Faculty Bibliography

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.

Background: Thyroseq next-generation sequencing assay and Afirma gene expression classifier (GEC) are used to risk-stratify thyroid nodules with indeterminate cytology: Bethesda III (atypia of undetermined significance, AUS/FLUS) and IV (suspicious for follicular neoplasm, SFN). In this study, we performed a paired comparison of both tests on the same group of indeterminate thyroid nodules with surgical followup.
Design(s): Of 645 AUS/FLUS/SFN cases with both molecular testing and surgical resection in 2014-2017, 40 cases had both Thyroseq (v2) and Afirma GEC performed on the same specimen. Cross-tabulations and ROC curves were created. McNemar tests were done to compare the performance of Thyroseq versus Afirma. The diagnostic performance of combined results were also examined: the combined result was called positive only if both Thyroseq and Afirma were positive/suspicious. Non-invasive follicular thyroid with papillary like nuclear features (NIFTP) on surgical resections was defined as ?positive.? Results: 20/40 (50%) cases were ?positive? on surgical pathology: 8 papillary thyroid carcinoma (PTC), 11 NIFTP, and 1 follicular carcinoma. Thyroseq and Afirma both showed high sensitivity and low specificity in diagnosing malignancy in indeterminate thyroid nodules. Next, the results of both tests were combined. The overall accuracy of combined testing was higher than either test alone (Figure 1). Compared to Afirma alone, the combined test had significantly higher specificity (30% vs 70%, p<0.05, Table 1), while the sensitivity declined from 90% to 75% (p=0.25, Table 1). Compared to Thyroseq alone, there was no significant difference in specificity (45% vs 70% p=0.06) or sensitivity (80% vs 75%, p=1.00, Table 1). Positive predictive value (PPV) improved compared to either test alone. Negative predictive value (NPV) improved compared to Thyroseq alone, and declined only slightly compared to Afirma alone.
Conclusion(s): Molecular testing of cytologically indeterminate thyroid nodules helps determine the extent of surgery. Low diagnostic performance metrics may limit the utility of molecular studies in distinguishing benign from malignant thyroid lesions. Our results show that the combined results of Thyroseq and Afirma improved the specificity and overall accuracy of molecular testing, and provided additional value in the surgical management of patients with indeterminate thyroid nodules. To the best of our knowledge, this is the first study that compares the performance of these two molecular tests on the same thyroid nodules

Introduction: In urine cytology, the atypical category suffers from interobserver variability and a wide range of risk of malignancy (ROM). This leads to confusion and inconsistent clinical management of patients with atypical urine diagnoses. Our study identified the rate of atypical diagnoses at our institution over a five-year period and examined the concurrent or follow-up surgical pathology diagnoses (SD) to understand the clinical significance of atypical urine specimens.
Material(s) and Method(s): A retrospective review of adult urine cytology specimens pre- 7/1/2014-6/30/2016 (TD) and post- 7/1/2017-6/30/2019 (TPS) implementation of the Paris System for Reporting Urinary Cytology was performed, which identified 10,132 total urine specimens. Of these, 2,457 specimens from 1,727 patients were categorized as "atypical." 177 cytology specimens were found to have corresponding urinary tract SD within 90 days. Pre- and post-Paris System (TD and TPS) urine cytology diagnoses were compared.
Result(s): The overall rate of "atypical" diagnoses was 2,457/10,132 (24.3%). 177 of 2,457 atypical specimens (7.2%) had corresponding urinary tract SD, of which the ROM was 37.9% (TD 37.8%, TPS 37.9%, p=0.992). 61 of 177 atypical urines (34.5%) were high grade (HGUC/CIS) on SD (TD 32.9%, TPS 35.8%). 66 of 177 atypical urines (37.3%) were low grade urothelial neoplasms (LGUNs), atypical, or dysplastic on SD (TD 39.0%, TPS 35.8%, p=0.660). 44 of 177 atypical urines (24.9%) were benign on SD (TD 23.2%, TPS 26.3%) (Table 1).
Conclusion(s): While the atypical diagnosis rate of nearly 1 in 4 urines is fairly high, over one-third of atypical results signified a high grade malignancy, and over an additional one-third of atypical urines represented LGUN, atypical, or dysplastic surgical pathology diagnoses. These findings emphasize the need for close follow-up in patients with atypical diagnoses on urine cytology. Our findings did not show a significant difference between pre and post TPS follow up data. [Formula presented]
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Introduction: Urothelial carcinomas (UC) of the upper urinary tract (UUT) are rare, and usually show higher grade and poorer prognosis than carcinomas of the bladder. The Paris System (TPS) has been integrated into our standard terminology for interpreting urine cytology. Here we compare TPS diagnoses to the traditional reporting system (TD) in interpreting UC of UUT and lower urinary tract (LUT) in correlation with surgical pathology diagnoses (SD).
Material(s) and Method(s): A search of the cytopathology database on urine specimens from 7/1/2014-6/30/2016 (TD) and 7/1/2017-6/30/2019 (TPS) with corresponding lesions in SD, yielded 14-TD cases and 19-TPS in UUT; and 178-TD and 243-TPS cases in LUT. The cytopathology diagnosis using TD and TPS were compared to their corresponding SD.
Result(s): In UUT, 51.5% (17/33) were UC on SD. High-grade UC (HGUC) was correctly identified in UUT in 100% (5/5) with TD, and 75%(3/4) with TPS. No low-grade (LG) diagnoses were rendered in TD or TPS though there were 8 low-grade urothelial neoplasms (LGUN). LGUN was classified as "atypical" (2/3-TD, 2/5-TPS) or "negative" (1/3-TD, 3/5-TPS). Rates of "atypical" diagnoses of UUT were 28.6% (TPS) and 26.3% (TD), with no HGUC on SD. The risk of LGUN with "atypical" diagnoses decreased using TPS from 75.0% (3/4) to 60.0% (3/5). In LUT, HGUC was correctly diagnosed in 55.0%(44/80) (TD) and 47.4%(46/97) (TPS). 4% of LGUNs were classified as LG (3/60-TPS, 1/40-TD). "Atypical" diagnoses for TD and TPS showed 29.5% (23/78) and 30.0% (27/90) risk of LGUN and 34.6%(27/78) and 37.8%(34/90) risk of HGUC respectively. (Table-1)
Conclusion(s): The TD and TPS systems showed high accuracy in reporting UUT-HGUC. However, urine cytology is not optimal to identify LGUN in both TD and TPS systems. Additionally, our results suggest that urine cytology may be more sensitive in detecting HGUC in UUT versus LUT samples.[Table presented]
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Introduction: Due to the diagnostic dilemma with indeterminate thyroid Bethesda categories III and IV (atypia of undetermined significance, AUS and Suspicious for follicular neoplasm, SFN), many laboratories utilize molecular testing to aid in risk stratification of these nodules. In this study, we evaluated the risk of malignancy (ROM) in AUS and SFN thyroid nodules with subsequent negative molecular (ThyroSeq) test results.
Material(s) and Method(s): This study was designed to evaluate the negative molecular thyroid fine needle aspiration (FNA) cases at a tertiary medical center in the metropolitan area. 109 cases of AUS and SFN thyroid FNAs over 3 years with surgical pathology follow up were included in the study.
Result(s): Of 109 AUS and SFN cases, 4 cases showed insufficient material for ThyroSeq testing (3.7%), 76 cases showed a molecular alteration (69.7%), and 29 cases were negative for an alteration on ThyroSeq (26.6%). Among the cases with negative ThyroSeq results, 26 cases were benign on surgical pathology (89.7%) (7/26 were follicular adenomas), and 3/29 cases were malignant on histopathology (papillary thyroid carcinoma) (ROM=10.3%, Table 1). AUS and SFN cases with molecular alterations showed a significantly higher ROM (ROM= 60.5%) compared to cases testing negative for molecular alterations (p<0.01, z = -4.61).
Conclusion(s): Our study found that indeterminate thyroid nodules that tested negative for a molecular alteration displayed an ROM of 10.3%. This ROM is comparable to the lower limit of ROM of FNA alone (without additional molecular testing data) in the AUS and SFN categories (10-30%), but is significantly lower than the ROM of indeterminate thyroid cases with known molecular mutations. Therefore, clinical follow-up is recommended for thyroid FNA indeterminate nodules, even those testing negative for a molecular alteration, due to the maintained, albeit lower, ROM. [Formula presented]
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Neutropenic enterocolitis (NE) is a predominantly cecum-based disease with high mortality seen in patients post chemotherapy. The pathogenesis of NE is poorly understood and probably multifactorial involving mucosal injury, neutropenia, and impaired host defense to intestinal organisms. The clinical presentation is characterized as ileocolonic inflammation and bowel wall thickening in patients with neutropenia, fever, and abdominal pain. The pathological features of NE include patchy necrosis, hemorrhage, ulcer, edema, perforation, infiltrating organisms, and characteristically, depletion of inflammatory cells (neutrophils). NE should always be considered as a possible diagnosis in immunosuppressed patients, especially those receiving chemotherapy. High clinical and histological diagnostic discordance rate exists. High index of clinical suspicion and prompt appropriate personalized management are essential to achieve a lower mortality rate.

Levodopa is the most effective therapy for the motor deficits of Parkinson's disease (PD), but long term treatment leads to the development of L-DOPA-induced dyskinesia (LID). Our previous studies indicate enhanced excitability of striatal cholinergic interneurons (ChIs) in mice expressing LID and reduction of LID when ChIs are selectively ablated. Recent gene expression analysis indicates that stimulatory H2 histamine receptors are preferentially expressed on ChIs at high levels in the striatum, and we tested whether a change in H2 receptor function might contribute to the elevated excitability in LID. Using two different mouse models of PD (6-hydroxydopamine lesion and Pitx3(ak/ak) mutation), we chronically treated the animals with either vehicle or l-DOPA to induce dyskinesia. Electrophysiological recordings indicate that histamine H2 receptor-mediated excitation of striatal ChIs is enhanced in mice expressing LID. Additionally, H2 receptor blockade by systemic administration of famotidine decreases behavioral LID expression in dyskinetic animals. These findings suggest that ChIs undergo a pathological change in LID with respect to histaminergic neurotransmission. The hypercholinergic striatum associated with LID may be dampened by inhibition of H2 histaminergic neurotransmission. This study also provides a proof of principle of utilizing selective gene expression data for cell-type-specific modulation of neuronal activity.