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Background: Reoperation in the neck can be challenging and is associated with increased complication rates and operative times. Here we analyze our methylene blue dye injection method to localize reoperative neck pathology in patients with thyroid cancer and lymph node metastases. Study Design: We retrospectively reviewed the records of all patients at a single university tertiary care center who had reoperative neck surgery for recurrent thyroid cancer between 2004 and 2009, and who also underwent intraoperative methylene blue dye injection. Outcomes measured were efficacy and safety of the injection technique as well as complication rates. Results: Fifty-three operations were performed in 44 patients (average age, 51.2 years [range 16 to 83 years]). Ninety-one percent (48 of 53) of the operations resulted in successful resection of recurrent disease. Of these, 96% (46 of 48) were guided successfully by blue dye injection. Thyroglobulin became undetectable in 42% (11 of 26) of patients. Neck pathology included the following thyroid cancers: papillary (48 of 53), follicular (2 of 53), medullary (2 of 53), and tall cell variant (1 of 53). Among these patients, there were a total of 26 central and 38 lateral neck dissections. The average number of previous neck dissections was 2 (range 1 to 5). The mean intraoperative ultrasound/injection time was 21.3 min (n = 13). Median operative time was 90 minutes (range 40 to 300 minutes). Complications included 2 permanent vocal cord paralyses, 1 instance of permanent hypocalcemia, and 3 instances of temporary hypocalcemia. There were no complications related to the dye injection. Conclusions: Intraoperative, ultrasound-guided, methylene blue dye injection is a safe and effective technique. It facilitates tumor localization and removal especially in patients requiring reoperative neck surgery. © 2012 American College of Surgeons.

Most patients with primary hyperparathyroidism can have a minimally invasive parathyroidectomy based on localization studies showing single-gland disease. In patients with a history of head and neck irradiation, due to the increased risk of multigland disease and risk of concurrent thyroid cancer, minimally invasive parathyroidectomy is considered by some to be a contraindication. We postulated that previous history of head and neck irradiation should not be a contraindication for minimally invasive parathyroidectomy and tested this hypothesis in a prospective cohort of patients undergoing parathyroidectomy for primary hyperparathyroidism.We performed a retrospective analysis of a prospective database of 491 consecutive parathyroidectomies performed between May 2005 and May 2007 at a tertiary referral medical center.Fifty-two (12.6%) patients had a history of head and neck irradiation and 360 (87.4%) had no exposure to radiation. The 2 groups had no significant difference in terms of gender or ethnicity. The radiation group was older, with an average age of 65.1 years versus 58.1 years (p0.0009). There was no significant difference in concurrent benign thyroid neoplasm, thyroid cancer, and type of parathyroid disease (single vs multigland) in the 2 groups. There was no significant difference in the operative approach used between the 2 groups (focused vs unilateral or bilateral).Head and neck irradiation should not be a contraindication for minimally invasive parathyroidectomy in patients with primary hyperparathyroidism in the setting of preoperative localization studies showing single-gland disease and no concurrent thyroid neoplasm. Furthermore, history of head and neck irradiation is associated with a later age of presentation for parathyroidectomy.

Background Although cervical endocrine operations are classified as clean cases, and prophylactic antibiotics (pABX) are generally not indicated, practice patterns vary. Study Design We distributed an Internet-based survey to all members of the American and International Associations for Endocrine Surgeons. As a second component of our study, University of California San Francisco hospital records were queried for all readmissions or reoperations within 30 days after thyroidectomy, parathyroidectomy, or neck dissections between January 1, 1999 and December 30, 2007. Results Of the 275 endocrine surgeons who responded, 62% "almost never" used pABX and 26.2% administered pABX "almost always." Surgeons' annual caseload (p = 0.21), their experience with past patients who had minor (p = 0.33) or severe (p = 0.83) surgical site infections (SSI) or adverse reactions to antibiotics (p = 0.78) were not associated with their likelihood to prescribe pABX. In the previous 3 years, most surgeons reported treating patients with minor SSIs, and 30% of surgeons treated more than 1 severe SSI. Surgeons who worked in community hospitals were more likely to give pABX than were surgeons in affiliated or university hospitals (49.6% vs 31.8% and 24.5%, respectively (p = 0.04). Unlike European (8.8%) or American surgeons (27.9%), surgeons in Asia were most likely to give pABX "almost always" (58.3%, p=0.0001). Two-thirds of surgeons would not want antibiotics if they, themselves, needed a cervical operation. Five of the 4,541 patients (0.11%) who underwent cervical operations were readmitted for infectious complications. Conclusions Infectious complications after endocrine cervical operations are rare and the use of preoperative antibiotics varies widely. Prescribing behavior appears dogmatic in that 90% of surgeons give preoperative antibiotics almost always or almost never.

To improve our understanding of the molecular mechanisms involved in malignant pheochromocytoma by examining differences in the gene expression profile between benign and malignant tumors.The molecular events involved in the malignant transformation of pheochromocytoma are poorly understood. There are also no reliable and uniformly accepted histopathologic criteria to distinguish benign from malignant pheochromocytoma.We performed genome-wide expression profiling of 58 pheochromocytomas (29 benign and sporadic, 16 benign and hereditary, 13 malignant) with technical and biologic replication.Unsupervised cluster analysis showed 3 main clusters of tumors that did not have complete concordance with the clinical and pathologic groupings of pheochromocytomas. Supervised cluster analysis showed almost completely separate clustering between benign and malignant tumors. The differentially expressed genes with known function belonged to 8 biologic process categories; signal transduction, transcription, protein transport, protein synthesis, smooth muscle contraction, ion transport, chemotaxis, and electron transport. Gene set enrichment analysis revealed significant correlation between the microarray profiles of malignant pheochromocytomas and several known molecular pathways associated with carcinogenesis and dedifferentiation. Ten differentially expressed genes had high diagnostic accuracy, and 5 of these genes (CFC1, FAM62B, HOMER1, LRRN3, TBX3, ADAMTS) in combination had an area under the receiver operating characteristic (ROC) curve of 0.96 for distinguishing benign versus malignant tumors.Differentially expressed genes between benign and malignant pheochromocytomas distinguish between these tumors with high diagnostic accuracy. Our findings provide new insight into the genes and molecular pathways that may be involved in malignant pheochromocytomas.

Background Pheochromocytomas vary in presentation, tumor size, and in catecholamine production. Whether pheochromocytoma size correlates with hormone levels, clinical presentation, and perioperative complications is not known. The goal of this study was to determine if tumor size and hormone level correlate according to the clinical presentation at diagnosis. Study Design We retrospectively analyzed all patients who underwent an adrenalectomy with a diagnosis of a pheochromocytoma from February 1996 to October 2008. We grouped patients according to their clinical presentation at diagnosis (routine biochemical screening, incidentaloma, classic symptoms, pheochromocytoma crisis) and obtained preoperative radiographic tumor size and catecholamine hormone levels. ANOVA was used for the group effects and the Kruskal–Wallis rank test was used for pairwise comparison between groups with the Sidak/Bonferroni method for multiplicity adjustment according to age, tumor size, and hormone level. The Pearson correlation coefficient was then calculated to determine if hormone level correlated with tumor size. Results Eighty-one of 107 patients had data available for complete analysis. The average age at diagnosis for all patients was 47.1 years, and the average tumor size was 4.9 cm. The average highest hormone ratio among all patients was 27.4. Tumor size and hormone ratio levels differed among all groups (p ≤ 0.03). A direct correlation (p = 0.014) was apparent between tumor size and hormone level. Complication rates also differed among the four groups of patients (p ≤ 0.02). Conclusions Our study showed that tumor size directly correlates with hormone level. Smaller tumors tend to secrete lower levels of catecholamines, but larger tumors have a wider variation in secretory potential. Larger tumors, however, produced the highest hormone ratios.

OBJECTIVE: To provide a review on current knowledge about the pathogenesis, epidemiology, and clinical complications of persistent hyperparathyroidism after kidney transplantation (3HPT) and to discuss the surgical approaches. BACKGROUND: 3HPT usually regresses within the first months after transplantation. Parathyroidectomy for 3HPT is therefore not usually needed. Consequently, few studies have been published regarding the best medical management for 3HPT and indications for parathyroidectomy. METHODS: Medical literature databases were searched for studies on the surgical treatment of 3HPT published in English. RESULTS: Forty-one studies were identified and included in this review. CONCLUSIONS: 3HPT most commonly occurs in patients who have severe secondary hyperparathyroidism at the time of transplantation. Indications for parathyroidectomy in patients with 3HPT include persistent severe hypercalcemia, defined as a serum calcium level greater than 11.5 mg/dl, unexplained renal function deterioration, or progressive bone mineral density loss. Published studies suggest that the best surgical approach for patients with 3HPT is subtotal parathyroidectomy or total parathyroidectomy with autotransplantation. 3HPT poses important health risks, particularly concerning bone density and the cardiovascular system. Because spontaneous improvement of parathyroid function is uncommon after 3 months of transplantation, waiting for more than 6 months before parathyroidectomy should be discouraged.

Objective: To examine the prevalence of BRAF mutation among thyroid cancer histologic subtypes and determine the association of BRAF mutation with indicators of poor prognosis for papillary thyroid cancer and patient outcome. Background Data: The appropriate extent of surgical treatment, adjuvant therapy and follow-up monitoring for thyroid cancer remains controversial. Advances in the molecular biology of thyroid cancer have helped to identify candidate markers of disease aggressiveness. A commonly found genetic alternation is a point mutation in the BRAF oncogene (BRAF V600E), which is primarily found in papillary thyroid cancer and is associated with more aggressive disease. Methods: BRAF V600E mutation status was determined in 347 tumor samples from 314 patients with thyroid cancer (245 with conventional papillary thyroid cancer, 73 with follicular thyroid cancer, and 29 with the follicular variant of papillary thyroid cancer). Univariate and multivariate analyses were performed to determine the association of BRAF V600E with clinicopathologic factors and patient outcome. Results: The prevalence of BRAF V600E mutation was higher in conventional papillary thyroid cancer (51.0%) than in follicular variant of papillary thyroid cancer (24.1%) and follicular thyroid cancer (1.4%) (P < 0.0001). In patients with conventional papillary thyroid cancer, BRAF V600E mutation was associated with older age (P = 0.0381), lymph node metastasis (P = 0.0323), distant metastasis (P = 0.045), higher TNM stage (I and II vs. III and IV, P = 0.0389), and recurrent and persistent disease (P = 0.009) with a median follow-up time of 6.0 years. Multivariate analysis showed that BRAF V600E mutation [OR (95% CI) = 4.2 (1.2-14.6)] and lymph node metastasis [OR (95% CI) = 7.75 (2.1-28.5)] were independently associated with recurrent and persistent disease in patients with conventional papillary thyroid cancer. Conclusions: BRAF V600E mutation is primarily present in conventional papillary thyroid cancer. It is associated with an aggressive tumor phenotype and higher risk of recurrent and persistent disease in patients with conventional papillary thyroid cancer. Testing for this mutation may be useful for selecting initial therapy and for follow-up monitoring.

There have been significant improvements in the management of medullary thyroid cancer (MTC), and consensus treatment guidelines have been established by numerous international and national societies. It is unclear if the advances in diagnosis and treatment of MTC have led to earlier diagnosis and more complete initial treatment of patients with MTC.Patients with MTC (n=1,070) were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database from 12 population-based cancer registries between 1973 and 2000. Four equal-time quartiles (group I=1973 to 1979, group II=1980 to 1986, group III=1987 to 1993, and group IV=1994 to 2000) were compared for changes in demographics, extent of disease, and treatment.Mean tumor size was significantly larger in 1988 than in 1989 through 2000 (p=0.044), but there was no significant trend toward smaller tumor size. The number of patients having total or near total thyroidectomy increased significantly in the latter two quartiles (p0.001) but not the number of patients having cervical lymph node dissection. Unfortunately, 15% of patients in group IV still had less than total or near total thyroidectomy, and 41% had no cervical lymph node dissection. There were no significant differences in age, gender, rate of lymph node or distant metastasis, SEER stage, TNM stage, and cause-specific mortality among the four time groups and annually.There was no significant trend toward earlier stage of disease at diagnosis and treatment and no significant increase in the survival of patients with MTC during a 28-year period. A high proportion of patients continue to receive less than optimal initial surgical treatment.

Background Minimally invasive parathyroid surgery with intraoperative parathyroid hormone testing has been reported to be as successful as a bilateral operation. This study aimed to determine whether the histologic findings and outcomes differ in patients with primary sporadic hyperparathyroidism treated by a focal or a bilateral parathyroid exploration with intraoperative parathyroid hormone testing. To make the two groups comparable all patients had a solitary parathyroid adenoma identified preoperatively. Study design Eighty unselected patients with primary hyperparathyroidism and a single abnormal parathyroid gland identified preoperatively by sestamibi scanning or ultrasonography were included in this study. All patients had intraoperative parathyroid hormone testing. Results Forty-five patients had standard bilateral neck explorations and 35 patients had focal neck explorations. In the bilateral neck exploration group a single adenoma was found in 38 patients (84%), a double adenoma in 3 patients (7%), hyperplasia in 3 patients (7%), and carcinoma in 1 patient (2%). In contrast, a single adenoma was identified in all patients in the focal neck exploration group. Sestamibi scanning and intraoperative parathyroid hormone assay were accurate in 87% and 84%, respectively, in the bilateral neck exploration group and in 96.9% and 94.3%, respectively, in the focal neck exploration group. All patients were normocalcemic (mean followup 17 months). Conclusions Patients with primary hyperparathyroidism having a bilateral exploration had about a 15% higher rate of multiple parathyroid tumors than did patient having a focal approach. Despite this observation all patients were normocalcemic postoperatively. This suggests that either some histologically abnormal parathyroid glands do not function or there will be recurrences in patients treated by a focused approach. Longterm followup will be necessary to determine whether patients treated by focal neck exploration will develop recurrent primary hyperparathyroidism.

Background: Parathyroid autotransplantation is a well-established method to prevent hypoparathyroidism during parathyroid and thyroid operations. The reported success rate of parathyroid autotransplantation ranges from 75% to 100%. Recurrent hyperparathyroidism may develop after parathyroid autotransplantation, especially after the transplantation of hyperplastic or adenomatous parathyroid tissue. Hyperparathyroidism recurs most frequently after subtotal parathyroidectomy or total parathyroidectomy and autotransplantation, in patients with renal failure and secondary hyperparathyroidism, and in patients with familial primary hyperparathyroidism or MEN I or MEN II syndrome. We report three patients who experienced primary hyperparathyroidism after autotransplantation of normal parathyroid tissue during thyroid operations (two patients) or after a long period of hypoparathyroidism. Study Design: We reviewed our records from 1983 to May 1998 and identified three patients in whom hyperparathyroidism developed after thyroid operations. Results: One patient had a thyroidectomy with left modified radical neck dissection for papillary thyroid cancer, followed by radiodine ablative therapy. Two patients had thyroid operations for benign thyroid disease. One of these patients had a history of radiation exposure for acne, and in the other one secondary hyperparathyroidism arose 6 years after a thyroidectomy for hyperthyroidism. Conclusions: Our study documents that hyperparathyroidism may develop after autotransplantation of histologically normal parathyroid tissue and after a period of hypoparathyroidism after thyroid operations. For this reason, it is important to mark the site of the parathyroid transplantation.

Goiters are estimated to develop in approximately 5% of the population. By definition, for a goiter to be considered mediastinal, at least 50% of the thyroid tissue must be located substernally. Mediastinal goiters can, in turn, be classified as primary or secondary. Primary mediastinal goiters, which represent about 1% of all mediastinal goiters, arise from accessory (ectopic) thyroid parenchyma located in the chest. These goiters are mainly intrathoracic and do not have any connection to thyroid tissue in the neck. Their blood supply originates from intrathoracic vessels. Secondary mediastinal goiters constitute the majority of mediastinal goiters and arise from downward extension of cervical thyroid tissue along the fascial planes of the neck. These goiters derive their blood supply from the superior and inferior thyroid arteries. This migration along the path of least resistance is assisted by negative mediastinal pressure generated by inspiration and swallowing. Most mediastinal goiters can be removed via a cervical incision, but patients with recurrent goiters can require a median sternotomy because of the development of parasitic mediastinal vessels. In this article, we present the case of a patient with a secondary mediastinal goiter who developed bleeding after its removal via a cervical incision, and report on the use of a Foley catheter to control the same.

Primary hyperparathyroidism (HPT) occurs in 0.2% to 0.5% of the population, with approximately 100,000 new cases appearing in the United States each year.1,2 Primary HPT is the most common cause of hypercalcemia in outpatients and second to cancer in the inpatient population. This disease has evolved from one presenting with the classic triad “painful bones, kidney stones, and abdominal groans” to one where the symptoms are subtle and detection commonly occurs because of documented hypercalcemia on routine biochemical testing.3,4 The classic manifestations of primary HPT are best divided into symptoms (what one feels) and associated conditions (what can be measured, such as kidney stones, osteopenia) of the disease (Table 1). Today patients with primary HPT encompass a broad spectrum ranging from “asymptomatic,” with no apparent associated conditions, mild-to-moderate symptoms with no associated conditions, associated conditions but no symptoms, and finally a few with profound symptoms or parathyrotoxicosis.5 TABLE 1. Symptoms and Associated Conditions in Patients With Primary Hyperparathyroidism Surgical excision of abnormal parathyroid tissue is the only definitive cure for primary HPT. Few would disagree that the best management for the patient with obvious symptoms or associated conditions of the disease or profound hypercalcemia (>12 mg/dL) is parathyroidectomy. The debate surrounds the issue of the best management of the “asymptomatic” patients or those with mild symptoms and no associated conditions of primary HPT. To address this issue, in 1990 the National Institutes of Health together with the National Institute of Diabetes and Digestive Kidney Diseases convened a consensus conference on the Diagnosis and Management of Asymptomatic Primary HPT. They concluded that there may be a subset of “asymptomatic” primary HPT patients who can be safely managed without operative intervention, and they defined a set of guidelines for operative intervention in these patients (Table 2). 2 The difficulties with these criteria are 2-fold: first, the definition of “asymptomatic” HPT is not clear, and second, the criteria for surgical intervention are not well-defined. Primarily, the criteria exclude many nonspecific physical and neuropsychological symptoms that appear to be more common in primary HPT and often improve after surgery.6–8 Furthermore, Burney et al9 as well as others,10,11 recently demonstrated in a prospective study that patients with primary HPT have significant functional health status impairment with dramatic improvement postoperatively that is independent of preoperative serum calcium levels. TABLE 2. NIH Criteria for Parathyroidectomy The purpose of this investigation was to describe the frequency of symptoms and associated conditions in patients with primary HPT versus patients with nontoxic surgical thyroid disease and to compare the frequency of preoperative symptoms and conditions related to primary HPT between patients who meet or fail to meet the NIH criteria for parathyroidectomy. In addition, we examined the differences in postoperative symptomatic improvement among patients who meet or fail to meet the NIH criteria.

Introduction: The histone deacetylase (HDAC) inhibitors are a heterogeneous group of compounds that alter the chromatin structure of neoplastic cells, causing cell-cycle arrest, redifferentiation, and apoptosis. TSA and FK228 are structurally different HDAC inhibitors that have been used for the treatment of several cancers in laboratory and clinical trials. The effects of TSA and FK228 on apoptosis have not been fully characterized or quantitated. We studied the effects of TSA and FK228 on apoptosis in a human follicular thyroid cancer cell line (FTC-236). Methods: We treated FTC-236 cells with TSA (25–100 ng/ml) and FK228 (0.1–1 ng/ml). Apoptosis was measured at 24 and 48 hours after treatment using annexin V-FITC labeling and flow cytometry. RNA was extracted at 24 and 48 hours and real-time PCR was performed to measure gene expression levels of bcl-2 and bcl-xl, two pro-survival proteins that function in the regulation of apoptosis. Results: At 48 hours after treatment, 6.4% of TSA-treated FTC-236 cells underwent apoptosis; 25.7% of FK228-treated cells underwent apoptosis in the same time period (p Conclusions: TSA and FK228 have differing effects on apoptosis and pro-survival gene expression in FTC-236 cells. A better understanding of the effects of HDAC inhibitors on apoptosis will allow clinicians to design treatment regimens based on the genetic profiles and tumor behavior of the targeted malignancies.

A 27-year-old white man was admitted in shock with a tender distended abdomen 5 years following significant thoraco-abdominal trauma. Immediately following resuscitation he had an emergency exploratory laparotomy because of his critical condition. At operation 3 liters of old and fresh blood were present intraperitoneally and the spleen was ruptured. The spleen was surrounded by and adherent to the omentum and adjacent viscera. Splenectomy was performed and recovery was uneventful. Histologic examination of the spleen confirmed the 5-year interval between injury and rupture. Delayed splenic rupture accounts for 14% of all splenic injuries and has a high mortality. This case represents the longest reported delay between splenic trauma and delayed rupture.

Twelve elderly patients without Waterhouse-Friderichsen syndrome or adrenal tumor who had spontaneous adrenal hemorrhage one to 33 days after operation are described. Seven of these patients had operations on the gastrointestinal tract, one on the biliary system, two on the genitourinary system and two on the central nervous system. Important factors relating to adrenal hemorrhage included: intra-abdominal sepsis in 5 patients, cancer in 4, pneumonia in 4, coagulation defects in 2, exogenous steroids in 2, and syphilis in one patient. Spontaneous adrenal hemorrhage should be considered in patients whose condition deteriorates rapidly after operation and in whom no other explanation is plausible. Its detection and appropriate therapy can be lifesaving.

Four patients with milk-alkali syndrome (MAS) presented with many of the characteristics of primary hyperparathyroidism including hypercalcemia, low or normal serum phosphorus levels, normal or increased urinary calcium levels, and inappropriately high or elevated serum parathyroid hormone levels. These laboratory findings differ from those classically described in MAS, i.e., hypercalcemia without hypercalciuria and a normal or high plasma phosphate level. Because the serum calcium level failed to return to normal after two weeks of hydration and a low calcium diet, and because of the inability to distinguish this syndrome from primary hyperparathyroidism, two of the four patients underwent neck exploration. Four normal parathyroid glands were histologically proven in each, and at autopsy in a third patient, there was no evidence of parathyroid hyperplasia or adenoma. Hypercalcemia eventually resolved in all patients with a low-calcium diet for as long as six months. Of the several features of MAS, hypercalcemia, alkalosis in the presence of azotemia, a history of increased calcium and alkali intake, and a response to dietary calcium restriction are helpful in differentiating this syndrome from primary hyperparathyroidism. Laboratory tests in patients with MAS may be confusing and the return to normocalcemia in response to a calcium deficient diet may be delayed.

Sixteen consecutive patients with the clinical diagnosis of hyperparathyroidism, nine with and seven without previous surgery, had computed tomography (CT) examinations preoperatively to evaluate the use of CT in localizing parathyroid adenomas. The patients were scanned at 5 mm intervals from the level of the hyoid bone to the lung apex. Scanning of the mediastinum was performed at 10 mm intervals from apex to lung base. Computed tomography correctly identified prospectively the site of the adenoma in 10 of 13 patients (77%), with surgically proven adenomas. In retrospect, all 13 adenomas could be identified. One false positive diagnosis of adenoma was made. Our study suggests that CT may be beneficial in the preoperative localization of parathyroid tumors, particularly in ectopic locations.

A novel method for localization of abnormal parathyroid glands involving color-processing of nuclear scintigrams of the neck after injection of Thallium-201 and Technetium pertechnetate is presented with surgical correlation. Preoperative localization of single parathyroid adenomas was successful in 88% of previously unoperated patients and in 85.7% of those with adenomas not located at previous surgery. Eighty-three per cent of glands with secondary hyperplasia, 66% of glands with primary hyperplasia, and one carcinoma were localized. No abnormal studies were seen in non-hyperparathyroid hypercalcemia, and no false positive studies were seen. Localization appeared related to larger adenomas (300-5000 mg), although one of 60 mg was localized. Color-comparison dual-isotype scintigraphy was useful for localization of parathyroid adenomas and hyperplastic glands and exceeded the reported sensitivity of either ultrasonography or computerized tomography. It deserves wider evaluation in preoperative management of at least hyperparathyroidism of the primary or persistent types.