Joel T. Adler

Pheochromocytoma: Current Approaches and Future Directions

Pheochromocytomas are rare catecholamine-secreting tumors that arise from chromaffin tissue within the adrenal medulla and extra-adrenal sites. Because of the excess secretion of hormones, these tumors often cause debilitating symptoms and a poor quality of life. While medical management plays a significant role in the treatment of pheochromocytoma patients, surgical excision remains the only cure. Improved medical management and surgical techniques and an increased understanding of hereditary disease have improved the outcome of pheochromocytoma patients with benign disease; however, the outcome of patients with malignant disease remains poor. In this review, we discuss the presentation, diagnosis, management, and future directions in the management of this disease.

Valproic Acid Activates Notch1 Signaling and Induces Apoptosis in Medullary Thyroid Cancer Cells

Objective:To examine the effects of valproic acid (VPA) on Notch1 expression and cancer cell proliferation in medullary thyroid cancer (MTC) cells. Background:Other than surgery, there are no effective treatments for MTC, a neuroendocrine malignancy that frequently metastasizes. We have previously shown that over-expression of Notch1 in MTC cells inhibits cell growth and hormone production. VPA, a drug long used for the treatment of epilepsy, has recently been identified as a potential Notch1 activator. We hypothesized that VPA might activate Notch1 signaling in MTC cells, with antiproliferative effects. Methods:Human MTC cells were treated with VPA (0–5 mM) and Western blotting was performed to measure levels of Notch1 pathway proteins and neuroendocrine tumor markers. After confirming that VPA is a Notch1 activator in MTC cells, we performed cell proliferation assay. Finally, to determine the mechanism of growth inhibition, we measured protein levels of various markers of apoptosis. Results:Notch1 was absent in MTC cells at baseline. VPA treatment resulted in an increase in both full-length and active Notch1 protein. Notch1 activation with VPA suppressed 2 neuroendocrine tumor markers, ASCL1 and chromogranin A. Importantly, VPA inhibited the growth of MTC cells in a dose-dependent manner. Immunoblot analysis demonstrated caspase activation and poly(ADP-ribose) polymerase cleavage, indicating the induction of apoptosis. Conclusions:VPA activates Notch1 signaling in MTC cells and inhibits their growth by inducing apoptosis. As the safety of VPA in human beings is well established, a clinical trial using this drug to treat patients with advanced MTC could be initiated in the near future.

New Trends in Parathyroid Surgery

yperparathyroidism is a relatively common disorder of bone and ineral metabolism caused by the oversecretion of parathyroid hormone PTH). The most common variation, primary hyperparathyroidism, has an nnual incidence in the USA of approximately 100,000 patients; its revalence is estimated to be between 0.2% and 1%. As awareness of alcium disorders increases, elevations in calcium are discovered and urther evaluated. Primary hyperparathyroidism is caused by 1 or more overactive arathyroid glands, resulting in an inappropriately elevated PTH and the isruption of bone and mineral metabolism. Secondary and tertiary yperparathyroidism are typically related to renal disease or other isorders of calcium metabolism. In patients with secondary hyperparahyroidism, the parathyroid glands become overactive in response to onsistently low serum calcium, leading to renal osteodystrophy. Tertiary yperparathyroidism typically occurs in patients with longstanding secndary hyperparathyroidism who undergo renal transplantation or rapid orrection of hypocalcemia. Parathyroid carcinoma, although uncommon, s an additional cause of hyperparathyroidism and can be associated with ebilitating symptoms. Surgery plays a role in the treatment of all causes of hyperparathyroidsm, whether it is a first-line treatment, after a biochemical diagnosis is ade. Traditionally, resection of the abnormal parathyroid glands is ccomplished by a bilateral, open exploration with evaluation of all 4 arathyroid glands. This has evolved to a minimally invasive operation ided by preoperative imaging and intraoperative adjuncts that lead to a uicker postoperative recovery and greater patient satisfaction with, quivalent cure rates. It is in this context that we summarize the recent advances in arathyroid surgery. Much has been debated about the appropriate reoperative imaging modalities, which intraoperative adjuncts are useul, and even how one should screen patients with hereditary causes of yperparathyroidism. In this review, we discuss the basic concepts of

Preserving function and quality of life after thyroid and parathyroid surgery

Endocrine disease has been recognised for thousands of years, but surgical treatment of endocrine disorders has only been widely used in the past century. Surgery is an effective treatment for hyperfunctioning glands and benign and malignant tumours. Advances in surgical technique have led to the development of short and safe operations with a high cure rate, and recent studies have not only assessed the success of the operations but also have focused on how these diseases affect patient-reported quality of life before and after surgery. In this Review, we summarise current approaches to surgical treatment of thyroid and parathyroid disease, focusing on how these approaches both preserve function and improve quality of life after surgery.

Histone deacetylase inhibitors upregulate Notch-1 and inhibit growth in pheochromocytoma cells.

BACKGROUND The histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) have been demonstrated recently to be strong Notch-1 activators. Upregulation of the Notch-1 pathway has been shown to limit growth and suppress hormonal secretion in neuroendocrine (NE) neoplasms. We hypothesized that HDAC inhibition would be an effective strategy to activate the Notch-1 pathway and inhibit growth and hormonal secretion in pheochromocytoma cells. METHODS Pheochromocytoma PC-12 cells were treated with up to 8 mmol/L VPA or 40 micromol/L SBHA for 2 days. NE tumor markers achaete-scute complex-like 1 (ASCL1) and chromogranin A (CgA) were measured by Western analysis after treatment. Growth was assessed by a cellular proliferation assay; Western analysis was used to determine the mechanism of growth regulation. RESULTS HDAC inhibitor treatment caused a dose-dependent decrease in ASCL1 and CgA while increasing the amount of active Notch-1 protein; with a 6-day treatment, dose-dependent growth inhibition and cleavage of the apoptotic markers caspase-3 and poly-ADP ribose phosphate was observed. CONCLUSION VPA and SBHA upregulate Notch-1 effectively, suppress NE tumor markers, and decrease growth via apoptosis of pheochromocytoma cells in vitro. Activation of the Notch-1 signaling pathway with HDAC inhibitors may represent a new strategy for treating pheochromocytomas.

Isolated Adrenal Mass in Patients with a History of Cancer: Remember Pheochromocytoma

In a patient with a history of cancer, an isolated adrenal mass is usually thought to be a metastasis. Although a biochemical work-up to rule out pheochromocytoma is recommended, some question its practicality. This study was undertaken to determine the incidence of functional adrenal lesions in patients with a history of cancer and examine predictive factors for the type of lesion. At a single institution, 33 patients with an isolated adrenal mass and a history of cancer underwent surgical treatment. Patients’ records were retrospectively analyzed for type of adrenal lesion and other diagnostic parameters. There were 20 males and 13 females with a mean age of 58±2 years. Of these, 20 (61%) had adrenal metastases, 8 (24%) had pheochromocytomas, and 5 (15%) had adrenal adenomas. Usual diagnostic criteria, including presenting symptoms, primary tumor, and other demographic characteristics, did not consistently predict the pathology of the lesion. Nearly 1 in 4 resected adrenal masses in patients with a history of cancer were pheochromocytomas. The high incidence of pheochromocytoma in this series supports a thorough work-up, irrespective of previous cancer. Therefore, remember one thing in patients with an isolated adrenal mass and a history of cancer: pheochromocytoma.

Combination therapy with histone deacetylase inhibitors and lithium chloride: a novel treatment for carcinoid tumors

In carcinoid cell lines, the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) activate the Notch1 pathway, whereas lithium inhibits glycogen synthase kinase-3β (GSK-3β). These compounds limit growth and decrease hormonal secretion in vitro. We hypothesized that lower-dose combination therapy of HDAC inhibitors and lithium chloride could achieve similar growth inhibition to that of the drugs alone. Gastrointestinal and pulmonary carcinoid cells were treated with either VPA or SBHA and lithium chloride for up to 48 hours. Western blot analysis was used to measure the effects on the Notch1 and GSK-3β pathways and the neuroendocrine tumor marker chromogranin A (CgA). Growth was measured by a cellular proliferation assay. With lower-dose combination therapy, a decrease in CgA was observed. The HDAC inhibitors increased the amount of active Notch1 protein, whereas treatment with lithium was associated with inhibition of GSK-3β. Moreover, growth was inhibited with lower-dose combination therapy. Treatment of carcinoid cells with either VPA or SBHA and lithium chloride suppresses the neuroendocrine marker CgA while upregulating Notch1 and inhibiting GSK-3β. This combination effectively reduces growth. Thus, lower-dose combination therapy may be a viable therapeutic approach for carcinoid tumors.

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]

Does Routine Use of Ultrasound Result in Additional Thyroid Procedures in Patients with Primary Hyperparathyroidism

BACKGROUND Minimally invasive parathyroidectomy for primary hyperparathyroidism depends on accurate preoperative imaging. Cervical ultrasound is commonly used to localize parathyroid adenomas, but can lead to discovery of concomitant thyroid gland pathology requiring modification of the operative approach. How the identification of incidental thyroid lesions affects patient management is unclear. STUDY DESIGN A prospective database of patients undergoing parathyroidectomy was analyzed for thyroid pathology discovered by ultrasound. Lesions were biopsied if indicated, and operative management was adjusted accordingly. Clinical data were correlated with operative decision-making. RESULTS Between July 2002 and November 2009, 310 patients with primary hyperparathyroidism underwent ultrasound. Concomitant thyroid pathology was noted in 89 (29%) patients. Thirty-seven patients (42% of pathology) underwent fine-needle aspiration of a thyroid nodule. Thirteen patients (4% of all patients) underwent a thyroid operation not related to parathyroid disease: 9 thyroid lobectomies for presumably benign nodules and 4 total thyroidectomies for malignancy. Two were for confirmed papillary thyroid cancer, and the other 2 were for an indeterminate biopsy that later proved to be papillary thyroid cancer. One lobectomy discovered microscopic papillary thyroid cancer independent of the biopsied nodule. In total, 5 (2% of all patients) malignancies were discovered. CONCLUSIONS Twenty-nine percent of patients with primary hyperparathyroidism had concomitant thyroid pathology on ultrasound. Forty-two percent of these patients underwent biopsy, and 2% had malignant pathology. Routine use of ultrasound in patients with primary hyperparathyroidism leads to discovery of unrecognized thyroid pathology and cancer.

Inhibition of Growth in Medullary Thyroid Cancer Cells with Histone Deacetylase Inhibitors and Lithium Chloride

BACKGROUND While representing only 3% of thyroid malignancies, medullary thyroid cancer (MTC) accounts for 14% of thyroid cancer deaths. MTC has a high rate of recurrence and lacks effective treatments. The histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) activate the Notch1 signaling pathway, while lithium chloride inhibits the glycogen synthase kinase-3ss (GSK-3ss) pathway. These compounds have been shown to limit growth and suppress hormonal secretion; thus, targeting different signaling pathways may be an effective treatment. METHODS MTC cells were treated with varying combinations of up to 20 mM lithium chloride with either 3 mM VPA or 20 muM SBHA for 48 h. Western analysis was used to measure the effects on Notch1, GSK-3ss, and neuroendocrine (NE) markers. Growth was assessed by a methylthiazolyldiphenyl-tetrazolium (MTT) bromide cellular proliferation assay. Western analysis was used to determine the mechanism of growth regulation. RESULTS Combination therapy increased active Notch1, inhibited the GSK-3ss pathway, and decreased NE markers. Additive inhibition of growth was observed with combination therapy. Lower-dose combination therapy achieved greater decreases on NE markers and growth than treatment with any of the drugs alone. Moreover, an increase in the cleavage of the apoptotic markers caspase-3 and PARP was observed. CONCLUSIONS Combination therapy with lithium chloride and HDAC inhibitors suppresses NE markers and decreases growth via apoptosis of MTC cells in vitro. With the possibility of increased efficacy and decreased toxicity, combination therapy may represent a new strategy to treat MTC.