Phase 2 clinical trial of sunitinib as adjunctive treatment in patients with advanced differentiated thyroid cancer.

OBJECTIVE: Our objective was to evaluate the efficacy and safety of sunitinib following at least one course of radioactive iodine treatment in patients with advanced differentiated thyroid cancer (DTC). The study endpoints included best response rate (including best objective response rate) and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, measurement of serum thyroglobulin (Tg), and toxicity evaluation. DESIGN AND METHODS: This was a single center, nonrandomized, open-label, phase 2 clinical trial. In total, 23 patients were enrolled and were treated with a starting daily, oral dose of 37.5  mg sunitinib. Patients were evaluated with imaging, laboratory tests, and physical examination periodically per protocol. RESULTS: The mean best response was a decrease of 17.2% (S.D. 22.8) in tumor sum from baseline. Six (26%) patients achieved a partial response (PR), and 13 (57%) had stable disease (SD) for a clinical benefit rate (PR+SD) of 83%. The overall median PFS was 241 days (interquartile limits, 114-518). No statistically significant difference was observed between the medians of the baseline and post-treatment Tg values (P=0.24). The most common adverse events included grades 1 and 2 decreases in blood cell counts (especially leukocytes), diarrhea, fatigue, hand-foot skin reaction, nausea, musculoskeletal pain, and hypertension. CONCLUSIONS: These data demonstrate that sunitinib exhibits significant anti-tumor activity in patients with advanced DTC. Since sunitinib was relatively well-tolerated, there is the potential for clinical benefit in these patients, and further investigation of this agent is warranted.

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.

Radiation safety in the treatment of patients with thyroid diseases by radioiodine 131I : practice recommendations of the American Thyroid Association.

BACKGROUND: Radiation safety is an essential component in the treatment of patients with thyroid diseases by ¹³¹I. The American Thyroid Association created a task force to develop recommendations that would inform medical professionals about attainment of radiation safety for patients, family members, and the public. The task force was constituted so as to obtain advice, experience, and methods from relevant medical specialties and disciplines. METHODS: Reviews of Nuclear Regulatory Commission regulations and International Commission on Radiological Protection [corrected] recommendations formed the basic structure of the recommendations. Members of the task force contributed both ideas and methods that are used at their respective institutions to aid groups responsible for treatments and that instruct patients and caregivers in the attainment of radiation safety. There are insufficient data on long-term outcomes to create evidence-based guidelines. RESULTS: The information was used to compile delineations of radiation safety. Factors and situations that govern implementation of safety practices are cited and discussed. Examples of the development of tables to ascertain the number of hours or days (24-hour cycles) of radiation precaution appropriate for individual patients treated with ¹³¹I for hyperthyroidism and thyroid cancer have been provided. Reminders in the form of a checklist are presented to assist in assessing patients while taking into account individual circumstances that would bear on radiation safety. Information is presented to supplement the treating physician's advice to patients and caregivers on precautions to be adopted within and outside the home. CONCLUSION: Recommendations, complying with Nuclear Regulatory Commission regulations and consistent with guidelines promulgated by the National Council on Radiation Protection and Measurement (NCRP-155), can help physicians and patients maintain radiation safety after treatment with ¹³¹I of patients with thyroid diseases. Both treating physicians and patients must be informed if radiation safety, an integral part of therapy with ¹³¹I, is to be attained. Based on current regulations and understanding of radiation exposures, recommendations have been made to guide physicians and patients in safe practices after treatment with radioactive iodine.

Graves' disease and thymic hyperplasia: the relationship of thymic volume to thyroid function.

BACKGROUND: Thymic hyperplasia is associated with Graves' disease, particularly in young patients. The degree of thymic transformation is minimal in most but not all patients. In the latter group radiological measurements of thyroid size and their change with treatment have rarely been reported. We present two patients with Graves' disease and relatively rapid resolution of thymic enlargement after successful treatment of their hyperthyroidism. SUMMARY: Three patients with thyrotoxicosis secondary to Graves' disease and marked thymic enlargement were seen at our institution during a 2-year period. On computed tomography (CT) studies their volumes were 67, 81, and 54 cm(3). Thymic hyperplasia in the setting of Graves' disease was the diagnosis of exclusion. Two of the patients returned for follow-up after successful treatment of thyrotoxicosis as requested. On repeat CT their thymic volumes had decreased by 72% and 78%, respectively. Two types of histological modifications of the thymus have been described in association with Graves' disease, namely, thymic parenchyma hyperplasia and medullary lymphoid hyperplasia. The mechanisms underlying thymic transformation in patients with Graves' hyperthyroidism are not completely elucidated, but autoimmune processes underlying Graves' disease are presumed to play a role. The clinical course of our patients is consistent with earlier literature, indicating that thymic enlargement may occur in conjunction with Graves' hyperthyroidism, and that it usually resolves as hyperthyroidism is treated, but there is little quantitative pre- and posttreatment of hyperthyroidism data. CONCLUSION: Although every patient must be individually considered, it appears that thymic hyperplasia can be diagnosed in most Graves' hyperthyroid patients by considering the clinical context and appropriate radiologic studies such as CT. Raising awareness of the association of thymic hyperplasia in patients with Graves' hyperthyroidism and its resolution with the reversibility of the hyperthyroid state should prevent unnecessary thymic evaluation and surgery with its attendant risks.

Thyroid and bone.

This article provides a summary of the numerous interactions between the thyroid gland and the skeleton, in the normal state, in disorders of thyroid function and as a result of thyroid malignancy. It recaps the current understanding of bone growth and development in the endochondral growth plate and the normal mechanisms of mature bone remodeling. The actions of thyroid hormones on these processes are described, and the clinical impact of thyroid disorders and their treatments on the bone are summarized. Finally, our current understanding of the physiology of bone metastases from thyroid cancer is covered.

The stumble-from pipe cleaner to bone builder.

OBJECTIVE: To review the history of the transition of bisphosphonate use from bench chemistry to clinical applications. METHODS: Pertinent medical literature, including limited-distribution as well as peer-reviewed publications, was reviewed. RESULTS: Bisphosphonates were originally developed to interfere with calcium deposition. An expanded understanding of bone physiology, as well as a growing appreciation of bisphosphonate chemistry, allowed a broadening range of clinical applications. CONCLUSION: The use of bisphosphonates in clinical medicine depended on a series of fortuitous events that, at the time, were "stumbles," not unlike the discoveries of Fleming and Newton. The logical sequence is more apparent in retrospect.

Simultaneous symptomatic Rathke's cleft cyst and GH secreting pituitary adenoma: a case report.

A case of symptomatic Rathke's cleft cyst and growth hormone (GH) secreting pituitary adenoma is described. A patient presented with a visual field deficit and a brain magnetic resonance imaging (MRI) study demonstrated compression of the optic chiasm by a large suprasellar cyst and a small lesion in the sellar consistent with a microadenoma. Preoperative clinical evaluation revealed mild acromegalic features, glucose intolerance, hypertension, hypercholesterolemia, and carpel tunnel syndrome, and blood testing confirmed an elevated insulin-like growth factor-1 (IGF-1). A modified transsphenoidal skull based approach was performed for selective transsphenoidal adenomectomy and decompression of the surprasellar cyst. The patient had an uneventful postoperative course with resolution of the visual field deficits and dysmenorrhea. Endocrine testing at two-month post procedure were normal. While there have been a small number of cases reported of concomitant pituitary adenomas and Rathke's cleft cysts, there is no report known to these authors of coexisting symptomatic lesions.

Use of GC clamps in DHPLC mutation scanning.

OBJECTIVE: Development of a systematic mutation detection assay strategy for denaturing high performance liquid chromatography (DHPLC). DESIGN: Adaptation of Guanine and Cytosine (GC)-clamping from denaturing gradient gel electrophoresis (DGGE) to DHPLC. METHODS: Three target sequences harboring known allelic variants were studied to develop a general DHPLC assay design strategy. These were exon 10 of the human RET (REarranged during Transfection) gene, exon 52 of the mouse Col1a2 gene, and exon 9 of the human FAS (APO-1, CD-95) gene. Available software was used to analyze melting curves and determine assay conditions. GC clamps of 20 bp or 36 bp were added to polymerase chain reaction (PCR) primers to introduce a high melting temperature (T(m)) domain to each of the target molecules. DHPLC was performed under partially denaturing conditions. RESULTS: DHPLC assays of PCR-amplified sequences can be developed using a personal computer. The following three steps allowed for mutation detection in all three targets. The target sequence should have a uniform T(m)GC clamps of length sufficient to introduce a second melting domain with a T(m) > or = 8 degrees above that of the target sequence should be appended to one of the primers. The DHPLC assay should be performed at the highest temperature at which the target sequence is predicted to be > or = 90% double stranded CONCLUSION: Addition of GC-clamps to primers facilitates mutation detection by DHPLC. The theoretical basis for this observation is identical to that underlying the utility of GC-clamps in DGGE.