Utility of ¹¹¹indium-pentetreotide scintigraphy in patients with neuroendocrine tumors.

BACKGROUND: Neuroendocrine (NE) tumors pose a diagnostic challenge with the need to utilize a combination of biochemical analysis, standard cross-sectional imaging, and more recently, nuclear medicine scans such as (111)indium-pentetreotide scintigraphy (somatostatin receptor scintigraphy, SRS; OctreoScan, Covidien Imaging Solutions, Hazelwood, MO). In this study we sought to evaluate the clinical utility of scintigraphy in the diagnosis and management of patients with NE tumors at a major university hospital. METHODS: A retrospective chart review was performed on all patients who underwent both (111)indium-pentetreotide scintigraphy and computed tomography/magnetic resonance imaging (CT/MRI) at a single institution between February 2001 and July 2008. Charts were reviewed for patient demographics, symptoms of NE disease, and results of biochemical testing, imaging studies, histopathologic diagnosis, and medical and/or surgical management. RESULTS: One hundred forty-five patients received (111)indium-pentetreotide scintigraphy (SRS) and concurrent cross-sectional imaging (CT/MRI) over the 7-year period studied. In the evaluation of primary disease, 60 % of tumors were localized by anatomic imaging, significantly greater than the 15 % detection rate achieved by SRS. In the evaluation of recurrent disease, 61 % of NE tumors were localized by cross-sectional imaging, significantly greater than the 31 % detection rate of SRS. Scintigraphy identified disease foci not seen on CT/MRI in just 8 of 74 of the cohort with evidence of disease and only altered the surgical management in 3 of 74 cases. CONCLUSIONS: Cross-sectional CT/MRI imaging is sufficient for the localization of NE tumors. (111)Indium-pentetreotide scintigraphy does not significantly alter the surgical management of patients with NE tumors, and we suggest that it be selectively reserved for patients with disease that is occult to cross-sectional imaging.

Changes in swallowing-related quality of life after parathyroidectomy for hyperparathyroidism: a prospective cohort study.

OBJECTIVE: To prospectively evaluate the impact of parathyroidectomy on swallowing-related quality of life using the Swallowing Quality Of Life (SWAL-QOL) validated outcomes assessment tool. BACKGROUND: Many patients with primary hyperparathyroidism report nonspecific symptoms, such as fatigue, irritability, cognitive impairment, sleep disturbances, and dysphagia. To date, there have been no prospective studies evaluating swallowing function before and after parathyroid surgery. METHODS: Patients undergoing parathyroidectomy from September 2007 to January 2009 completed the SWAL-QOL questionnaire before and one year after surgery. Data were collected on demographic and clinicopathologic variables. Comparisons were made to determine the effect of surgery on patients' perceptions of swallowing function. RESULTS: Of 151 eligible patients, 102 (68%) completed the study. The mean patient age was 60 years, and 79% were female. A total of 73 patients (67%) had minimally invasive parathyroidectomies, whereas the remainder had bilateral explorations. In all, 83 patients (81%) had a parathyroid adenoma, 16 patients (16%) had hyperplasia, and 3 patients (3%) had a double adenoma on final pathologic interpretation. Mean preoperative SWAL-QOL scores were <90 for 4 of the 11 domains, indicating the perception of oropharyngeal dysphagia and diminished quality of life. Following parathyroidectomy, significant improvements were demonstrated in eight SWAL-QOL domains. CONCLUSIONS: Many patients with parathyroid disease have the perception of abnormal swallowing function. In these patients with symptoms of dysphagia, parathyroid surgery leads to significant improvements in many aspects of swallowing-related quality of life measured by the SWAL-QOL instrument. This study represents the first use of a condition-specific instrument to assess swallowing-related quality of life for patients with parathyroid disease before and after parathyroid surgery.

Resveratrol induces Notch2-mediated apoptosis and suppression of neuroendocrine markers in medullary thyroid cancer.

BACKGROUND: Currently, complete surgical resection is the only curative option for medullary thyroid cancer (MTC). Previous work has shown the Notch pathway is a potent tumor suppressor in MTC and that resveratrol activates the Notch pathway in carcinoid cancer, a related neuroedocrine malignancy. In this study, we hypothesized that the effects observed on carcinoid cells could be extended to MTC. METHODS: MTC cells treated with varying doses of resveratrol were assayed for viability by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Western blot analysis for achaete-scute complex-like 1 (ASCL1), chromogranin A (CgA), full-length and cleaved caspase 3, and poly-ADP ribose polymerase (PARP) was performed. Quantitative real-time polymerase chain reaction (qPCR) was used to measure relative mRNA expression. RESULTS: Treatment with resveratrol resulted in growth suppression and an increase in the cleavage of caspase-3 and PARP. A dose-dependent inhibition of ASCL1, a neuroedocrine transcription factor, was observed at the protein and mRNA levels. Protein levels of CgA, a marker of hormone secretion, were also reduced after treatment with resveratrol. A dose-dependent induction of Notch2 mRNA was observed by qPCR. CONCLUSIONS: Resveratrol suppresses in vitro growth, likely through apoptosis, as demonstrated by cleavage of caspase-3 and PARP. Furthermore, resveratrol decreased neuroedocrine markers ASCL1 and chromogranin A. Induction of Notch2 mRNA suggests that this pathway may be central in the anti-MTC effects observed.

The necessity and reliability of intraoperative parathyroid hormone (PTH) testing in patients with mild hyperparathyroidism and PTH levels in the normal range.

BACKGROUND: Intraoperative parathyroid hormone (IoPTH) testing is useful in the management of hyperparathyroidism. The successful removal of hypersecreting parathyroids is indicated by a decrease in PTH levels >50% within 15 min. A subset of patients with mild hyperparathyroidism will actually have starting PTH levels in the normal range. We sought to determine if IoPTH testing is necessary in these patients and if the 50% rule delineating surgical cure is reliable. METHODS: A retrospective review was performed on all patients who underwent parathyroidectomy for hyperparathyroidism at a single institution from 3/2001 to 8/2008. RESULTS: Of the 1,001 patients, 142 (14%) had mild hyperparathyroidism and normal baseline PTH levels (<65 pg/ml). Their mean PTH was 59 ± 1 pg/ml. During surgery, 105 (74%) had a >50% decline in PTH levels after resection of hyperfunctioning parathyroid glands, and their operations were terminated. In contrast, 37 (26%) patients did not have a >50% decline in PTH levels leading to further surgical exploration. In these 37 patients, the PTH levels fell by >50% after the removal of the additional glands in 25 patients (17.6%) and dropped after 20 min in 7 patients (4.9%). In 5 patients (3.5%) the IoPTH did not drop. Of the 142 total patients, 91 had single adenomas and 51 patients had multi-gland disease. All patients (100%) were cured (normal serum calcium after 6 months). CONCLUSIONS: Intraoperative PTH testing plays an important role in the operative management in 14% of patients with mild hyperparathyroidism. Importantly, a 50% decline in IoPTH level within 15 min of parathyroidectomy is 96.5% reliable in predicting cure in these patients with PTH starting in the normal range.

Clinical efficacy of fine-needle aspiration biopsy of thyroid nodules in males.

BACKGROUND: It has recently been suggested that the use of fine-needle aspiration (FNA) biopsy of thyroid nodules in male patients is associated with an unacceptably high false-negative rate in the detection of thyroid malignancy. We hypothesize that FNA biopsy is an accurate preoperative tool for detecting thyroid cancer in men, and that false negative rates are significantly lower than recently reported. MATERIALS AND METHODS: A retrospective database analysis was performed on all male patients who underwent thyroid surgery from May 1994 through January 2007 at a single institution. The results of preoperative FNA biopsies were compared with final surgical pathologic results. FNA biopsy results were reported as benign, malignant, inconclusive (i.e., follicular neoplasm), or nondiagnostic; final surgical pathology was reported as benign or malignant. RESULTS: Of 1205 patients who underwent thyroidectomy, 273 (23%) were male. Preoperative FNA biopsy results were obtained in 60% of these male patients and were read as benign in 45/165 (27%) patients, malignant in 47/165 (28%) patients, inconclusive in 66/165 (40%) patients, and nondiagnostic in 7/165 (4%) patients. In male patients with cytology reported as benign, 3/45 (6.7%) FNAs were determined to be malignant on final pathology. CONCLUSIONS: Our study determined that FNA biopsy of thyroid nodules in male patients has an acceptably low false-negative rate of 6.7% and is, therefore, an accurate and useful diagnostic tool. We recommend preoperative FNA biopsy for all male patients presenting with thyroid nodules as a standard of practice.

MG-132 inhibits carcinoid growth and alters the neuroendocrine phenotype.

BACKGROUND: Carcinoid cancers are the most common neuroendocrine (NE) tumors, and limited treatment options exist. The inhibition of glycogen synthase kinase-3beta (GSK-3beta) has been shown to be a potential therapeutic target for the treatment of carcinoid disease. In this study, we investigate the ability of MG-132, a proteasome inhibitor, to inhibit carcinoid growth, the neuroendocrine phenotype, and its association with GSK-3beta. MATERIALS AND METHODS: Human pulmonary (NCI-H727) and gastrointestinal (BON) carcinoid cells were treated with MG-132 (0-4microM). Cellular growth was measured by the 3-[4,5-dimethylthiazole-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Levels of total and phosphorylated GSK-3beta and the NE markers chromogranin A (CgA), Achaete-Scute complex-like 1 (ASCL1), as well as the apoptotic markers poly (ADP-ribose), polymerase (PARP), and cleaved caspase-3 were determined by Western blot. RESULTS: Treating carcinoid cells with MG-132 resulted in growth inhibition, a dose-dependent inhibition of CgA and ASCL1, as well as an increase in the levels of cleaved PARP and cleaved caspase-3. Additionally, an increase in the level of phosphorylated GSK-3beta was observed. CONCLUSION: MG-132 inhibits cellular growth and the neuroendocrine phenotype. This proteasome inhibitor warrants further preclinical investigation as a possible therapeutic strategy for intractable carcinoid disease.

ACTH-producing carcinoma of the pituitary with refractory Cushing's Disease and hepatic metastases: a case report and review of the literature.

BACKGROUND: Pituitary carcinomas are rare neuroendocrine tumors affecting the adenohypophysis. The hallmark of these lesions is the demonstration of distant metastatic spread. To date, few well-documented cases have been reported in the literature. CASE PRESENTATION: Here, we report the case of a fatal pituitary carcinoma evolving within two years from an adrenocorticotrophic hormone (ACTH)-secreting macroadenoma and review the global literature regarding this rare neuroendocrine tumor. CONCLUSION: Pituitary carcinomas are extremely rare neoplasms, representing only 0.1% to 0.2% of all pituitary tumors. To date, little is understood about the molecular basis of malignant transformation. The latency period between initial presentation of a pituitary adenoma and the development of distal metastases marking carcinoma is extremely variable, and some patients may live well over 10 years with pituitary carcinoma.

Carcinoid tumors.

Carcinoid tumors are rare, slow-growing neuroendocrine tumors arising from the enterochromaffin cells disseminated throughout the gastrointestinal and bronchopulmonary systems. Though they have been traditionally classified based on embryologic site of origin, morphologic pattern, and silver affinity, newer classification systems have been developed to emphasize the considerable clinical and histopathologic variability of carcinoid tumors found within each embryologic site of origin. These neoplasms pose a diagnostic challenge because they are often innocuous at the time of presentation, emphasizing the need for a multidisciplinary diagnostic approach using biochemical analysis, standard cross-sectional imaging, and newer advances in nuclear medicine. Similarly, treatment of both primary and disseminated carcinoid disease reflects the need for a multidisciplinary approach, with surgery remaining the only curative modality. The prognosis for patients with these tumors is generally favorable; however, it can be quite variable and is related to the location of the primary tumor, extent of metastatic disease at initial presentation, and time of diagnosis.

Novel targets for the treatment and palliation of gastrointestinal neuroendocrine tumors.

Gastrointestinal (GI) neuroendocrine tumors (NETs), for example, carcinoids, are rare neoplasms characterized by the production of bioactive markers, such as 5-HT and chromogranin A. With the exception of surgery, there are limited curative and palliative treatments available for this type of tumor. Therefore, there is a great need to develop new pharmacological strategies to reduce tumor burden and control symptoms in patients with metastatic carcinoid tumors and the carcinoid syndrome. In this review, several pathways thought to be involved in GI NET carcinogenesis are discussed, and novel approaches that are currently in development to target these pathways are highlighted.

What is the effect of stoma construction on surgical site infection after colorectal surgery?

INTRODUCTION: The aim of our study was to evaluate the effect of stoma creation on deep and superficial surgical site infections after an index colorectal surgical procedure. METHODS: We designed a retrospective cohort study from the National Surgical Quality Improvement Program. We evaluated all patients who underwent colorectal surgery procedures from January 2005 to December 2009 with or without creation of a stoma and sought to identify the effect of stoma creation on deep and superficial surgical site infections. RESULTS: A total of 79,775 patients underwent colorectal procedures (laparoscopic 30.7%, open 69.3%), while 8,113 patients developed a surgical site infection (10.2%). The univariate analysis revealed that surgical site infections were much more common in patients with a stoma compared to those with no stoma (11.8% vs. 9.5%, p < 0.0001). On multivariate analysis, stoma construction during the index colorectal procedure (OR 1.3, CI 1.2 to 1.4), ASA class ≥2, smoking, and abnormal body mass index were associated with surgical site infection. CONCLUSIONS: The construction of a stoma with colorectal procedures is associated with a higher risk of surgical site infection. Although the stoma effect on surgical site infection is attenuated with laparoscopic techniques, the association remained statistically significant.

Hesperetin, a potential therapy for carcinoid cancer.

BACKGROUND: The investigators' laboratory has demonstrated that the Notch1 signaling pathway acts as a tumor suppressor in carcinoid tumors. The aim of this study was to examine hesperetin, a flavonoid, as a potential Notch1 activator and carcinoid tumor suppressor. METHODS: A high-throughput drug screen revealed hesperetin as a Notch1 activator. Human gastrointestinal carcinoid (BON) cell growth after hesperetin treatment was assessed with a 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay. Western blots were used to measure neuroendocrine tumor markers, human achaete-scute complex-like 1, and chromogranin A. Notch1 expression was measured using western blot analysis and real-time polymerase chain reaction. RESULTS: Hesperetin induced cell death in a dose-dependent manner and reduced achaete-scute complex-like 1 and chromogranin A expression, with a concomitant rise in Notch1 levels. It also induced Notch1 messenger ribonucleic acid, indicating regulation at the transcriptional level. CONCLUSION: Hesperetin induces Notch1 expression in carcinoid cells, subsequently suppressing tumor cell proliferation and bioactive hormone production. This provides evidence for further study into hesperetin as a potential treatment for carcinoid cancer.

Identification and validation of Notch pathway activating compounds through a novel high-throughput screening method.

BACKGROUND: Carcinoids are neuroendocrine (NE) tumors with limited treatment options. Notch activation has been shown to suppress growth and hormone production in carcinoid cells. METHODS: The purpose of this study was to provide a process for identifying Notch activating compounds via high-throughput screening (HTS) and to validate the effects of the strongest hit from the 7264 compounds analyzed: resveratrol (RESV). RESULTS: Treatment of carcinoid cells with RESV resulted in up-regulation of the Notch signaling pathway as measured by suppression of its downstream target achaete-scute complex-like 1. Luciferase reporter assays incorporating the centromere-binding factor 1 binding site also confirmed the functional activity of RESV-induced Notch. Because activation of the Notch pathway has been shown to suppress carcinoid proliferation, RESV treatment of carcinoid cells led to a dose-dependent inhibition of cellular growth. Immunoblotting revealed phosphorylation of cdc2 (Tyr15) and up-regulation of p21Cip1/Waf, markers of cell cycle arrest, with RESV treatment. Flow cytometry confirmed the mechanism of RESV-induced growth inhibition is S phase cell cycle arrest. Furthermore, because Notch has been shown to inhibit bioactive hormone production from NE tumors, RESV also suppressed expression of the NE peptides/hormones chromogranin A and serotonin. RNA interference assays demonstrated that the hormone suppressing capacity of RESV was due to up-regulation of the Notch2 isoform. CONCLUSIONS: HTS can be used to identify novel Notch activating compounds, which may have the potential to suppress carcinoid tumor growth and the associated endocrinopathies. Cancer 2011. © 2010 American Cancer Society.

Identification of a novel Raf-1 pathway activator that inhibits gastrointestinal carcinoid cell growth.

Carcinoids are neuroendocrine tumors (NET) that secrete hormones, including serotonin, resulting in the malignant carcinoid syndrome. In addition to the significant morbidity associated with the syndrome, carcinoids are frequently metastatic at diagnosis, and untreated mortality at 5 years exceeds 70%. Surgery is the only curative option, and the need for other therapies is clear. We have previously shown that activation of Raf-1 inhibits carcinoid cell proliferation. We investigated the ability of leflunomide (LFN), a Food and Drug Administration-approved medication for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide (TFN) as a potential anti-NET treatment. LFN and TFN inhibit the in vitro proliferation of gastrointestinal carcinoid cells and induce G(2)-M phase arrest. Daily oral gavage of nude mice with subcutaneous xenografted carcinoid tumors confirms that LFN can inhibit NET growth in vivo. Treatment with TFN suppresses the cellular levels of serotonin and chromogranin A, a glycopeptide co-secreted with bioactive hormones. Additionally, TFN reduces the level of achaete-scute complex-like 1 (ASCL1), a NET marker correlated with survival. These effects are associated with the activation of the Raf-1/mitiogen-activated protein kinase kinase/extracellular signal-regulated kinase-1/2 pathway, and blockade of mitiogen-activated protein kinase kinase signaling reversed the effects of TFN on markers of the cell cycle and ASCL1 expression. In summary, LFN and TFN inhibit carcinoid cell proliferation in vitro and in vivo and alter the expression of NET markers. This compound thus represents an attractive target for further clinical investigation.

Nonoperative management of primary hyperparathyroidism: the exception rather than the rule.

The spectrum of classical primary hyperparathyroidism (pHPT) has expanded from a disabling disease to a largely asymptomatic one, leading to considerable uncertainty regarding which patients with pHPT will truly benefit from operative therapy. In the hands of an experienced endocrine surgeon, parathyroidectomy (PTx) is associated with a greater than 95% cure rate and long-term complication rates of less than 5%. We believe that all patients with pHPT should be referred to an experienced endocrine surgeon for consideration of PTx. Furthermore, our preference is to offer surgical intervention to all patients with pHPT who do not have prohibitive medical comorbidities. The purpose of this article is to outline the anticipated benefits of PTx in patients with nonclassical symptoms of pHPT with regard to improvement of the present condition, prevention of future complications or both.

Medullary thyroid carcinoma: targeted therapies and future directions.

Medullary thyroid cancer (MTC) is a rare neuroendocrine neoplasm that accounts for approximately 5% of all thyroid malignancies. The natural history of MTC is characterized by early lymph node and distant metastases, making complete surgical cure often impossible. Conventional chemotherapy and external beam radiation have been largely ineffective in altering the natural history of MTC. Therefore, there is a great need to develop novel therapeutic strategies to affect symptom control and reduce tumor burden in patients with widely disseminated disease. Here, we review several pathways which have been shown to be vital in MTC tumorigenesis and focus on the pathways of interest for which targeted drug therapies are currently being developed.

Accuracy of fine-needle aspiration biopsy for predicting neoplasm or carcinoma in thyroid nodules 4 cm or larger.

HYPOTHESIS: All thyroid nodules 4 cm or larger should be surgically removed regardless of fine-needle aspiration biopsy (FNAB) results because of an unacceptably high rate of false-negative preoperative biopsy results in these large nodules. DESIGN: Retrospective cohort study. SETTING: Single-institution, tertiary academic referral center. PATIENTS: A retrospective analysis was performed on all patients who underwent surgery for a thyroid nodule 4 cm or larger from May 1, 1994, through January 31, 2007. MAIN OUTCOME MEASURES: Preoperative FNAB results were correlated with final surgical pathologic results. The FNAB results were reported as nondiagnostic, benign, inconclusive (follicular neoplasm), or malignant, whereas the final surgical pathologic data were reported as benign or malignant. RESULTS: Of 155 patients who underwent a thyroidectomy for a nodule 4 cm or larger, 21 patients (13.5%) had a clinically significant thyroid carcinoma within the nodule on final pathologic analysis. Preoperative cytologic testing of the mass was performed on 97 patients, and the results read as benign for 52, inconclusive for 23, nondiagnostic for 11, and malignant for 11. In lesions 4 cm or larger, 26 of 52 FNAB results reported as benign (50.0%) turned out to be either neoplastic (22) or malignant (4) on final pathologic analysis. Among patients with nondiagnostic FNAB results, the risk of malignant neoplasms was 27.3%. CONCLUSIONS: In patients with thyroid nodules 4 cm or larger, the FNAB results are highly inaccurate, misclassifying half of all patients with reportedly benign lesions. Furthermore, those patients with a nondiagnostic FNAB result display a high risk of differentiated thyroid carcinoma. Therefore, we recommend that diagnostic lobectomy be strongly considered in patients with thyroid nodules 4 cm or larger regardless of FNAB cytologic test results.

Tautomycin suppresses growth and neuroendocrine hormone markers in carcinoid cells through activation of the Raf-1 pathway.

BACKGROUND: Carcinoids are neuroendocrine (NE) tumors with limited treatment options. Raf-1 pathway activation has been shown to suppress hormone production in carcinoid cells. We investigated a novel treatment for carcinoid cell growth based on pharmacologic Raf-1 activation using the compound tautomycin (TTY). METHODS: Human carcinoid cells were treated with TTY for 48 hours. Western blot analysis was used to demonstrate Raf-1 pathway activation by phosphorylation of ERK1/2 and to determine the effect on NE tumor markers. Cellular growth was measured by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. RESULTS: Treatment with TTY resulted in dose-dependent activation of the Raf-1 pathway. Furthermore, a significant decrease in NE tumor markers was seen. Importantly, TTY inhibited carcinoid cellular growth and induced the cell-cycle inhibitors p21 and p27. CONCLUSION: TTY activates the Raf-1 pathway, limits carcinoid cell growth, and suppresses NE marker production in vitro. This new compound warrants further investigation in animal models of carcinoid cancer.

Multi-targeted approach in the treatment of thyroid cancer.

While accounting for only 1% of solid organ malignancies (9% in women), thyroid carcinoma is the most common malignancy of the endocrine system. Although most patients have a favorable prognosis, over 1,500 people will die from thyroid carcinoma each year. The spectrum of disease types range from papillary thyroid cancer, which is a well-differentiated indolent tumor, to anaplastic carcinoma, a poorly differentiated fulminant cancer. With advances in diagnostic methods, surgical techniques, and clinical care of patients with thyroid carcinoma, the current management of thyroid cancer demands a multidisciplinary approach. The majority of patients with well-differentiated thyroid carcinoma of follicular cell origin are cured with adequate surgical management; however, some thyroid malignancies such as medullary thyroid carcinoma (MTC) or poorly differentiated thyroid carcinomas frequently metastasize, precluding patients from a curative resection. As such, novel palliative and therapeutic strategies are needed for this patient population. Here, we explore the current management of thyroid carcinoma, including surgical management of the primary tumor, lymph node disease, and locoregional recurrence. Likewise, we explore the application of current molecular techniques, reviewing nearly two decades of data that have begun to elucidate critical genetic pathways and therapeutic drug targets which may be important in specific thyroid tumor types.