Citations

Abstract ECT2 is an activator of RHO GTPases that is essential for cytokinesis. In addition, ECT2 was identified as an oncoprotein when expressed ectopically in NIH/3T3 fibroblasts. However, oncogenic activation of ECT2 resulted from N-terminal truncation, and such truncated ECT2 proteins have not been found in patients with cancer. In this study, we observed elevated expression of full-length ECT2 protein in preneoplastic colon adenomas, driven by increased ECT2 mRNA abundance and associated with APC tumor-suppressor loss. Elevated ECT2 levels were detected in the cytoplasm and nucleus of colorectal cancer tissue, suggesting cytoplasmic mislocalization as one mechanism of early oncogenic ECT2 activation. Importantly, elevated nuclear ECT2 correlated with poorly differentiated tumors, and a low cytoplasmic:nuclear ratio of ECT2 protein correlated with poor patient survival, suggesting that nuclear and cytoplasmic ECT2 play distinct roles in colorectal cancer. Depletion of ECT2 reduced anchorage-independent cancer cell growth and invasion independent of its function in cytokinesis, and loss of Ect2 extended survival in a KrasG12D Apc-null colon cancer mouse model. Expression of ECT2 variants with impaired nuclear localization or guanine nucleotide exchange catalytic activity failed to restore cancer cell growth or invasion, indicating that active, nuclear ECT2 is required to support tumor progression. Nuclear ECT2 promoted ribosomal DNA transcription and ribosome biogenesis in colorectal cancer. These results support a driver role for both cytoplasmic and nuclear ECT2 overexpression in colorectal cancer and emphasize the critical role of precise subcellular localization in dictating ECT2 function in neoplastic cells. Significance: ECT2 overexpression and mislocalization support its role as a driver in colon cancer that is independent from its function in normal cell cytokinesis.

AbstractGain of 1q22 at diagnosis portends poorer outcomes in multiple myeloma (MM), but the prognostic significance of acquired 1q22 gain is unknown. We identified 63 MM patients seen at Mayo Clinic from 1/2004 to 12/2019 without 1q22 gain at diagnosis who acquired it during follow up and compared them to 63 control patients who did not acquire 1q22 gain with similar follow up. We also compared outcomes in the acquired 1q22 gain group with outcomes in 126 patients with 1q22 gain present at diagnosis. The incidence of acquired 1q22 gain was 6.1% (median follow‐up 6.8 years); median time to acquisition was 5.0 years (range: 0.7–11.5 years). Abnormalities on baseline fluorescence in situ hybridization (FISH) included trisomies (54%) and monosomy 13 (39%); 16 (25%) had high‐risk (HR) translocations or del(17p). Median progression‐free survival with front line therapy was 29.5 months in patients with acquired 1q22 gain, versus 31.4 months in control patients (p = .34) and 31.2 months in patients with de novo 1q22 gain (p = .04). Median overall survival (OS) from diagnosis was 10.9 years in patients with acquired 1q22 gain, versus 13.0 years in control patients (p = .03) and 6.3 years in patients with de novo 1q22 gain (p = .01). Presence of HR FISH at baseline increased risk of 1q22 gain acquisition. We demonstrate that acquisition of 1q22 gain is a significant molecular event in MM, associated with reduced OS. Among HR patients for whom this clonal evolution is determined, a risk‐adapted approach and/or clinical trial should be considered.

Background: Lateral meniscal oblique radial tears (LMORT) occur frequently in conjunction with anterior cruciate ligament (ACL) disruption and are anatomically distinct from meniscus root tears. Hypothesis/Purpose: The purpose of this study was to characterize the effects of LMORT types 3 (LMORT3) and 4 (LMORT4) lesions on joint stability and meniscal extrusion in ACL-deficient knees. Our hypothesis was that both lesions would promote significant increases in anterior translation and meniscal extrusion, with the LMORT4 lesion having a greater effect. Study Design: Controlled laboratory study. Methods: Two matched pairs of cadaveric knees (n = 4) were used to optimize the testing sequence. Additional cadaveric knees with LMORT3 (n = 8) and LMORT4 (n = 8) lesions created after ACL transection underwent robotic kinematic testing for anterior drawer and pivot-shift simulations with associated ultrasound-measured meniscal extrusion at clinically relevant knee flexion angles. Results: Optimization testing showed no differences on the effect of LMORT4 lesions for anterior translation and lateral meniscal extrusion with ACL-intact versus ACL-deficient knees. ACL deficiency and LMORT3 and LMORT4 lesions with ACL deficiency were associated with significantly greater anterior translation compared with ACL-intact state for both anterior drawer and pivot-shift testing at all flexion angles ( P < .001). ACL deficiency with either LMORT3 or LMORT4 lesion was associated with significantly greater anterior translation than was ACL deficiency only ( P < .005) for anterior drawer testing at 90° of flexion. Meniscal extrusion was greater with LMORT3 and LMORT4 lesions compared with ACL deficiency only ( P < .05) for anterior drawer at 60° of flexion and for pivot shift at 15° of flexion. The LMORT4 lesion demonstrated increased anterior translation for anterior drawer ( P = .003) at 60° of flexion (12%) as well as for pivot shift at 15° of flexion (7%) and 30° of flexion (13%) ( P < .005) compared with ACL deficiency only. Conclusion: In this cadaveric model, the addition of an LMORT3 or LMORT4 lesion increased anterior laxity for both the anterior drawer and the pivot shift when compared with an isolated ACL tear. Lateral meniscal extrusion was also exacerbated by these LMORT lesions. Clinical Relevance: LMORT lesions, distinct from meniscus root tears, occur frequently in conjunction with ACL tears. This study characterized the biomechanical consequences of LMORT3 and LMORT4 lesions on joint stability and meniscal function, highlighting the importance of diagnosing and treating LMORT lesions at the time of ACL reconstruction.

AbstractIntroductionThe optimal colonoscopy withdrawal time is still a controversial topic. While several studies demonstrate that longer withdrawal time improves adenoma detection rate, others have contradicted these findings.MethodsThree independent reviewers performed a comprehensive review of all original articles published from inception to January 2021 and included studies reporting comparison of the two cohorts—(i) ≥ 6 but less than 9 min of colonoscopy withdrawal time (CWT) and (ii) ≥ 9 min of CWT. The outcome measures were the following: (i) adenoma detection rate (ADR), (ii) advanced ADR, and (iii) sessile serrated adenoma detection rate (SDR). The meta‐analysis was performed, and the statistics were two‐tailed.ResultsA total of seven studies met the inclusion criteria after a thorough search of the literature was completed. The analysis revealed that ≥ 9 min of CWT had significantly higher odds of adenoma detection as compared with 6–9 min of CWT (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.30–1.82; I2 = 93.7). Additionally, a significantly higher odds of sessile serrated adenoma detection (OR 1.68, 95% CI 1.28–2.22; I2 = 0) and a trend towards higher odds of advanced adenoma detection (OR 1.38, 95% CI 0.98–1.95, I2 = 90) were seen with CWT of at least 9 min when compared with 6–9 min of CWT.ConclusionThis systematic review and meta‐analysis analysis provides further evidence that at least 9 min of CWT cohort had significantly higher ADR and SDR as compared with the at least 6 min but less than 9 min of cohort.

AbstractPurposeEye‐tracking approaches have been used to understand the visual search process in radiology. However, previous eye‐tracking work in computer tomography (CT) has been limited largely to single cross‐sectional images or video playback of the reconstructed volume, which do not accurately reflect radiologists' visual search activities and their interactivity with three‐dimensional image data at a computer workstation (e.g., scroll, pan, and zoom) for visual evaluation of diagnostic imaging targets. We have developed a platform that integrates eye‐tracking hardware with in‐house‐developed reader workstation software to allow monitoring of the visual search process and reader‐image interactions in clinically relevant reader tasks. The purpose of this work is to validate the spatial accuracy of eye‐tracking data using this platform for different eye‐tracking data acquisition modes.MethodsAn eye‐tracker was integrated with a previously developed workstation designed for reader performance studies. The integrated system captured real‐time eye movement and workstation events at 1000 Hz sampling frequency. The eye‐tracker was operated either in head‐stabilized mode or in free‐movement mode. In head‐stabilized mode, the reader positioned their head on a manufacturer‐provided chinrest. In free‐movement mode, a biofeedback tool emitted an audio cue when the head position was outside the data collection range (general biofeedback) or outside a narrower range of positions near the calibration position (strict biofeedback). Four radiologists and one resident were invited to participate in three studies to determine eye‐tracking spatial accuracy under three constraint conditions: head‐stabilized mode (i.e., with use of a chin rest), free movement with general biofeedback, and free movement with strict biofeedback. Study 1 evaluated the impact of head stabilization versus general or strict biofeedback using a cross‐hair target prior to the integration of the eye‐tracker with the image viewing workstation. In Study 2, after integration of the eye‐tracker and reader workstation, readers were asked to fixate on targets that were randomly distributed within a volumetric digital phantom. In Study 3, readers used the integrated system to scroll through volumetric patient CT angiographic images while fixating on the centerline of designated blood vessels (from the left coronary artery to dorsalis pedis artery). Spatial accuracy was quantified as the offset between the center of the intended target and the detected fixation using units of image pixels and the degree of visual angle.ResultsThe three head position constraint conditions yielded comparable accuracy in the studies using digital phantoms. For Study 1 involving the digital crosshairs, the median ± the standard deviation of offset values among readers were 15.2 ± 7.0 image pixels with the chinrest, 14.2 ± 3.6 image pixels with strict biofeedback, and 19.1 ± 6.5 image pixels with general biofeedback. For Study 2 using the random dot phantom, the median ± standard deviation offset values were 16.7 ± 28.8 pixels with use of a chinrest, 16.5 ± 24.6 pixels using strict biofeedback, and 18.0 ± 22.4 pixels using general biofeedback, which translated to a visual angle of about 0.8° for all three conditions. We found no obvious association between eye‐tracking accuracy and target size or view time. In Study 3 viewing patient images, use of the chinrest and strict biofeedback demonstrated comparable accuracy, while the use of general biofeedback demonstrated a slightly worse accuracy. The median ± standard deviation of offset values were 14.8 ± 11.4 pixels with use of a chinrest, 21.0 ± 16.2 pixels using strict biofeedback, and 29.7 ± 20.9 image pixels using general biofeedback. These corresponded to visual angles ranging from 0.7° to 1.3°.ConclusionsAn integrated eye‐tracker system to assess reader eye movement and interactive viewing in relation to imaging targets demonstrated reasonable spatial accuracy for assessment of visual fixation. The head‐free movement condition with audio biofeedback performed similarly to head‐stabilized mode.

AbstractThe study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.

Purpose Nearly all health care professionals engage in continuous professional development (CPD), yet little is known about the cost and cost-effectiveness of physician CPD. Clarification of key concepts, comprehensive identification of published work, and determination of research gaps would facilitate application of existing evidence and planning for future investigations. The authors sought to systematically map study themes, methods, and outcomes in peer-reviewed literature on the cost and value of physician CPD. Method The authors conducted a scoping review, systematically searching MEDLINE, Embase, PsycInfo, and Cochrane Library databases for comparative economic evaluations of CPD for practicing physicians through April 2020. Two reviewers, working independently, screened all articles for inclusion. Three reviewers iteratively reviewed all included articles to inductively identify key features including participants, educational interventions, study designs, cost ingredients, and cost analyses. Two reviewers then independently reexamined all included articles to code these features. Results Of 3,338 potentially eligible studies, 111 were included. Physician specialties included internal, family, or general medicine (80 studies [72%]), surgery (14 studies [13%]), and medicine subspecialties (7 studies [6%]). Topics most often addressed general medicine (45 studies [41%]) or appropriate drug use (37 studies [33%]). Eighty-seven studies (78%) compared CPD with no intervention. Sixty-three studies (57%) reported the cost of training, and 79 (71%) evaluated the economic impact (money saved/lost following CPD). Training cost ingredients (median 3 itemized per study) and economic impact ingredients (median 1 per study) were infrequently and incompletely identified, quantified, or priced. Twenty-seven studies (24%) reported cost–impact expressions such as cost-effectiveness ratio or net value. Nineteen studies (17%) reported sensitivity analyses. Conclusions Studies evaluating the costs and economic impact of physician CPD are few. Gaps exist in identification, quantification, pricing, and analysis of cost outcomes. The authors propose a comprehensive framework for appraising ingredients and a preliminary reference case for economic evaluations.

Abstract Purpose: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non–Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4+ Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis. Experimental Design: We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4+ T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments. Results: Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT–mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA–mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. In silico and experimental validation suggest two targets (miR-126→ SIPR2 and miR-145 → ROCK1) resulting in reduced RhoA-GTPase activity and T–B-cell interaction. Conclusions: Unique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.