Dina M. Elaraj

The role of interleukin 1 in growth and metastasis of human cancer xenografts.

BACKGROUND: Interleukin 1 (IL-1) is a pluripotent cytokine that promotes angiogenesis, tumor growth, and metastasis in experimental models; its presence in some human cancers is associated with aggressive tumor biology. The purpose of these studies was to characterize the role of IL-1 in human cancers and determine if inhibition of IL-1 via its receptor antagonist, IL-1Ra, alters tumor growth and metastatic potential. METHODS: IL-1 mRNA or protein levels were determined in clinical tumor samples, cancer cell lines, and xenografts using quantitative reverse transcription-PCR or ELISA. Biological activity of tumor-derived IL-1 protein was shown via induction of permeability across endothelial cell monolayers. The effects of recombinant IL-1Ra on tumor lines in culture (cell proliferation and IL-8 secretion) and in xenograft models (tumor growth, metastatic potential, and intratumoral levels of IL-8 and VEGF) were characterized. The effects of IL-1Ra-mediated regression of xenograft growth on angiogenic proteins (IL-8 and VEGF) were evaluated in an IL-1-producing melanoma (SMEL) xenograft model. RESULTS: IL-1 mRNA was highly expressed in more than half of all tested metastatic human tumor specimens including non-small-cell lung carcinoma, colorectal adenocarcinoma, and melanoma tumor samples. Constitutive IL-1 mRNA expression was identified in several cancer cell lines; tumor supernatant from these cell lines produced a significant increase in endothelial cell monolayer permeability, a hallmark event in early angiogenesis, in an IL-1-dependent manner. Moreover, systemic recombinant IL-1Ra resulted in significant inhibition of xenograft growth and neovessel density of IL-1-producing, but not non-IL-1-producing, tumor cell lines. Subsequent analysis of SMEL, a melanoma cell line with constitutive IL-1 production, showed that neither exogenous IL-1 nor IL-1Ra altered tumor cell proliferation rates in vitro. Gene expression analyses of IL-1Ra-treated SMEL xenografts showed a >3-fold down-regulation of 100 genes compared with control including a marked down-regulation of IL-8 and VEGF. CONCLUSIONS: These data show that the IL-1 gene is frequently expressed in metastases from patients with several types of human cancers. IL-1Ra inhibits xenograft growth in IL-1-producing tumors but has no direct antiproliferative effects in vitro; decreased tumor levels of IL-8 and VEGF may be an early surrogate of IL-1Ra-mediated antitumor activity. IL-1Ra may have a role alone or with other agents in the treatment of human cancers.

American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: Executive summary of recommendations

The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas are systematically developed statements to assist health care providers in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual circumstances.

Results of initial operation for hyperparathyroidism in patients with multiple endocrine neoplasia type 1

BACKGROUND Hyperparathyroidism in patients with multiple endocrine neoplasia type 1 (MEN1) is characterized by multiglandular disease and a propensity for recurrence after parathyroidectomy (PTx). This study analyzes outcomes of a cohort of MEN1 patients undergoing initial PTx at one institution. METHODS Between April 1960 and September 2002, 92 patients with MEN1 underwent initial PTx. Outcomes were analyzed based on extent of parathyroid resection. RESULTS Fourteen percent had 2.5 or fewer glands resected, 69% had subtotal PTx, and 17% had total PTx (88% with immediate autotransplantation). The initial surgical cure rate was 98%. Excluding 6 patients lost to follow-up, 33% have developed recurrent hyperparathyroidism (in 46% after < or =2.5 PTx, in 33% after subtotal, and in 23% after total PTx). Median recurrence-free survival was not statistically significantly different between subtotal versus total PTx, but it was longer for subtotal and total PTx compared with lesser resection (16.5 vs 7.0 years, respectively, P=.03). The incidence of severe hypoparathyroidism was 46% after total versus 26% after subtotal PTx. CONCLUSIONS Subtotal and total PTx result in durable control of MEN1-associated hyperparathyroidism and have longer recurrence-free intervals compared with lesser resection. The high incidence of severe hypoparathyroidism after total PTx suggests that subtotal PTx is the initial operation of choice in this setting.

A pilot study of antiangiogenic therapy with bevacizumab and thalidomide in patients with metastatic renal cell carcinoma.

The use of antiangiogenic agents represents a promising strategy for the treatment of patients with metastatic renal cell carcinoma. Objective responses to single-agent thalidomide have been described, and a randomized study showed that bevacizumab (a neutralizing antibody against vascular endothelial growth factor) delayed time to progression of metastatic renal cancer. A pilot study combining these two agents was performed. Sequential cohorts of 10 and 12 patients (crossing over from placebo therapy in the aforementioned randomized bevacizuamab trial) were treated with low-dose bevacizumab alone or bevacizumab plus the maximum tolerated dose of thalidomide as determined by intrapatient escalation. Toxicity, objective responses, and time to progression were the endpoints of this study. Patients tolerated thalidomide and bevacizumab well, with more than 50% of patients escalating to at least 500 mg/d thalidomide. Grades 1 and 2 sensory neuropathy limited thalidomide dose escalation in 3 of 12 patients. The incidence of grades 3 and 4 toxicity was not different between patients treated with bevacizumab alone versus bevacizumab plus thalidomide. There were no objective responses and no difference in progression-free survival between the groups (2.4 months for bevacizumab alone, 3.0 months for bevacizumab plus thalidomide). Combination antiangiogenic therapy with bevacizumab plus thalidomide in patients with renal cell carcinoma is associated with similar toxicity and progression-free survival compared with bevacizumab alone. This study illustrates a clinical trial design for rapidly testing the feasibility and safety of combining antiangiogenic agents, an approach that will be necessary for rapidly evaluating the many potential combinations of antiangiogenic agents.

Are Additional Localization Studies and Referral Indicated for Patients With Primary Hyperparathyroidism Who Have Negative Sestamibi Scan Results

HYPOTHESIS Additional imaging studies are useful to select patients who are candidates for minimally invasive parathyroidectomy, and referral is not indicated when results from a preoperative sestamibi scan are negative. DESIGN, SETTING, AND PATIENTS Prospective analysis of 492 operations for primary hyperparathyroidism from May 2005 to May 2007 at a tertiary care center. MAIN OUTCOME MEASURES Accuracy of imaging studies, pathologic findings, and biochemical cure. RESULTS Among the patients, 96% were cured. Of the sestamibi scan results, 91% were positive and 82% were true-positive. Ultrasonography results were positive in 51% of patients with negative sestamibi scan results, and 43% were true-positive. Patients with positive sestamibi scan results compared with those with negative sestamibi scan results had a higher rate of single-gland disease (87% vs 63%, respectively) and lower rates of double adenoma (6% vs 22%, respectively) and asymmetric hyperplasia (7% vs 15%, respectively) (P<.001). In patients with positive sestamibi scan results compared with those with negative sestamibi scan results, there was no significant difference in the rate of ectopic parathyroid glands (18% vs 12%, respectively) but there was a significant difference in cure rate (97% vs 89%, respectively) (P=.008). CONCLUSIONS Additional imaging with neck ultrasonography is helpful for selecting minimally invasive parathyroidectomy in most patients with primary hyperparathyroidism who have negative sestamibi scan results. Referral for parathyroidectomy may be considered in patients with negative sestamibi scan results because these results are associated with multigland disease and lower cure rates.

Waiting for change: symptom resolution after adrenalectomy for Cushing's syndrome.

BACKGROUND The debilitating symptoms and physical changes from Cushings syndrome may resolve after treatment, but the time course to resolution is not well established. METHODS Between February 1995 and May 2007, 60 patients underwent adrenalectomy for Cushings syndrome. Pre-operative and operative variables were collected from a prospective database. Long-term follow-up was obtained via patient survey. RESULTS Unilateral adrenalectomy was performed in 53% and a bilateral adrenalectomy in 47% of patients. Median time to diagnosis was 24 months (range, 1-384). Three percent had intra-operative complications, and 28% developed post-operative complications. Steroids were required post-operatively for a median of 30 months after unilateral adrenalectomy (range, 0-96). At a median follow-up of 3.7 years (range, 0-13.3), 85% of patients are still alive. The majority of the physical changes resolved after adrenalectomy. The time to symptom resolution varied from a few weeks to up to 4 years. Most of the physical changes resolved by a mean of 7-9 months after surgery. Quality of life improved in 78% of patients, with 68% improving dramatically (P < .001). CONCLUSION Adrenalectomy can provide excellent palliation of the symptoms of cortisol excess and can dramatically improve patient quality of life, but both patients and physicians must know that these changes may take years.

Denosumab for Management of Parathyroid Carcinoma-Mediated Hypercalcemia

CONTEXT Most of the morbidity and mortality from parathyroid cancer is due to PTH-mediated hypercalcemia. Classically, management mainly consists of surgical resection, chemotherapy, and alleviation of hypercalcemia using bisphosphonates and calcium receptor agonists. The use of denosumab in the treatment of parathyroid cancer-mediated hypercalcemia has not been reported. OBJECTIVE The aim of this report is to describe the effect of denosumab on parathyroid cancer-induced hypercalcemia. SUBJECT, MEASURES, AND RESULT: The patient is a 39-year-old man with metastatic parathyroid cancer who presented at age 35. His calcium levels initially responded to surgery, bisphosphonates, calcium receptor agonist, and chemotherapy (dacarbazine). However, his disease progressed, and his hypercalcemia became refractory to these measures in the setting of rising PTH levels. The addition of denosumab, a humanized monoclonal antibody inhibiting receptor activator of nuclear factor κB ligand resulted in successful management of his hypercalcemia for an additional 16 months. CONCLUSIONS Denosumab can be effective in the treatment of refractory hypercalcemia in parathyroid cancer. It may also be of potential use in settings of benign hyperparathyroid-related hypercalcemia such as parathyromatosis, where hypercalcemia is not amenable to surgery or medical therapy with bisphosphonates and calcium receptor agonists.

Cost-effectiveness analysis of repeat fine-needle aspiration for thyroid biopsies read as atypia of undetermined significance

BACKGROUND The 2007 National Cancer Institute (NCI) conference on Thyroid Fine-Needle Aspiration (FNA) introduced the category atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS). Repeat FNA in 3 to 6 months was recommended for low-risk patients. Compliance with these recommendations has been suboptimal. We hypothesized that repeat FNA would be more effective than diagnostic lobectomy, with decreased costs and improved rates of cancer detection. METHODS Cost-effectiveness analysis was performed in which we compared diagnostic lobectomy with repeat FNA. A Markov model was developed. Outcomes and probabilities were identified from literature review. Third-party payer costs were estimated in 2010 US dollars. Outcomes were weighted by use of the quality-of-life utility factors, yielding quality-adjusted life years (QALYs). Monte Carlo simulation and sensitivity analysis were used to examine the uncertainty of probability, cost, and utility estimates. RESULTS The diagnostic lobectomy strategy cost

Cost Effectiveness of Intraoperative Pathology Examination during Diagnostic Hemithyroidectomy for Unilateral Follicular Thyroid Neoplasms

8,057 and produced 23.99 QALYs. Repeat FNA cost

Adequate surgery for papillary thyroid cancer

2,462 and produced 24.05 QALYs. Repeat FNA was dominant until the cost of FNA increased to