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Objective We report the results of a retrospective five-year study within a veteran population aimed at correlating abnormal thyroid fine-needle aspiration (FNA) diagnosis with associated molecular testing to the histology of the surgical resection. Methods A retrospective analysis of abnormal thyroid FNAs with associated molecular testing and surgical outcome was conducted from January 1, 2015 to December 31, 2020. Aspirates were classified using the Bethesda system for reporting thyroid cytopathology, including atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), suspicious for malignancy (SM), and malignant. Pertinent data, including patient demographics, imaging, and ancillary testing were reviewed. A thyroid cancer mutation panel assessing the most common mutations and rearrangements associated with neoplasia was utilized. The results of molecular testing were directly compared and correlated with final cytological and histological diagnosis. Results A total of 1850 thyroid aspirates were performed, 200 of which were given an abnormal cytologic diagnosis. Thirty-six samples were submitted for molecular testing and subsequent surgical follow-up. Four were called malignant on cytology. 32 were placed in an indeterminate category (89%). Within indeterminate cases: 53% exhibited positive molecular mutations (n=17), 34% no mutation detected (n=11), and 13% insufficient quantity for testing (n=4). Upon surgical resection in the mutation-positive group: 18% had no malignancy (n=3), and the remaining 82% were positive for malignancy (n=14). Mutations in the histologically malignant group included: 57% BRAF (n=8), 21% NRAS (n=3), 7% HRAS (n=1), 7% KRAS (n=1), and 7% PAX8/PPAR gamma (n=1). In indeterminate cases with no mutation detected, 10 cases were found to be benign, and one case of malignancy was diagnosed. The probability of indeterminate diagnosis in combination with no mutation yielded a 91% chance of benign entity and 9% chance of malignancy. We demonstrated 93% sensitivity and 91% negative predictive value (NPV) for the risk of malignancy in indeterminate cytology specimens with ancillary molecular testing. There was 77% specificity and 82% positive predictive value (PPV) for our data set. Conclusions In indeterminate samples, the detection of a mutation was highly predictive of malignancy and a strong indicating factor for surgery with a high sensitivity and NPV. Molecular testing refined or established the diagnosis in 89% of the cases. Our results indicate that molecular testing of thyroid nodules enhances the accuracy of FNA cytology and the subsequent surgical outcome.
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Objective This project aims to use our robust women's health patient data to analyze the correlation between cytology and high-risk human papillomavirus (Hr-HPV) testing, study the performance of Hr-HPV testing for detecting cytology lesions, and examine epidemiologic measures of human papillomavirus (HPV) infections in the women's veteran population. Methods We collected patient data from 2014 to 2020 from our computerized patient record system. We performed HPV assays using the cobas® 4800 system (Roche Diagnostics, Basel, Switzerland). The cobas HPV assay detects HPV 16, HPV 18, and 12 other HPV types (31, 33, 35, 39, 45, 51, 56, 58, 59, 66, and 68). We organized cytology results and Hr-HPV assays with Microsoft Access and Microsoft Excel (Microsoft Corporation, Washington, USA) for analysis. Results A total of 9437 cervical specimens were co-tested. High-grade cytology lesions - high-grade intraepithelial lesion (HSIL) or higher and atypical squamous cells, cannot exclude HSIL (ASC-H) - were overwhelmingly positive for Hr-HPV (94.1% and 87.2%, respectively). Low-grade cytology lesions - low-grade squamous intraepithelial lesion ((LSIL) and atypical squamous cells of undetermined significance (ASC-US) - were positive for Hr-HPV in lower percentages (72.6% and 54.9%, respectively). Hr-HPV testing had a sensitivity of 91.3%, a specificity of 93.1%, a positive predictive value of 16.4%, and a negative predictive value of 99.8% for detecting high-grade cytology lesions. Hr-HPV testing had a lower performance for detecting low-grade cytology lesions. Ten cases had high-grade cytology and negative Hr-HPV test. Out of 10 such patients, nine showed no dysplasia (six) or low-grade dysplasia (three) on subsequent biopsy. Overall, 14.4% of tests were positive for Hr-HPV. The highest positive Hr-HPV test rates were in the third and eighth decades of life, 25.1% and 22.0%, respectively. However, the eighth decade consisted of a small sample of only 50 women. In women over 30 years of age with Hr-HPV infections, HPV types 16 and 18 were present in 11.7% and 6.4% of tests, respectively. Other HPV types were present in 82.3% of tests. Conclusions Hr-HPV testing has a high performance in detecting high-grade cytology lesions and a lower performance for detecting low-grade cytology lesions. However, studies show that LSIL rarely progresses to cervical intraepithelial neoplasia grade 3 or higher (CIN3+), suggesting minimal to no impact on cervical cancer screening. We believe our findings are in accordance with recent studies and affirm the guidelines that recommend primary Hr-HPV testing as the preferred screening method. The percentage of positive Hr-HPV tests and rates for age and HPV types 16 and 18 in our women's veteran population suggest similar HPV prevalence to that of the general US population.
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Here we demonstrate that treatment with SAHA (suberoylanilide hydroxamic acid), a known inhibitor of histone deacetylases (HDACs), alone induced p21 and/or p27 expressions but decreased the mRNA and protein levels of Bcr-Abl, which was associated with apoptosis of Bcr-Abl-expressing K562 and LAMA-84 cells. Cotreatment with SAHA and imatinib (Gleevec) caused more down-regulation of the levels and auto-tyrosine phosphorylation of Bcr-Abl and apoptosis of these cell types, as compared with treatment with either agent alone (P <.05). This finding was also associated with a greater decline in the levels of phospho-AKT and Bcl-x(L). Significantly, treatment with SAHA also down-regulated Bcr-Abl levels and induced apoptosis of CD34(+) leukemia blast progenitor cells derived from patients who had developed progressive blast crisis (BC) of chronic myelocytic leukemia (CML) while receiving therapy with imatinib. Taken together, these findings indicate that cotreatment with SAHA enhances the cytotoxic effects of imatinib and may have activity against imatinib-refractory CML-BC.
