Donald L. Bodenner

Binding of estrogen receptor with estrogen conjugated to bovine serum albumin (BSA)

BackgroundThe classic model of estrogen action requires that the estrogen receptor (ER) activates gene expression by binding directly or indirectly to DNA. Recent studies, however, strongly suggest that ER can act through nongenomic signal transduction pathways and may be mediated by a membrane bound form of the ER. Estradiol covalently linked to membrane impermeable BSA (E2-BSA) has been widely used as an agent to study these novel membrane-associated ER events. However, a recent report suggests that E2-BSA does not compete for E2 binding to purified ER in vitro. To resolve this apparent discrepancy, we performed competition studies examining the binding of E2 and E2-BSA to both purified ER preparations and ER within intact cells. To eliminate potential artifacts due to contamination of commercially available E2-BSA preparations with unconjugated E2 (usually between 3–5%), the latter was carefully removed by ultrafiltration.ResultsAs previously reported, a 10-to 1000-fold molar excess of E2-BSA was unable to compete with 3H-E2 binding to ER when added simultaneously. However, when ER was pre-incubated with the same concentrations of E2-BSA, the binding of 3H-E2 was significantly reduced. E2-BSA binding to a putative membrane-associated ER was directly visualized using fluorescein labeled E2-BSA (E2-BSA-FITC). Staining was restricted to the cell membrane when E2-BSA-FITC was incubated with stable transfectants of the murine ERα within ER-negative HeLa cells and with MC7 cells that endogenously produce ERα. This staining appeared highly specific since it was competed by pre-incubation with E2 in a dose dependent manner and with the competitor ICI-182,780.ConclusionsThese results demonstrate that E2-BSA does bind to purified ER in vitro and to ER in intact cells. It seems likely that the size and structure of E2-BSA requires more energy for it to bind to the ER and consequently binds more slowly than E2. More importantly, these findings demonstrate that in intact cells that express ER, E2-BSA binding is localized to the cell membrane, strongly suggesting a membrane bound form of the ER.

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

Purpose: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC). Experimental Design: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review. Results: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%–49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%–89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9–3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0–not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction. Conclusions: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications. Clin Cancer Res; 22(1); 44–53. ©2015 AACR.

Hypothyroidism in patients with multiple myeloma following treatment with thalidomide

Thalidomide is used for the management of several diseases, including the treatment of patients with multiple myeloma who have relapsed(1–3). As the number of patients receiving thalidomide for longer periods of time increases, several previously unrecognized adverse events have been observed (4 – 6). We observed symptomatic hypothyroidism, characterized by a high serum thyroid-stimulating hormone (TSH) level and low thyroxine level, in a patient with multiple myeloma during therapy with thalidomide. Indeed, known adverse effects of thalidomide, such as bradycardia, lethargy, and constipation, are potential manifestation of hypothyroidism. This led us to evaluate thyroid function tests, when available, in multiple myeloma patients who had received thalidomide in our clinical trials.

The Impact of Exercise Training Compared to Caloric Restriction on Hepatic and Peripheral Insulin Resistance in Obesity

CONTEXT It has been difficult to distinguish the independent effects of caloric restriction versus exercise training on insulin resistance. OBJECTIVE Utilizing metabolic feeding and supervised exercise training, we examined the influence of caloric restriction vs. exercise training with and without weight loss on hepatic and peripheral insulin resistance. DESIGN, PARTICIPANTS, AND INTERVENTION Thirty-four obese, older subjects were randomized to: caloric restriction with weight loss (CR), exercise training with weight loss (EWL), exercise training without weight loss (EX), or controls. Based on an equivalent caloric deficit in EWL and CR, we induced matched weight loss. Subjects in the EX group received caloric compensation. Combined with [6,6(2)H(2)]glucose, an octreotide, glucagon, multistage insulin infusion was performed to determine suppression of glucose production (SGP) and insulin-stimulated glucose disposal (ISGD). Computed tomography scans were performed to assess changes in fat distribution. RESULTS Body weight decreased similarly in EWL and CR, and did not change in EX and controls. The reduction in visceral fat was significantly greater in EWL (-71 +/- 15 cm(2)) compared to CR and EX. The increase in SGP was also almost 3-fold greater (27 +/- 2%) in EWL. EWL and CR promoted similar improvements in ISGD [+2.5 +/- 0.4 and 2.4 +/- 0.9 mg x kg fat-free mass (FFM)(-1) x min(-1)], respectively. CONCLUSIONS EWL promoted the most significant reduction in visceral fat and the greatest improvement in SGP. Equivalent increases in ISGD were noted in EWL and CR, whereas EX provided a modest improvement. Based on our results, EWL promoted the optimal intervention-based changes in body fat distribution and systemic insulin resistance.

A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine‐refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1‐VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1‐FGFR4), platelet‐derived growth factor receptor α (PDGFRα), ret proto‐oncogene (RET), and v‐kit Hardy‐Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine‐refractory, differentiated thyroid cancer (RR‐DTC).

Incidence of thyroid carcinoma in fluorodeoxyglucose positron emission tomography-positive thyroid incidentalomas

OBJECTIVE: Fluorodeoxyglucose (FDG) whole body positron emission tomography (PET) scan may show clinically occult second lesions. Such lesions in the thyroid are increasingly common. There are several recent reports of a high probability of malignancy in these lesions ranging from 14% to 63%. STUDY DESIGN AND SETTING: This is a retrospective review of 15,711 PET scans at a multi-disciplinary thyroid clinic at a tertiary care university medical center. Twenty-two patients were referred with thyroid PET “incidentalomas.” The review included 18 FDG-PET scans, ultrasound guided fine needle aspiration biopsies, and thyroid surgery pathology. Aspiration cytology or pathology were the main outcome measures. RESULTS: Three patients had malignancy of the PET-positive thyroid lesions. Papillary thyroid micro carcinomas were detected in four of the specimens that showed a benign pathology of the dominant nodule. CONCLUSION: Our experience shows a 14% malignancy rate for the dominant (imaged) nodule and a total malignancy rate of 32% when the incidental micro carcinomas are included. Both of these rates are significantly lower than results published previously.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: POSTOPERATIVE HYPOPARATHYROIDISM - DEFINITIONS AND MANAGEMENT

Abbreviations: BID = bis in die DSPTC = diffuse sclerosing papillary thyroid cancer FNA = fine-needle aspiration HT = Hashimoto thyroiditis iPTH = intact parathyroid hormone 25OHD = 25-hydroxy vitamin D PTH = parathyroid hormone TPO = thyroid peroxidase US = ultrasonography

Outpatient Thyroid Surgery Data from the University Health System (UHC) Consortium

Objective Describe data from patients undergoing outpatient thyroid surgeries for benign and malignant disease at academic medical centers in the United States. Study Design Retrospective database search. Setting The University Health System Consortium (UHC), Oak Brook, Illinois, data compiled from discharge summaries. Subjects and Methods Discharge data were collected from the first quarter of 2005 through the fourth quarter of 2010. Searching strategy was based on diagnosis of thyroid disease and patients undergoing thyroid surgery across all UHC facilities. Demographic information was collected as well as charges. Complications were also evaluated in this analysis. Results During the study period, 38,362 outpatient thyroidectomies were performed from our sample, 32% for thyroid cancer. More total thyroidectomies (43%) and fewer hemithyroidectomies (36%) were being performed overall; 64.1% of patients stayed 23 hours. Conclusion This is one of the largest series reporting outcomes for outpatient thyroid surgery. Since these surgeries appear to be shifting to an outpatient setting, this report reflects the experience with the majority of endocrine surgeries from the UHC database being performed presently. These results are derived from teaching hospitals and their affiliates and may not reflect the entirety of thyroid surgery in the United States.

Preoperative 4D CT Localization of Nonlocalizing Parathyroid Adenomas by Ultrasound and SPECT-CT

Objective To evaluate 4-dimensional (4D) computed tomography (CT) for the localization of parathyroid adenomas previously considered nonlocalizing on ultrasound and single-photon emission CT with CT scanning (SPECT-CT). To measure radiation exposure associated with 4D-CT and compared it with SPECT-CT. Study Design Case series with chart review. Setting University tertiary hospital. Subjects and Methods Nineteen adults with primary hyperparathyroidism who underwent preoperative 4D CT from November 2013 through July 2014 after nonlocalizing preoperative ultrasound and technetium-99m SPECT-CT scans. Sensitivity, specificity, predictive values, and accuracy of 4D CT were evaluated. Results Nineteen patients (16 women and 3 men) were included with a mean age of 66 years (range, 39-80 years). Mean preoperative parathyroid hormone level was 108.5 pg/mL (range, 59.3-220.9 pg/mL), and mean weight of the excised gland was 350 mg (range, 83-797 mg). 4D CT sensitivity and specificity for localization to the patient’s correct side of the neck were 84.2% and 81.8%, respectively; accuracy was 82.9%. The sensitivity for localizing adenomas to the correct quadrant was 76.5% and 91.5%, respectively; accuracy was 88.2%. 4D CT radiation exposure was significantly less than the radiation associated with SPECT-CT (13.8 vs 18.4 mSv, P = 0.04). Conclusion 4D CT localizes parathyroid adenomas with relatively high sensitivity and specificity and allows for the localization of some adenomas not observed on other sestamibi-based scans. 4D CT was also associated with less radiation exposure when compared with SPECT-CT based on our study protocol. 4D CT may be considered as first- or second-line imaging for localizing parathyroid adenomas in the setting of primary hyperparathyroidism.

Characterization of hyperparathyroidism in youth and adolescents: A literature review

OBJECTIVES To systematically review the preoperative diagnostic modalities, surgical treatments, and glandular pathologies associated with primary hyperparathyroidism in children and adolescents under 20 years of age. METHODS We searched PUBMED, Cochrane databases, OVID, Web of Science (SCIE and SSCI), CINAHL, and Health Source: Nursing academic for articles involving surgical management of primary hyperparathyroidism in the pediatric population on 5/2012. SELECTION CRITERIA Literature review, database review, and retrospective review studies date were used from 1986 until 2012. Ages ranged for 0-19 years old. RESULTS Of the 230 cases of pediatric primary hyperparathyroidism reported since 1987, solitary adenomas (SA), multiple gland hyperplasia disease (MGHD), double adenomas (DA), and normal parathyroid gland pathology occurred in 80%, 16.5%, 0.9%, and 2.6% respectively. Of the MGHD patients (38 pts), 1/2 (19 pts) of the cases were attributed to MEN I, MEN II, or familial non MEN hyperparathyroidism. Tc(99m)-sestamibi and ultrasound were 86% (37/43) and 74.5% (70/94) sensitive, respectively for localizing parathyroid disease. CONCLUSIONS Limited data exists on pediatric and adolescent patients with primary hyperparathyroidism. Sufficient data exists demonstrating single adenomas are most common and young patients are usually more symptomatic than adults. One may conclude that spontaneous primary hyperparathyroidism may be approached and managed similarly to adults. The incidence of primary hyperparathyroidism in this population may be under appreciated and a lower threshold for ordering a screening serum calcium should be considered.