Cam-type femoroacetabular impingement-correlations between alpha angle versus volumetric measurements and surgical findings.

AIM: Determine correlations of 3DCT cam-type femoroacetabular impingement (FAI) measurements with surgical findings of labral tear and cartilage loss. METHODS: Digital search of symptomatic cam-type FAI from July 2013 to August 2016 yielded 43 patients. Two readers calculated volumes of femoral head, bump, and alpha angles on 3DCT images. Correlations between CT and surgical findings, inter-, and intra-reader reliabilities were assessed using Spearman rank correlation and intraclass correlation coefficients (ICC). RESULTS: Thirteen men and 14 women aged 37 ± 10 (mean ± SD) years were included. Most common clinical finding was positive flexion-adduction-internal rotation (70.4%). Twenty-seven labral tears and 20 cartilage defects were surgically detected. Significant correlations existed between femoral bump, head volumes, and extent of the labral tear (p = 0.008 and 0.003). No significant correlations were found between the alpha angles at 12 to 3 o'clock and the extent of labral tear (p = 0.2, 0.8, 0.9, and 0.09) or any measurement with the cartilage loss (p values for alpha 12 to 3, bump, and head volumes = 0.7, 0.3, 0.9, 0.9, 0.07, and 0.2). Inter- and intra-reader reliabilities were excellent to moderate for femoral head and bump volumes (ICC = 0.85, 0.52, and 0.8, 0.5) and moderate to poor for alpha angles (ICC = 0.48, 0.40, 0.05, 0.25 and 0.3, 0.24, 0.29, 0.49). CONCLUSION: Three dimensional volumetric measurements of cam-type FAI significantly correlate with the extent of intraoperative labral tears. Superior inter- and intra-reader reliability to that of alpha angles renders it a more clinically relevant measurement for quantifying cam morphology. KEY POINTS: • The 3DCT bump volume and femoral head volume showed significant correlations with the extent of labral tear (p values = 0.008 and 0.003). • No significant correlations were seen between alpha angles and the extent of labral tear (p values > 0.05). • Inter- and intra-reader reliability was excellent to moderate (ICC = 0.85 and 0.52, 0.8, and 0.5) for femoral head and bump volumes while inter- and intra-reader reliability was fair to poor (ICC = 0.48, 0.40, 0.05, 0.25 and 0.3, 0.24, 0.29, 0.49) for alpha angles.

Isolated Right-Sided Varicocele: Is Further Workup Necessary?

OBJECTIVE: Unilateral left varicoceles are common and considered benign. Unilateral right varicoceles are reportedly associated with a pathologic process, namely malignancy affecting the retroperitoneum, for which further imaging is often recommended. The purpose of this study was to test the hypothesis that this correlation between unilateral right varicocele and malignancy may be weaker than once suggested, particularly in the absence of other clinical signs of malignancy. MATERIALS AND METHODS: Medical charts and imaging at one institution were reviewed for all patients reported to have right varicocele. Follow-up cross-sectional imaging and clinical records and surgical and medical history were reviewed for possible nonmalignant or malignant causes of varicocele. RESULTS: Ninety-six patients with unilateral right varicocele diagnosed by means of ultrasound were identified. Twenty-nine (30.2%) patients were excluded because of confounding factors (infection, testicular mass, intrascrotal surgery). Among the other 67, 55 had available follow-up information, 39 with cross-sectional imaging. Right-sided varicocele was attributable to nonmalignant causes in 16 of the 55 subjects (29.1%) and to malignancy in two subjects: one with metastatic disease of undetermined primary and one with confluent liver masses. Both patients presented with other signs of malignancy and represented only 3.6% of the cohort who underwent follow-up. CONCLUSION: In this cohort, patients with right-sided varicocele attributable to malignancy presented with additional signs of metastatic disease. Nonmalignant causes were more common. Therefore, confounding conditions should be considered when incidental isolated right varicocele is identified. Health care costs, patient anxiety, and unnecessary harm can be substantially reduced through modulation of follow-up recommendations based on additional findings at presentation.

The Impact of Patterns in Linkage Disequilibrium and Sequencing Quality on the Imprint of Balancing Selection.

Regions under balancing selection are characterized by dense polymorphisms and multiple persistent haplotypes, along with other sequence complexities. Successful identification of these patterns depends on both the statistical approach and the quality of sequencing. To address this challenge, at first, a new statistical method called LD-ABF was developed, employing efficient Bayesian techniques to effectively test for balancing selection. LD-ABF demonstrated the most robust detection of selection in a variety of simulation scenarios, compared against a range of existing tests/tools (Tajima's D, HKA, Dng, BetaScan, and BalLerMix). Furthermore, the impact of the quality of sequencing on detection of balancing selection was explored, as well, using: (i) SNP genotyping and exome data, (ii) targeted high-resolution HLA genotyping (IHIW), and (iii) whole-genome long-read sequencing data (Pangenome). In the analysis of SNP genotyping and exome data, we identified known targets and 38 new selection signatures in genes not previously linked to balancing selection. To further investigate the impact of sequencing quality on detection of balancing selection, a detailed investigation of the MHC was performed with high-resolution HLA typing data. Higher quality sequencing revealed the HLA-DQ genes consistently demonstrated strong selection signatures otherwise not observed from the sparser SNP array and exome data. The HLA-DQ selection signature was also replicated in the Pangenome samples using considerably less samples but, with high-quality long-read sequence data. The improved statistical method, coupled with higher quality sequencing, leads to more consistent identification of selection and enhanced localization of variants under selection, particularly in complex regions.

Association of Combined Focal 22q11.22 Deletion and IKZF1 Alterations With Outcomes in Childhood Acute Lymphoblastic Leukemia.

IMPORTANCE: Alterations in the IKZF1 gene drive B-cell acute lymphoblastic leukemia (B-ALL) but are not routinely used to stratify patients by risk because of inconsistent associations with outcomes. We describe a novel deletion in 22q11.22 that was consistently associated with very poor outcomes in patients with B-ALL with IKZF1 alterations. OBJECTIVE: To determine whether focal deletions within the λ variable chain region in chromosome 22q11.22 were associated with patients with B-ALL with IKZF1 alterations with the highest risk of relapse and/or death. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 1310 primarily high-risk pediatric patients with B-ALL who were taken from 6 independent clinical cohorts, consisting of 3 multicenter cohorts (AALL0232 [2004-2011], P9906 [2000-2003], and patients with Down syndrome who were pooled from national and international studies) and 3 single-institution cohorts (University of Utah [Salt Lake City], Children's Hospital of Philadelphia [Philadelphia, Pennsylvania], and St. Jude Children's Hospital [Memphis, Tennessee]). Data analysis began in 2011 using patients from the older studies first, and data analysis concluded in 2021. EXPOSURES: Focal 22q11.22 deletions. MAIN OUTCOMES AND MEASURES: Event-free and overall survival was investigated. The hypothesis that 22q11.22 deletions stratified the prognostic effect of IKZF1 alterations was formulated while investigating nearby deletions in VPREB1 in 2 initial cohorts (n = 270). Four additional cohorts were then obtained to further study this association (n = 1040). RESULTS: This study of 1310 patients with B-ALL (717 male [56.1%] and 562 female patients [43.9%]) found that focal 22q11.22 deletions are frequent (518 of 1310 [39.5%]) in B-ALL and inconsistent with physiologic V(D)J recombination. A total of 299 of 1310 patients with B-ALL had IKZF1 alterations. Among patients with IKZF1 alterations, more than half shared concomitant focal 22q11.22 deletions (159 of 299 [53.0%]). Patients with combined IKZF1 alterations and 22q11.22 deletions had worse outcomes compared with patients with IKZF1 alterations and wild-type 22q11.22 alleles in every cohort examined (combined cohorts: 5-year event-free survival rates, 43.3% vs 68.5%; hazard ratio [HR], 2.18; 95% CI, 1.54-3.07; P < .001; 5-year overall survival rates, 66.9% vs 83.9%; HR, 2.05; 95% CI, 1.32-3.21; P = .001). While 22q11.22 deletions were not prognostic in patients with wild-type IKZF1 , concomitant 22q11.22 deletions in patients with IKZF1 alterations stratified outcomes across additional risk groups, including patients who met the IKZF1plus criteria, and maintained independent significance in multivariate analysis for event-free survival (HR, 2.05; 95% CI, 1.27-3.29; P = .003) and overall survival (HR, 1.83; 95% CI, 1.01-3.34; P = .05). CONCLUSIONS AND RELEVANCE: This cohort study suggests that 22q11.22 deletions identify patients with B-ALL and IKZF1 alterations who have very poor outcomes and may offer a new genetic biomarker to further refine B-ALL risk stratification and treatment strategies.

Clinical utility of custom-designed NGS panel testing in pediatric tumors.

BACKGROUND: Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Previously, the standard approach was single-gene or focused multigene testing, but many centers have moved towards broad-based next-generation sequencing (NGS) panels. Here, we report the laboratory validation and clinical utility of a large cohort of clinical NGS somatic sequencing results in diagnosis, prognosis, and treatment of a wide range of pediatric cancers. METHODS: Subjects were accrued retrospectively at a single pediatric quaternary-care hospital. Sequence analyses were performed on 367 pediatric cancer samples using custom-designed NGS panels over a 15-month period. Cases were profiled for mutations, copy number variations, and fusions identified through sequencing, and their clinical impact on diagnosis, prognosis, and therapy was assessed. RESULTS: NGS panel testing was incorporated meaningfully into clinical care in 88.7% of leukemia/lymphomas, 90.6% of central nervous system (CNS) tumors, and 62.6% of non-CNS solid tumors included in this cohort. A change in diagnosis as a result of testing occurred in 3.3% of cases. Additionally, 19.4% of all patients had variants requiring further evaluation for potential germline alteration. CONCLUSIONS: Use of somatic NGS panel testing resulted in a significant impact on clinical care, including diagnosis, prognosis, and treatment planning in 78.7% of pediatric patients tested in our institution. Somatic NGS tumor testing should be implemented as part of the routine diagnostic workup of newly diagnosed and relapsed pediatric cancer patients.

3D CT segmentation of CAM type femoroacetabular impingement-reliability and relationship of CAM lesion with anthropomorphic features.

OBJECTIVE:: Evaluate feasibility and reliability of 3DCT semi-automatic segmentation and volumetrics of CAM lesions in femoroacetabular impingement and determine correlations with anthropometrics. METHODS:: A consecutive series of 43 patients with CAM type FAI underwent 3DCT. 20 males and 23 females (30 unilateral and 13 bilateral symptomatic hips) were included. 56 CAM lesions and femoral heads were segmented by two readers. Radial images were obtained for alpha angles. Pearson and ICC correlations were used for analysis. RESULTS:: In 43 patients (male: female = 1 : 1.15), mean ± SD of age, height, BMI were 36.6 ± 11.47 years, 1.72 ± 0.10 meters and 26.25 ± 4.31 kg m-². Femoral head and bumps were segmented in 4 min. Inter reader reliability was good to excellent for volumetrics and poor for alpha angles. Mean ± SD of CAM lesion and femoral head volumes were significantly larger (6.7 ± 2.5 cc3 and 62.9 ± 10.8 cc3) for males than females (p < 0.001) and these increased with increasing patient height (Pearson correlation and p-values = 0.45, 0.0006; 0.82, < 0.0001 respectively). CONCLUSION:: Volumetric analysis of CAM lesion shows better inter reader reliability than alpha angle measurements. CAM and femoral head volumes exhibit significant positive correlations with patient heights and male gender that may aid in pre-operative planning for femoroplasty. ADVANCES IN KNOWLEDGE:: Femoral head & CAM volumes are segmented three times faster than alpha angles with superior inter reader reliability than alpha angles. Femoral head & CAM volumes are significantly larger in males and positively correlate with patients' heights.