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Pamela Brock, Jennifer L Geurts, Paulien Van Galen, Erica Blouch, James Welch, Amy Kunz, Lauren Desrosiers, Jennifer Gauerke and Samuel Hyde

The Genetic Counseling Working Group from the 16th International Workshop on Multiple Endocrine Neoplasia (MEN 2019) convened to discuss contemporary challenges and opportunities in the area of genetic counseling for individuals and families affected by hereditary endocrine neoplasia syndromes. As healthcare professionals with multidisciplinary training in human genetics, risk assessment, patient education, psychosocial counseling, and research methodology, genetic counselors bring a unique perspective to working toward addressing these challenges and identifying their subsequent opportunities. This Working Group focused on the following broad areas: (1) genetic counseling resources for endocrine neoplasias, (2) candidate gene discovery, (3) implications of increasingly sensitive and expansive genetic testing technologies for both the germline and the tumors, and (4) situating clinical diagnoses for hereditary endocrine neoplasia syndromes in the context of present-day knowledge.

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Elizabeth G Grubbs, Ronald M Lechan, Beth Edeiken-Monroe, Gilbert J Cote, Chardria Trotter, Arthur S Tischler and Robert F Gagel

Forty years ago, physicians caring for the J-kindred, a 100+ member family with multiple endocrine neoplasia type 2A (MEN2A), hypothesized that early thyroidectomy based on measurement of the biomarker calcitonin could cure patients at risk for development of medullary thyroid carcinoma (MTC). We re-evaluated 22 family members with proven RET proto-oncogene mutations (C634G) who underwent thyroidectomy and central lymphadenectomy between 1972 and 1994 based on stimulated calcitonin abnormalities. Current disease status was evaluated by serum calcitonin measurement and neck ultrasound in 18 of the 22 prospectively screened patients. The median age of the cohort at thyroidectomy was 16.5 years (range 9–24). The median duration of follow-up at the time of examination was 40 years (range 21–43) with a median current age of 52 years (range 34–65). Fifteen of the 18 patients had no detectable serum calcitonin (<2 pg/mL). Three had detectable serum calcitonin measurements, inappropriately elevated following total thyroidectomy. None of the 16 patients imaged had an abnormal ultrasound. Survival analysis shows no MTC-related deaths in the prospectively screened patients, whereas there were many in prior generations. Early thyroidectomy based on biomarker testing has rendered 15 of 18 MEN2A patients (83%) calcitonin-free with a median follow-up period of 40 years. There have been no deaths in the prospectively screened and thyroidectomized group. We conclude that early thyroidectomy and central lymph node dissection is an effective prophylactic treatment for hereditary MTC.

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Giampaolo Trivellin, Fabio R Faucz, Adrian F Daly, Albert Beckers and Constantine A Stratakis

We recently described X-linked acrogigantism (X-LAG) in sporadic cases of infantile gigantism and a few familial cases of pituitary gigantism in the context of the disorder known as familial isolated pituitary adenomas. X-LAG cases with early onset gigantism (in infants or toddlers) shared copy number gains (CNG) of the distal long arm of chromosome X (Xq26.3). In all patients described to date with Xq26.3 CNG and acro-gigantism, the only coding gene sequence shared by all chromosomal defects was that of GPR101. GPR101 is a class A, rhodopsin-like orphan guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) with no known endogenous ligand. We review what is known about GPR101, specifically its expression profile in human and animal models, the evidence supporting causation of X-LAG and possibly other roles, including its function in growth, puberty and appetite regulation, as well as efforts to identify putative ligands.

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C R C Pieterman, S M Sadowski, J E Maxwell, M H G Katz, K E Lines, C M Heaphy, A Tirosh, J E Blau, N D Perrier, M A Lewis, J P Metzcar, D M Halperin, R V Thakker and G D Valk

The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27–29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.

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Patricia L M Dahia, Roderick Clifton-Bligh, Anne-Paule Gimenez-Roqueplo, Mercedes Robledo and Camilo Jimenez

Pheochromocytomas and paragangliomas (PPGLs) are adrenal or extra-adrenal autonomous nervous system-derived tumors. Most PPGLs are benign, but approximately 15% progress with metastases (mPPGLs). mPPGLs are more likely to occur in patients with large pheochromocytomas, sympathetic paragangliomas, and norepinephrine-secreting tumors. Older subjects, those with larger tumors and synchronous metastases, advance more rapidly. Germline mutations of SDHB, FH, and possibly SLC25A11, or somatic MAML3 disruptions relate to a higher risk for metastatic disease. However, it is unclear whether these mutations predict outcome. Once diagnosed, there are no well-established predictors of outcome in mPPGLs, and aggressive tumors have few therapeutic options and limited response. High-specific activity (HSA) metaiodine-benzyl-guanidine (MIBG) is the first FDA approved treatment and shows clinical effectiveness for MIBG-avid mPPGLs. Ongoing and future investigations should involve validation of emerging candidate outcome biomarkers, including somatic ATRX, TERT, and microRNA disruptions and identification of novel prognostic indicators. Long-term effect of HSA-MIBG and the role of other radiopharmaceuticals should be investigated. Novel trials targeting molecular events prevalent in SDHB/FH mutant tumors, such as activated hypoxia inducible factor 2 (HIF2), angiogenesis, or other mitochondrial defects that might confer unique vulnerability to these tumors should be developed and initiated. As therapeutic options are anticipated to expand, multi-institutional collaborations and well-defined clinical and molecular endpoints will be critical to achieve higher success rates in improving care for patients with mPPGLs.

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Nancy D Perrier, Andrew Arnold, Jessica Costa-Guda, Naifa L Busaidy, Ha Nguyen, Hubert H Chuang and Maria Luisa Brandi

This report summarizes published data on parathyroid cancer, with the inclusion of topics discussed at MEN2019: 16th International Workshop on Multiple Endocrine Neoplasia, 27–29 March 2019, Houston, TX, USA. An expert panel on parathyroid cancer was constituted by the Steering Committee to address key questions in the field. The objectives were to recap open forum discussion of interested parties from multiple disciplines. The expert panel met in a closed session to consult on the data to be highlighted on the evidence-based results and on the future directions. Preceding the Conference, members of the expert panel conducted an extensive literature search. All presentations were based upon the best peer-reviewed information taking into account the historical and current literature. Questions were developed by the expert panel on parathyroid carcinoma. A comprehensive literature search for relevant studies was undertaken. This report represents the expert panel’s synthesis of the conference material placed in a context designed to be relevant to clinicians and those engaged in cutting-edge studies of parathyroid carcinoma. This document not only provides a summary of our current knowledge but also places recent advances in its management into a context that should enhance future advances in our understanding of parathyroid carcinoma.

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Vladimir Vasilev, Adrian F Daly, Giampaolo Trivellin, Constantine A Stratakis, Sabina Zacharieva and Albert Beckers

Familial isolated pituitary adenoma (FIPA) is one of the most frequent conditions associated with an inherited presentation of pituitary tumors. FIPA can present with pituitary adenomas of any secretory/non-secretory type. Mutations in the gene for the aryl-hydrocarbon receptor interacting protein (AIP) have been identified in approximately 20% of FIPA families and are the most frequent cause (29%) of pituitary gigantism. Pituitary tumors in FIPA are larger, occur at a younger age and display more aggressive characteristics and evolution than sporadic adenomas. This aggressiveness is especially marked in FIPA kindreds with AIP mutations. Special attention should be paid to young patients with pituitary gigantism and/or macroadenomas, as AIP mutations are prevalent in these groups. Duplications on chromosome Xq26.3 involving the gene GPR101 lead to X-linked acrogigantism (X-LAG), a syndrome of pituitary gigantism beginning in early childhood; three kindreds with X-LAG have presented in the setting of FIPA. Management of pituitary adenomas in the setting of FIPA, AIP mutations and GPR101 duplications is often more complex than in sporadic disease due to early onset disease, aggressive tumor growth and resistance to medical therapy.

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Ramona Dadu, Rozita Bagheri-Yarmand, Matthew D Ringel, Elizabeth G Grubbs, Mark Zafereo, Gilbert Cote, Robert F Gagel, Bruce G Robinson, Kenna R Shaw and Mimi I Hu

The 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) held in Houston, TX, USA, focused on emerging topics in the pathogenesis and therapy of malignant endocrine tumors associated with MEN syndromes. With MEN-2 syndromes, the most common malignancy is medullary thyroid carcinoma (MTC). In the spirit of the original MEN meeting workshop model, the conference included didactic lectures and interactive working groups of clinicians and researchers focused on the state of science in MTC and ongoing challenges or unmet needs in the understanding of MTC and to develop strategies to address these issues.

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Camilo Jimenez, Sasan Fazeli and Alejandro Román-Gonzalez

Metastatic pheochromocytomas and paragangliomas are rare, highly vascular tumors that spread primarily to the lymph nodes, skeletal tissue, lungs, and liver. Tumor morbidity is related to their size, location, hormonal activity, vascular nature, and rate of progression. Systemic therapies for this indication are limited. Only high-specific-activity iodine-131 metaiodobenzylguanidine is approved in the Unites States for treatment of these patients, and not all patients are candidates for this radiopharmaceutical. Antiangiogenic medications are currently being evaluated in prospective clinical trials for patients with metastatic pheochromocytomas and paragangliomas, and preliminary results have been encouraging. Antiangiogenic medications frequently offer antineoplastic effects with sometimes durable responses. However, cardiovascular toxicity and the development of tumor resistance may limit their efficacy. Experience derived from clinical trials is being used to identify mechanisms to effectively improve drug toxicity and possibly prevent the emergence of resistance. Therefore, antiangiogenic medications represent a therapeutic option for patients with metastatic pheochromocytomas and paragangliomas. Furthermore, in the world of oncology, there is strong scientific interest in the development of clinical trials that combine antiangiogenic medications with other modalities such as immunotherapy, radiopharmaceuticals, and hypoxia inhibitors since these combinations may substantially enhance clinical outcomes, including survivorship. In this review, we examine the progress made to date on antiangiogenic treatments for patients with metastatic pheochromocytomas and paragangliomas.

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Kenzo Nakano, Toshihiko Masui, Akitada Yogo, Yuichiro Uchida, Asahi Sato, Yosuke Kasai, Kazuyuki Nagai, Takayuki Anazawa, Yoshiya Kawaguchi and Shinji Uemoto

Although pancreatic neuroendocrine neoplasms (PanNENs) are generally indolent, patients with distant metastasis have a dismal prognosis. Recently, the autophagy inhibitor chloroquine (CQ) has been shown to suppress the tumour growth of PanNENs, but the detailed mechanisms have not been elucidated. Furthermore, these results were obtained from poorly differentiated cell lines rather than well-differentiated cell lines, which is the most prevalent type in this tumour. To explore the mechanism and efficacy of CQ on PanNENs, we applied CQ to cell lines and evaluated the resulting apoptosis and endoplasmic reticulum (ER) stress. CQ treatment induced ER stress, and an unfolded protein response was activated through the PERK-eIF2α-ATF4 pathway, resulting in the expression of the pro-apoptotic protein C/EBP homologous protein (CHOP), which reflects ER-stress-mediated apoptotic cell death. Furthermore, hydroxychloroquine (HCQ) was effective in Men1 heterozygous-deficient (Men1+/ΔN3-8) mice, a mouse PanNEN model that is considered to correspond to human low-grade PanNEN. HCQ administration decreased tumour size in Men1+/ΔN3-8 mice. In the HCQ group, histological analyses revealed that proliferative activity was unchanged, but apoptosis was accelerated, accompanied by CHOP expression. These results suggest that autophagy inhibition by CQ/HCQ could be used for the treatment of PanNEN, including the well-differentiated type.