Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations.

CONTEXT: Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume. OBJECTIVE: To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation. DESIGN: Single-arm, open-label study of liothyronine. SETTING: National Institutes of Health. PARTICIPANTS: Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation. INTERVENTION: Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4). OUTCOMES: Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c. RESULTS: There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism. CONCLUSION: Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.

Medullary Thyroid Carcinoma: An Update on Imaging.

Medullary thyroid carcinoma (MTC), arising from the parafollicular C cells of the thyroid, accounts for 1-2% of thyroid cancers. MTC is frequently aggressive and metastasizes to cervical and mediastinal lymph nodes, lungs, liver, and bones. Although a number of new imaging modalities for directing the management of oncologic patients evolved over the last two decades, the clinical application of these novel techniques is limited in MTC. In this article, we review the biology and molecular aspects of MTC as an important background for the use of current imaging modalities and approaches for this tumor. We discuss the modern and currently available imaging techniques-advanced magnetic resonance imaging (MRI)-based techniques such as whole-body MRI, dynamic contrast-enhanced (DCE) technique, diffusion-weighted imaging (DWI), positron emission tomography/computed tomography (PET/CT) with 18F-FDOPA and 18F-FDG, and integrated positron emission tomography/magnetic resonance (PET/MR) hybrid imaging-for primary as well as metastatic MTC tumor, including its metastatic spread to lymph nodes and the most common sites of distant metastases: lungs, liver, and bones.

Thyroid Abnormalities in Patients With Extreme Insulin Resistance Syndromes.

CONTEXT: Insulin and leptin may increase growth and proliferation of thyroid cells, underlying an association between type 2 diabetes and papillary thyroid cancer (PTC). Patients with extreme insulin resistance due to lipodystrophy or insulin receptor mutations (INSR) are treated with high-dose insulin and recombinant leptin (metreleptin), which may increase the risk of thyroid neoplasia. OBJECTIVE: The aim of this study was to analyze thyroid structural abnormalities in patients with lipodystrophy and INSR mutations and to assess whether insulin, IGF-1, and metreleptin therapy contribute to the thyroid growth and neoplasia in this population. DESIGN: Thyroid ultrasound characteristics were analyzed in 81 patients with lipodystrophy and 11 with INSR (5 homozygous; 6 heterozygous). Sixty patients were taking metreleptin. RESULTS: The prevalence of thyroid nodules in children with extreme insulin resistance (5 of 30, 16.7%) was significantly higher than published prevalence for children (64 of 3202; 2%), with no difference between lipodystrophy and INSR. Body surface area-adjusted thyroid volume was larger in INSR homozygotes vs heterozygotes or lipodystrophy (10.4 ± 5.1, 3.9 ± 1.5, and 6.2 ± 3.4 cm2, respectively. Three patients with lipodystrophy and one INSR heterozygote had PTC. There were no differences in thyroid ultrasound features in patients treated vs not treated with metreleptin. CONCLUSION: Children with extreme insulin resistance had a high prevalence of thyroid nodules, which were not associated with metreleptin treatment. Patients with homozygous INSR mutation had thyromegaly, which may be a novel phenotypic feature of this disease. Further studies are needed to determine the etiology of thyroid abnormalities in patients with extreme insulin resistance.

Fibrous dysplasia for radiologists: beyond ground glass bone matrix.

Fibrous dysplasia (FD) is a congenital disorder arising from sporadic mutation of the α-subunit of the Gs stimulatory protein. Osseous changes are characterised by the replacement and distortion of normal bone with poorly organised, structurally unsound, fibrous tissue. The disease process may be localised to a single or multiple bones. In McCune-Albright syndrome (MAS), fibrous dysplasia is associated with hyperfunction of endocrine organs and overproduction of melanin in the skin, while Mazabraud syndrome FD is associated with intramuscular myxomas. In radiology, FD is very often automatically associated with the term "ground glass matrix". However, FD is a complex disease, and knowledge of its unique pathogenesis and course are crucial to understanding imaging findings and potential complications. This article aims to not only summarise the spectrum of radiological findings of osseous and extra-osseous abnormalities associated with FD but also to highlight the pathological base of the disease evolution, corresponding imaging changes and complications based on the disease distribution. We also have provided current recommendations for clinical management and follow-up of patients with FD. TEACHING POINTS: • FD is often a part of complex disease, involving not only bone but also multiple other organs. • FD lesions are characterised by age-related histological, radiographical and clinical transformations. • Radiologists play a crucial role in the identification of osseous complications associated with FD. • The craniofacial form of the disease is the most common type of FD and the most difficult form to manage. • Patients with McCune-Albright syndrome may have different extra-skeletal abnormalities, which often require follow-up.

The Role of Integrins αMß2 (Mac-1, CD11b/CD18) and αDß2 (CD11d/CD18) in Macrophage Fusion.

The subfamily of ß2 integrins is implicated in macrophage fusion, a hallmark of chronic inflammation. Among ß2 family members, integrin Mac-1 (αMß2, CD11b/CD18) is abundantly expressed on monocyte/macrophages and mediates critical adhesive reactions of these cells. However, the role of Mac-1 in macrophage fusion leading to the formation of multinucleated giant cells remains unclear. Moreover, the role of integrin αDß2 (CD11d/CD18), a receptor with recognition specificity overlapping that of Mac-1, is unknown. We found that multinucleated giant cells are formed in the inflamed mouse peritoneum during the resolution phase of inflammation, and their numbers were approximately twofold higher in wild-type mice than in Mac-1(-/-) mice. Analyses of isolated inflammatory peritoneal macrophages showed that IL-4-induced fusion of Mac-1-deficient cells was strongly reduced compared with wild-type counterparts. The examination of adhesive reactions known to be required for fusion showed that spreading, but not adhesion and migration, was reduced in Mac-1-deficient macrophages. Fusion of αDß2-deficient macrophages was also significantly decreased, albeit to a smaller degree. Deficiency of intercellular adhesion molecule 1, a counter-receptor for Mac-1 and αDß2, did not alter the fusion rate. The results indicate that both Mac-1 and αDß2 support macrophage fusion with Mac-1 playing a dominant role and suggest that Mac-1 may mediate cell-cell interactions with a previously unrecognized counter-receptor(s).

Spinal metastases due to thyroid carcinoma: an analysis of 202 patients.

BACKGROUND: Spinal metastases (SMs) due to thyroid cancer (TC) are associated with significantly reduced quality of life. The goal of this study is to analyze the clinical manifestations, presentation, and treatments of TC SMs, and to describe specific features of SMs associated with different TC types. PATIENTS AND METHODS: A retrospective analysis of 202 TC SM patients treated at Medstar Washington Hospital Center (37) and collected from the literature (165) was performed. RESULTS: The mean age of patients with SMs was 56.9±14.7 years, and the female-to-male ratio was 2.1:1. Of all patients, 29% (28% of follicular thyroid cancer [FTC] and 37% of papillary thyroid cancer [PTC]) had SMs only. Twenty-nine percent of all patients and 54% of patients with single-site SMs had neither bone non-SMs nor solid organ metastases at the time of presentation. Thirty-five percent of patients had SMs as an initial presentation of TC. TC patients presenting with SMs had a lower rate of other bone and visceral involvement compared with patients whose SMs were diagnosed at the time of thyroid surgery or during follow-up (p<0.05). SMs were more often the initial manifestation of FTC (41% vs. 24%), while PTC SMs were more commonly diagnosed after TC diagnosis (76% vs. 59%; p<0.05). PTC SMs were more frequently diagnosed as synchronous (63% vs. 36% in FTC) versus FTC SMs that developed as metachronous metastases (64% vs. 37% in PTC; p<0.01). All FTC SMs developed within 82 (0-372) months and all PTC SMs within 35 (0-144) months (p<0.01). In FTC SMs as TC manifestation, solid organ metastases involvement was less common than in FTC SMs that were found after TC diagnosis (34% vs. 67%; p<0.01); multisite FTC SMs compared to solitary FTC SMs were associated with the development of other bone nonspinal metastases (82% vs. 30%; p<0.01) and solitary organ metastases (65% vs. 41%; p<0.01). These correlations were not observed in PTC SMs. FTC patients often had neural structure compression (myelopathy/radiculopathy; 72% vs. 36% in PTC), while PTC patients frequently were asymptomatic (38% vs. 5% in FTC; p<0.01). FTC SMs more commonly were (131)I-avid (p<0.01). FTC patients required surgery more frequently (72% vs. 55% in PTC; p<0.05). CONCLUSIONS: Our study reveals that a significant part of TC SMs patients have solitary spinal involvement at the time of presentation and may be considered for aggressive treatment with the intention to improve quality of life and survival. FTC SMs and PTC SMs appear to have distinct presentations, behavior, and treatment modalities, and should be categorized separately for treatment and follow-up planning.

Current treatment modalities for spinal metastases secondary to thyroid carcinoma.

BACKGROUND: The spine is the most common site of bone metastases due to thyroid cancer, which develop in more than 3% of patients with well-differentiated thyroid cancer. Nearly half of patients with bone metastases from thyroid cancer develop vertebral metastases. Spinal metastases are associated with significantly reduced quality of life due to pain, neurological deficit, and increased mortality. SUMMARY: Treatment options for patients with thyroid spinal metastases include radioiodine therapy, pharmacologic therapy, and surgical treatments, with recent advances in radiosurgery and minimally invasive spinal surgery as well. Therapeutic interventions require a multidisciplinary approach and aim to control pain, preserve or improve neurologic function, optimize local tumor control, and improve quality of life. We have proposed a three-tiered approach to the management and practical algorithms for patients with spinal metastases from thyroid carcinoma. CONCLUSIONS: The introduction of novel and improved techniques for the treatment of spinal metastases has created the opportunity to significantly improve control of metastatic tumor growth and the quality of life for the patients with spinal metastases from thyroid cancer. In order for these options to be effectively used, a multidisciplinary approach must be applied in the management of the patients with thyroid spinal metastases.

Monocyte-derived cells of the brain and malignant gliomas: the double face of Janus.

OBJECTIVE: Monocyte-derived cells of the brain (MDCB) are a diverse group of functional immune cells that are also highly abundant in gliomas. There is growing evidence that MDCB play essential roles in the pathogenesis of gliomas. The aim of this review was to collate and systematize contemporary knowledge about these cells as they relate to glioma progression and antiglioblastoma therapeutic modalities with a view toward improved effectiveness of therapy. METHODS: We reviewed relevant studies to construct a summary of different MDCB subpopulations in steady state and in malignant gliomas and discuss their role in the development of malignant gliomas and potential future therapies. RESULTS: Current studies suggest that MDCB subsets display different phenotypes and differentiation potentials depending on their milieu in the brain and exposure to tumoral influences. MDCB possess specific and unique functions, including those that are protumoral and those that are antitumoral. CONCLUSIONS: Elucidating the role of mononuclear-derived cells associated with gliomas is crucial in designing novel immunotherapy strategies. Much progress is needed to characterize markers to identify cell subsets and their specific regulatory roles. Investigation of MDCB can be clinically relevant. Specific MDCB populations potentially can be used for glioma therapy as a target or as cell vehicles that might deliver cytotoxic substances or processes to the glioma microenvironment.

Monocyte galactose/N-acetylgalactosamine-specific C-type lectin receptor stimulant immunotherapy of an experimental glioma. Part 1: stimulatory effects on blood monocytes and monocyte-derived cells of the brain.

OBJECTIVES: Immunotherapy with immunostimulants is an attractive therapy against gliomas. C-type lectin receptors specific for galactose/N-acetylgalactosamine (GCLR) regulate cellular differentiation, recognition, and trafficking of monocyte-derived cells. A peptide mimetic of GCLR ligands (GCLRP) was used to activate blood monocytes and populations of myeloid-derived cells against a murine glioblastoma. METHODS: The ability of GCLRP to stimulate phagocytosis by human microglia and monocyte-derived cells of the brain (MDCB) isolated from a human glioblastoma was initially assessed in vitro. Induction of activation markers on blood monocytes was assayed by flow cytometry after administration of GCLRP to naive mice. C57BL/6 mice underwent stereotactic intracranial implantation of GL261 glioma cells and were randomized for tumor size by magnetic resonance imaging, which was also used to assess increase in tumor size. Brain tumor tissues were analyzed using flow cytometry, histology, and enzyme-linked immunosorbent assay with respect to tumor, peritumoral area, and contralateral hemisphere regions. RESULTS: GCLRP exhibited strong stimulatory effect on MDCBs and blood monocytes in vitro and in vivo. GCLRP was associated with an increased percentage of precursors of dendritic cells in the blood (P = 0.003), which differentiated into patrolling macrophages in tumoral (P = 0.001) and peritumoral areas (P = 0.04), rather than into dendritic cells, as in control animals. Treatment with GCLRP did not result in a significant change in survival of mice bearing a tumor. CONCLUSIONS: In vitro and in vivo activation of monocytes was achieved by administration of GCLR to mice. GCLRP-activated blood monocytes were recruited to the brain and exhibited specific phenotypes corresponding with tumor region (glioma, peritumoral zone, and contralateral glioma-free hemisphere). GCLRP treatment alone was associated with increased glioma mass as the result of the infiltration of phagocytic cells. Regional specificity for MDCB may have significant tumor treatment implications.

Monocyte galactose/N-acetylgalactosamine-specific C-type lectin receptor stimulant immunotherapy of an experimental glioma. Part II: combination with external radiation improves survival.

BACKGROUND: A peptide mimetic of a ligand for the galactose/N-acetylgalactosamine-specific C-type lectin receptors (GCLR) exhibited monocyte-stimulating activity, but did not extend survival when applied alone against a syngeneic murine malignant glioma. In this study, the combined effect of GCLRP with radiation was investigated. METHODS: C57BL/6 mice underwent stereotactic intracranial implantation of GL261 glioma cells. Animals were grouped based on randomized tumor size by magnetic resonance imaging on day seven. One group that received cranial radiation (4 Gy on days seven and nine) only were compared with animals treated with radiation and GCLRP (4 Gy on days seven and nine combined with subcutaneous injection of 1 nmol/g on alternative days beginning on day seven). Magnetic resonance imaging was used to assess tumor growth and correlated with survival rate. Blood and brain tissues were analyzed with regard to tumor and contralateral hemisphere using fluorescence-activated cell sorting analysis, histology, and enzyme-linked immunosorbent assay. RESULTS: GCLRP activated peripheral monocytes and was associated with increased blood precursors of dendritic cells. Mean survival increased (P < 0.001) and tumor size was smaller (P < 0.02) in the GCLRP + radiation group compared to the radiation-only group. Accumulation of dendritic cells in both the tumoral hemisphere (P < 0.005) and contralateral tumor-free hemisphere (P < 0.01) was associated with treatment. CONCLUSION: Specific populations of monocyte-derived brain cells develop critical relationships with malignant gliomas. The biological effect of GCLRP in combination with radiation may be more successful because of the damage incurred by tumor cells by radiation and the enhanced or preserved presentation of tumor cell antigens by GCLRP-activated immune cells. Monocyte-derived brain cells may be important targets for creating effective immunological modalities such as employing the receptor system described in this study.