Breast cancer prevention in older women: an algorithm to choose an optimal preventive agent.

BACKGROUND: Breast cancer is a significant cause of morbidity and mortality in older women. The current study presents new, comprehensive guidelines for providing chemoprevention to older women. OBJECTIVE: The objective of this study was to develop and pilot test a chemopreventive choice algorithm to assess its feasibility for older women at high risk of breast cancer. DESIGN: The study observed outcomes of 23 older adult females being treated with one of the four different chemopreventive agents. A novel algorithm protocol was utilized for individualized chemopreventive selection. SETTING: The study was conducted in a high-risk outpatient clinic for older women. PARTICIPANTS: Older outpatient females at high risk (N=23) were offered chemopreventive options based on individual criteria. INTERVENTION: Literature review for breast cancer chemopreventive agents informed our development of a logic-based algorithm to guide treatment protocol and chemopreventive choice optimization. Selective estrogen receptive modulators (SERMs) were avoided in women with endometrial cancer risk (ie, pre-hysterectomy individuals), but used in women with low thromboembolic event (TE) risk. Raloxifene was used with osteoporotic women. Aromatase inhibitors (AIs) were used in women with high TE risk. Women without TE risks are advised to take SERMs. When bone density decreased due to AI use, women were switched to raloxifene. MEASUREMENTS/RESULTS: Of 23 participants of age ranging from 59 to 80 years (mean=72.6), two women developed estrogen receptor-positive breast cancer. Two participants, one who declined chemoprevention and one treated with an AI, developed breast cancer. All initial chemopreventive agents were selected according to the algorithm. Although minor adverse events occurred, each was managed by discontinuation or replacement of the chemopreventive agent. Discontinuation was most commonly due to side effect concerns or cost rather than experienced side effects. CONCLUSION: Outcomes of the initial utilization of the chemopreventive agent choice algorithm support the viability of the protocol, but further evaluation with a larger and more diverse sample is required.

Relationship of Vitamin D Deficiency and Intraoperative Parathyroid Hormone Elevation in Completion and Total Thyroidectomy.

OBJECTIVE: To quantify how frequently intraoperative parathyroid hormone levels increase during thyroid surgery and to explore a possible relationship between secondary hyperparathyroidism due to vitamin D deficiency and elevation in intraoperative parathyroid hormone. STUDY DESIGN: Case series with chart review. SETTING: Tertiary academic center. SUBJECTS AND METHODS: A total of 428 consecutive patients undergoing completion and total thyroidectomy by the senior author over a 7-year period were included for analysis. All patients had baseline and postexcision intraoperative parathyroid hormone levels as well as vitamin D levels from the same laboratory. Institute of Medicine criteria were employed for vitamin D stratification (>30, normal; 20-29.9, insufficient; <20, deficient) . Other data analyzed include sex, age, neck dissection status, and parathyroid autotransplantation. RESULTS: A total of 118 patients (27.6%) had an intraoperative parathyroid hormone elevation above baseline. Patients with vitamin D deficiency were significantly more likely to experience hormone elevation ( P = .04). When parathyroid hormone rose, it did so by a mean 32.1 pg/mL. Patients with vitamin D deficiency demonstrated significantly larger hormone increases ( P = .03). CONCLUSION: Elevation in intraoperative parathyroid hormone levels above baseline after completion and total thyroidectomy occurs in over one-fourth of cases and is significantly associated with vitamin D deficiency. This study is the first to report this observation. We hypothesize that vitamin D deficiency in these patients may create a subclinical secondary hyperparathyroidism that leads to intraoperative parathyroid hormone elevation when the glands are manipulated. Additional studies will be needed to explore this physiologic mechanism and its clinical significance.

Structural alterations in tumor-draining lymph nodes before papillary thyroid carcinoma metastasis.

BACKGROUND: The purpose of this study was to define and characterize the thyroid tumor-draining lymph nodes in genetically engineered mice harboring thyroid-specific expression of oncogenic BrafV600E with and without Pten insufficiency. METHODS: After intratumoral injection of methylene blue, the lymphatic drainage of the thyroid gland was visualized in real time. The thyroid gland/tumor was resected en bloc with the respiratory system for histological analysis. RESULTS: Although mice harboring BrafV600E mutations were smaller in body size compared with their wild-type (WT) littermates, the size of their thyroid glands and deep cervical lymph nodes were significantly larger. Additionally, the tumor-draining lymph nodes showed increased and enlarged lymphatic sinuses that were distributed throughout the cortex and medulla. Tumor-reactive lymphadenopathy and histiocytosis, but no frank metastases, were observed in all mice harboring BrafV600E mutations. CONCLUSIONS: The tumor-draining lymph nodes undergo significant structural alterations in immunocompetent mice, and this may represent a primer for papillary thyroid carcinoma (PTC) metastasis.

Postoperative Calcium Management in Same-Day Discharge Thyroid and Parathyroid Surgery.

OBJECTIVE: To describe a safe and effective postoperative prophylactic calcium regimen for same-day discharge thyroid and parathyroid surgery. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral academic institution. SUBJECTS AND METHODS: In total, 162 adult patients who underwent total thyroidectomy, completion thyroidectomy, unilateral parathyroidectomy, parathyroidectomy with bilateral neck exploration, or revision parathyroidectomy were identified preoperatively to be candidates for same-day discharge. All patients in this study were successfully discharged the same day on our standard prophylactic calcium regimen. RESULTS: Less than 1% (1/162) of patients re-presented to the hospital within 30 days of surgery, and that patient was successfully discharged from the emergency department after negative workup for hypocalcemia. There was no significant difference between preoperative and postoperative calcium levels in the total/completion thyroidectomy groups (9.3 vs 9.2 mg/dL, respectively; P = .14). The average postoperative calcium level in the parathyroid group was well within normal limits (9.5 mg/dL), and the difference in postoperative calcium levels between revision and primary parathyroidectomy cases was not significantly different (P = .34). CONCLUSION: The reported calcium regimen demonstrates a safe, effective, and objective means of postoperative calcium management in outpatient thyroid and parathyroid surgery in appropriately selected patients.

Hyperparathyroidism Associated with Long-Term Proton Pump Inhibitors Independent of Concurrent Bisphosphonate Therapy in Elderly Adults.

OBJECTIVES: To measure the effect of proton pump inhibitors (PPIs), with and without concurrent bisphosphonates, on parathyroid hormone (PTH), vitamin D, and calcium. DESIGN: Retrospective chart review of individuals 60 years and older. Subjects with reduced renal function (creatinine >1.3 mg/dL) and low vitamin D (<30 ng/mL) were excluded. SETTING: Academic geriatric outpatient center in southern midwest. PARTICIPANTS: Individuals aged 60 and older with concurrent calcium, PTH, vitamin D, and creatinine laboratory measurements (N = 80) meeting labeled criteria. MEASUREMENTS: Serum calcium, PTH, vitamin D, and creatinine. RESULTS: Chronic PPI exposure was associated with statistically significantly higher PTH (65.5 vs 30.3 pg/mL, P < .001; normal range 10-55 pg/mL) and lower calcium (9.1 vs 9.4 mg/dL, P = .02; normal range 8.5-10.5 mg/dL) than no PPI exposure. Chronic PPI exposure with concurrent BP therapy was associated with statistically significantly higher PTH (65.2 vs 43.4 pg/mL, P = .05) and lower calcium (9.2 vs 9.6 mg/dL, P = .04) than BP therapy only. CONCLUSION: Based on the present study, chronic PPI exposure in elderly adults is associated with mild hyperparathyroidism regardless of concurrent oral BP administration.

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.

Comparison of Intraoperative versus Postoperative Parathyroid Hormone Levels to Predict Hypocalcemia Earlier after Total Thyroidectomy.

OBJECTIVE: To determine differences in the mean parathyroid hormone (PTH) levels for normocalcemic and hypocalcemic total thyroidectomy patients who were tested for PTH during the intraoperative or early postoperative period. DATA SOURCES: MEDLINE, the Cochrane Database, and other databases from 1960 to 2014 in the English language and specific to humans for relevant articles. REVIEW METHODS: Studies were included if PTH was obtained within 24 hours of thyroidectomy. Studies were excluded (1) if only a hemithyroidectomy was performed, (2) if means of studied PTH values were not reported in the article, or (3) if the time of the PTH draw fell outside of defined "intraoperative" or "early postoperative" windows. PTH values were divided into 3 groups: preoperative (control group), intraoperative (ie, discharge decisions were based on PTH values drawn in the operating room), and early postoperative (ie, PTH values at 1 to 4 hours after surgery were used as a guide). RESULTS: The reported means of perioperative PTH levels and percentage of patients who developed hypocalcemia were collected from 14 studies. PTH evaluated at both the intraoperative and early postoperative periods was significantly lower in patients who became hypocalcemic versus patients who remained normocalcemic. There was no significant difference when PTH was measured intraoperatively or early postoperatively. CONCLUSION: Intraoperative PTH has no significant disadvantage versus early postoperative PTH when used as a clinical guide for discharge after thyroidectomy.

Trends in Robotic Thyroid Surgery in the United States from 2009 Through 2013.

BACKGROUND: The objective of this study was to describe national trends in robotic thyroid surgery from 2009 through 2013. METHODS: The University HealthSystem Consortium (UHC) database was searched for patients undergoing robotic thyroidectomy (RT) from 2009 through 2013. Another U.S. institution's RT data, not included in the UHC database, were also evaluated. Patient demographics, institutional volume, comorbid conditions, complications, and cost information were analyzed. RESULTS: Sixty-one institutions performed 484 RT during the study period. From 2009 through 2011, U.S. annual RT volume increased from 39 cases to 140. Annual volume dropped to 69 cases in 2012 and 93 cases in 2013. Higher-volume centers reported lower complication rates (p<0.02). Hematoma formation (3.7%) was the most common complication, and there was one death. More than 10% of patients were obese. Brachial plexus injury and axillary skin flap perforations were reported in <1% of cases. Mean cost for a total RT was $13,287 ($5,125-42,444). CONCLUSIONS: From 2009 through early 2011, there was a steady increase in RT volume, especially among high-volume institutions. In mid-to-late 2011, there was a noticeable drop in RT volume, which significantly altered the projected trajectory of the procedure in this country. Despite higher complication rates, lower-volume centers perform the majority of RT and are also responsible for recent increases in RT utilization patterns in the United States.

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

BACKGROUND: 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). METHODS: Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death. Previous VEGFR-targeted therapy was permitted. The primary endpoint was the objective response rate (ORR) based on independent imaging review. Secondary endpoints included progression-free survival (PFS) and safety. Serum levels of 51 circulating cytokines and angiogenic factors also were assessed. RESULTS: After ≥14 months of follow-up, patients had an ORR of 50% (95% confidence interval [CI], 37%-63%) with only partial responses reported. The median time to response was 3.6 months, the median response duration was 12.7 months, and the median PFS was 12.6 months (95% CI, 9.9-16.1 months). The ORR for patients who had received previous VEGF therapy (n = 17) was 59% (95% CI, 33%-82%). Lower baseline levels of angiopoietin-2 were suggestive of tumor response and longer PFS. Grade 3 and 4 treatment-emergent adverse events, regardless of their relation to treatment, occurred in 72% of patients and most frequently included weight loss (12%), hypertension (10%), proteinuria (10%), and diarrhea (10%). CONCLUSIONS: In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Cancer 2015;121:2749-2756. © 2015 American Cancer Society.

Metastatic Follicular Thyroid Carcinoma Secreting Thyroid Hormone and Radioiodine Avid without Stimulation: A Case Report and Literature Review.

Introduction. This is an extremely rare case of a patient with metastatic follicular thyroid cancer who continued to produce thyroid hormone and was iodine scan positive without stimulation after thyroidectomy and radioiodine (I-131) therapy. Patient Findings. A 76-year-old Caucasian male was diagnosed with metastatic follicular thyroid carcinoma on lung nodule biopsy. Total thyroidectomy was performed and he was ablated with 160 mCi of I-131 after recombinant human thyrotropin (rhTSH) stimulation. Whole body scan (WBS) after treatment showed uptake in bilateral lungs, right sacrum, and pelvis. The thyroglobulin decreased from 2,063 to 965 four months after treatment but rapidly increased to 2,506 eleven months after I-131. Thyroid stimulating hormone (TSH) remained suppressed and free T4 remained elevated after I-131 therapy without thyroid hormone supplementation. He was treated with an additional 209 mCi with WBS findings positive in lung and pelvis. Despite I-131, new metastatic lesions were noted in the left thyroid bed and large destructive lesion to the first cervical vertebrae four months after the second I-131 dose. Conclusions. This case is exceptional because of its rarity and also due to the dissociation between tumor differentiation and aggressiveness. The metastatic lesions continued to secrete thyroid hormone and remained radioiodine avid with rapid progression after I-131 therapy.

Acute lysine supplementation does not improve hepatic or peripheral insulin sensitivity in older, overweight individuals.

CONTEXT: Lysine supplementation may have a positive influence on the regulation of glucose metabolism but it has not been tested in the geriatric population. OBJECTIVE: We evaluated the impact of acute lysine supplementation using three randomized experimental scenarios: 1) oral glucose alone (control), 2) oral glucose and low-dose lysine (2 grams), and oral glucose and high dose lysine (5 grams) lysine in 7 older (66 ± 1 years/age), overweight/obese (BMI = 28 ± 2 kg/m(2)) individuals. METHODS: We utilized a dual tracer technique (i.e., [6,6-(2)H2] glucose primed constant infusion and 1-[(13)C] glucose oral ingestion) during an oral glucose tolerance test (OGTT) to examine differences in hepatic and peripheral insulin sensitivity under all three scenarios. RESULTS: Post-absorptive plasma glucose and insulin concentrations were not different between the three trials. Similarly, the response of glucose and insulin concentrations during the oral glucose tolerance tests (OGTT) was similar in the three trials. The results of the Matsuda index (ISI/M) were also not different between the three trials. As an index of hepatic insulin sensitivity, there were no significant differences in the endogenous glucose rate of appearance (glucose Ra) for control, 2 g lysine and 5 g lysine (1.2 ± 0.1, 1.1 ± 0.1, 1.3 ± 0.1 mg•kg(-1)•min(-1)), respectively. With respect to peripheral insulin sensitivity, there were no significant differences in the glucose rate of disappearance (glucose Rd) for control, 2 g lysine and 5 g lysine (4.2 ± 0.1, 4.3 ± 0.2, and 4.5 ± 0.4 mg•kg(-1)•min(-1)), respectively. CONCLUSIONS: Previous studies in younger participants have suggested that lysine may have a beneficial effect on glucose metabolism. However, acute lysine supplementation in the older population does not facilitate beneficial changes in glucose Ra or glucose Rd.

Vitamin D deficiency: a simple algorithm employing weekly administration of 50,000 IU of vitamin D.

OBJECTIVE: Vitamin D deficiency affects parathyroid hormone levels and is endemic in the American population due to diet and lifestyle. The aim of this study was to evaluate a treatment algorithm using weekly doses of 50,000 IU of Vitamin D2 for thyroid and parathyroid surgery patients. STUDY DESIGN: Prospective, non-randomized. SETTING: University health sciences center. SUBJECTS AND METHODS: Patients at a thyroid center being treated for benign and malignant thyroid diseases or parathyroid disease. Subjects with total vitamin D levels less than 30 ng/dl were prospectively treated with weekly doses of 50,000 IU of vitamin D2 (D2) for durations dependent upon initial vitamin D (25-hydroxyvitamin D) levels. Vitamin D levels were measured after the treatment intervals and change in levels from baseline was determined. RESULTS: Subjects receiving 8 weeks of therapy demonstrated an average increase in vitamin D level of 13.4 ng/ml, 10 weeks of therapy showed an increase of 16.35 ng/ml, and 12 weeks showed an average increase of 21.6 ng/ml. The treatment groups had success rates of 82%, 75%, and 71% after 8, 10, and 12 weeks of therapy respectively. When only compliant patients were evaluated (defined as greater than 3-ng/ml increase after therapy), the success rates after 8, 10, and 12 weeks increased to 95%, 79%, and 71% respectively. CONCLUSIONS: A simple algorithm using 50,000 IU of vitamin D2 corrects its deficiency in the majority of subjects treated. This is a simple method of treatment for thyroid and parathyroid patients who are vitamin D deficient. Thyroid and parathyroid conditions are frequently treated by otolaryngologists and vitamin D deficiency can complicate their diagnosis and/or management.

Conservative management of thyroglobulin-positive, nonlocalizable thyroid carcinoma.

BACKGROUND: The purpose of this study was to demonstrate a role for observation of patients with differentiated thyroid cancer (DTC) with persistent, nonlocalizable disease. METHODS: Our study was conducted on outpatients seen at our institution from 1999 to 2009 having total thyroidectomy, radioactive iodine (RAI) ablation, measurable serum thyroglobulin (Tg), and no evidence of disease on whole body or positron emission tomography (PET) scans. RESULTS: Nineteen patients in our study group aged 20 to 73 with an average follow-up of 5.5 years (range, 2-12 years); all were treated with postoperative RAI (99-210 mCi, average 119). Mean Tg ranged from 0.41 to 4.34. Tg levels remained stable or gradually decreased in all patients. CONCLUSION: After total thyroidectomy and RAI therapy, patients may present with mildly elevated Tg values without localizable disease. These patients may have additional RAI treatments based on the Tg elevation. However, our clinical experience has shown that many of these patients will have Tg levels that either achieve stability or decrease over time without further treatment.

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.

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.

Hormone, relationships of parathyroid gamma counts, and adenoma mass in minimally invasive parathyroidectomy.

OBJECTIVE: To better understand relationships of parathyroid hormone (PTH) production, adenoma gamma counts, and adenoma mass in patients undergoing minimally radioguided invasive parathyroidectomy for primary hyperparathyroidism from single-gland disease. STUDY DESIGN: A prospective review of 104 patients operated on by a single surgeon. SETTING: University tertiary hospital. SUBJECTS: Adults who have primary hyperparathyroidism due to a single gland. RESULTS: There were 23 men and 81 women with an average age of 63 years. The mean (SD) adenoma mass was 0.78 (0.69) g (median, 0.57 g). The mean (SD) percent of background for the adenoma was 120.2 (90.5). Preoperative PTH and percent of background gamma count of the adenoma showed a likely correlation with a Spearman ρ value of 0.2039 and a P value of .037. There were significant correlations between both percent of background of the adenoma and adenoma mass (Spearman ρ = 0.4991 and P < .0001). Preoperative PTH and adenoma mass also showed a significant positive correlation (Spearman ρ = 0.308 and P = .002). CONCLUSION: There exist correlations between gland mass, radioactivity, and PTH level. Adenoma radiation counts do not appear to be a proxy for changes in PTH levels measured during surgery as has been reported. Intraoperative PTH has been shown by others not to be necessary when doing radioguided parathyroid surgery if the Norman rule is observed. However, a radioguided technique and intraoperative PTH can provide complementary information in making an assessment of completion of parathyroid procedures.