Role of Sonographic Characteristics of Thyroid Bed Lesions Identified Following Thyroidectomy in the Diagnosis or Exclusion of Recurrent Cancer.

Background US of the thyroid bed in patients with thyroid cancer often depicts small lesions, but it is unclear whether US characteristics of lesions can help predict cancer recurrence. Purpose To determine whether size or US features of lesions in the thyroid bed after thyroidectomy in conjunction with clinical features can help predict thyroid cancer recurrence. Materials and Methods With use of a US reporting database, all patients imaged between July 2006 and June 2016 with an indication of post-thyroidectomy follow-up were retrospectively identified. Recorded data included patient demographic characteristics; date of thyroidectomy; thyroid cancer type; presence, size, and US characteristics of thyroid bed lesions; and results of fine-needle aspiration (FNA). Images were reviewed for lesions that underwent FNA. The Fisher exact test was used for analysis. Results A total of 1885 patients (mean age ± standard deviation, 48 years ± 15; 1493 female patients) underwent 5732 US examinations. Most patients (1541 of 1885 [82%]) had papillary cancer. Overall, 3163 thyroid bed lesions were reported in 5732 US examinations (40.4%). More than half of these lesions (1860 of 3163 [58.8%]) had a maximum measurement of 6 mm or greater. FNA was performed in 144 of the 3163 lesions (4.6%), of which 61 (42.4%) were malignant, 33 (22.9%) were benign, and 50 (34.7%) were nondiagnostic. Five nondiagnostic lesions eventually proved malignant. Only the presence of punctate echogenicities in the lesion (28 of 61 malignant lesions [45.9%]; three of 33 benign lesions [9%]; 12 of 50 nondiagnostic lesions [24%]; P < .001) or the history of positive lymph nodes at thyroidectomy (44 of 61 malignant lesions [72.1%]; 10 of 33 benign lesions [30%]; 19 of 50 nondiagnostic lesions [38%]; P < .001) were associated with malignancy. Of 3019 thyroid bed lesions that did not undergo FNA, three were malignant and 2248 showed no growth at follow-up US ranging from 6 months to 10 years and are presumed benign. Of the 1303 lesions smaller than 6 mm, only two (0.2%) were malignant. Conclusion Small lesions are commonly found in the thyroid bed after thyroidectomy, and most are likely to be benign. Lesions smaller than 6 mm with no punctate echogenicities had a minimal risk for malignancy. © RSNA, 2021 See also the editorial by Grant and Malhi in this issue.

Effect of Low-dose and Standard-dose Aspirin on PGE2 Biosynthesis Among Individuals with Colorectal Adenomas: A Randomized Clinical Trial.

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE2, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults (N = 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8-12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 ± 14.6 (mean ± S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (-4.7 ± 14.8) compared with no decrease (0.8 ± 11.8) in the placebo group (P = 0.015; mean duration of treatment = 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (-15%; P = 0.018) or 325 mg/day (-28%; P < 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.

Structure of the Mucosal and Stool Microbiome in Lynch Syndrome.

The gut microbiota has been associated with colorectal cancer (CRC), but causal alterations preceding CRC have not been elucidated. To prospectively assess microbiome changes prior to colorectal neoplasia, we investigated samples from 100 Lynch syndrome patients using 16S rRNA gene sequencing of colon biopsies, coupled with metagenomic and metatranscriptomic sequencing of feces. Colectomy and CRC history represented the largest effects on microbiome profiles. A subset of Clostridiaceae were depleted in stool corresponding with baseline adenomas, while Desulfovibrio was enriched both in stool and in mucosal biopsies. A classifier leveraging stool metatranscriptomes resulted in modest power to predict interval development of preneoplastic colonic adenoma. Predictive transcripts corresponded with a shift in flagellin contributors and oxidative metabolic microenvironment, potentially factors in local CRC pathogenesis. This suggests that the effectiveness of prospective microbiome monitoring for adenomas may be limited but supports the potential causality of these consistent, early microbial changes in colonic neoplasia.

Crossover recombination and synapsis are linked by adjacent regions within the N terminus of the Zip1 synaptonemal complex protein.

Accurate chromosome segregation during meiosis relies on the prior establishment of at least one crossover recombination event between homologous chromosomes. Most meiotic recombination intermediates that give rise to interhomolog crossovers are embedded within a hallmark chromosomal structure called the synaptonemal complex (SC), but the mechanisms that coordinate the processes of SC assembly (synapsis) and crossover recombination remain poorly understood. Among known structural components of the budding yeast SC, the Zip1 protein is unique for its independent role in promoting crossover recombination; Zip1 is specifically required for the large subset of crossovers that also rely on the meiosis-specific MutSγ complex. Here we report that adjacent regions within Zip1's N terminus encompass its crossover and synapsis functions. We previously showed that deletion of Zip1 residues 21-163 abolishes tripartite SC assembly and prevents robust SUMOylation of the SC central element component, Ecm11, but allows excess MutSγ crossover recombination. We find the reciprocal phenotype when Zip1 residues 2-9 or 10-14 are deleted; in these mutants SC assembles and Ecm11 is hyperSUMOylated, but MutSγ crossovers are strongly diminished. Interestingly, Zip1 residues 2-9 or 2-14 are required for the normal localization of Zip3, a putative E3 SUMO ligase and pro-MutSγ crossover factor, to Zip1 polycomplex structures and to recombination initiation sites. By contrast, deletion of Zip1 residues 15-20 does not detectably prevent Zip3's localization at Zip1 polycomplex and supports some MutSγ crossing over but prevents normal SC assembly and Ecm11 SUMOylation. Our results highlight distinct N terminal regions that are differentially critical for Zip1's roles in crossing over and SC assembly; we speculate that the adjacency of these regions enables Zip1 to serve as a liaison, facilitating crosstalk between the two processes by bringing crossover recombination and synapsis factors within close proximity of one another.

Encephalopathy in neonates with subgaleal hemorrhage is a key predictor of outcome.

BACKGROUND: Subgaleal hemorrhage (SGH) is reported to be associated with severe hemodynamic instability, coagulopathy, and even mortality. The importance of the presence or absence of neonatal encephalopathy in predicting SGH outcomes has not been explored. The aim of this study was to determine the relationship of clinical encephalopathy to short-term outcomes in neonates with SGH. METHODS: Neonates ≥35 weeks gestation, diagnosed radiologically with SGH between 2010 and 2017, were included. Cases were divided into encephalopathic and non-encephalopathic. Demographic, clinical, and outcome data were compared between groups. RESULTS: Of 54,048 live births, 56 had SGH, of them 13 (23%) had encephalopathy. When compared to the non-encephalopathic neonates, encephalopathic neonates had lower Apgar scores, lower hemoglobin, lower platelet count, longer neonatal intensive care unit stay, two (15%) deaths, and four (31%) required blood transfusion. No non-encephalopathic infant with SGH died or required blood transfusion. Notably, on magnetic resonance imaging (MRI), a majority of subgaleal collections had either no or minimal blood products. CONCLUSIONS: In the absence of encephalopathy, SGH is not associated with adverse short-term outcome. Neurological assessment is likely to identify infants at higher risk for adverse outcome. The absence of MRI signal consistent with blood in subgaleal collection warrants further research.

ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED): a study protocol for a randomized controlled trial.

BACKGROUND: Although aspirin is recommended for the prevention of colorectal cancer, the specific individuals for whom the benefits outweigh the risks are not clearly defined. Moreover, the precise mechanisms by which aspirin reduces the risk of cancer are unclear. We recently launched the ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED) trial to address these uncertainties. METHODS/DESIGN: ASPIRED is a prospective, double-blind, multidose, placebo-controlled, biomarker clinical trial of aspirin use in individuals previously diagnosed with colorectal adenoma. Individuals (n = 180) will be randomized in a 1:1:1 ratio to low-dose (81 mg/day) or standard-dose (325 mg/day) aspirin or placebo. At two study visits, participants will provide lifestyle, dietary and biometric data in addition to urine, saliva and blood specimens. Stool, grossly normal colorectal mucosal biopsies and cytology brushings will be collected during a flexible sigmoidoscopy without bowel preparation. The study will examine the effect of aspirin on urinary prostaglandin metabolites (PGE-M; primary endpoint), plasma inflammatory markers (macrophage inhibitory cytokine-1 (MIC-1)), colonic expression of transcription factor binding (transcription factor 7-like 2 (TCF7L2)), colonocyte gene expression, including hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) and those that encode Wnt signaling proteins, colonic cellular nanocytology and oral and gut microbial composition and function. DISCUSSION: Aspirin may prevent colorectal cancer through multiple, interrelated mechanisms. The ASPIRED trial will scrutinize these pathways and investigate putative mechanistically based risk-stratification biomarkers. TRIAL REGISTRATION: This protocol is registered with the U.S. National Institutes of Health trial registry, ClinicalTrials.gov, under the identifier NCT02394769 . Registered on 16 March 2015.