Browsing by Author "Paschke, Ralf"

Now showing 1 - 4 of 4
  • Thumbnail Image
    ItemOpen Access
    Cost-effectiveness analysis of molecular testing for cytologically indeterminate thyroid nodules
    (2022-12-21) Dharampal, Navjit; Smith, Kristine; Harvey, Adrian; Paschke, Ralf; Rudmik, Luke; Chandarana, Shamir
    Abstract Background Thyroid nodules affect up to 65% of the population. Although fine needle aspirate (FNA) cytology is the gold standard for diagnosis, 15–30% of results are indeterminate. Molecular testing may aid in the diagnosis of nodules and potentially reduce unnecessary surgery. However, these tests are associated with significant costs. The objective of this study was to evaluate the cost-effectiveness of Afirma, a commercially available molecular test, in cytologically indeterminate thyroid nodules. Methods The base case was a solitary thyroid nodule with no additional high-risk features and an indeterminate FNA. Decision tree analysis was performed from the single payer perspective with a 1-year time horizon. Costing data were collected through micro-costing methodology. A probabilistic sensitivity analysis was performed. The primary outcome was the incremental cost effectiveness ratio (ICER) of cost per thyroid surgery avoided. Results Over 1 year, mean cost estimates were $8176.28 with 0.58 effectiveness for the molecular testing strategy and $6016.83 with 0.07 effectiveness for current standard management. The ICER was $4234.22 per surgery avoided. At a willingness-to-pay (WTP) threshold of $5000 per surgery avoided, molecular testing is cost-effective with 63% certainty. Conclusion This cost-effectiveness analysis suggests utilizing Afirma for indeterminate solitary thyroid nodules is a cost-effective strategy for avoiding unnecessary thyroid surgery. With a $5000 WTP threshold, molecular testing has a 63% chance of being the more cost-effective strategy. The cost effectiveness varies based on the cost of the molecular test and the value of Afirma for patients with indeterminate thyroid nodules depends on the WTP threshold to avoid unnecessary thyroid surgery. Graphical Abstract
  • Thumbnail Image
    ItemOpen Access
    Development, Validation, and Implementation of Cytologically Indeterminate Thyroid Nodule Molecular Testing
    (2024-04-17) Stewardson, Paul; Eszlinger, Markus; Paschke, Ralf; Demetrick, Douglas J.; Bose, Pinaki; Morris, Donald; Wiseman, Sam M.
    Introduction: Genetic testing is increasingly used to diagnose or rule out thyroid cancer in indeterminate fine-needle aspirations. The research in this dissertation aimed to locally develop and validate a novel molecular test (ThyroSPEC), explore ancillary risk stratification, and measure the impacts of introducing molecular testing at the population level including for therapy selection. Methods: Comprehensive clinical data were collected prospectively for the first 615 consecutive patients with indeterminate thyroid nodules (ITNs) in a centralized healthcare system following implementation of ThyroSPEC. Accuracy of molecular testing and the impact of the introduction of molecular testing were calculated. A 16-miRNA panel was developed and validated in 127 air-dried smear indeterminate thyroid FNAC specimens and 157 liquid thyroid FNAC specimens. In a separate study on therapy selection, 86 high risk thyroid cancer patients were retrospectively identified and screened for NTRK fusions and RET fusions/mutations with molecular tests including ThyroSPEC. Results: A locally developed, low-cost molecular test achieved an NPV of 76-91% and a PPV of 46-65% in ITNs using only residual biopsy material. Following implementation of molecular testing, diagnostic yield increased 14% (p=0.2442) and repeat FNAs decreased by 24% (p=0.05). A miRNA expression classifier achieved sensitivity of 100% and specificity of 83% in the air-dried smear sample type as an adjunct to ThyroSPEC. However, miRNA expression was indistinguishable between benign and malignant tumors in local liquid cytology specimens. Molecular testing of advanced thyroid cancer patients resulted in the detection of NTRK or RET fusions in up to 40% of systematically defined patient subsets. Conclusion: Introduction of molecular testing offers clinical benefits, even in a low resection rate setting, and directly influences surgical decision-making. ThyroSPEC improved preoperative risk stratification of indeterminate thyroid nodules but requires further stratification for negative test results and intermediate risk mutations. This research also presented a novel miRNA expression classifier that could be used to incrementally risk stratify indeterminate air-dried smear FNAC and suggests that methanol-based preservation of thyroid liquid FNAC may hinder use of miRNA expression levels for molecular diagnostics. Our findings also indicate that ThyroSPEC may be suitable to detect NTRK and RET fusions in advanced thyroid cancers.
  • Thumbnail Image
    ItemOpen Access
    Malignancy risk of hyperfunctioning thyroid nodules compared with non-toxic nodules: systematic review and a meta-analysis
    (2021-02-25) Lau, Lorraine W.; Ghaznavi, Sana; Frolkis, Alexandra D.; Stephenson, Alexandra; Robertson, Helen L.; Rabi, Doreen M.; Paschke, Ralf
    Abstract Background Hyperfunctioning or hot nodules are thought to be rarely malignant. As such, current guidelines recommend that hot nodules be excluded from further malignancy risk stratification. The objective of this systematic review and meta-analysis is to compare the malignancy risk in hot nodules and non-toxic nodules in observational studies. Methods Ovid MEDLINE Daily and Ovid MEDLINE, EMBASE, Scopus, and Web of Science databases were searched. Observational studies which met all of the following were included: (1) use thyroid scintigraphy for nodule assessment, (2) inclusion of both hyperfunctioning and non-functioning nodules based on scintigraphy, (3) available postoperative histopathologic nodule results, (4) published up to November 12, 2020 in either English or French. The following data was extracted: malignancy outcomes include malignancy rate, mapping of the carcinoma within the hot nodule, inclusion of microcarcinomas, and presence of gene mutations. Results Among the seven included studies, overall incidence of malignancy in all hot thyroid nodules ranged from 5 to 100% in comparison with non-toxic nodules, 3.8–46%. Odds of malignancy were also compared between hot and non-toxic thyroid nodules, separated into solitary nodules, multiple nodules and combination of the two. Pooled odds ratio (OR) of solitary thyroid nodules revealed a single hot nodule OR of 0.38 (95% confidence interval (CI) 0.25, 0.59), toxic multinodular goiter OR of 0.51 (95% CI 0.34, 0.75), and a combined hot nodule OR of 0.45 (95% CI 0.31, 0.65). The odds of malignancy are reduced by 55% in hot nodules; however, the incidence was not zero. Conclusions Odds of malignancy of hot nodules is reduced compared with non-toxic nodules; however, the incidence of malignancy reported in hot nodules was higher than expected. These findings highlight the need for further studies into the malignancy risk of hot nodules.
  • Thumbnail Image
    ItemOpen Access
    Thyroid Stimulating Hormone Receptor Mutations in Non-Autoimmune Hyperthyroidism
    (2020-08-24) Stephenson, Alexandra; Paschke, Ralf; Robbins, Stephen M.; Grewal, Savraj S.
    Non-autoimmune hyperthyroidism (NAH) is rare and occurs due to a constitutively activating thyroid stimulating hormone receptor (TSHR) germline mutation. Germline mutations in TSHR lead to sporadic and familial NAH (SNAH, FNAH) whereas somatic mutations lead to hot thyroid adenoma (HTA). The role and prevalence of TSHR mutations in NAH have been reported to vary significantly. Furthermore, the result of these mutations appears to vary across different reports. Most interestingly, there is also a proposed role for TSHR in thyroid carcinoma. This thesis seeks to determine the true prevalence of TSHR mutations in HTA (the subset of NAH where the most samples are available), explore the phenotype of germline NAH, provide an overview of all TSHR associated disorders and begin to unravel the role of TSHR in carcinoma. This is done in 4 chapters. The first uses targeted NGS technology to determine the true prevalence of TSHR mutations in NAH (specifically HTA). This found that TSHR is the sole gene responsible for the development of HTA (96% mutation positive in an optimal subset of samples). The second chapter explores the phenotype of germline NAH, the variability of presentation, the consequences of late diagnosis, and the possible role of TSHR in bone through literature review and two novel case reports. The third chapter is an all-encompassing look at disorders associated with the TSHR including thyroid carcinoma, as documented by the TSHR mutation database. Thyroid carcinoma is further explored in the fourth chapter which outlines preliminary results and background for a plan to further evaluate TSHR’s role in thyroid carcinogenesis. This thesis concludes that TSHR signaling is solely responsible for HTA, that NAH can have variable presentations and requires early total thyroidectomy, and that TSHR undeniably plays a role in thyroid carcinoma that warrants further exploration.