwent invasive coronary angiography (ICA) were included. AMM was defined as one of: pH < 7.1, lactate > 2 mmol/L, serum potassium < 2.8 or >6.0 mEq/L. The initial ECG following ROSC but prior to ICA was adjudicated by 2 experienced readers using classic ST elevation myocardial infarction [STEMI] and expanded criteria and their combination to predict ATCO on ICA. Results152 consecutive patients (mean age 58 years, 76% male) met inclusion criteria. AMM was present in 77%; and 42% had ATCO on ICA. Sensitivity, specificity, PPV, NPV using classic STEMI criteria were 50%, 98%, 94%, 72% (c-statistic 0.74); whereas for combined (STEMI + expanded) criteria they were 69%, 88%, 81%, 79% respectively (c-statistic 0.79). Inter-observer agreement (kappa) was 0.7 for classic STEMI criteria, and 0.66 for combined criteria. Agreement between readers was consistently higher when ATCO was absent and with NMM (kappa 0.78), but lower in AMM (kappa 0.6). ConclusionsDespite experienced ECG readers, there was only modest overall concordance in predicting ATCO in the context of resuscitated OHCA. Significant interobserver variations were noted dependent on metabolic milieu and angiographic ATCO. These observations fundamentally question the role of the 12-lead ECG as primary triaging tool for early angiography among patients with OHCA.

Computer-aided segmentation on MRI for prostate radiotherapy, Part I: Quantifying human interobserver variability of the prostate and organs at risk and its impact on radiation dosimetry

Background and purposeQuantifying the interobserver variability (IoV) of prostate and periprostatic anatomy delineation on prostate MRI is necessary to inform its use for treatment planning, treatment delivery, and treatment quality assessment. Materials and methodsTwenty five prostate cancer patients underwent MRI-based low-dose-rate prostate brachytherapy (LDRPBT). The patients were scanned with a 3D T2-weighted sequence for treatment planning and a 3D T2/T1-weighted sequence for quality assessment. Seven observers involved with the LDRPBT workflow delineated the prostate, external urinary sphincter (EUS), seminal vesicles, rectum, and bladder on all 50 MRIs. IoV was assessed by measuring contour similarity metrics, differences in organ volumes, and differences in dosimetry parameters between unique observer pairs. Measurements from a group of 3 radiation oncologists (G1) were compared against those from a group consisting of the other 4 clinical observers (G2). ResultsIoV of the prostate was lower for G1 than G2 (Matthew’s correlation coefficient [MCC], G1 vs. G2: planning–0.906 vs. 0.870, p < 0.001; postimplant–0.899 vs. 0.861, p < 0.001). IoV of the EUS was highest of all the organs for both groups, but was lower for G1 (MCC, G1 vs. G2: planning–0.659 vs. 0.402, p < 0.001; postimplant–0.684 vs. 0.398, p < 0.001). Large differences in prostate dosimetry parameters were observed (G1 maximum absolute prostate ΔD90: planning–76.223 Gy, postimplant–36.545 Gy; G1 maximum absolute prostate ΔV100: planning–13.927%, postimplant–8.860%). ConclusionsWhile MRI is optimal in the management of prostate cancer with radiation therapy, significant interobserver variability of the prostate and external urinary sphincter still exist.

Impact of Pathology Review in Adverse Histological Characteristics and pT Stages of Upper Tract Urothelial Cancer in a Multicenter Study.

PurposePathology reviews for upper urinary tract cancer (UTUC) remained scarce in the literature. Here, we reported the interobserver variation among the review and local pathologies of featured histologic characteristics for UTUC.MethodsPatients who underwent definitive surgical treatments for UTUC were retrospectively reviewed for eligibility of pathology review. In the Taiwan UTUC Collaboration cohort, 212 cases were reviewed, of which 154 cases were eligible for pathology review. Agreement between original pathology and review pathology was measured by the total percentage of agreement and by simple kappa statistics. The prognostic impact was analyzed by the Cox regression model with the estimation of hazard ratios (HR) and 95% confidence intervals.ResultsThere were 80 women and 74 men enrolled in this study, and the median age at treatment was 71.7 years. The agreement is moderate agreement for surgical margin status (87.7%; κ = 0.61), tumor grade (82.5%; κ = 0.43), tumor invasiveness (76.6%; κ = 0.45), lymphovascular invasion (70.8%; κ = 0.42) and T stage (67.5%; κ = 0.52). The interobserver agreements for perineural invasion and variant histology identification were slight. Kaplan–Meier analysis for disease-free survival revealed comparable results in local and review pathology for localized (Tis, Ta, T1–2) or advanced T stage (T3–4).ConclusionsPathology review of UTUC had minimal impact on clinical practice based on current available disease treatment guidelines. However, significant interobserver variations were observed in featured adverse histopathological characters.

Echocardiographic assessment of radial right ventricular function in heart transplant recipients.

AimsRight ventricular (RV) allograft dysfunction is present in half of all heart transplant (HT) recipients. Non‐invasive assessment of RV function in the setting of rejection is not well described. We outline an echocardiographic technique, short‐axis fractional area change (SAXFAC), to evaluate RV function in the HT population and correlate this with the grade of pathologic rejection.Methods and resultsWe retrospectively reviewed the electronic medical records of 110 people who received a HT between 1 January 2015 and 29 February 2020 and had no evidence of rejection. One hundred eighty‐two transthoracic echocardiograms (TTEs) completed up to 1 year from the date of transplantation were analysed for the target acoustic window, the parasternal mid‐ventricular short‐axis view. Sixty‐one TTEs from 23 healthy transplants were deemed appropriate for SAXFAC determination. Thirty‐three organ recipients with at least grade 1R allograft rejection were also identified, and their TTEs screened for SAXFAC analysis. Two expert readers independently calculated SAXFAC as follows: RV end‐diastolic area minus end‐systolic area divided by end‐diastolic area. Using commercially available software (Epsilon, Ann Arbor, Michigan), we quantified RV radial strain, longitudinal strain, and apical fractional area change (FAC). Twenty‐eight transplant recipients with grade 0R or 1R rejection and nine patients with clinically significant rejection completed the study analysis. SAXFAC demonstrated significant variability in the entire population with an inverse relationship to severity of allograft rejection (P ≤ 0.01). Radial strain and FAC were also associated with clinically significant rejection (P ≤ 0.01).ConclusionsShort‐axis fractional area change is a simple two‐dimensional technique to assess RV function in HT recipients and showed no significant inter‐observer variability. In our small, single‐centre, retrospective case series, lower SAXFAC values were associated with clinically significant allograft rejection. The small sample size and infrequent occurrence of rejection make our observations hypothesis‐generating only. We advocate dedicated RV SAXFAC imaging planes be included when assessing allograft function.

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

GestAltNet: aggregation and attention to improve deep learning of gestational age from placental whole-slide images

The placenta is the first organ to form and performs the functions of the lung, gut, kidney, and endocrine systems. Abnormalities in the placenta cause or reflect most abnormalities in gestation and can have life-long consequences for the mother and infant. Placental villi undergo a complex but reproducible sequence of maturation across the third-trimester. Abnormalities of villous maturation are a feature of gestational diabetes and preeclampsia, among others, but there is significant interobserver variability in their diagnosis. Machine learning has emerged as a powerful tool for research in pathology. To capture the volume of data and manage heterogeneity within the placenta, we developed GestaltNet, which emulates human attention to high-yield areas and aggregation across regions. We used this network to estimate the gestational age (GA) of scanned placental slides and compared it to a baseline model lacking the attention and aggregation functions. In the test set, GestaltNet showed a higher r2 (0.9444 vs. 0.9220) than the baseline model. The mean absolute error (MAE) between the estimated and actual GA was also better in the GestaltNet (1.0847 weeks vs. 1.4505 weeks). On whole-slide images, we found the attention sub-network discriminates areas of terminal villi from other placental structures. Using this behavior, we estimated GA for 36 whole slides not previously seen by the model. In this task, similar to that faced by human pathologists, the model showed an r2 of 0.8859 with an MAE of 1.3671 weeks. We show that villous maturation is machine-recognizable. Machine-estimated GA could be useful when GA is unknown or to study abnormalities of villous maturation, including those in gestational diabetes or preeclampsia. GestaltNet points toward a future of genuinely whole-slide digital pathology by incorporating human-like behaviors of attention and aggregation.The authors used artificial intelligence to estimate gestational age from scanned whole-slide images of placenta. They developed attention and aggregation deep learning methods because of the large volume of data and tissue heterogeneity. This study provides proof-of-concept in unannotated, unknown images with high accuracy.

Clinical Applications of In Vivo Confocal Microscopy in Keratorefractive Surgery.

To review the contribution of in vivo confocal microscopy (IVCM) to the understanding of corneal wound healing following refractive surgery, and its role in the diagnosis and management of complications arising from keratorefractive procedures. Review of the basic science and clinical literature relating to the study of keratorefractive surgical procedures using IVCM. Extensive research using IVCM has generated a comprehensive understanding of tissue responses after corneal refractive surgery. Epithelial thickness and stromal keratocyte density can be quantified postoperatively and studied longitudinally. Corneal nerve loss and subsequent reinnervation has been characterized and differs significantly between laser refractive techniques. IVCM has also been used to study complications arising from postoperative inflammation (diffuse lamellar keratitis, central toxic keratopathy, ring keratitis, and ectasia), infection (microbial keratitis), and neuropathy (dry eye and neuralgia). This imaging technique can have a critical role in the diagnosis of these complications and subsequent monitoring of treatment response. Manual processing of IVCM images is time-consuming and there may be significant interobserver and intraobserver variability with poor repeatability. However, increasing automation and the use of artificial intelligence is improving the speed and accuracy of image analysis. IVCM has historically been confined to a research setting because image capture and subsequent processing was extremely labor intensive. However, advances in both hardware and software capabilities promise to allow the use of IVCM in routine clinical practice. Real-time evaluation of the cornea at a cellular level will be particularly useful in patients with inflammatory, infectious, or neuropathic complications of keratorefractive surgery. [J Refract Surg. 2021;37(7):493-503.].

Repeatability of PDA diameter measurements on echocardiography.

Diameter of the patent ductus arteriosus (PDA) on transthoracic echocardiography (TTE) is used as a marker of haemodynamic significance. We aimed to assess the intra- and inter-observer variability in PDA diameter in babies born at ≤ 30weeks' gestation. TTEs for 56 infants were performed by a single neonatologist. Cineloops were stored without measurement annotations. PDAs were measured on 2-dimensional (2D) and Colour Doppler. A second, blinded neonatologist repeated measurements on the same cineloops. The scanning neonatologist repeated measurements at a later date, blinded to original measurements. Inter-observer results showed repeatability coefficients of 1.57 (2D) and 2.18 (Colour), and repeatability index of 73% (2D) and 91% (Colour). Intra-observer results showed repeatability coefficients of 0.99 (2D) and 1.32 (Colour), and repeatability index of 43% (2D) and 49% (Colour).Conclusion: There is significant inter- and intra-observer variability in measurements of PDA diameter, even on the same cineloops. We advise caution when using diameter alone as a marker of haemodynamic significance, and recommend using multiple parameters to determine haemodynamic significance of PDA. What is Known: • PDA is associated with numerous comorbidities such as bronchopulmonary dysplasia, necrotising enterocolitis, intraventricular haemorrhage and mortality. • PDA diameter is commonly measured on transthoracic echocardiography and used as a marker of haemodynamic significance. • A previous, smaller study has shown there may be poor repeatability of PDA diameter measurements in serial echocardiograms. What is New: • There is significant inter-observer variability in 2D and Colour Doppler measurements of PDA internal diameter on TTE in preterm infants. • There is moderate intra-observer correlation of repeated measurements on the same imaging in both 2D and Colour Doppler imaging.

Interobserver variability in organ at risk delineation in head and neck cancer

BackgroundIn radiotherapy inaccuracy in organ at risk (OAR) delineation can impact treatment plan optimisation and treatment plan evaluation. Brouwer et al. showed significant interobserver variability (IOV) in OAR delineation in head and neck cancer (HNC) and published international consensus guidelines (ICG) for OAR delineation in 2015. The aim of our study was to evaluate IOV in the presence of these guidelines.MethodsHNC radiation oncologists (RO) from each Belgian radiotherapy centre were invited to complete a survey and submit contours for 5 HNC cases. Reference contours (OARref) were obtained by a clinically validated artificial intelligence-tool trained using ICG. Dice similarity coefficients (DSC), mean surface distance (MSD) and 95% Hausdorff distances (HD95) were used for comparison.ResultsFourteen of twenty-two RO (64%) completed the survey and submitted delineations. Thirteen (93%) confirmed the use of delineation guidelines, of which six (43%) used the ICG. The OARs whose delineations agreed best with the OARref were mandible [median DSC 0.9, range (0.8–0.9); median MSD 1.1 mm, range (0.8–8.3), median HD95 3.4 mm, range (1.5–38.7)], brainstem [median DSC 0.9 (0.6–0.9); median MSD 1.5 mm (1.1–4.0), median HD95 4.0 mm (2.3–15.0)], submandibular glands [median DSC 0.8 (0.5–0.9); median MSD 1.2 mm (0.9–2.5), median HD95 3.1 mm (1.8–12.2)] and parotids [median DSC 0.9 (0.6–0.9); median MSD 1.9 mm (1.2–4.2), median HD95 5.1 mm (3.1–19.2)]. Oral cavity, cochleas, PCMs, supraglottic larynx and glottic area showed more variation. RO who used the consensus guidelines showed significantly less IOV (p = 0.008).ConclusionsAlthough ICG for delineation of OARs in HNC exist, they are only implemented by about half of RO participating in this study, which partly explains the delineation variability. However, this study highlights that guidelines alone do not suffice to eliminate IOV and that more effort needs to be done to accomplish further treatment standardisation, for example with artificial intelligence.

Challenges in Cytology Specimens With Hürthle Cells.

In fine-needle aspirations (FNA) of thyroid, Hürthle cells can be found in a broad spectrum of lesions, ranging from non-neoplastic conditions to aggressive malignant tumors. Recognize them morphologically, frequently represents a challenging for an adequately diagnosis and are associated with a significant interobserver variability. Although the limitations of the morphologic diagnosis still exist, the interpretation of the context where the cells appear and the recent advances in the molecular knowledge of Hürthle cells tumors are contributing for a more precise diagnosis. This review aims to describe the cytology aspects of all Hürthle cells neoplastic and non-neoplastic thyroid lesions, focusing on the differential diagnosis and reporting according to The Bethesda System for Reporting Thyroid Cytology (TBSRTC). New entities according to the latest World Health Organization (WHO) classification are included, as well as an update of the current molecular data.

Reliability of histopathologic diagnosis of fibrotic interstitial lung disease:\xa0an international collaborative standardization project

BackgroundCurrent interstitial lung disease (ILD) diagnostic guidelines assess criteria across clinical, radiologic and pathologic domains. Significant interobserver variation in histopathologic evaluation has previously been shown but the specific source of these discrepancies is poorly documented. We sought to document specific areas of difficulty and develop improved criteria that would reduce overall interobserver variation.MethodsUsing an internet-based approach, we reviewed selected images of specific diagnostic features of ILD histopathology and whole slide images of fibrotic ILD. After an initial round of review, we confirmed the presence of interobserver variation among our group. We then developed refined criteria and reviewed a second set of cases.ResultsThe initial round reproduced the existing literature on interobserver variation in diagnosis of ILD. Cases which were pre-selected as inconsistent with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) were confirmed as such by multi-observer review. Cases which were thought to be in the spectrum of chronic fibrotic ILD for which UIP/IPF were in the differential showed marked variation in nearly all aspects of ILD evaluation including extent of inflammation and extent and pattern of fibrosis. A proposed set of more explicit criteria had only modest effects on this outcome. While we were only modestly successful in reducing interobserver variation, we did identify specific reasons that current histopathologic criteria of fibrotic ILD are not well defined in practice.ConclusionsAny additional classification scheme must address interobserver variation in histopathologic diagnosis of fibrotic ILD order to remain clinically relevant. Improvements to tissue-based diagnostics may require substantial resources such as larger datasets or novel technologies to improve reproducibility. Benchmarks should be established for expected outcomes among clinically defined subgroups as a quality metric.

Are HFpEF and HFmrEF So Different? The Need to Understand Distinct Phenotypes.

Traditionally, patients with heart failure (HF) are divided according to ejection fraction (EF) threshold more or <50%. In 2016, the ESC guidelines introduced a new subgroup of HF patients including those subjects with EF ranging between 40 and 49% called heart failure with midrange EF (HFmrEF). This group is poorly represented in clinical trials, and it includes both patients with previous HFrEF having a good response to therapy and subjects with initial preserved EF appearance in which systolic function has been impaired. The categorization according to EF has recently been questioned because this variable is not really a representative of the myocardial contractile function and it could vary in relation to different hemodynamic conditions. Therefore, EF could significantly change over a short-term period and its measurement depends on the scan time course. Finally, although EF is widely recognized and measured worldwide, it has significant interobserver variability even in the most accredited echo laboratories. These assumptions imply that the same patient evaluated in different periods or by different physicians could be classified as HFmrEF or HFpEF. Thus, the two HF subtypes probably subtend different responses to the underlying pathophysiological mechanisms. Similarly, the adaptation to hemodynamic stimuli and to metabolic alterations could be different for different HF stages and periods. In this review, we analyze similarities and dissimilarities and we hypothesize that clinical and morphological characteristics of the two syndromes are not so discordant.

Comparing the inter-observer reliability of the Tada formula among neurosurgeons while estimating the intracerebral haematoma volume

ObjectiveTo compare the inter-observer reliability among neurosurgeons while estimating the intracerebral haematoma (ICH) volume by the Tada formula and assess its influence on predicting the severity and prognosis of various ICHs. MethodsWe obtained clinical data from 262 consecutive patients with spontaneous ICH. The haematoma volume was independently calculated and compared by 3D Slicer and eight neurosurgeons. The inter-observer reliability was obtained by calculating the intraclass correlation coefficients (ICC) and Cohen’s kappa score (kappa), within different shape and volume ICH subgroups. We conducted the receiver operating characteristic analysis to assess the predictive value of the ICH volume evaluated for clinical features, including the Glasgow Coma Scale at the onset of the disease, ICH-related surgical treatments, the length of stay in the intensive care unit, the length of hospitalisation, the modified Rankin Scale score at discharge, and in-hospital deaths. ResultsThe median haematoma volume was 17.4 ml (range, 7.3–34.7 ml). The estimated volumes were significantly different among neurosurgeons (p < 0.001). Six out of eight neurosurgeons demonstrated obvious deviations from the 3D Slicer software (p < 0.001). Round (ICC: 0.947) and tapered (ICC: 0.954) haematomas were more consistently evaluated between the neurosurgeons. We observed a substantial strength of agreement between neurosurgeons with kappa> 0.693 and ICC: 0.938 in the entire volume range, and slight to fair strength of agreement with kappa> 0.175 and ICC: 0.689 between 20 ml and 40 ml volume interval. All estimated volumes had a positive predictive value for clinical features, with the area under the curve > 0.5 (p < 0.05). However, the 3D Slicer software performed relatively better than most neurosurgeons. ConclusionsThere exists a significant inter-observer variability among neurosurgeons when utilizing the Tada formula, thus demonstrating significant implications for ICH-related clinical practices and researches.

Target coverage of daily cone-beam computed tomography in breath-hold image-guided radiotherapy for gastric lymphoma.

Objectives:We evaluated retrospectively the daily target coverage using cone-beam computed tomography (CBCT) in breath-hold image-guided radiotherapy (BH-IGRT) for gastric lymphoma.Methods:BH-IGRT was performed using a prescribed dose of 30.6 Gy in 17 fractions for the whole stomach. We assessed the target coverage of the whole stomach on daily CBCT images [daily clinical target volume (CTV)], which was delineated individually by two observers. We evaluated V95% (percentage of volume receiving ≥95% of the prescribed dose) of daily CTV.Results:In total, 102 fractions from 6 patients were assessed. The mean V95% of daily CTV was 97.2%, which was over 95%. In two of six patients, the V95% of daily CTV was over 95% for either observer in all fractions. One patient had significant interobserver variation (p = 0.013). In 95 fractions (93%), the V95% of daily CTV was over 95% for either observer.Conclusion:Daily target coverage for CTV in BH-IGRT for gastric lymphoma seems to be favorable, even when using CBCT.Advances in knowledge:A previous study ascertained good daily target coverage in BH-IGRT for gastric lymphoma using in-room CT. Even when using CBCT in our study, daily target coverage for CTV in BH-IGRT for gastric lymphoma seems to be favorable.

'Snapshot' of an annual data from a large South Indian Renal Biopsy Registry.

Results from biopsy registries are important to know about the prevalence of renal diseases. In large studies done over several years, significant interobserver variability could have existed. Single-year biopsy registry data are analyzed in this study. The study included 481 renal biopsy specimens including 65 from allografts. Primary glomerulonephritis constituted 37.74% and secondary glomerular diseases constituted 32.21% of native kidney biopsies. Minimal change disease was the most common primary glomerular disease, followed by membranous nephropathy (MN). Lupus nephritis was the most common secondary glomerular disease. This study included specimens from 34 geriatric patients and MN was the most common lesion in that age group. Acute cellular rejection was the most common diagnosis in renal allograft biopsies.

Ultrasound grading of thyroid nodules using the BTA U-scoring guidelines - Is there evidence of intra-and interobserver variability?

U-score ultrasound classification (graded U1-U5) is widely used to grade thyroid nodules based on benign and malignant sonographic features. It is well established that ultrasound is an operator-dependent imaging modality and thus more susceptible to subjective variances between operators when using imaging-based scoring systems. We aimed to assess whether there is any intra- or interobserver variability when U-scoring thyroid nodules and whether previous thyroid ultrasound experience has an effect on this variability. A total of 14 ultrasound operators were identified (five experienced thyroid operators, five with intermediate experience and four with no experience) and were asked to U-score images from 20 thyroid cases shown as a single projection, with and without Doppler flow. The cases were subsequently rescored by the 14 operators after six weeks. The first and second round U-scores for the three operator groups were then analysed using Fleiss' kappa to assess interobserver variability and Cochran's Q test to determine any intraobserver variability. We found no significant interobserver variability on combined assessment of all operators with fair agreement in round 1 (Fleiss' kappa = 0.30, p <0.0001) and slight agreement in round 2 (Fleiss' kappa = 0.19, p < 0.0001). Cochran's Q test revealed no significant intraobserver variability in all 14 operators between round 1 and round 2 (all p>0.05). We found no statistically significant inter- or intraobserver variability in the U-scoring of thyroid nodules between all participants reinforcing the validity of this scoring method in clinical practice, allaying concerns regarding potential subjective biases in reporting.

A Personalized Clinical-Decision Tool to Improve the Diagnostic Accuracy of Myelodysplastic Syndromes

Background While histo- and cytomorphological examinations are central to the diagnosis of myelodysplastic syndromes (MDS), significant inter-observer variability exists. The diagnosis can be challenging in pancytopenic patients (pts) without evidence of dysplasia and is contingent on observer expertise. We developed and externally validated a geno-clinical model that uses mutational data and peripheral blood counts/clinical variables to distinguish MDS from other myeloid malignancies. Methods Clinical and genomic data, including commercially available next-generation sequencing panels, were obtained for patients (pts) treated at the Cleveland Clinic (CC; 652 pts), Munich Leukemia Laboratory (MLL; 1509 pts), and the University of Pavia in Italy (UP, 536 pts). All patients had carried a diagnosis of MDS, chronic myelomonocytic leukemia (CMML), MDS/myeloproliferative neoplasm overlap (MDS/MPN), myeloproliferative neoplasm (MPN; either polycythemia vera, essential thrombocythemia, or myelofibrosis), clonal cytopenia of undetermined significance (CCUS), or idiopathic cytopenia of undetermined significance (ICUS). All diagnoses were established with bone marrow aspiration and according to World Health Organization 2017 criteria. The training cohort included data from CC and UP and randomly divided into learner (80%) and test (20%) cohorts. The final model was independently validated in the MLL cohort. A machine learning algorithm was used to build the model; multiple extraction algorithms were used to extract genomic/clinical variables on both the cohort and individual levels. Performance was evaluated according to the area under the curve of the receiver operating characteristic (ROC-AUC) and accuracy matrices. Results Among the 2697 pts included from all sites, the median age was 70 years [36 - 86]. Median hemoglobin (Hb) was 10.4g/dl [6.9 - 15.7], median platelet count (PLT) was 132 k/dL [14 - 722], median WBC count was 5.3 k/dL [1.4 - 49.9], median ANC was 2.8 k/dL [0.3 - 27.7], median monocyte count was 0.3 k/dL [0 - 9.9], and median lymphocyte count (ALC) was 1.1 k/dL [0.1 - 5.4], and median peripheral blast percentage 0% [0 - 8]. The most commonly mutated genes in all patients were (list top 5 genes) and among pts with MDS were SF3B1 (27%), TET2 (25%), ASXL1 (19%), SRSF2 (16%), and DNMT3A (11%); among patients with MDS-MPN/CMML, the most commonly mutated genes were MDS-MPN/CMML (TET2 46%, ASXL1 34%, SRSF2 29%, RUNX1 13%, CBL 12%) ; among patients with MPNs, the most commonly mutated genes were (JAK2 64%, ASXL1 27%, TET2 14%, DNMT3A 8%, U2AF1 7%); among patients with CCUS the most commonly mutated genes were (TET2 41%, DNMT3A 27%, ASXL1 19%, SRSF2 17%, ZRSR2 10%). The most important features for model predictions (ranked from the most to the least important) included: number of mutations detected/sample, peripheral blast percentage, AMC, JAK2 status, Hb, basophil count, age, eosinophil count, ALC, WBC, EZH2 mutation status, ANC, mutation status of KRAS and SF3B1, platelets, and gender. The final model achieved an average AUROC of 0.95 (95% CI 0.93-0.96) when applied to the test cohort and 0.93 (95% CI 0.91 - 0.94) when it was applied to the MLL cohort. The model also provides individual-level explanations for predictions, providing top differential diagnoses and individual-level explanations of how features influence a putative diagnosis (Figure 1b). Conclusions We developed and externally validated a highly accurate and interpretable model that can distinguish MDS from other myeloid malignancies using clinical and mutational data from a large international cohort. The model can provide personalized interpretations of its outcome and can aid physicians and hematopathologists in recognizing MDS with high accuracy when encountering pts with pancytopenia and with a suspected diagnosis of MDS. Disclosures Sekeres: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Bristol Myers Squib: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy. Gerds:Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Apexx Oncology: Consultancy; Celgene: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; AstraZeneca/MedImmune: Consultancy; Gilead Sciences: Research Funding; Pfizer: Research Funding. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Nazha:Jazz: Research Funding; Incyte: Speakers Bureau; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee.

Hürthle cell lesions of the thyroid: Progress made and challenges remaining.

Hürthle cell-predominant thyroid fine needle aspirations (FNA) are encountered frequently in routine practice, yet they are often challenging to diagnose accurately and are associated with significant interobserver variability. This is largely due to the ubiquity of Hürthle cells in thyroid pathology, ranging from nonneoplastic conditions to aggressive malignancies. Although limitations in cytomorphologic diagnoses likely will remain for the foreseeable future, our knowledge of the molecular pathogenesis of Hürthle cell neoplasia and application of molecular testing to cytologic material have increased dramatically within the past decade. This review provides context behind the challenges in diagnosis of Hürthle cell lesions and summarizes the more recent advances in diagnostic tools.