Browse
Department of Endocrinology, St Bartholomew’s Hospital, Barts Health NHS Trust. West Smithfield, London, UK
Search for other papers by N Tufton in
Google Scholar
PubMed
Search for other papers by R J Hearnden in
Google Scholar
PubMed
Search for other papers by D M Berney in
Google Scholar
PubMed
Department of Endocrinology, St Bartholomew’s Hospital, Barts Health NHS Trust. West Smithfield, London, UK
Search for other papers by W M Drake in
Google Scholar
PubMed
Search for other papers by L Parvanta in
Google Scholar
PubMed
Search for other papers by J P Chapple in
Google Scholar
PubMed
Department of Endocrinology, St Bartholomew’s Hospital, Barts Health NHS Trust. West Smithfield, London, UK
Search for other papers by S A Akker in
Google Scholar
PubMed
Emerging evidence suggests the composition of the tumour microenvironment (TME) correlates with clinical outcome and that each tumour type has a unique TME including a variable population of inflammatory cells. We performed immunohistochemistry on 65 phaeochromocytoma and paraganglioma (PPGL) tumour samples with 20 normal adrenal medulla samples for comparison. The immune cells assessed were macrophages, lymphocytes and neutrophils, and we compared the proportion of infiltration of these immune cells with clinical and histopathological factors. There was a higher proportion of immune cells in tumour tissue compared to non-neoplastic adrenal medulla tissue, with a predominance of macrophages. There was a higher proportion of M2:M1 macrophages and T-helper lymphocytes in aggressive tumours compared to indolent ones. For SDHB-associated tumours, there was a higher proportion of M2 macrophage infiltration, with higher M2:M1 in aggressive SDHB PPGLs compared to indolent tumours. These data demonstrate that immune cells do infiltrate the TME of PPGLs, confirming that PPGLs are immunologically active tumours. Differences in the TME of PPGLs were observed between aggressive and indolent tumours. These differences could potentially be exploited as an aid in predicting tumour behaviour.
Search for other papers by Marie-Claude Hofmann in
Google Scholar
PubMed
Search for other papers by Muthusamy Kunnimalaiyaan in
Google Scholar
PubMed
Search for other papers by Jennifer R Wang in
Google Scholar
PubMed
Search for other papers by Naifa L Busaidy in
Google Scholar
PubMed
Search for other papers by Steven I Sherman in
Google Scholar
PubMed
Search for other papers by Stephen Y Lai in
Google Scholar
PubMed
Search for other papers by Mark Zafereo in
Google Scholar
PubMed
Search for other papers by Maria E Cabanillas in
Google Scholar
PubMed
Protein kinases play critical roles in cell survival, proliferation, and motility. Their dysregulation is therefore a common feature in the pathogenesis of a number of solid tumors, including thyroid cancers. Inhibiting activated protein kinases has revolutionized thyroid cancer therapy, offering a promising strategy in treating tumors refractory to radioactive iodine treatment or cytotoxic chemotherapies. However, despite satisfactory early responses, these drugs are not curative and most patients inevitably progress due to drug resistance. This review summarizes up-to-date knowledge on various mechanisms that thyroid cancer cells develop to bypass protein kinase inhibition and outlines strategies that are being explored to overcome drug resistance. Understanding how cancer cells respond to drugs and identifying novel molecular targets for therapy still represents a major challenge for the treatment of these patients.
Department of Paediatric Endocrinology, Barts Health NHS Trust, London, UK
Search for other papers by Sasha R Howard in
Google Scholar
PubMed
Search for other papers by Sarah Freeston in
Google Scholar
PubMed
Search for other papers by Barney Harrison in
Google Scholar
PubMed
Search for other papers by Louise Izatt in
Google Scholar
PubMed
Search for other papers by Sonali Natu in
Google Scholar
PubMed
Search for other papers by Kate Newbold in
Google Scholar
PubMed
Search for other papers by Sabine Pomplun in
Google Scholar
PubMed
Search for other papers by Helen A Spoudeas in
Google Scholar
PubMed
Search for other papers by Sophie Wilne in
Google Scholar
PubMed
Department of Paediatric Endocrine Surgery, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Search for other papers by Tom R Kurzawinski in
Google Scholar
PubMed
Department of Clinical Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Search for other papers by Mark N Gaze in
Google Scholar
PubMed
This guideline is written as a reference document for clinicians presented with the challenge of managing paediatric patients with differentiated thyroid carcinoma up to the age of 19 years. Care of paediatric patients with differentiated thyroid carcinoma differs in key aspects from that of adults, and there have been several recent developments in the care pathways for this condition; this guideline has sought to identify and attend to these areas. It addresses the presentation, clinical assessment, diagnosis, management (both surgical and medical), genetic counselling, follow-up and prognosis of affected patients. The guideline development group formed of a multi-disciplinary panel of sub-speciality experts carried out a systematic primary literature review and Delphi Consensus exercise. The guideline was developed in accordance with The Appraisal of Guidelines Research and Evaluation Instrument II criteria, with input from stakeholders including charities and patient groups. Based on scientific evidence and expert opinion, 58 recommendations have been collected to produce a clear, pragmatic set of management guidelines. It is intended as an evidence base for future optimal management and to improve the quality of clinical care of paediatric patients with differentiated thyroid carcinoma.
Search for other papers by Masaki Shiota in
Google Scholar
PubMed
Search for other papers by Shusuke Akamatsu in
Google Scholar
PubMed
Search for other papers by Shigehiro Tsukahara in
Google Scholar
PubMed
Search for other papers by Shohei Nagakawa in
Google Scholar
PubMed
Search for other papers by Takashi Matsumoto in
Google Scholar
PubMed
Search for other papers by Masatoshi Eto in
Google Scholar
PubMed
Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. However, treatment resistance emerges after hormonal manipulation in most prostate cancers, and it is attributable to a number of mechanisms, including AR amplification and overexpression, AR mutations, the expression of constitutively active AR variants, intra-tumor androgen synthesis, and promiscuous AR activation by other factors. Although various AR mutations have been reported in prostate cancer, specific AR mutations (L702H, W742L/C, H875Y, F877L, and T878A/S) were frequently identified after treatment resistance emerged. Intriguingly, these hot spot mutations were also revealed to change the binding affinity of ligands including steroids and antiandrogens and potentially result in altered responses to AR pathway inhibitors. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Since clinical data between AR mutations and the efficacy of AR pathway inhibitors are accumulating, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy. However, there are few reviews on clinical significance of AR hot spot mutations in prostate cancer. Then, this review summarized the clinical landscape of AR mutations and discussed their potential implication for clinical utilization.
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina
Search for other papers by Maria Eugenia Sabatino in
Google Scholar
PubMed
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina
Search for other papers by Juan Pablo Petiti in
Google Scholar
PubMed
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina
Search for other papers by Liliana del Valle Sosa in
Google Scholar
PubMed
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina
Search for other papers by Pablo Anibal Pérez in
Google Scholar
PubMed
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina
Search for other papers by Silvina Gutiérrez in
Google Scholar
PubMed
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina
Search for other papers by Carolina Leimgruber in
Google Scholar
PubMed
Search for other papers by Alexandra Latini in
Google Scholar
PubMed
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina
Search for other papers by Alicia Inés Torres in
Google Scholar
PubMed
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina
Search for other papers by Ana Lucía De Paul in
Google Scholar
PubMed
Search for other papers by Kreepa G Kooblall in
Google Scholar
PubMed
Search for other papers by Victoria J Stokes in
Google Scholar
PubMed
Search for other papers by Omair A Shariq in
Google Scholar
PubMed
Search for other papers by Katherine A English in
Google Scholar
PubMed
Search for other papers by Mark Stevenson in
Google Scholar
PubMed
Search for other papers by John Broxholme in
Google Scholar
PubMed
Search for other papers by Benjamin Wright in
Google Scholar
PubMed
Search for other papers by Helen E Lockstone in
Google Scholar
PubMed
Search for other papers by David Buck in
Google Scholar
PubMed
Search for other papers by Simona Grozinsky-Glasberg in
Google Scholar
PubMed
Search for other papers by Christopher J Yates in
Google Scholar
PubMed
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK
Search for other papers by Rajesh V Thakker in
Google Scholar
PubMed
Search for other papers by Kate E Lines in
Google Scholar
PubMed
Multiple endocrine neoplasia type 1 (MEN1), caused by mutations in the MEN1 gene encoding menin, is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic neuroendocrine tumours (NETs). Development of these tumours is associated with wide variations in their severity, order and ages (from <5 to >80 years), requiring life-long screening. To improve tumour surveillance and quality of life, better circulating biomarkers, particularly for pancreatic NETs that are associated with higher mortality, are required. We, therefore, examined the expression of circulating miRNA in the serum of MEN1 patients. Initial profiling analysis followed by qRT-PCR validation studies identified miR-3156-5p to be significantly downregulated (−1.3 to 5.8-fold, P < 0.05–0.0005) in nine MEN1 patients, compared to matched unaffected relatives. MEN1 knock-down experiments in BON-1 human pancreatic NET cells resulted in reduced MEN1 (49%, P < 0.05), menin (54%, P < 0.05) and miR-3156-5p expression (20%, P < 0.005), compared to control-treated cells, suggesting that miR-3156-5p downregulation is a consequence of loss of MEN1 expression. In silico analysis identified mortality factor 4-like 2 (MOR4FL2) as a potential target of miR-3156-5p, and in vitro functional studies in BON-1 cells transfected with either miR-3156-5p mimic or inhibitors showed that the miR-3156-5p mimic significantly reduced MORF4L2 protein expression (46%, P < 0.005), while miR-3156-5p inhibitor significantly increased MORF4L2 expression (1.5-fold, P < 0.05), compared to control-treated cells, thereby confirming that miR-3156-5p regulates MORF4L2 expression. Thus, the inverse relationship between miR-3156-5p and MORF4L2 expression represents a potential serum biomarker that could facilitate the detection of NET occurrence in MEN1 patients.
Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, UK
Search for other papers by Paul Benjamin Loughrey in
Google Scholar
PubMed
Search for other papers by Federico Roncaroli in
Google Scholar
PubMed
Search for other papers by Estelle Healy in
Google Scholar
PubMed
Search for other papers by Philip Weir in
Google Scholar
PubMed
Search for other papers by Madhu Basetti in
Google Scholar
PubMed
Search for other papers by Ruth T Casey in
Google Scholar
PubMed
Search for other papers by Steven J Hunter in
Google Scholar
PubMed
Search for other papers by Márta Korbonits in
Google Scholar
PubMed
Pituitary neuroendocrine tumours (PitNETs) associated with paragangliomas or phaeochromocytomas are rare. SDHx variants are estimated to be associated with 0.3–1.8% of PitNETs. Only a few case reports have documented the association with MAX variants. Prolactinomas are the most common PitNETs occurring in patients with SDHx variants, followed by somatotrophinomas, clinically non-functioning tumours and corticotrophinomas. One pituitary carcinoma has been described. SDHC, SDHB and SDHA mutations are inherited in an autosomal dominant fashion and tumorigenesis seems to adhere to Knudson’s two-hit hypothesis. SDHD and SDHAF2 mutations most commonly have paternal inheritance. Immunohistochemistry for SDHB or MAX and loss of heterozygosity analysis can support the assessment of pathogenicity of the variants. Metabolomics is promising in the diagnosis of SDHx-related disease. Future research should aim to further clarify the role of SDHx and MAX variants or other genes in the molecular pathogenesis of PitNETs, including pseudohypoxic and kinase signalling pathways along with elucidating epigenetic mechanisms to predict tumour behaviour.
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
Reina Sofía University Hospital, Córdoba, Spain
CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain
Search for other papers by Manuel D Gahete in
Google Scholar
PubMed
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
Reina Sofía University Hospital, Córdoba, Spain
CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain
Search for other papers by Natalia Herman-Sanchez in
Google Scholar
PubMed
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
Reina Sofía University Hospital, Córdoba, Spain
CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain
Search for other papers by Antonio C Fuentes-Fayos in
Google Scholar
PubMed
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
Reina Sofía University Hospital, Córdoba, Spain
CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain
Search for other papers by Juan L Lopez-Canovas in
Google Scholar
PubMed
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
Reina Sofía University Hospital, Córdoba, Spain
CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain
Search for other papers by Raúl M Luque in
Google Scholar
PubMed
The dysregulation of the splicing process has emerged as a novel hallmark of metabolic and tumor pathologies. In breast cancer (BCa), which represents the most diagnosed cancer type among women worldwide, the generation and/or dysregulation of several oncogenic splicing variants have been described. This is the case of the splicing variants of HER2, ER, BRCA1, or the recently identified by our group, In1-ghrelin and SST5TMD4, which exhibit oncogenic roles, increasing the malignancy, poor prognosis, and resistance to treatment of BCa. This altered expression of oncogenic splicing variants has been closely linked with the dysregulation of the elements belonging to the macromolecular machinery that controls the splicing process (spliceosome components and the associated splicing factors). In this review, we compile the current knowledge demonstrating the altered expression of splicing variants and spliceosomal components in BCa, showing the existence of a growing body of evidence supporting the close implication of the alteration in the splicing process in mammary tumorigenesis.
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
Search for other papers by Anastasia Alataki in
Google Scholar
PubMed
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
Search for other papers by Mitch Dowsett in
Google Scholar
PubMed
Endocrine therapies are the main treatment strategies for the clinical management of hormone-dependent breast cancer. Despite prolonged time to recurrence in the adjuvant setting and the initial clinical responses in the metastatic setting, many patients eventually encounter tumour relapse due to acquired resistance to these agents. Other patients experience a lack of tumour regression at the beginning of treatment indicating de novo resistance that significantly limits its efficacy in the clinic. There is compelling evidence that human epidermal growth factor receptor-2 (HER2) overexpression contributes to resistance to endocrine therapies in oestrogen receptor-positive (ER+) breast cancer. ER+/HER2+ tumours comprise about 10% of all breast cancer cases and about 60% of the whole set of HER2+ tumours. Most patients with primary ER+/HER2+ disease will receive antibody-based HER2-targeted therapy, but this is generally for no more than one year while endocrine treatment is usually for at least 5 years. A number of HER2-kinase inhibitors are also now in clinical use or in clinical trials, and the interaction of these with endocrine treatment may differ from that of antibody treatment. In this review article, we aim to summarise knowledge on molecular mechanisms of breast cancer resistance to endocrine therapies attributable to the impact of HER2 signalling on endocrine sensitivity, to discuss data from clinical trials addressing the role of HER2 in the development of endocrine resistance in the metastatic, neoadjuvant and adjuvant settings and to explore rational new therapeutic strategies.
Search for other papers by Adriana Albani in
Google Scholar
PubMed
Search for other papers by Luis Gustavo Perez-Rivas in
Google Scholar
PubMed
Search for other papers by Sicheng Tang in
Google Scholar
PubMed
Search for other papers by Julia Simon in
Google Scholar
PubMed
Search for other papers by Kristin Elisabeth Lucia in
Google Scholar
PubMed
Search for other papers by Paula Colón-Bolea in
Google Scholar
PubMed
Search for other papers by Jochen Schopohl in
Google Scholar
PubMed
Search for other papers by Sigrun Roeber in
Google Scholar
PubMed
Search for other papers by Michael Buchfelder in
Google Scholar
PubMed
Search for other papers by Roman Rotermund in
Google Scholar
PubMed
Search for other papers by Jörg Flitsch in
Google Scholar
PubMed
Search for other papers by Jun Thorsteinsdottir in
Google Scholar
PubMed
Search for other papers by Jochen Herms in
Google Scholar
PubMed
Medicover Neuroendocrinology, Munich, Germany
Search for other papers by Günter Stalla in
Google Scholar
PubMed
Search for other papers by Martin Reincke in
Google Scholar
PubMed
Search for other papers by Marily Theodoropoulou in
Google Scholar
PubMed
Cushing’s disease is a rare but devastating and difficult to manage condition. The somatostatin analogue pasireotide is the only pituitary-targeting pharmaceutical approved for the treatment of Cushing’s disease but is accompanied by varying efficacy and potentially severe side effects. Finding means to predict which patients are more likely to benefit from this treatment may improve their management. More than half of corticotroph tumours harbour mutations in the USP8 gene, and there is evidence of higher somatostatin receptor 5 (SSTR5) expression in the USP8-mutant tumours. Pasireotide has a high affinity for SSTR5, indicating that these tumours may be more sensitive to treatment. To test this hypothesis, we examined the inhibitory action of pasireotide on adrenocorticotrophic hormone synthesis in primary cultures of human corticotroph tumour with assessed USP8 mutational status and in immortalized murine corticotroph tumour cells overexpressing human USP8 mutants frequent in Cushing’s disease. Our in vitro results demonstrate that pasireotide exerts a higher antisecretory response in USP8-mutant corticotroph tumours. Overexpressing USP8 mutants in a murine corticotroph tumour cell model increased endogenous somatostatin receptor 5 (Sstr5) transcription. The murine Sstr5 promoter has two binding sites for the activating protein 1 (AP-1) and USP8 mutants possibly to mediate their action by stimulating AP-1 transcriptional activity. Our data corroborate the USP8 mutational status as a potential marker of pasireotide response and describe a potential mechanism through which USP8 mutants may regulate SSTR5 gene expression.