Thyroid cancer - basic and translational

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Shovan Dutta Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, Ohio, USA
Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA

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Jeffrey A Knauf Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, Ohio, USA
Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Department of Otolaryngology-Head & Neck Surgery, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA

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The development of mouse models for thyroid cancer has significantly advanced over the years, enhancing our understanding of thyroid tumorigenesis, molecular pathways and treatment responses. The earliest mouse models of thyroid cancer relied on hormone, radiation or chemical carcinogenesis to induce tumors. However, as our understanding of the genetic alterations driving thyroid cancer has expanded, more sophisticated genetic engineering techniques have been employed to create models with thyroid-specific expression of these driver mutations. While driver mutations can initiate tumorigenesis, they are often insufficient to sustain cancer progression and invasion, which significantly limits their usefulness in studying advanced thyroid cancers. Recent studies exploring the genomic landscape of advanced thyroid cancer have identified several cooperating mutations, which are secondary genetic alterations that work alongside driver mutations to promote thyroid tumor progression. Indeed, mice with a combination of oncogenic drivers and common cooperating alterations have been developed, demonstrating that these alterations function in conjunction with the oncogenic driver to promote the progression to advanced thyroid cancer. These models provide important preclinical tools to explore how cooperating alterations influence the response to therapies, particularly those targeting the oncogenic driver. This review will focus on recent publications that broaden the scope of advanced thyroid cancer models by combining thyroid-specific oncogenic driver expression with various cooperating mutations.

Open access
Wiame Potonnier APHP, Hôpital Pitié-Salpêtrière, Service d’Anatomie et de Cytologie Pathologiques, Sorbonne Université, Paris, France

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Erell Guillerm APHP, Hôpital Pitié-Salpêtrière, Département de Génétique, Unité fonctionnelle d’Oncogénétique et Angiogénétique Moléculaire, Sorbonne Université, GRC no. 16 Tumeurs Thyroïdiennes, Paris, France

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Claude Bigorgne APHP, Hôpital Pitié-Salpêtrière, Service d’Anatomie et de Cytologie Pathologiques, Sorbonne Université, Paris, France

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Cécile Ghander APHP, Hôpital Pitié-Salpêtrière, Service des Pathologies Thyroïdiennes et Tumorales Endocrines, Sorbonne Université, GRC no. 16 Tumeurs Thyroïdiennes, Paris, France

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Malanie Roy APHP, Hôpital Pitié-Salpêtrière, Service des Pathologies Thyroïdiennes et Tumorales Endocrines, Sorbonne Université, GRC no. 16 Tumeurs Thyroïdiennes, Paris, France

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Florence Coulet APHP, Hôpital Pitié-Salpêtrière, Département de Génétique, Unité fonctionnelle d’Oncogénétique et Angiogénétique Moléculaire, Sorbonne Université, Paris, France

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François Ansart APHP, Hôpital Pitié-Salpêtrière, Service des Pathologies Thyroïdiennes et Tumorales Endocrines, Sorbonne Université, Paris, France

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Fabrice Menegaux APHP, Hôpital Pitié-Salpêtrière, Service de Chirurgie Générale, Viscérale et Endocrinienne, Sorbonne Université, GRC no. 16 Tumeurs Thyroïdiennes, Paris, France

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Laurence Leenhardt APHP, Hôpital Pitié-Salpêtrière, Service des Pathologies Thyroïdiennes et Tumorales Endocrines, Sorbonne Université, GRC no. 16 Tumeurs Thyroïdiennes, Paris, France

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Isabelle Brocheriou APHP, Hôpital Pitié-Salpêtrière, Service d’Anatomie et de Cytologie Pathologiques, Sorbonne Université, GRC no. 16 Tumeurs Thyroïdiennes, Paris, France

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Gabrielle Deniziaut APHP, Hôpital Pitié-Salpêtrière, Service d’Anatomie et de Cytologie Pathologiques, Sorbonne Université, GRC no. 16 Tumeurs Thyroïdiennes, Paris, France

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Camille Buffet APHP, Hôpital Pitié-Salpêtrière, Service des Pathologies Thyroïdiennes et Tumorales Endocrines, Sorbonne Université, GRC no. 16 Tumeurs Thyroïdiennes, CNRS UMR 7371, INSERM U1146, Laboratoire d’Imagerie Biomédicale (LIB), Paris, France

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Objective

Fine-needle aspiration (FNA) cytological analysis fails to confirm the benignity or malignancy of Bethesda III, IV and V thyroid nodules. Molecular tests performed on FNA samples have demonstrated interesting results in improving the diagnosis of these nodules. The aim of this study was to assess the performance of a large next-generation sequencing (NGS) panel in thyroid nodules with indeterminate cytology (Bethesda III, IV and V).

Methods

Retrospective, monocentric study including 121 patients with cytologically indeterminate thyroid nodules (Bethesda III, IV and V) who underwent a routine FNA procedure for molecular testing using the AmpliSeq general cancer NGS panel, with an available final histological diagnosis. The main objective was to estimate the negative predictive value (NPV) of malignancy of the AmpliSeq panel in Bethesda III and IV thyroid nodules. Performance assessment (sensitivity, specificity, positive predictive value (PPV) and NPV) was carried out in the grouped categories III and IV, in the overall cohort and in each Bethesda category. The final histological diagnosis was used as the designated gold standard.

Results

Histologically, 86 nodules were benign and 35 nodules were malignant. Molecular analysis yielded a positive result in 40 nodules. Panel performances assessed in the grouped categories Bethesda III and IV demonstrated a 55.0% (95% CI: 31.5; 76.9) sensitivity, a 76.9% (95% CI: 66.0; 85.7) specificity, a 37.9% (95% CI: 25.7; 51.9) PPV and an 87.0% (95% CI: 80.2; 91.7) NPV, considering a 20% prevalence of malignancy.

Conclusions

The performances of the AmpliSeq panel are promising; however, the NPV is not sufficient to avoid diagnostic surgery in cytologically indeterminate thyroid nodules.

Significance statement

Different ancillary molecular tests have been marketed in the USA and are integrated into the management of thyroid nodules with indeterminate cytology. Unfortunately, none of these molecular tests are currently available in France and clinicians lack effective tools for the management of these nodules. The aim of this work was to assess the performance of a large general-cancer targeted NGS panel in a series of thyroid nodules with indeterminate cytology (i.e. Bethesda III and IV categories and, to some extent, the Bethesda V category), managed in a French university medical center referral for thyroid tumors.

Open access
Olivia W Lee Laboratory of Genetic Susceptibility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

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Danielle M Karyadi Laboratory of Genetic Susceptibility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

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Stephen W Hartley Laboratory of Genetic Susceptibility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

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Weyin Zhou Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Bethesda, Maryland, USA

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Mitchell J Machiela Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

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Shahriar A Zamani Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

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Liudmyla Yu Zurnadzhy Laboratory of Morphology of the Endocrine System, V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine

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John N Weinstein Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Young Joo Park Department of Internal Medicine and Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea

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Jeong-Sun Seo Asian Genome Institute, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea
Precision Medicine Institute, Macrogen Inc, Seoul, Republic of Korea

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Gerry A Thomas Department of Surgery and Cancer, Imperial College London, Charing Cross Hospital, London, United Kingdom

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Tetiana I Bogdanova Laboratory of Morphology of the Endocrine System, V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine

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Mykola D Tronko Department of Fundamental and Applied Problems of Endocrinology, V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine

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Lindsay M Morton Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

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Stephen J Chanock Laboratory of Genetic Susceptibility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

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Deletion of the long q arm of chromosome 22 (22qDEL) is the most frequently identified recurrent somatic copy number alteration observed in papillary thyroid carcinoma (PTC). Since its role in PTC is not fully understood, we conducted a pooled analysis of genomic characteristics and clinical correlates in 1094 primary tumors from four published PTC genomic studies. The majority of PTC cases with 22qDEL exhibited arm-level loss of heterozygosity (86%); nearly all PTC cases with 22qDEL had losses in 22q12 and 13, which together constitute 70% of the q arm. Our analysis confirmed that 22qDEL occurs more frequently with RAS point mutations (50.4%), particularly HRAS (70.3%), compared with other PTC drivers (9.3%), supporting the conclusion that 22qDEL is unlikely to be a solitary driver of PTC but possibly an important co-factor in carcinogenesis, particularly in PTCs with RAS driver mutations. Differential RNA expression analyses revealed downregulation of most genes located on chromosome 22 in cases with 22qDEL compared to those without 22qDEL. Many differentially expressed genes are drawn from immune response and regulation pathways. These findings highlight the value of further investigations into the contributions of 22qDEL events to PTC, perhaps mediated through immune perturbations.

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Vincenzo Condello Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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C Christofer Juhlin Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden

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In recent years, germline mutations in the microRNA (miRNA) processor genes DICER1 and DGCR8 have been coupled to the development of thyroid follicular nodular disease (TFND), thereby casting new light on the etiology of this enigmatic, benign condition in non-iodine-deficient regions. Moreover, DICER1 and DGCR8 mutations have also been reported in rare subsets of follicular cell-derived thyroid carcinomas. Specifically, truncating germline or missense somatic DICER1 mutations have been reported in small subsets of pediatric and adolescent follicular thyroid carcinoma (FTC) and poorly differentiated thyroid carcinoma (PDTC). Similarly, a recurrent somatic mutation of the DGCR8 gene has been observed in highly aggressive FTCs and in some indolent cases of encapsulated follicular variant of papillary thyroid carcinoma. The reason why identical mutations in the same miRNA processor gene can lead to such a myriad of thyroid conditions, ranging from benign TFND to FTCs and PDTCs, remains unclear. This review highlights key features of miRNA regulator gene mutations in thyroid disease and explores their potential roles as drivers or progression events in tumor development.

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Hyun-Jin Lee Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Chung-Ang University College of Medicine, Seoul, South Korea

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Young-Sool Hah Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, South Korea

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So Young Cheon Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, South Korea

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Seong Jun Won Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Chae Dong Yim Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Somi Ryu Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Seung-Jun Lee Department of Convergence of Medical Sciences, Gyeongsang National University, Jinju, South Korea

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Ji Hyun Seo Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea
Department of Pediatrics, Gyeongsang National University College of Medicine, Jinju, South Korea

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Jung Je Park Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Objective

This study examined the effect of sirtuin 4 (SIRT4), a NAD+-dependent deacetylase, on the proliferation and progression of papillary thyroid carcinoma (PTC).

Methods

Data from The Cancer Genome Atlas (TCGA) were analyzed to identify SIRT4 expression in thyroid cancer. Subsequently, the correlation between SIRT4 expression and clinical characteristics was examined in 205 PTC tissue samples. In vitro assays using three human thyroid cancer cell lines (B-CPAP, TPC-1, and SNU-790) were conducted to assess the effects of regulated SIRT4 expression on cell growth, apoptosis, invasion, and migration. Furthermore, in vivo experiments were performed in a xenograft mouse model.

Results

Gene Expression Omnibus (GEO) and TCGA data indicated that SIRT4 expression is lower in thyroid cancer and SIRT4 downregulation is associated with poor overall survival. In PTC tissues, positive SIRT4 expression was associated with decreased extracapsular extension. In in vitro experiments using three human thyroid cancer cell lines, overexpression of SIRT4 decreased cell survival, clonogenic potential, and invasion and migratory capabilities, as well as inducing apoptosis and increasing reactive oxygen species levels. SIRT4 overexpression upregulated E-cadherin and downregulated N-cadherin, suggesting its potential involvement in the regulation of epithelial–mesenchymal transition. These findings were confirmed in vivo using a xenograft mouse model.

Conclusion

This study provides novel insight into the potential contribution of SIRT4 to the regulation of the pathological progression of PTC. The data suggest that SIRT4 plays a tumor-suppressive role in PTC by inhibiting growth, survival, and invasive potential. Future research should investigate the molecular mechanisms underlying these effects of SIRT4.

Open access
Fabio Hecht Université Paris-Saclay, Orsay, France
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France

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Laura Valerio Université Paris-Saclay, Orsay, France
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France

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Carlos Frederico Lima Gonçalves Université Paris-Saclay, Orsay, France
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France

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Marylin Harinquet Université Paris-Saclay, Orsay, France
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France

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Rabii Ameziane El Hassani Laboratoire de Biologie des Pathologies Humaines ‘BioPatH’, Université Mohammed V de Rabat, Faculté des Sciences, BP1014 Rabat, 10001, Morocco

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Denise P Carvalho Laboratório de Fisiologia Endócrina Doris Rosenthal, nstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Stephane Koundrioukoff UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France
Sorbonne Université, Paris, France

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Jean-Charles Cadoret Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France

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Corinne Dupuy Université Paris-Saclay, Orsay, France
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France

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Objective

Ionizing radiation generates genomic instability by promoting the accumulation of chromosomal rearrangements. The oncogenic translocation RET/PTC1 is present in more than 70% of radiation-induced thyroid cancers. Both RET and CCDC6, the genes implicated in RET/PTC1, are found within common fragile sites – chromosomal regions prone to DNA breakage during slight replication stress. Given that irradiated cells become more susceptible to genomic destabilization due to the accumulation of replication-stress-related double-strand breaks (DSBs), we explored whether RET and CCDC6 exhibit DNA breakage under replicative stress several days post-irradiation of thyroid cells.

Methods

We analyzed the dynamic of DNA replication in human thyroid epithelial cells (HThy-ori-3.1) 4 days post a 5-Gy exposure using molecular DNA combing. The DNA replication schedule was evaluated through replication-timing experiments. We implemented a ChIP-qPCR assay to determine whether the RET and CCDC6 genes break following irradiation.

Results

Our study indicates that replicative stress, occurring several days post-irradiation in thyroid cells, primarily causes DSBs in the RET gene. We discovered that both the RET and CCDC6 genes undergo late replication in thyroid cells. However, only RET’s replication rate is notably delayed after irradiation.

Conclusion

The findings suggest that post-irradiation in the RET gene causes a breakage in the replication fork, which could potentially invade another genomic area, including CCDC6. As a result, this could greatly contribute to the high prevalence of chromosomal RET/PTC rearrangements seen in patients exposed to external radiation.

Open access
Zhaoqi Zhang Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
Department of Nuclear Medicine, The Fourth hospital of Hebei Medical University, Shijiazhuang, Hebei, China

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Josef Yu Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Eva Rainer Department of Biomedical Imaging and Image-guided Therapy, Division of General and Pediatric Radiology, Medical University of Vienna, Vienna, Austria

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Lindsay Hargitai Department of General Surgery, Medical University of Vienna, Vienna, Austria

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Zewen Jiang Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Georgios Karanikas Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Tatjana Traub-Weidinger Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Richard Crevenna Department of Physical Medicine, Rehabilitation and Occupational Medicine, Medical University of Vienna, Vienna, Austria.

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Marcus Hacker Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Shuren Li Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Objective

Correct diagnosis and prognostic evaluation of medullary thyroid cancer (MTC) are crucial to treat patients. The purpose of this study was to evaluate the diagnostic and prognostic value of [18F]F-DOPA PET/CT in patients with MTC.

Methods

We reviewed MTC patients who underwent [18F]F-DOPA PET/CT from June 2008 to November 2023. Clinical characteristics, follow-up data, and the following [18F]F-DOPA PET/CT parameters were recorded: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and SUVmean of multiple organs. The diagnostic value of PET/CT for the detection of tumor lesions was calculated. Serum basal calcitonin (bCt) and stimulated calcitonin (sCt) were determined. Receiver operating characteristics, Kaplan–Meier, and Cox regression analyses were performed.

Results

In total, 109 patients (50 women, 59 men; average age, 55 ± 14 years) were included in the analysis. The patient-related sensitivity, specificity, and accuracy of [18F]F-DOPA PET/CT were 95%, 93%, and 94%, respectively. The lesion-related sensitivity, specificity, and accuracy were 65%, 99%, and 72%, respectively. The optimal cutoff values of bCt, sCt, and CEA to obtain positive [18F]F-DOPA PET/CT results were 64 pg/mL, 1808 pg/mL, and 4 µg/L, respectively. Patients with negative [18F]F-DOPA PET/CT had longer overall survival than patients with positive [18F]F-DOPA PET/CT results (P = 0.017). Significant positive correlations were found between bCt, sCt, and CEA with SUVmax, SUVmean, and MTV of [18F]F-DOPA PET/CT (P < 0.001). [18F]F-DOPA PET/CT results and MTV may be useful for the evaluation of the prognosis of patients with recurrent MTC, while age and MTV were independent prognostic factors in patients with primary MTC. For all patients, SUVmean of the left kidney, liver, aorta, and pancreas might be used to independently predict OS.

Conclusion

[18F]F-DOPA PET/CT had great value for diagnosis and prognostic assessment in patients with MTC. The DOPA PET/CT parameter SUVmean and MTV showed significant association with OS.

Open access
Carla Colombo Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Daniele Ceruti Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Massimiliano Succi Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Simone De Leo Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy

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Matteo Trevisan Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Claudia Moneta Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Laura Fugazzola Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Background

Fatigue is a frequent adverse event during systemic treatments for advanced thyroid cancer, often leading to reduction, interruption, or discontinuation. We were the first group to demonstrate a correlation between fatigue and primary adrenal insufficiency (PAI).

Aim

The objective was to assess the entire adrenal function in patients on systemic treatments.

Methods

ACTH, cortisol and all the hormones produced by the adrenal gland were evaluated monthly in 36 patients (25 on lenvatinib, six on vandetanib, and five on selpercatinib). ACTH stimulation tests were performed in 26 cases.

Results

After a median treatment period of 7 months, we observed an increase in ACTH values in 80–100% of patients and an impaired cortisol response to the ACTH test in 19% of cases. Additionally, dehydroepiandrosterone sulphate, ∆-4-androstenedione and 17-OH progesterone levels were below the median of normal values in the majority of patients regardless of the drug used. Testosterone in females and oestradiol in males were below the median of normal values in the majority of patients on lenvatinib and vandetanib. Finally, aldosterone was below the median of the normal values in most cases, whilst renin levels were normal. Metanephrines and normetanephrines were always within the normal range. Replacement therapy with cortisone acetate improved fatigue in 14/17 (82%) patients with PAI.

Conclusion

Our data confirm that systemic treatments for advanced thyroid cancer can lead to impaired cortisol secretion. A reduction in the other hormones secreted by the adrenal cortex has been first reported and should be considered in the more appropriate management of these fragile patients.

Open access
Abdul Rehman Syed University of Calgary, Calgary, Alberta, Canada

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Aakash Gorana Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada

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Erik Nohr Alberta Precision Laboratories, Molecular Pathology Program, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Xiaoli-Kat Yuan Precision Oncology Hub Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada

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

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Sana Ghaznavi Arnie Charbonneau Cancer Institute, Department of Medicine, Section of Endocrinology, University of Calgary, Calgary, Alberta, Canada

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Debbie Lamb Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada

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

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Markus Eszlinger Department of Oncology, Cumming School of Medicine, and Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada

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Ralf Paschke Departments of Medicine, Section of Endocrinology, 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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Context

Two-thirds of metastatic differentiated thyroid cancer (DTC) patients have radioiodine (RAI)-resistant disease, resulting in poor prognosis and high mortality. For rare NTRK and RET fusion-positive metastatic, RAI-resistant thyroid cancers, variable success of re-induction of RAI avidity during treatment with NTRK or RET inhibitors has been reported.

Case presentation and results

We report two cases with RAI-resistant lung metastases treated with larotrectinib: an 83-year-old male presenting with an ETV6::NTRK3 fusion-positive tumor with the TERT promoter mutation c.-124C>T, and a 31-year-old female presenting with a TPR::NTRK1 fusion-positive tumor (and negative for TERT promoter mutation). Post larotrectinib treatment, diagnostic I-123 whole body scan revealed unsuccessful RAI-uptake re-induction in the TERT-positive tumor, with a thyroid differentiation score (TDS) of −0.287. In contrast, the TERT-negative tumor exhibited successful I-131 reuptake with a TDS of −0.060.

Conclusion

As observed for RAI-resistance associated with concurrent TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.

Open access
Hélène Théodon Department of Thyroid and Endocrine Tumors, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Erell Guillerm Department of Oncogenetic, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Johanna Wassermann Department of Oncology, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Gabrielle Deniziaut Department of Pathology, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Loïc Jaffrelot Department of Oncology, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Jérome Denis Department of Endocrine and Oncology Biochemistry, Sorbonne Université, Pitié-Salpêtrière Hospital, Paris, France

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Nathalie Chereau Department of Endocrine Surgery, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Claude Bigorgne Department of Pathology, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Wiame Potonnier Department of Pathology, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Florence Coulet Department of Oncogenetic, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Laurence Leenhardt Department of Thyroid and Endocrine Tumors, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Camille Buffet Department of Thyroid and Endocrine Tumors, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Objective

Tumor molecular genotyping plays a key role in improving the management of advanced thyroid cancers. Molecular tests are classically performed on formalin-fixed, paraffin-embedded (FFPE) carcinoma tissue. However alternative molecular testing strategies are needed when FFPE tumoral tissue is unavailable. The objective of our study was to retrospectively assess the performance of targeted DNA and RNA-based next-generation sequencing (NGS) on the fine needle aspirate from thyroid cancer cervical recurrences to determine if this strategy is efficient in clinical practice.

Design/Methods

A retrospective study of 33 patients who had had DNA and/or RNA-based NGS on ultrasound (US)-guided fine needle aspirates of cervical thyroid cancer recurrences in our Department from July 2019 to September 2022.

Results

In total, 34 DNA and 32 RNA-based NGS analyses were performed. Out of the 34 DNA-based NGS performed, 27 (79%) were conclusive allowing the identification of an oncogenic driver for 18 patients (53%). The most common mutation (n = 13) was BRAF c.1799T>A. Out of the 32 RNA-based NGS performed, 26 were interpretable (81%) and no gene fusion was found. The identification of a BRAFV600E mutation was decisive for one patient in our series, who was prescribed dabrafenib and trametinib.

Conclusion

NGS performed on fine needle aspirates of neck lymph node metastases enabled the identification of an oncogenic driver alteration in 53% of the cases in our series of advanced thyroid cancer patients and could significantly alter patient management.

Significance statement

This paper shows that thyroid cancer genotyping on the fine needle aspirate (FNA) of a metastatic neck lymph node recurrence can be performed efficiently. This strategy of genotyping appears particularly effective and safe when FFPE tissue is unavailable and when the spread of the disease requires systemic treatment. To the best of our knowledge, our data regarding DNA and RNA next generation sequencing on FNA of metastatic neck recurrences are the first ever published.

Open access