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Experimental models for pheochromocytoma and paraganglioma are needed for basic pathobiology research and for preclinical testing of drugs to improve treatment of patients with these tumors, especially patients with metastatic disease. The paucity of models reflects the rarity of the tumors, their slow growth, and their genetic complexity. While there are no human cell line or xenograft models that faithfully recapitulate the genotype or phenotype of these tumors, the past decade has shown progress in development and utilization of animal models, including a mouse and a rat model for SDH-deficient pheochromocytoma associated with germline Sdhb mutations. There are also innovative approaches to preclinical testing of potential treatments in primary cultures of human tumors. Challenges with these primary cultures include how to account for heterogeneous cell populations that will vary depending on the initial tumor dissociation and how to distinguish drug effects on neoplastic vs normal cells. The feasible duration for maintaining cultures must also be balanced against time required to reliably assess drug efficacy. Considerations potentially important for all in vitro studies include species differences, phenotype drift, changes that occur in the transition from tissue to cell culture, and the O2 concentration in which cultures are maintained.
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CEINGE Biotecnologie Avanzate Scarl, Naples, Italy
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Anaplastic thyroid cancer (ATC) is a rare thyroid tumor that frequently originates from the dedifferentiation of a well-differentiated papillary or follicular thyroid cancer. Type 2 deiodinase (D2), responsible for the activation of the thyroid hormone thyroxine into tri-iodothyronine (T3), is expressed in normal thyroid cells and its expression is strongly downregulated in papillary thyroid cancer. In skin cancer, D2 has been associated with cancer progression, dedifferentiation, and epithelial–mesenchymal transition. Here, we show that D2 is highly expressed in anaplastic compared to papillary thyroid cancer cell lines and that D2-derived T3 is required for ATC cell proliferation. D2 inhibition is associated with G1 growth arrest and induction of cell senescence, together with reduced cell migration and invasive potential. Finally, we found that mutated p5372R(R248W), frequently found in ATC, is able to induce D2 expression in transfected papillary thyroid cancer cells. Our results show that the action of D2 is crucial for ATC proliferation and invasiveness, providing a potential new therapeutic target for the treatment of ATC.
Department of Endocrinology and Diabetes, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Academic Department of Surgery, Australian National University, Canberra, Australia
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Centre for Endocrinology, William Harvey Institute, Barts and the London School of Medicine, London, UK
Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
Search for other papers by Ashley B Grossman in
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Obesity T2D and Immunometabolism Research Group, Faculty of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
Division of Biomedical Sciences - Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry, UK
Search for other papers by Georgios K Dimitriadis in
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Parathyroid carcinoma is one of the least common endocrine malignancies and accounts for approximately 1% of all patients with primary hyperparathyroidism. A systematic review of peer-reviewed literature published between January 2000 and March 2022 via Medline, Embase, Cochrane Central Register of Controlled Trials, EudraCT, ClinicalTrials.gov, CINAHL and SCOPUS was conducted. Manuscripts were eligible if they included data on adult non-pregnant populations with parathyroid carcinoma. No restrictions regarding interventions, comparators or duration of follow-up were imposed. Single case reports, reviews or meta-analyses were excluded. Outcomes of interest were molecular pathogenesis, clinical presentation, differential diagnosis, treatment, follow-up and overall survival. Study quality was evaluated using the Newcastle–Ottawa Scale for observational studies.
This review included 75 studies from 17 countries, reporting on more than 3000 patients with parathyroid carcinoma. CDC73 mutation has been recognised as playing a pivotal role in molecular pathogenesis. Parathyroid carcinoma typically presents with markedly increased calcium and parathyroid hormone levels. The most frequently described symptoms were bone and muscle pain or weakness. En bloc resection remains the gold standard for the surgical approach. The 5-year overall survival ranged from 60 to 93%, with resistant hypercalcaemia a significant cause of mortality. Emerging evidence indicating that targeted therapy, based on molecular biomarkers, presents a novel treatment option. The rarity of PC and need for personalised treatment warrant multidisciplinary management in a ‘centre of excellence’ with a track record in PC management.
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
Department of Endocrinology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
Department of Endocrinology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
Department of Endocrinology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
Search for other papers by Cristina L Ronchi in
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Treatment for advanced adrenocortical carcinoma (ACC) consists of mitotane alone or combined with etoposide, doxorubicin, and cisplatin (EDP). Although both therapies are widely used, markers of response are still lacking. Since inflammation-based scores have been proposed as prognostic factors in ACC, we aimed to investigate their role in predicting the response to first-line chemotherapy.
We performed a retrospective analysis of patients with advanced ACC treated with mitotane monotherapy or EDP ± mitotane. Clinical parameters (tumour stage at diagnosis, resection status, Ki67, time from diagnosis to treatment start, performance status, plasma mitotane levels, time in mitotane target ≥ 80%, clinically overt cortisol hypersecretion), and pretreatment inflammation-based scores (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio, derived neutrophil-to-lymphocyte ratio) were investigated. The primary endpoints were overall survival (OS) and time-to-progression (TTP) from treatment initiation, the secondary endpoint was the best objective response to treatment.
We included 90 patients (59% = women, median age = 51 years) treated with mitotane monotherapy (n = 40) or EDP ± mitotane (n = 50). In the mitotane monotherapy cohort, NLR ≥ 5 and PLR ≥ 190 predicted shorter OS (hazard ratio (HR): 145.83, 95% CI: 1.87–11,323.83; HR: 165.50, 95% CI: 1.76–15,538.04, respectively), remaining significant at multivariable analysis including clinical variables. NLR was also associated with shorter TTP (HR: 2.58, 95% CI: 1.28–5.20), but only at univariable analysis. Patients with NLR ≥ 5 showed a worse treatment response than those with NLR < 5 (P = 0.040). In the EDP ± mitotane cohort, NLR ≥ 5 predicted shorter OS (HR: 2.52, 95% CI: 1.30–4.88) and TTP (HR: 1.95, 95% CI: 1.04–3.66) at univariable analysis.
In conclusion, inflammation-based scores, calculated from routinely measured parameters, may help predict response to chemotherapy in advanced ACC.
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Precision medicine (PM) aims to maximize the risk–benefit balance of medical decisions by integrating individual patient and disease characteristics. This approach is gaining increasing recognition from clinicians, healthcare systems, pharmaceutical companies, patients, and governments. Nuclear medicine plays a critical role in PM by its virtue of providing critical information at every step of disease management, digital markers, and companion diagnostics/therapeutics. It is anticipated that technological breakthroughs and new tracers will continue to position nuclear medicine among the significant players in PM.
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Comprehensive Cancer Centre Mainfranken, University of Wuerzburg Medical Centre, Wuerzburg, Germany
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Department of Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany
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Comprehensive Cancer Centre Mainfranken, University of Wuerzburg Medical Centre, Wuerzburg, Germany
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Histopathological differentiation in pediatric adrenocortical carcinoma (pACC) is difficult and clinical prediction and stratification scores are not evaluated yet. Therefore, this review aims to summarize current evidence on the value and accuracy of the two commonly used scoring systems (Weiss/Armed Forces Institute of Pathology (AFIP)) pACC. On this base, one might be able to evaluate if patients may benefit from a unique scoring system. For this, we performed a systematic review of the published literature and included 128 patients in our analysis. The majority (72%) of the pACCs had a good clinical course. The follow-up time ranged from 0 to 420 months with a mean age of 5.6 years at diagnosis. Patients with a good clinical course were younger (mean 4.8 years) than patients with a poor outcome (mean 7.6 years). Comparing the two scoring systems, the specificity of the Weiss score was very low (25%), whereas the sensitivity was 100%. According to the AFIP score, specificity (77%) was higher than the Weiss score, whereas the sensitivity of the AFIP score was minimal lower with 92%. Age differences were recognizable as the specificity was lower in infants <4 years (20%) than in older children (32%). In contrast, the specificity of the AFIP score was higher in infants <4 years (82%) than in older age groups (76%). Summarizing our results, we could show that the Weiss score is not a suitable tool for the prediction of malignancy in pACC in comparison with the AFIP score, but further efforts may seek to ensure early and accurate stratification through augmented scoring.
Search for other papers by Cesar Luiz Boguszewski in
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The association between growth hormone (GH) and carcinogenesis has long been postulated. The rationale for this association is that several components of the GH axis play an important role in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis and have been tested as targets for cancer therapy. Epidemiological and clinical studies have examined the association between height, growth patterns, and insulin-like growth factor 1 (IGF1) levels with the most common types of malignancies, while genome-wide association studies have revealed several height-associated genes linked to cancer and/or metastasis-driving pathways. In this context, a permissive role of the GH–IGF signaling system in the link between height and cancer risk has also been investigated. In animal and human models, genetic defects associated with GH deficiency or resistance are associated with protection from tumor development, while the risk of malignancies in acromegaly or in patients exposed to recombinant GH therapy has long been a matter of concern and scrutiny. In this review, we present a narrative and historical review covering the potential relations among height, growth patterns, GH axis, and cancer.
Département de Médecine Génomique des Tumeurs et des Cancers, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
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Biomedical Research Networking Centre on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain
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Mays Cancer Center at UTHSCSA, San Antonio, Texas, USA
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Paragangliomas (PGL) of the adrenal (also known as pheochromocytomas) or extra-adrenal neural crest-derived cells are highly heritable tumors, usually driven by single pathogenic variants that occur mutually exclusively in genes involved in multiple cellular processes, including the response to hypoxia, MAPK/ERK signaling, and WNT signaling. The discovery of driver mutations has led to active clinical surveillance with outcome implications in familial PGL. The spectrum of mutations continues to grow and reveal unique mechanisms of tumorigenesis that inform tumor biology and provide the rationale for targeted therapy. Here we review recent progress in the genetics and molecular pathogenesis of PGLs and discuss new prospects for advancing research with new disease models and ongoing clinical trials presented at the recent International Symposium of Pheochromocytomas and Paragangliomas (ISP2022) held in October 2022 in Prague.
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Division of Surgery, Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
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Lymphatic metastasis is the leading cause responsible for recurrence and progression in papillary thyroid cancer (PTC), where dysregulation of long non-coding RNAs (lncRNAs) has been extensively demonstrated to be implicated. However, the specific lymphatic node metastatsis-related lncRNAs remain not identified in PTC yet. Lymphatic node metastatsis-related lncRNA, MFSD4A-AS1, was explored in the PTC dataset from The Cancer Genome Atlas and our clinical samples. The roles of MFSD4A-AS1 in lymphatic metastasis were investigated in vitro and in vivo. Bioinformatic analysis, luciferase assay and RNA immunoprecipitation assay were performed to identify the potential targets and the underlying pathway of MFSD4A-AS1 in lymphatic metastasis of PTC. MFSD4A-AS1 was specifically upregulated in PTC tissues with lymphatic metastasis. Upregulating MFSD4A-AS1 promoted mesh formation and migration of human umbilical vein endothelial cells and invasion and migration of PTC cells. Importantly and consistently, MFSD4A-AS1 promoted lymphatic metastasis of PTC cells in vivo by inducing the lymphangiogenic formation and enhancing the invasive capability of PTC cells. Mechanistic dissection further revealed that MFSD4A-AS1 functioned as competing endogenous RNA to sequester miR-30c-2-3p, miR-145-3p and miR-139-5p to disrupt the miRNA-mediated inhibition of vascular endothelial growth factors A and C, and further activated transforming growth factor (TGF)-β signaling by sponging miR-30c-2-3p that targeted TGFBR2 and USP15, both of which synergistically promoted lymphangiogenesis and lymphatic metastasis of PTC. Our results unravel novel dual mechanisms by which MFSD4A-AS1 promotes lymphatic metastasis of PTC, which will facilitate the development of anti-lymphatic metastatic therapeutic strategy in PTC.
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Graphical abstract
Abstract
Minimalistic management options such as active surveillance and thyroid lobectomy are increasingly being accepted as reasonable management options for properly selected patients with low-risk papillary thyroid cancer. Leveraging technologies developed for the treatment of benign thyroid nodules, ultrasound-guided percutaneous thermal ablation is now being evaluated as a potential additional minimalistic management option for small, intrathyroidal, low-risk papillary thyroid cancer. Published retrospective data on more than 5000 low-risk papillary thyroid cancer patients treated with thermal ablation indicate that with appropriate training and proper patient selection, these technologies can be safely and effectively applied to papillary microcarcinomas. When compared to immediate surgery, thermal ablation appears to have lower complication rates with similar short-term rates of recurrence. Proper patient selection is facilitated by the use of a clinical framework which integrates imaging characteristics, patient characteristics, and medical team characteristics to classify a patient as ideal, appropriate, or inappropriate for minimalistic management options (active surveillance, thyroid lobectomy, or thermal ablation). While retrospective in nature and lacking randomized prospective clinical trial data, currently available data do support the proposition that thermal ablation technologies reliably destroy papillary thyroid microcarcinoma lesions and are associated with clinically acceptable oncologic outcomes when done by experienced teams in properly selected patients.
