Susan C. Pitt

Secondary and Tertiary Hyperparathyroidism, State of the Art Surgical Management

This article reviews the current surgical management of patients with secondary and tertiary hyperparathyroidism. The focus is on innovative surgical strategies that have improved the care of these patients over the past 10 to 15 years. Modalities such as intraoperative parathyroid hormone monitoring and radioguided probe utilization are discussed.

Thyroid hormone replacement after thyroid lobectomy

BACKGROUND The purpose of this study was to determine the incidence of and identify risk factors for postoperative hypothyroidism in patients undergoing thyroid lobectomy. METHODS We retrospectively reviewed patients who underwent a thyroid lobectomy for benign disease from May 2004 to December 2007. Patients with known hypothyroidism or on preoperative thyroid hormone replacement were excluded. RESULTS In this study, 14.3% of patients developed hypothyroidism and required thyroid hormone supplementation. These hypothyroid patients had a higher mean pre-operative thyroid-stimulating hormone (TSH) and lower mean free thyroxine (T4) serum levels compared with euthyroid patients (TSH, 2.12 vs 1.35 microIU/mL [P = .006]; free T4, 1.03 vs 1.34 ng/dL [P = .01]). When stratified into 3 groups based on their preoperative TSH measurement (< or =1.5, 1.51-2.5, and > or =2.51 microIU/mL), the rate of hypothyroidism increased significantly at each level (13.5%, 20.5%, and 41.3%, respectively [P < .001]). In addition, patients with Hashimotos thyroiditis were significantly more likely to become hypothyroid (odds ratio, 3.78; 95% confidence interval, 2.17-6.60). CONCLUSION After thyroid lobectomy, approximately 1 in 7 patients experience hypothyroidism requiring thyroid hormone treatment. Patients with preoperative TSH levels >1.5 microIU/mL, lower free T4 levels, and Hashimotos thyroiditis are at increased risk and should be counseled and followed appropriately.

Contralateral papillary thyroid cancer: does size matter?

BACKGROUND The optimal extent of thyroidectomy for papillary thyroid cancer (PTC) <1 cm is controversial. Our aim was to identify the rate and factors predictive of contralateral PTC in these patients. METHODS We examined 228 patients with PTC who underwent either completion or total thyroidectomy and analyzed the predictive value of tumor size, histology, margin status, capsular invasion, extrathyroid extension, multifocality, and node metastases. RESULTS We observed no differences in the rate of contralateral disease in patients with primary PTC > or =1 cm compared with those having disease <1 cm, 30% versus 24%, respectively (P = .43). Multifocality was the only factor predictive of contralateral PTC in patients with tumors <1 cm (P = .02). Patients with tumors <.5 cm also had a comparable rate of contralateral disease (27%). CONCLUSIONS The presence of contralateral PTC appears to be unrelated to the size of the primary tumor. Furthermore, in patients with PTC <1 cm, multifocality is a risk factor for PTC in the contralateral lobe.

A rising ioPTH level immediately after parathyroid resection: are additional hyperfunctioning glands always present? An application of the Wisconsin Criteria.

Objective:This study was designed to determine if a rising intraoperative parathyroid hormone (ioPTH) level following parathyroid resection indicates multiple hyperfunctioning glands and to determine the appropriate intraoperative management. Summary Background Data:IoPTH monitoring is commonly used to guide parathyroid surgery. A significant rise in the ioPTH immediately after resection of a single parathyroid is often perceived to be indicative of the presence of additional hyperfunctioning glands. Methods:A total of 797 consecutive patients underwent parathyroidectomy for primary hyperparathyroidism with ioPTH monitoring. Patients with an elevated 5 minute ioPTH were extensively studied. Operative success was defined as normocalcemia 6 months after surgery. Results:Of the 797 patients, 108 (14%) had a rising ioPTH 5 minutes after resection of a single parathyroid. Of these 108 patients, 36 (33%) continued to have elevated ioPTH levels and further exploration revealed additional hyperfunctioning glands. Importantly, in the majority of patients (n = 72 or 67%), the ioPTH started to fall after an additional 5 minutes (10 minutes after resection). The ioPTH declined by more than 50% from the 5 minute elevated value in 30%, 89%, and 99% of patients at 10, 15, and 20 minutes after resection, respectively. Importantly, this fall correctly predicted operative success in 100% of patients after removal of a single abnormal gland. Conclusions:A rising ioPTH level immediately after parathyroidectomy is observed in 14% of patients. The majority of these patients do not have additional hyperfunctioning glands. Most of patients fell below 50% of the 5 minute elevated value within 20 minutes of gland resection and in all cases this fall correctly predicted operative success.

Tertiary hyperparathyroidism: is less than a subtotal resection ever appropriate? A study of long-term outcomes.

BACKGROUND Our aim was to examine the outcomes of patients with tertiary hyperparathyroidism (3-HPT) who had limited resection of 1 or 2 parathyroids. METHODS We reviewed 140 patients with 3-HPT who underwent parathyroidectomy (PTX) at a single institution. Patients were analyzed according to their operation-limited PTX versus subtotal or total PTX. RESULTS The limited PTX group consisted of 29 patients who underwent resection of 1 (n = 12) or 2 (n = 17) parathyroids. The other 111 patients had subtotal (n = 104), total (n = 3), and/or reoperative PTX (n = 12). The mean +/- SEM follow-up was 79 +/- 5 months. Eucalcemia was achieved in 94% of the patients. All patients with persistent (n = 2) hypercalcemia underwent subtotal PTX (P = not significant [NS] vs limited PTX). In a logistic regression model, the extent of operation was not associated with the development of recurrent disease. Additionally, the incidence of permanent hypocalcemia was 7% after subtotal or total PTX versus 0% after limited resection (P = NS). CONCLUSION Long-term outcomes in patients with 3-HPT appear to be similar after appropriate limited resection of 1 or 2 parathyroid glands compared to subtotal or total PTX. Therefore, a strategy of limited parathyroid resection seems appropriate for patients with 3-HPT when the disease is limited to 1 or 2 glands.

Tautomycetin and tautomycin suppress the growth of medullary thyroid cancer cells via inhibition of glycogen synthase kinase-3β

Medullary thyroid cancer (MTC) is a relatively uncommon neuroendocrine tumor that arises from the calcitonin-secreting parafollicular cells of the thyroid gland. Unfortunately, MTC frequently metastasizes, precluding curative surgical resection and causing significant morbidity. Thus, there is an urgent need for new treatment modalities. Tautomycin and tautomycetin are antifungal antibiotics isolated from Streptomyces spiroverticillatus and Streptomyces griseochromogens, respectively. Glycogen synthase kinase-3β is a serine/threonine protein kinase that regulates multiple cellular processes and is important in various cancers, including MTC. Treatment with tautomycin and tautomycetin decreased neuroendocrine markers, suppressed hormonal secretion, and inhibited growth through apoptosis in MTC cells. Importantly, we describe a novel action of these compounds: inhibition of glycogen synthase kinase-3β.[Mol Cancer Ther 2009;8(4):914–20]

Phosphatidylinositol 3-Kinase-Akt Signaling in Pulmonary Carcinoid Cells

BACKGROUND In several types of cancer, upregulation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling facilitates tumor cell growth and inhibits apoptosis. Previous reports demonstrated that this pathway promotes growth, survival, and chemotherapy resistance in non-small cell and small cell lung cancer cells. But the importance of PI3K-Akt signaling has not been explored in pulmonary carcinoids. In this study, our objective was to establish the role of the PI3K-Akt signal transduction pathway in pulmonary carcinoid cells. STUDY DESIGN Human pulmonary carcinoid NCI-H727 cells were treated with LY294002 (0 to 100 microM), a well-known PI3K inhibitor, or transfected with Akt1 small interfering RNA (75 nM). Cellular proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for up to 8 days. Western blot analysis was performed for expression of active, phosphorylated Akt (pAkt), total Akt, Akt1, and the neuroendocrine markers chromogranin A and achaete-scute complex-like1. RESULTS Treatment of NCI-H727 cells with LY294002 significantly reduced tumor cell growth (85.3%). Similarly, Akt1 small interfering RNA transfection led to diminished tumor cell proliferation (31.3%). A dose-dependent decrease in chromogranin A and achaete-scute complex-like1 production was observed with both PI3K inhibition and Akt1 RNA interference. Expression of Akt1 was reduced at all time points by transient Akt1 small interfering RNA transfection. CONCLUSIONS The PI3K-Akt pathway plays a role in both tumor cell growth and neuroendocrine hormone secretion in human pulmonary carcinoid cells. Inhibition of Akt1, PI3K-Akt signaling, or a downstream mediator of this pathway may provide therapeutic approaches for patients with pulmonary carcinoid tumors.

Radioguided parathyroidectomy for hyperparathyroidism in the reoperative neck

BACKGROUND The purpose of this study was to determine if radioguided parathyroidectomy (RGP) is effective for hyperparathyroidism (HPT) in the reoperative neck. METHODS We retrospectively reviewed all patients with HPT and a history of neck surgery who underwent RGP over a 7-year period. Data are reported as mean +/- SEM. RESULTS We identified 110 patients with primary (n = 94), secondary (n = 7), or tertiary (n = 9) HPT who underwent 138 previous neck operations. The average hospital stay was 0.6 +/- 0.1 days. The in and ex vivo counts obtained with the gamma probe were 310 +/- 26 and 130 +/- 13, respectively. The ex vivo percentage of background was 69% +/- 9%, and virtually all resected parathyroids had ex vivo counts > or =20%. After RGP, 96% of patients were cured, and 5% experienced complications (all transient). Cure rates after RGP decreased as the number of previous neck operations increased (P = .002). Additionally, reoperative neck patients with single adenomas were more likely to experience cure than patients with hyperplasia (P = .02). CONCLUSION These results illustrate that RGP is valuable in treatment of the reoperative neck. In addition, RGP allows similar lengths of stay, efficacy, and complication rates as those reported for patients undergoing initial parathyroidectomy.

The phosphatidylinositol 3-kinase/akt signaling pathway in medullary thyroid cancer.

In the United States, an estimated 33, 550 cases of thyroid cancer were diagnosed in 2007 according to the American Cancer Society. Medullary thyroid cancer (MTC) accounts for approximately 5% of these carcinomas and arises from calcitonin-secreting parafollicular C cells.1 While up to 25% of MTCs are hereditary, the majority of cases are sporadic. Hereditary forms of MTC include both multiple endocrine neoplasia 2 types (MEN 2A and MEN 2B) and familial MTC. Mutations of the RET (Rearranged during Transfection) proto-oncogene on chromosome 10q11 are present in over 95% of hereditary MTCs and about 25% of sporadic MTCs.2 Dominant-activating or gain-of-function mutations in the RET proto-oncogene lead to the constitutive activation of receptor tyrosine kinases and downstream pathways involved in cell survival and proliferation.

Influence of Morbid Obesity on Parathyroidectomy Outcomes in Primary Hyperparathyroidism

BACKGROUND We sought to evaluate the influence of morbid obesity in patients undergoing parathyroidectomy for primary hyperparathyroidism (pHPT). METHODS All patients with pHPT who underwent parathyroidectomy at a single institution between July 2002 and October 2008 were included. Body mass index (BMI), laboratory values, operative findings, and outcomes were examined. RESULTS Two hundred thirteen of the 776 patients identified (28%) were morbidly obese (BMI>or=35 kg/m2). When compared with nonmorbidly obese patients, the morbidly obese patients were younger, had higher preoperative intact parathyroid hormone (iPTH) levels, heavier parathyroids, and required overnight stay more often (P<.05 for all). However, the rates of complications, eucalcemia, and recurrence were similar for all patients. CONCLUSION In this study, more than a quarter of the patients who underwent parathyroidectomy for pHPT were morbidly obese and had significantly higher preoperative iPTH levels, heavier parathyroids, and longer hospital stay but similar rates of complications and operative success.