Surgical resection of synchronously metastatic adrenocortical cancer.

INTRODUCTION: Metastatic adrenocortical carcinoma (ACC) is rapidly fatal, with few options for treatment. Patients with metachronous recurrence may benefit from surgical resection. The survival benefit in patients with hematogenous metastasis at initial presentation is unknown. METHODS: A review of all patients undergoing surgery (European Network for the Study of Adrenal Tumors) stage IV ACC between January 2000 and December 2012 from two referral centers was performed. Kaplan-Meier estimates were analyzed for disease-free and overall survival (OS). RESULTS: We identified 27 patients undergoing surgery for stage IV ACC. Metastases were present in the lung (19), liver (11), and brain (1). A complete resection (R0) was achieved in 11 patients. The median OS was improved in patients undergoing R0 versus R2 resection (860 vs. 390 days; p = 0.02). The 1- and 2-year OS was also improved in patients undergoing R0 versus R2 resection (69.9 %, 46.9 % vs. 53.0 %, 22.1 %; p = 0.02). Patients undergoing neoadjuvant therapy (eight patients) had a trend towards improved survival at 1, 2, and 5 years versus no neoadjuvant therapy (18 patients) [83.3 %, 62.5 %, 41.7 % vs. 56.8 %, 26.6 %, 8.9 %; p = 0.1]. Adjuvant therapy was associated with improved recurrence-free survival at 6 months and 1 year (67 %, 33 % vs. 40 %, 20 %; p = 0.04) but not improved OS (p = 0.63). Sex (p = 0.13), age (p = 0.95), and location of metastasis (lung, p = 0.51; liver, p = 0.67) did not correlate with OS after operative intervention. Symptoms of hormonal excess improved in 86 % of patients. CONCLUSION: Operative intervention, especially when an R0 resection can be achieved, following systemic therapy may improve outcomes, including OS, in select patients with stage IV ACC. Response to neoadjuvant chemotherapy may be of use in defining which patients may benefit from surgical intervention. Adjuvant therapy was associated with decreased recurrence but did not improve OS.

Streamlining variability in hospital charges for standard thyroidectomy: Developing a strategy to decrease waste.

BACKGROUND: We assessed the efficiency, consistency, and appropriateness of perioperative processes for standard (total) thyroidectomy and devised a valuable strategy to decrease variability and waste. METHODS: Our multidisciplinary team evaluated <23-hour stay standard thyroidectomy performed by 3 surgical endocrinologists. We used the nominal group technique, process flowcharts, and root cause analysis to evaluate 6 perioperative processes. Anticipated decreases in costs, charges, and resources from improvements were calculated. RESULTS: Median total charge for standard thyroidectomy was $27,363 (n = 80; $48,727 variation). Perioperative coordination between surgery and anesthesia clinics could eliminate unnecessary testing (potential decrease in charges of $1,505). Nonoperating room time was less in the outpatient operating room (43 vs 52 minutes; P < .001). Consistent scheduling could decrease charges by $585.49 per case. By decreasing 20% of nondisposable instruments on the surgical tray, we could decrease sterile processing costs by $13.30 per case. Modification of postoperative orders could decrease charges by $643 per patient. Overall, this comprehensive analysis identified an anticipated decrease in cost/charge of >$200,000 annually. CONCLUSION: Perioperative process analyses revealed wide variability for a single, presumed uniform procedure. Systematic assessment helped to identify opportunities to improve efficiency, decrease unnecessary waste and procedures/instrument usage, and focus on patient-centered, quality care. This multidisciplinary strategy could substantially decrease costs/charges for common operative procedures.

A single parathyroid hormone level obtained 4 hours after total thyroidectomy predicts the need for postoperative calcium supplementation.

BACKGROUND: Parathyroid hormone (PTH) levels after total thyroidectomy have been shown to predict the development of symptomatic hypocalcemia and the need for calcium supplementation. This study aimed to determine whether a PTH level drawn 4 hours postoperatively is as effective as a level drawn on postoperative day 1 (POD1) in predicting this need. STUDY DESIGN: This is a single-institution retrospective review of 4-hour and POD1 PTH levels in patients who underwent total thyroidectomy from January 2012 to September 2012. If POD1 PTH was ≥10 pg/mL, patients did not routinely receive supplementation; if PTH was <10 pg/mL, patients received oral calcium with or without calcitriol. RESULTS: Of 77 patients, 20 (26%) had a 4-hour PTH <10 pg/mL; 18 (90%) of these patients had a POD1 PTH <10 pg/mL. No patient with a 4-hour PTH ≥10 pg/mL had a POD1 PTH <10 pg/mL. All 18 patients with POD1 PTH <10 pg/mL received calcium supplementation. Three additional patients received supplementation due to reported symptoms or surgeon preference. A 4-hour PTH ≥10 pg/mL compared with a POD1 PTH had a similar ability to predict which patients would not need calcium supplementation; sensitivity was 98% vs 98%, specificity was 90% vs 86%, and and negative predictive value was 95% vs 95%. Of 21 patients who received supplementation, 13 (62%) also received calcitriol, including 9 patients (69%) with a 4-hour PTH <6 pg/mL. CONCLUSIONS: A single PTH level obtained 4 hours after total thyroidectomy that is ≥10 pg/mL accurately identifies patients who do not need calcium supplementation or additional monitoring of serum calcium levels. Same-day discharge, if deemed safe, can be accomplished with or without calcium supplementation based on the 4-hour PTH level. Greater consideration should be given to calcitriol supplementation in patients with a 4-hour PTH <6 pg/mL.

Predicting the need for calcium and calcitriol supplementation after total thyroidectomy: results of a prospective, randomized study.

BACKGROUND: The optimal protocol for the detection and treatment of postthyroidectomy hypoparathyroidism is unknown. We sought to identify and treat patients at risk for symptomatic hypocalcemia on the basis of a single parathyroid hormone (PTH) obtained the morning after surgery (POD1). METHODS: We performed a prospective, randomized study of total thyroidectomy patients who had POD1 calcium and PTH (pg/mL) levels. Randomization was determined by POD1 PTH: if ≥ 10, patients received no supplementation unless symptomatic; if <10, patients were randomized to calcium, calcium and calcitriol, or no supplementation. RESULTS: Of 143 patients, 112 (78%) had a POD1 PTH ≥ 10. Hypocalcemic symptoms were transiently reported in 11 (10%) and managed with outpatient calcium. Of 31 patients with PTH <10, 15 (48%) developed symptoms, including 5 who required intravenous calcium. On multivariate logistic regression analysis, when we adjusted for postoperative calcium level and performance of central neck dissection, we found that predictors of hypocalcemic symptoms were younger age (odds ratio 1.59, 95% confidence interval 1.07-2.32) and a PTH <10 (odds ratio 1.08, 95% confidence interval 1.04-1.12). There were no patient or treatment-related factors that predicted a POD1 PTH <10. CONCLUSION: A single POD1 PTH level <10 can accurately identify those patients at risk for clinically significant hypocalcemia. All total thyroidectomy patients with a postoperative PTH ≥ 10 can be safely discharged without supplementation. Given the small number of patients with PTH <10, it is unclear whether both calcium and calcitriol are needed for these higher-risk patients.

The value of postoperative parathyroid hormone levels in predicting the need for long-term vitamin D supplementation after total thyroidectomy.

BACKGROUND: Few studies have examined the need for vitamin D supplementation after total thyroidectomy. This study examines the role of postoperative day (POD) 1 serum calcium and parathyroid hormone (PTH) levels in predicting the need for long-term vitamin D supplementation after total thyroidectomy. METHODS: A retrospective, single institutional study of patients who underwent total thyroidectomy between January 2007 and December 2008 was performed. Data collected included extent of surgery, final pathology, postoperative calcium (mg/dl) and PTH (pg/ml) values, and duration of vitamin D supplementation. Patients were divided into 4 groups based on POD1 PTH values: group 1 (<5.0); group 2 (5.0-10); group 3 (10.1-20); and group 4 (>20). RESULTS: Of the 104 patients, 26 were in group 1, 12 in group 2, 18 in group 3, and 48 in group 4, with median PTH values of <2.5, 8.2, 14.1, and 30 pg/ml, respectively. All 7 (7%) patients who required vitamin D supplementation >1 month were in group 1. The positive predictive value of POD1 PTH <5.0 in predicting supplementation >1 month was 27% (sensitivity 100%, specificity 80%). Seventy-eight patients had a POD1 PTH level ≥5, and none required vitamin D supplementation >1 month (100% negative predictive value). The positive predictive value of various POD1 calcium thresholds (<7.5, <8.0, and <8.5 mg/dl) was 17, 14, and 15%, respectively. CONCLUSIONS: Postoperative PTH levels better predict long-term hypocalcemia requiring vitamin D supplementation than serum calcium levels. A PTH level ≥5.0 may identify patients who can be safely discharged without routine vitamin D supplementation.

Sodium butyrate activates Notch1 signaling, reduces tumor markers, and induces cell cycle arrest and apoptosis in pheochromocytoma.

BACKGROUND: Pheochromocytoma is a neuroendocrine (NE) tumor of the adrenal medulla for which surgical resection is the only therapy. However, 10-46% of tumors are metastatic or have malignant features, and are often inoperable. Our lab has demonstrated the importance of the Notch1 signaling pathway in NE neoplasia, indicating that this pathway could be a target for emergent treatments in pheochromocytoma. It has recently become clear that histone deacetylase (HDAC) inhibitors influence Notch1 signaling. We hypothesized that the HDAC inhibitor Sodium Butyrate (NaB) might activate Notch1 in pheochromocytoma resulting in altered tumor cell proliferation. METHODS: Pheochromocytoma (PC-12) cells were treated with increasing concentrations of NaB. MTT cellular proliferation assay was used to determine the effect of NaB on PC-12 cell growth. Expression of Notch1, NE markers, and cell cycle proteins was studied using Western analysis. RESULTS: Untreated PC-12 cells lack Notch1 activity. Treatment with NaB led to a dose-dependent induction of Notch1 signaling, reduction of NE markers ASCL1 and CgA, and a significant reduction in cellular proliferation. Levels of expression of cyclin D1, p21, cleaved PARP, and cleaved caspase 3 proteins indicated the presence of cell cycle arrest and apoptosis following NaB treatment. CONCLUSION: NaB activated Notch1 signaling, inhibited cellular proliferation, reduced NE markers, and induced cell cycle arrest and apoptosis in pheochromocytoma cells. This data indicates that activation of Notch1 signaling is a promising potential therapy or palliative measure for pheochromocytoma that warrants further investigation.

Utility of intraoperative PTH for primary hyperparathyroidism due to multigland disease.

BACKGROUND: Surgical resection is the only curative therapy for patients with primary hyperparathyroidism (1HPT). Although cure rates of parathyroidectomy are generally high, failure is most often due to unrecognized multigland disease (MGD), which compromises 15-20% of patients with 1HPT. The use of intraoperative PTH (ioPTH) monitoring is well established for single-gland disease. Controversy remains over the utility of ioPTH in MGD, with concern for false-positive results leading to prematurely concluding the operation and leaving behind abnormal parathyroid tissue, risking future recurrence. The aim of this study was to determine the utility of ioPTH monitoring for MGD. METHODS: Between November 2000 and March 2008, data were prospectively collected on 755 patients with 1HPT who underwent parathyroidectomy. PTH samples were collected pre-incision, and then at 5, 10, and 15 min after excision of suspected abnormal parathyroid gland(s). Surgical cure was defined as a drop of greater than 50% in PTH level. Patients were clinically cured if they became normocalcemic postoperatively and remained so for 6 months. The data were analyzed to determine how accurately ioPTH predicted success or failure of parathyroidectomy. RESULTS: Of the 755 patients, 163 (21.5%) were found to have MGD on pathology. Intraoperative PTH monitoring was used in 161 of these cases. In 146/161 cases (90.7%), the ioPTH level fell by at least 50% after removal of all suspected abnormal glands. All of these patients (100%) remained normocalcemic postoperatively. In 15/161 cases (9.3%), the PTH level did not fall by >50%. For 11/15 cases (73%), patients remained hypercalcemic postoperatively or had recurrence. However, in the remaining four cases, the patients became normocalcemic postoperatively despite failure of the PTH to fall by >50%. In each of these patients, PTH levels fell by 40-50%. CONCLUSIONS: ioPTH monitoring accurately predicted success or failure of parathyroidectomy in 97.5% (157/161) of patients with MGD. A fall of ioPTH by >50% can be used as a highly accurate predictor of cure in patients with MGD. Therefore, ioPTH monitoring is a very useful tool in patients with 1HPT and MGD.