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Ralf Paschke
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Silvia Cantara
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Anna Crescenzi
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Barbara Jarzab
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Thomas J. Musholt
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Manuel Sobrinho Simoes
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Molecular fine-needle aspiration (FNA) cytology diagnostics has the potential to address the inherent limitation of FNA cytology which is an indeterminate (atypia of undetermined significance/follicular lesion of undetermined significance follicular neoplasm) cytology. Because of the emerging role of molecular FNA cytology diagnostics, the European Thyroid Association convened a panel of international experts to review methodological aspects, indications, results, and limitations of molecular FNA cytology diagnostics. The panel reviewed the evidence for the diagnostic value of mutation panel assessment (including at least BRAF, NRAS, HRAS, KRAS, PAX8/PPARG, RET/PTC) of targeted next generation sequencing and of a microarray gene expression classifier (GEC) test in the diagnostic assessment of an indeterminate cytology thyroid nodule. Moreover, possible surgical consequences of molecular FNA diagnostic results of thyroid nodules and the evidence that analysis of a molecular FNA diagnostic panel of somatic mutations or a microarray GEC test can alter the follow-up were reviewed. Molecular tests may help clinicians to drive patient care and the surgical decision if the analysis is performed in specialized laboratories. These molecular tests require standardization of performance characteristics and appropriate calibration as well as analytic validation before clinical interpretation.

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Jiahui Wu Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Xunyang Hu Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Paula Seal EFW Radiology, Calgary, Alberta, Canada
Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Parthiv Amin Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Brendan Diederichs Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
Mayfair Radiology, Calgary, Alberta, Canada

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Ralf Paschke Section of Endocrinology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
Departments of Medicine, Oncology, Pathology and Laboratory Medicine, Biochemistry and Molecular Biology, and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Objective

The aim of this study was to prospectively evaluate the quality of postoperative neck ultrasound (POU) for thyroid cancer patients after implementing European Thyroid Association (ETA) guideline-based POU assessment.

Methods

Our analysis involved 672 differentiated thyroid cancer patients. POU report quality was compared between the implementation radiology group (IRG), which implemented ETA guideline-based assessment in 2018, and all non-implementation radiology groups (NIRG). Differences in POU quality were evaluated before and after the implementation of guideline-based assessment. Additionally, we evaluated the ability of serum thyroglobulin (Tg) level <0.2 ng/mL or between 0.21 and 0.99 ng/mL and normal POU lesion status at 1-year follow-up to predict the absence of persistent disease or relapse at 3-year follow-up.

Results

IRG had significantly higher mean utility scores for POU reports of abnormal thyroid bed nodules compared to NIRG (P < 0.001). IRG's POU reports for suspicious nodules and lymph nodes were considered sufficient in 94% and 85% of cases, respectively, compared to 45% and 68% for NIRG. For patients with normal US lesion status and Tg <0.2 ng/mL or Tg 0.21–0.99 ng/mL at 1-year follow-up, the negative predictive values were 96% for both.

Conclusions

Implementation of 2013 ETA POU-reporting guidelines allowed for the provision of high-quality POU reports, which may lead to increased accuracy in assessing the response to treatment and in estimating the risk of recurrence of thyroid cancer and likely reduce unnecessary repeat POU or FNA.

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Luisa Paschke Department of Endocrinology and Nephrology, Division of Endocrinology, University Clinic Leipzig, Leipzig, Germany
Department of Endocrinology and Nephrology, Division of Nephrology, University Clinic Leipzig, Leipzig, Germany

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Thomas Lincke Department of Radiology, Division of Nuclear Medicine, University Clinic Leipzig, Leipzig, Germany

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Katja Sibylle Mühlberg Department of Angiology, University Clinic Leipzig, Leipzig, Germany

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Wolfram J. Jabs Department of Nephrology, Vivantes Clinics, Berlin, Germany

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Tom H. Lindner Department of Endocrinology and Nephrology, Division of Nephrology, University Clinic Leipzig, Leipzig, Germany

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Ralf Paschke Division of Endocrinology, University of Calgary, Calgary, Alberta, Canada

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Cabozantinib and lenvatinib have been approved for the treatment of progressive medullary thyroid cancer and radioiodine-resistant thyroid cancer, respectively. Both phase III trials of cabozantinib and lenvatinib reported that renal adverse events (AEs) rarely occurred. The cabozantinib phase III study reported no AEs related to renal toxicity. In the lenvatinib phase III trial grade 3 (CTCAE), proteinuria (urinary protein ≥3.5 g/24 h) was found in 10.0% of the lenvatinib and 0.0% of the placebo patients. We report a 23-year-old patient with metastatic medullary thyroid cancer who was enrolled in the phase III trial, comparing cabozantinib to placebo and a 67-year-old patient with metastatic, papillary thyroid carcinoma who was undergoing treatment with lenvatinib during his enrollment in the phase III trial. The first patient had a normal kidney function initially, but developed end-stage chronic kidney disease unexpectedly on cabozantinib and additional zoledronate infusion. Whereas the second patient suffered from a dramatic aggravation of his known mild chronic renal insufficiency (KDOQI stage 2) due to long standing hypertension and atherosclerosis during the treatment with lenvatinib. These severe AEs due to anti-VEGF tyrosine kinase inhibitor treatment were unknown so far. In conclusion, these 2 cases argue for increased awareness for the possibility of renal failure as a consequence of anti-VEFG treatment. Predisposing conditions like known mild chronic renal insufficiency with only mild proteinuria and with atherosclerosis or precipitating co-medications like zoledronate infusion need to be accounted for to prevent these severe AEs.

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Markus Eszlinger Department of Oncology and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada, and Institute of Pathology, University Hospital Halle, Halle, Germany

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Alexandra Stephenson Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada

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Shideh Mirhadi Program in Cell Biology, Hospital for Sick Children, and Department of Molecular Genetics, University of Toronto, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada

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Konrad Patyra Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland

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Michael F Moran Program in Cell Biology, Hospital for Sick Children, and Department of Molecular Genetics, University of Toronto, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada

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Moosa Khalil Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Jukka Kero Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland
Department of Pediatrics, Turku University Hospital, Turku, Finland

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Ralf Paschke Department of Oncology and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada, and Institute of Pathology, University Hospital Halle, Halle, Germany
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada
Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
Department of Medicine, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada

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Objective

Nonautoimmune hyperthyroidism (NAH) is rare and occurs due to a constitutively activating thyroid stimulating hormone receptor (TSHR) mutation. In contrast to other thyroid nodules, no further evaluation for malignancy is recommended for hot thyroid nodules. In the first model for NAH in mice nearly all homozygous mice had developed papillary thyroid cancer by 12 months of age.

Methods

To further evaluate these mice, whole exome sequencing and phosphoproteome analysis were employed in a further generation of mice to identify any other mutations potentially responsible and to identify the pathways involved in thyroid carcinoma development.

Results

Only three genes (Nrg1, Rrs1, Rasal2) were mutated in all mice examined, none of which were known primary drivers of papillary thyroid cancer development. Wild-type and homozygous TSHR D633H knockin mice showed distinct phosphoproteome profiles with an enrichment of altered phosphosites found in ERK/mitogen-activated protein kinase (MAPK) signaling. Most importantly, phosphosites with known downstream effects included BRAF p.S766, which forms an inhibitory site: a decrease of phosphorylation at this site suggests an increase in MEK/ERK pathway activation. The decreased phosphorylation at BRAF p.S766 would suggest decreased AMP-activated protein kinase (AMPK) signaling, which is supported by the decreased phosphorylation of STIM1 p.S257, a downstream AMPK target.

Conclusion

The modified phosphoproteome profile of the homozygous mice in combination with human literature suggests a potential signaling pathway from constitutive TSHR signaling and cAMP activation to the activation of ERK/MAPK signaling. This is the first time that a specific mechanism has been identified for a possible involvement of TSH signaling in thyroid carcinoma development.

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Cosimo Durante Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy

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Laszlo Hegedüs Department of Endocrinology, Odense University Hospital, Odense, Denmark

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Agnieszka Czarniecka M. Sklodowska-Curie National Research, Institute of Oncology Gliwice Branch, Gliwice, Poland

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Ralf Paschke Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Gilles Russ Thyroid and Endocrine Tumors Department, Pitié-Salpêtrière Hospital, Sorbonne University GRC N°16, Paris, France

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Fernando Schmitt Faculty of Medicine of University of Porto, CINTESIS@RISE and Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Porto, Portugal

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Paula Soares Institute of Investigation and Innovation in Health (I3S), Faculty of Medicine of the University of Porto, Porto, Portugal

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Tamas Solymosi Endocrinology and Metabolism Clinic, Bugat Hospital, Gyöngyös, Hungary

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Enrico Papini Department of Endocrine and Metabolic Diseases, Regina Apostolorum Hospital, Albano, Rome, Italy

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With the widespread use of sensitive imaging techniques, which include neck visualization, a conspicuous number of thyroid nodules emerge and demand attention. Most lesions are benign, asymptomatic, and do not warrant treatment. In the case of cancer diagnosis, most are small, intrathyroidal and indolent neoplasms that can safely be managed conservatively. There is a pronounced need for more cost-effective, risk-adapted approaches to the management of this highly prevalent condition, taking the wishes of the patient into consideration. Thus, the present guidelines aim at providing a clinical practice guide for the initial workup and the subsequent management of adult individuals harboring thyroid nodules. Importantly, these guidelines are not intended to cover the management of thyroid malignancy. The manuscript and the specific recommendations were developed by reconciling the best available research evidence with the knowledge and clinical experience of the panelists and updating aspects of a number of previous European Thyroid Association guidelines.

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Markus Eszlinger Departments of Oncology, Pathology and Laboratory Medicine, Biochemistry and Molecular Biology, and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada
Institute of Pathology, University Hospital Halle (Saale), Halle (Saale), Germany

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Paul Stewardson Department of Medical Science and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada

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John B McIntyre Precision Oncology Hub Laboratory, Alberta Health Services, Tom Baker Cancer Centre, Calgary, Alberta, Canada

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Adrian Box Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Moosa Khalil Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Martin Hyrcza Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Konstantin Koro Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Dean Ruether Section of Medical Oncology, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Jiahui Wu Department of Medical Science and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Ralf Paschke Departments of Medicine, Oncology, Pathology and Laboratory Medicine, Biochemistry and Molecular Biology, and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada

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Objective

The aim of the study was to identify patients with NTRK fusion-positive or RET fusion/mutation-positive thyroid cancers, who could benefit from neurotrophic tyrosine kinase receptor (NTRK) or receptor tyrosine kinase (RET) inhibitors.

Methods

Patients were identified in the Calgary prospective thyroid cancer database (N= 482). Patients were ‘pre-screened’ with clinically available MassARRAY® BRAF test, Colon Panel, Melanoma Panel, or ThyroSPEC™. Mutation-negative tumors were ‘screened’ for NTRK fusions and RET fusions/mutations with the Oncomine™ Comprehensive Assay v3 (OCAv3).

Results

A total of 86 patients were included in 1 of 2 separate analyses. Analysis A included 42 patients with radioactive iodine (RAI)-resistant distant metastases. After pre-screening, 20 BRAF and RAS mutation-negative patients underwent OCAv3 screening, resulting in the detection of 4 patients with NTRKfusions and 4 patients with RET fusions (8/20, 40% of analyzed patients). Analysis B included 44 patients, 42 with American Thyroid Association (ATA) high and intermediate risk of recurrence and 2 with medullary thyroid carcinoma. During pre-screening, 1 patient with an NTRK fusion, 1 patient with a RET fusion, and 30 patients with BRAF mutations were identified. The remaining 9 patients received OCAv3 screening, resulting in detection of 1 patient with an NTRKfusion and 1 with a RET fusion (4/11, 36% of analyzed patients).

Conclusions

Our findings indicate a higher rate of NTRK fusions and RETfusions in patients with thyroid cancer with RAI-resistant distant metastases and ATA high or intermediate risk of recurrence. This highlights the importance of early screening to enable intervention with a NTRK or RET inhibitor.

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