Ejigayehu G. Abate

Review of Hypoparathyroidism

Hypoparathyroidism is a rare endocrine disorder in which parathyroid hormone (PTH) production is abnormally low or absent, resulting in low serum calcium and increased serum phosphorus. The most common cause of hypoparathyroidism is parathyroid gland injury or inadvertent removal during thyroid surgery. Current treatments include supplementation with calcium and active vitamin D, with goal albumin-corrected serum calcium level in the low-normal range of 8–9 mg/dl. Complications of the disease include renal dysfunction, nephrocalcinosis, kidney stones, extracellular calcifications of the basal ganglia, and posterior subcapsular cataracts, as well as low bone turnover and increased bone density. Until January 2015, hypoparathyroidism was the only classic endocrine disease without an available hormone replacement. Recombinant human PTH 1-84, full-length PTH, is now available for a selected group of patients with the disease who are not well controlled on the current standard therapy of calcium and active vitamin D. In addition, the role of PTH replacement on quality of life, intracerebral calcifications, cataracts, improving bone turnover, and reduction of renal complications of the disease remains to be further investigated.

Managing anaplastic thyroid carcinoma

Anaplastic thyroid cancer is one of the most lethal malignancies, with dismal prognosis, resistance to multimodal treatments and a median survival of only 5–6 months. Advances in the discovery of genetic pathway aberrations involved in this aggressive disease have been made, and multiple novel therapies targeting these pathways are undergoing clinical trials. So far, there is no single effective treatment for this disease; however, multimodal therapies with a combination of surgery, radiation and chemotherapy hold some promise. We conducted a PubMed search using the words thyroid neoplasm, anaplastic thyroid carcinoma, anaplastic thyroid cancer and anaplastic thyroid neoplasm, revealing 1673 publications. We review the pathophysiology, current treatments and advances made in identifying the alterations in genetic pathways, as well as novel therapies targeting these pathways.

Tumor induced osteomalacia secondary to anaplastic thyroid carcinoma: A case report and review of the literature

Context Tumor induced osteomalacia related to anaplastic thyroid cancer has never been reported. Objective We describe a case of tumor induced osteomalacia (TIO) in a patient with a fibroblast growth factor 23 (FGF-23) secreting anaplastic thyroid carcinoma. The current imaging modalities are reviewed. Design and intervention Clinical, biochemical, and radiological assessments were done, including computer tomography (CT) of the neck and skull to thigh positron emission tomography (PET)/CT. The patient underwent surgical tumor debulking three days after presentation due to airway compromise. Molecular studies of the resected tissue were performed using reverse transcriptase–polymerase chain reaction (RT-PCR) and gel electrophoresis for the phosphaturic mesenchymal tumor FGF-23. Results Resected tissue demonstrated features of anaplastic thyroid cancer with positive markers for FGF-23 protein, consistent with a FGF-23 secreting paraneoplastic tumor. The patients metastatic burden rapidly progressed as demonstrated by a dramatic rise in serum FGF-23 levels and worsening hypophosphatemia in concert with progression of the metastatic lesions on PET/CT. Conclusion We believe that our patients rapidly progressive anaplastic thyroid cancer was responsible for persistent hypophosphatemia and osteomalacia, substantiated by the finding of FGF-23 protein within the thyroid tumor cells. Our case indicates that anaplastic thyroid cancer can cause TIO.

Anaplastic Thyroid Carcinoma: Clinical Aspects

Anaplastic thyroid carcinoma (ATC) is more common in women than in men, with a ratio of 1.9:1. The tumor occurs in older individuals and has a median (mean) age of 69 (66.5) years. ATC often exists coincidentally with, or in patients with a history of, differentiated thyroid cancer, suggesting a dedifferentiated process. ATC comprises only 3.8 % of thyroid cancers worldwide and is seen more frequently in regions of iodine deficiency. Iodine supplementation has reduced the frequency by 40–80 %. ATC usually presents with the sudden onset of a neck mass. The tumor produces both airway and esophageal obstructive symptoms including dyspnea, dysphagia, hoarseness (due to recurrent laryngeal nerve involvement), pain, cough, and hemoptysis, and death occurs shortly thereafter. The median tumor size at onset is 6.8 cm but may be as large as 25 cm. Initial imaging is required to assess the extent of disease, and FDG-PET is particularly helpful in locating disease locations. Metastatic disease at presentation occurs commonly, with lung and mediastinal lesions being identified most frequently. Other sites include the bone, liver, brain, heart, adrenal glands, and kidney, many of these being sites rarely affected by differentiated thyroid cancers. Initial evaluation should include not only anatomic staging but an assessment of the patient’s performance status, after which, a realistic discussion of the patient’s therapeutic options and desire for aggressive versus palliative management should be held. Restaging and goals of care should be reassessed after initial therapy and periodically thereafter. Causes of death are both from local obstructive complications and distant metastases.

Anaplastic Thyroid Carcinoma: Prognosis

Anaplastic thyroid cancer (ATC) has a dismal prognosis, with a median overall survival of only 4.9 months and 1-year survival of 20 %. Stage IVA (intrathyroidal) tumors have the best prognosis, while IVC patients (distant metastases) have the worst. The most favorable prognosis is seen in patients with an incidental focus of ATC, but even these uncommon patients do not all survive, indicating that microscopic metastases are present early and aggressive therapy is required. Unfortunately, the median frequency of stage IVA lesions is only 10 %, compared to 40.1 % and 45.8 % for stages IVB and IVC, respectively. Predictors of survival in many but not all studies include completeness of surgical resection, delivery of higher doses of external radiation, smaller tumor size, and locoregionally confined disease. Younger age is more favorable in some studies, while gender does not affect survival. Historically, most studies using combination therapy have not prolonged survival, although several recent reports using multimodal therapy have shown some promise. In a few studies, elevated white blood cell counts, dyspnea, dysphagia, and higher intensity of uptake on FDG-PET imaging have been associated with a worse prognosis. What remains unexplained is why some patients present with stage IVA disease, while most are more advanced. A better understanding of the critical genetic abnormalities present in each stage is needed in order to design better therapies to improve survival.

Unravelling the best combination of therapies to treat anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is rare and associated with a short life expectancy. The majority of patients have coexisting differentiated thyroid carcinoma or long standing history of goiter. All anaplastic thyroid cancer is considered as stage IV disease as patients usually present with locally advanced and metastatic disease. The American Joint Committee on Cancer (AJCC) TNM staging defines Stage IVA disease is localized to the thyroid, stage IVB disease as the tumor has spread outside of the thyroid gland but contained within the neck, and IVC with distant metastasis beyond the neck. Life expectancy is typically months with median survival of 5 months and 2 year survival of 0%. There is no effective treatment to date, and clinical trials are difficult to conduct given the short survival and aggressive nature of the disease. ATC typically has multiple genomic mutations. Single agents are ineffective in management of anaplastic thyroid cancer. The first American Thyroid Association guideline for management of anaplastic thyroid cancer was published in 2012 [1]. Once the diagnosis of ATC is confirmed, staging and resectability of the tumor should be assessed by ultrasound and CT scan, MRI or PET scan of neck, chest and abdomen. ATC has high 18 F-fluorodeoxyglucose (FDG) uptake, so FDGPET imaging can complement traditional imaging modalities and detect metastatic foci not readily visible otherwise. Discussion regarding prognosis with the patient is necessary as well as risks and benefit of treatment [1,2]. Multimodality treatment (combination of surgery, radiation and chemotherapy) is the most effective therapy that has been shown to improve outcome for stages IVA, and resectable stage IVB disease with a 1 year survival up to 70%, 2 year survival of 60%, and 50% living beyond 2.5 years with a median survival of 5 years [3,4]. Current treatment guidelines recommend surgical resection if possible for locoregional disease (stage IVA and resectable IVB) and stabilization of airway patency in all patients. Most experts recommend aggressive multimodality treatment in those with tumor found incidentally (i.e. small focus of incidental ATC found during surgery for differentiated thyroid cancer) [1]. Unresectable stage IVB disease may respond to aggressive therapy consisting of radiation with or without chemotherapy followed by surgery if surgery can be performed safely after reduction in burden of disease. Patients with stage IVC disease may be enrolled in clinical trials or hospice/palliative care depending on patient’s choices. Radiotherapy in the form of intensity-modulated radiation therapy (IMRT), where multiple small photons are directed precisely to the tumor while reducing radiation to the surrounding areas, and external beam radiation therapy (EBRT) can be used. Radiation can be given alone or in combination with chemotherapy. In the SEER registry, all-cause mortality from anaplastic thyroid cancer was reduced to approximately 70% at 6 months and 81% at 1 year with combination of radiation therapy and R0/R1 resection (complete resection with no residual tumor; microscopic residual tumor presence respectively)[5]. Radiation therapy should be started as soon as possible after recovery from neck surgery, usually within 2–3 weeks. Effective chemotherapy includes the taxanes (paclitaxel or docetaxel), doxorubicin alone or a taxane with carboplatin or doxorubicin. If the tumor is not resectable (R2 resection) but localized in the neck (stage IVB disease), then radiotherapy with >40–45 Gy IMRT or EBRT ± chemotherapy with taxane and carboplatin or doxorubicin can be given. The majority of ATC patients present with metastatic disease (stage IVC). Currently, there is no effective therapy for stage IVC disease; however, new promising combination treatments are on the horizon. In patients who elect to proceed with aggressive therapy, locoregional radiation alone or in combination with total thyroidectomy with lymph node dissection if resectable (R0/R1) is somewhat effective for palliative treatment. Systemic chemotherapy combination of taxane/ carboplatin or doxorubicin and enrollment in a clinical trial should be considered. Currently there are few clinical trials targeting genetic aberrations commonly seen in ATC. Identifying genomic alterations will provide potential targets for new therapies. The genetic mechanisms involved in the development of anaplastic thyroid cancer are complex. Hallmarks of all cancers are self-sufficiency in growth signals and evasion of programmed cell death. Tyrosine kinase receptors/RAS/RAF/MAPK and RAS/PI3K/Akt/mTOR are the major signaling pathways involved in cell proliferation, protein synthesis and cell survival of ATC. In addition, inactivating mutations in the tumor suppressor phosphatase and tensin homolog (PTEN) and tumor protein gene (TP53) play an

Follow-Up of the Patient with an Implanted Cardiac Defibrillator

Since the initial development of the implantable defibrillator in the 1970s by Michel Mirowski, and commercial introduction in 1985, national surveys and industry analysts have estimated that more than 160,000 implants have been performed in the United States (1). Multicenter randomized trials have demonstrated the effectiveness of the implantable cardioverter-defibrillator (ICD) for reducing mortality in high-risk patient groups (2,3). It has been estimated that more than 700,000 patients are eligible for an ICD in the United States. The newest generation of ICDs are capable of defibrillation of ventricular fibrillation, pace termination of ventricular tachycardia, single or dual chamber pacing, and cardiac resynchronization therapy (CRT) depending on the model. In addition, ICDs now have multiple additional features including extensive programming options, detailed event histories, and real-time telemetry. Unfortunately, even with the most recent generation of ICDs, adverse clinical events such as inappropriate detection (providing tachycardia therapy when no ventricular arrhythmia was present) and lead failures remain relatively common, approaching 50% in the first 2 years (4,5). In addition, a multicenter study that analyzed terminal events in patients with first-generation ICDs, found that approximately 15% of patients who had sudden death presumed secondary to arrhythmias had ICDs that indicated battery depletion (5,6). Finally during 2005 a number of well publicized recalls for potentially fatal device malfunction caused both the public and physicians to question the reliability of ICD therapy. This chapter reviews the basic follow-up of ICDs, and how to troubleshoot an ICD suspected of malfunction.

An Uncommon Cause of Asymptomatic Primary Hyperparathyroidism

Asymptomatic hyperparathyroidism developed in a 65-yr-old man with a history of metastatic papillary thyroid carcinoma. Pertinent laboratory values were: calcium, 10.8 mg/dl (2.70 mmol/liter) [reference range, 8.9– 10.1 mg/dl (2.22–2.52 mmol/liter)]; intact PTH, 135.1 pg/ml (14.3 pmol/liter) [15–50 pg/ml (1.6–5.3 pmol/liter)]; and albumin, 4.5 g/dl (45 g/liter) [3.5–5.0 g/dl (35–50 g/liter)]. Phosphorus, creatinine, and 25-hydroxyvitamin D levels were within normal limits. Thyroid ultrasound for follow-up of his thyroid cancer revealed a 3.0 1.3 0.7-cm cystic mass in the left thyroid bed (Fig. 1A). Twenty-five milliliters of clear fluid were removed from the cyst, revealing an intact PTH of 821 pg/ml (87.1 pmol/liter). Serum calcium was 9.0 mg/dl (2.25 mmol/liter) at 6 months and 9.1 mg/dl (2.27 mmol/liter) at 24 months, with intact PTH 56.5 pg/ml (6 ng/liter) and reduction of the cyst to 0.7 0.6 0.7 cm (Fig. 1B). Parathyroid cysts are rare. An uncommon cause of primary hyperparathyroidism is a functional parathyroid cyst (1). Few parathyroid cysts (10–15%) are functional (presenting with hyperparathyroidism) (2). Functional cysts are treated with surgical excision (3, 4), although successful treatment with aspiration has been described in one case report (3). They mimic thyroid and thymic cysts, thus presenting a diagnostic challenge (4). The presence of elevated intact PTH in aspirated fluid is diagnostic. Parathyroid cysts have absent uptake on radioiodine thyroid scans and rarely are positive on sestamibi parathyroid scans (5). Ultrasound, computed tomography, and magnetic resonance imaging show a cystic cervical or mediastinal mass (5). Aspiration of a functioning parathyroid cyst can be both diagnostic and therapeutic. Acknowledgments