Citations

Purpose To determine whether metabolic syndrome (MetS) is a risk factor for various forms of optic neuropathy including non-arteritic anterior ischaemic optic neuropathy (NAION). Methods This population-based analysis identified patients ≥40 years of age in Olmsted County, Minnesota, USA using the Rochester Epidemiology Project 2005–2018. Patients with MetS were identified if three or more of the five standard criteria for diagnosing MetS were present: systemic hypertension, hyperglycaemia, hypertriglyceridaemia, reduced high-density lipoprotein cholesterol (hypoalphalipoproteinaemia) and central adiposity defined by increased body mass index. Charts of patients identified as having an optic neuropathy were reviewed to record specific diagnoses and compared with patients without ocular pathology other than cataract. The odds ratio (OR) of association with MetS was calculated and adjusted for age, sex and race with multivariate analysis for the various optic neuropathies. Results Patients with MetS were more likely to have an optic neuropathy than those without (OR 2.2, p<0.001). After adjusting for age, sex and race, the only optic neuropathy found to be significantly associated with MetS was NAION (OR 6.17, p=0.002). For patients with NAION, though each individual component of MetS was individually significantly associated with MetS, further analysis suggested that hypertriglyceridaemia, hypoalphalipoproteinaemia and hyperglycaemia were likely the key drivers in the overall significance between NAION and MetS. Conclusion Patients with MetS were more likely to have NAION. Further studies are needed to determine whether MetS is a modifiable risk factor for NAION.

Abstract Objectives To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). Methods A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. Results Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. Conclusions Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Background: The American Foregut Society (AFS) is dedicated to advancing patient care and digestive health within the realm of foregut disease. One of the most common and debilitating esophageal conditions is gastroesophageal reflux disease (GERD). The Hill grade is an endoscopic classification of the esophagogastric junction (EGJ) based on the appearance of the gastroesophageal flap valve from a retroflexed view of the hiatus. This endoscopic classification provides insight into the anatomic disruption of the EGJ which has been shown to correlate with GERD. However, clinical utilization of this classification by endoscopists has been limited due to the perceived relevance and subjectivity of the classification. With the advent of endoscopic treatment options for GERD, there is renewed enthusiasm to develop a grading system of the EGJ that can objectively define anatomical impairment and reduce interobserver grading variability. Methods: The AFS convened a 13-member working group tasked with reviewing the Hill grade classification and formulating a proposal for its revision utilizing a modified Delphi method. This white paper summarizes the output from this working group. Results: The working group concluded that all components of the antireflux barrier—the lower esophageal sphincter and its sling fibers, the crural diaphragm, and the gastroesophageal flap valve—contribute to EGJ integrity. Using defined objective parameters of extent of hiatal axial herniation and crural disruption and presence or absence of a flap valve, the new AFS classification stratifies EGJ integrity from normal (grade 1) to increasing degrees of EGJ disruption (grade 2-4) beginning with loss of the flap valve and progressing to increasing degrees of crural disruption and hiatus hernia. This AFS classification also stipulates appropriate endoscopic methodology to utilize in making the assessment and provides a basic nomenclature for communication among endoscopists. Conclusions: The AFS endoscopic classification of the EGJ expands on the Hill classification by including assessment of axial hiatal hernia length (L), hiatal aperture diameter (D), and presence or absence of the flap valve (F) making it more comprehensive - LDF components. Future directions include validation studies correlating the ability of the AFS classification in predicting the presence and severity of GERD.

OBJECTIVE The purpose of this study was to evaluate the safety and efficacy of a posterior facet replacement device, the Total Posterior Spine (TOPS) System, for the treatment of one-level symptomatic lumbar stenosis with grade I degenerative spondylolisthesis. Posterior lumbar arthroplasty with facet replacement is a motion-preserving alternative to lumbar decompression and fusion. The authors report the preliminary results from the TOPS FDA investigational device exemption (IDE) trial. METHODS The study was a prospective, randomized controlled FDA IDE trial comparing the investigational TOPS device with transforaminal lumbar interbody fusion (TLIF) and pedicle screw fixation. The minimum follow-up duration was 24 months. Validated patient-reported outcome measures included the Oswestry Disability Index (ODI) and visual analog scale (VAS) for back and leg pain. The primary outcome was a composite measure of clinical success: 1) no reoperations, 2) no device breakage, 3) ODI reduction of ≥ 15 points, and 4) no new or worsening neurological deficit. Patients were considered a clinical success only if they met all four measures. Radiographic assessments were made by an independent core laboratory. RESULTS A total of 249 patients were evaluated (n = 170 in the TOPS group and n = 79 in the TLIF group). There were no statistically significant differences between implanted levels (L4–5: TOPS, 95% and TLIF, 95%) or blood loss. The overall composite measure for clinical success was statistically significantly higher in the TOPS group (85%) compared with the TLIF group (64%) (p = 0.0138). The percentage of patients reporting a minimum 15-point improvement in ODI showed a statistically significant difference (p = 0.037) favoring TOPS (93%) over TLIF (81%). There was no statistically significant difference between groups in the percentage of patients reporting a minimum 20-point improvement on VAS back pain (TOPS, 87%; TLIF, 64%) and leg pain (TOPS, 90%; TLIF, 88%) scores. The rate of surgical reintervention for facet replacement in the TOPS group (5.9%) was lower than the TLIF group (8.8%). The TOPS cohort demonstrated maintenance of flexion/extension range of motion from preoperatively (3.85°) to 24 months (3.86°). CONCLUSIONS This study demonstrates that posterior lumbar decompression and dynamic stabilization with the TOPS device is safe and efficacious in the treatment of lumbar stenosis with degenerative spondylolisthesis. Additionally, decompression and dynamic stabilization with the TOPS device maintains segmental motion.

AbstractPediatric pulmonary malignancy can be primary or metastatic, with the latter being by far the more common. With a few exceptions, there are no well‐established evidence‐based guidelines for imaging pediatric pulmonary malignancies, although computed tomography (CT) is used in almost all cases. The aim of this article is to provide general imaging guidelines for pediatric pulmonary malignancies, including minimum standards for cross‐sectional imaging techniques and specific imaging recommendations for select entities.

Abstract Background Risk factors for the pathogenesis of chronic rhinosinusitis (CRS) remain largely undetermined, which is likely due to the heterogeneity of the disease. White blood cell counts have been largely unexplored as a risk factor for CRS even though different types of white blood cells are involved in the inflammatory process of CRS. Objective To investigate causal associations between different types of white blood cells on risk of CRS utilizing a Mendelian randomization (MR) analysis. Methods A two-sample MR analysis was performed using respective GWAS summary statistics for the exposure traits (neutrophil count, eosinophil count, basophil count, lymphocyte count, and monocyte count) and outcome trait (CRS). For the exposure traits, the European Bioinformatics Institute database of complete GWAS summary data was used. For the outcome trait, summary statistics for CRS GWAS were obtained from FinnGen. Primary analysis for MR was performed using inverse-variance weighted two-sample MR. Sensitivity analyses included weighted median, MR-Egger, and MR-PRESSO (raw and outlier-corrected). Results Eosinophils were associated with CRS (OR = 1.55 [95%CI 1.38,1.73]; p = 4.3E-14). Eosinophil results were similar across additional MR methods. MR results did not demonstrate significant causal relationships between neutrophils, lymphocytes, monocytes, or basophils with CRS. No significant pleiotropic bias was observed. Conclusions In a two-sample MR analysis, a potential causal link between blood eosinophil counts and CRS has been demonstrated. In addition, causal relationships between blood counts among other white blood cell types and CRS were not found. Further studies involving genetic variation in CRS are needed to corroborate genetic causal effects for CRS.

In this study, we used whole-exome sequencing of a cohort of 45 advanced-stage, treatment-naïve Nigerian (NG) primary prostate cancer tumors and 11 unmatched nontumor tissues to compare genomic mutations with African American (AA) and European American (EA) The Cancer Genome Atlas (TCGA) prostate cancer. NG samples were collected from six sites in central and southwest Nigeria. After whole-exome sequencing, samples were processed using GATK best practices. BRCA1 (100%), BARD1 (45%), BRCA2 (27%), and PMS2(18%) had germline alterations in at least two NG nontumor samples. Across 111 germline variants, the AA cohort reflected a pattern [BRCA1 (68%), BARD1 (34%), BRCA2 (28%), and PMS2 (16%)] similar to NG samples. Of the most frequently mutated genes, BRCA1 showed a statistically (P ≤ 0.05) higher germline mutation frequency in men of African ancestry (MAA) and increasing variant frequency with increased African ancestry. Disaggregating gene-level mutation frequencies by variants revealed both ancestry-linked and NG-specific germline variant patterns. Driven by rs799917 (T&gt;C), BRCA1 showed an increasing mutation frequency as African ancestry increased. BRCA2_rs11571831 was present only in MAA, and BRCA2_rs766173 was elevated in NG men. A total of 133 somatic variants were present in 26 prostate cancer–associated genes within the NG tumor cohort. BRCA2 (27%), APC (20%), ATM (20%), BRCA1 (13%), DNAJC6 (13%), EGFR (13%), MAD1L1 (13%), MLH1 (11%), and PMS2 (11%) showed mutation frequencies &gt;10%. Compared with TCGA cohorts, NG tumors showed statistically significant elevated frequencies of BRCA2, APC, and BRCA1. The NG cohort variant pattern shared similarities (cosign similarities ≥0.734) with Catalogue of Somatic Mutations in Cancer signatures 5 and 6, and mutated genes showed significant (q &lt; 0.001) gene ontology (GO) and functional enrichment in mismatch repair and non-homologous repair deficiency pathways. Here, we showed that mutations in DNA damage response genes were higher in NG prostate cancer samples and that a portion of those mutations correlate with African ancestry. Moreover, we identified variants of unknown significance that may contribute to population-specific routes of tumorigenesis and treatment. These results present the most comprehensive characterization of the NG prostate cancer exome to date and highlight the need to increase diversity of study populations. Significance: MAA have higher rates of prostate cancer incidence and mortality, however, are severely underrepresented in genomic studies. This is the first study utilizing whole-exome sequencing in NG men to identify West African ancestry-linked variant patterns that impact DNA damage repair pathways.

AbstractPrimary hepatic malignancies are relatively rare in the pediatric population, accounting for approximately 1%–2% of all pediatric tumors. Hepatoblastoma and hepatocellular carcinoma are the most common primary liver malignancies in children under the age of 5 years and over the age of 10 years, respectively. This paper provides consensus‐based imaging recommendations for evaluation of patients with primary hepatic malignancies at diagnosis and follow‐up during and after therapy.

Neoadjuvant chemotherapy (NAC) remains the cornerstone of the treatment for triple negative breast cancer (TNBC), with the goal of complete eradication of disease. However, for patients with residual disease after NAC, recurrence and mortality rates are high and the identification of novel therapeutic targets is urgently needed. We quantified tyrosine phosphorylation (pTyr)-mediated signaling networks in chemotherapy sensitive (CS) and resistant (CR) TNBC patient-derived xenografts (PDX), to gain novel therapeutic insights. The antitumor activity of SFK inhibition was examined in vivo. Treated tumors were further subjected to phosphoproteomic and RNAseq analysis, to identify the mechanism of actions of the drug. We identified Src Family Kinases (SFKs) as potential therapeutic targets in CR TNBC PDXs. Treatment with dasatinib, an FDA approved SFK inhibitor, led to inhibition of tumor growth in vivo. Further analysis of post-treatment PDXs revealed multiple mechanisms of actions of the drug, confirming the multi-target inhibition of dasatinib. Analysis of pTyr in tumor specimens suggested a low prevalence of SFK-driven tumors, which may provide insight into prior clinical trial results demonstrating a lack of dasatinib antitumor activity in unselected breast cancer patients. Taken together, these results underscore the importance of pTyr characterization of tumors, in identifying new targets, as well as stratifying patients based on their activated signaling networks for therapeutic options. Our data provide a strong rationale for studying SFK inhibitors in biomarker-selected SFK-driven TNBC.