Notable Publications from the UPMC Division of Endocrinology and Metabolism

UPMC Division of Endocrinology Metabolism faculty recently published two notable research articles on molecular testing in thyroid nodules and gestational diabetes mellitus.

Publication #1

Skaugen JM, Taneja C, Liu JB, Wald AI, Nikitski AV, Chiosea SI, Seethala R, Ohori NP, Karslioglu-French E, Carty SE, Nikiforova MN, Yip L, Nikiforov YE. Performance of a Multigene Genomic Classifier in Thyroid Nodules with Suspicious for Malignancy Cytology. Thyroid. 2022 Jul. doi: 10.1089/thy.2022.0282. Epub ahead of print. PMID: 35864811.

Background: Molecular testing is increasingly used to refine the probability of cancer and assess recurrence risk in thyroid nodules with Bethesda III/IV fine needle aspiration (FNA) cytology. However, limited data exists for Bethesda V (suspicious for malignancy, SFM). This study evaluated the performance of ThyroSeq v3 (TSv3) in thyroid nodules with SFM cytology.

Methods: In this single-institution retrospective cohort study, consecutive thyroid FNA samples diagnosed as SFM with TSv3 testing and known surgical outcome were identified. Clinical, pathology, and molecular findings were reviewed. TSv3 Cancer Risk Classifier was used to determine molecular risk groups (MRGs). For test-negative cases diagnosed as cancer/NIFTP, TSv3 was performed on the resected tumors.

Results: Among 128 SFM samples studied, 100 (78.1%) were TSv3 positive, and 28 (21.9%) were negative. The cancer prevalence on surgery was 82.8%. Among test-positive samples, 95% were malignant and 5% benign. Among test-negative samples, 17 (60.7%) were benign and 11 (39.3%) malignant. Overall, TSv3 had sensitivity of 89.6% (95% CI, 82.4%-94.1%) and specificity of 77.3% (95% CI, 56.6%-89.9%). For a cancer prevalence of 50-75% expected in SFM cytology by the Bethesda system, negative predictive value (NPV) was expected to range from 71.2% to 88.1% and positive predictive value (PPV) from 79.8% to 92.2%. Among test-positive nodules, 20% were MRG-Low (mostly RAS-like alterations), 66% MRG-Intermediate (mostly BRAF-like alterations), and 14% MRG-High. Among patients with cancer, 65 (61.3%) were ATA low risk, 25 (23.6%) intermediate risk, and 6 (5.7%) high risk. During the mean follow-up of 51.2 months (range: < 1 to 470 months), 12 (13.0%) patients had disease recurrence, which was more common in MRG-High (54.6%) compared to MRG-Intermediate (9.5%) and MRG-Low (0%) cancers (p<0.001). Upon re-examining tumors with false-negative results, half of evaluable cases had alterations likely missed due to limiting FNA sampling, and the remainder represented low-risk tumors. Potentially targetable alterations were identified in 10 samples.

Conclusions: In this large series of SFM thyroid nodules, TSv3 further improved cancer prediction and detected RAS-like, BRAF-like, high-risk, and potentially targetable alterations, all of which may inform more optimal patient management. MRGs were associated with recurrence-free survival, offering potential preoperative cancer risk stratification.

Publication #2

Feng Y, Xu D, Cai X, Xu M, Garbacz WG, Ren S, Jurczak MJ, Yu C, Wang H, Xie W. Gestational Diabetes Sensitizes Mice to Future Metabolic Syndrome That Can Be Relieved by Activating CAR. Endocrinology. 2022 Jul 1; 163(7):bqac061. doi: 10.1210/endocr/ bqac061. PMID: 35524740.

Background: Diabetes and related metabolic syndrome are common metabolic disorders. Gestational diabetes mellitus (GDM) is rather prevalent in the clinic. Although most GDM resolves after therapeutic intervention and/or after delivery, the long-term health effect of GDM remains to be better understood. The constitutive androstane receptor (CAR), initially characterized as a xenobiotic receptor, was more recently proposed to be a therapeutic target for obesity and type 2 diabetes mellitus (T2DM).

Methods: In this study, high-fat diet (HFD) feeding was used to induce GDM. Upon delivery, GDM mice were returned to chow diet until the metabolic parameters were normalized. Parous non-GDM control females or metabolically normalized GDM females were then subjected to HFD feeding to induce nongestational obesity and T2DM.

Results: Our results showed that GDM sensitized mice to metabolic abnormalities induced by a second hit of HFD. Treatment with the CAR agonist 1,4-bis [2-(3,5 dichloropyridyloxy)] benzene efficiently attenuated GDM-sensitized and HFD-induced obesity and T2DM, including decreased body weight, improved insulin sensitivity, inhibition of hyperglycemia and hepatic steatosis, increased oxygen consumption, and decreased adipocyte hypertrophy.

Conclusion: In conclusion, our results have established GDM as a key risk factor for the future development of metabolic disease. We also propose that CAR is a therapeutic target for the management of metabolic disease sensitized by GDM.