MANAGEMENT OF HYPERPARATHYROIDISM IN KIDNEY TRANSPLANTATION CANDIDATES: A NEED FOR CONSENSUS.

Objective: To assess the evolving standards of care for hyperparathyroidism in kidney transplant candidates. Methods: An 11-question, Institutional Review Board-approved survey was designed and reviewed by multiple institutions. The questionnaire was made available to the American Society of Transplantation's Kidney Pancreas Community of Practice membership via their online hub from April through July 2019. Results: Twenty percent (n = 41) of kidney transplant centers responded out of 202 programs in the United States. Forty-one percent (n = 17) of respondents believed medical literature supports the concept that a serum parathyroid hormone level greater than 800 pg/mL could endanger the survival of a transplanted kidney and therefore makes transplantation in an affected patient relatively or absolutely contraindicated. Sixty-six percent (n = 27) said they occasionally recommend parathyroidectomy for secondary hyperparathyroidism prior to transplantation, and 66% (n = 27) recommend parathyroidectomy after transplantation based on persistent, unsatisfactory posttransplantation parathyroid hormone levels. Forty-six percent (n = 19) prefer subtotal parathyroidectomy as their choice; 44% (n = 18) had no standard preference. Endocrine surgery and otolaryngology were the most common surgical specialties consulted to perform parathyroidectomy in kidney transplant candidates. The majority of respondents (71%, n = 29) do not involve endocrinologists in the management of kidney transplantation candidates. Conclusion: Our survey shows wide divergence of clinical practice in the area of surgical management of kidney transplantation candidates with hyperparathyroidism. We suggest that medical/surgical societies involved in the transplantation care spectrum convene a multidisciplinary group of experts to create a new section in the kidney transplantation guidelines addressing the collaborative management of parathyroid disease in transplantation candidates. Abbreviations: AACE = American Association of Clinical Endocrinologists; AAES = American Association of Endocrine Surgeons; AHNS = American Head and Neck Society; CKD = chronic kidney disease; CKD-MBD = chronic kidney disease-mineral and bone disorder; ESRD = end-stage renal disease; HPT = hyperparathyroidism; KDIGO = Kidney Disease Improving Global Outcomes; KT = kidney transplantation; KTC = kidney transplant candidate; PTH = parathyroid hormone; PTX = parathyroidectomy; US = ultrasonography.

STATISTICAL COMPARISON OF AFIRMA GSC AND AFIRMA GEC OUTCOMES IN A COMMUNITY ENDOCRINE SURGICAL PRACTICE: EARLY FINDINGS.

OBJECTIVE: The Veracyte Afirma Gene Expression Classifier (GEC) has been the most widely used negative predictive value molecular classifier for indeterminate cytology thyroid nodules since January 2011. To improve the specificity and further reduce unnecessary thyroid surgeries, a second-generation assay (Afirma Genetic Sequence Classifier [GSC]) was released for clinical use in August 2017. We report 11 months of clinical outcomes experience with the GSC and compare them to our 6.5-year experience with the GEC. METHODS: We searched our practice registry for FNAB nodules with Afirma results from January 2011through June 2018. GEC versus GSC results were compared overall, in oncocytic and nononcocytic aspirates and by pathologic outcomes. RESULTS: GSC identified less indeterminate cytology nodules as suspicious (38.8%; 54/139) when compared to GEC (58.4%; 281/481). There was a decrease of in the percentage of oncocytic fine-needle aspiration thyroid biopsy (FNAB) subjects classified as suspicious in the GSC group, with 86 of 104 oncocytic indeterminates (82.7%) classified as suspicious by GEC and 12 of 34 (35.3%) classified as suspicious by GSC. The surgery rate in patients with oncocytic aspirates fell from 56% in the GEC group to 31% in the GSC-evaluated group (45%). Pathology analysis demonstrated a false-negative percentage for an incomplete surgical group of 9.5% for GEC and 1.2% for GSC. CONCLUSION: Our GSC data suggest that the GSC further reduces surgery in indeterminate thyroid nodules by improving the specificity of Afirma technology without compromising sensitivity. A primary determinant for this change is a significant improvement in the specificity of the Afirma GSC test in oncocytic FNAB aspirates. ABBREVIATIONS: FNAB = fine-needle aspiration biopsy; GEC = Gene Expression Classifier; GSC = Genetic Sequence Classifier.

COMMUNITY ENDOCRINE SURGICAL EXPERIENCE WITH FALSE-NEGATIVE AFIRMA GEC® RESULTS: 2011-2017.

OBJECTIVE: Afirma Gene Expression Classifier® (Afirma GEC) molecular analysis (Veracyte, Inc, San Francisco, CA) is a negative predictive value test developed to reduce the number of thyroidectomies in thyroid nodule patients with indeterminate cytology. GEC technology has reportedly reduced unnecessary thyroid surgery, but few studies have examined Afirma GEC false-negative rates, since usually patients with GEC benign nodules do not undergo surgery for definitive diagnosis. Occasionally, Afirma GEC benign patients require removal of their thyroid nodules for other reasons; this work describes the incidence of malignancy and noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) in this population. METHODS: We reviewed our community endocrine surgical practice database for patients who had undergone thyroid surgery from January 2011 through April 2017 despite benign Afirma GEC results. RESULTS: Afirma GEC testing was completed for 475 patients during the study period. Surgery was clinically indicated for other reasons in 42 of the 193 patients (22%) with Afirma GEC benign results. Malignancy or NIFTP in the targeted nodule was found in the final histologic evaluation of 14 of the 42 Afirma GEC benign surgical patients. The Afirma GEC false-negative percentage for our incomplete surgical group (FNP-ISG), defined as the surgically proven false negatives divided by the total Afirma GEC benign patients, was 7.3%. CONCLUSION: Our high surgical rate in Afirma GEC benign nodules reveals an FNP-ISG of 7.3% in our community endocrine surgical patient population; this value exceeds the 5.7% reported in the multicenter 2012 Afirma GEC validation study. ABBREVIATIONS: Afirma GEC = Afirma Gene Expression Classifier; FNA = fine-needle aspiration; FNP = false-negative percentage; FNP-ISG = false-negative percentage for an incomplete surgical group; NIFTP = noninvasive follicular thyroid neoplasms with papillary-like nuclear features.

Surgical utility of Afirma: effects of high cancer prevalence and oncocytic cell types in patients with indeterminate thyroid cytology.

OBJECTIVE: The Afirma Gene Expression Classifier (GEC) molecular marker assay was developed for the purpose of improving surgical decision-making with indeterminate fine-needle aspiration (FNA) biopsies of thyroid nodules. In this paper, we analyze the performance of the GEC over 27 months in a community hospital-based thyroid surgery practice. METHODS: We began using GEC and Thyroid Cytopathology Partners (TCP) exclusively for thyroid FNA analysis in January 2011, shortly after the Afirma GEC became commercially available. In this paper, we focus on patients with indeterminate FNA results and the outcomes of GEC analysis, with particular attention paid to the calculation of the negative predictive value (NPV) of the Afirma test. RESULTS: We performed 645 FNAs in 519 patients over 27 months. Overall, 58 FNAs (9%) were read as indeterminate, with 36 of these classified as suspicious by GEC (62%), 20 characterized as GEC benign (34%), and 2 determined to be inadequate due to low mRNA content. Of the 36 suspicious GEC patients, 30 underwent thyroidectomy, and 21 of the 30 had malignant final pathology. Of the 20 benign GEC patients, 5 underwent thyroid surgery, and 2 were discovered to have malignancies. The NPV for the Afirma GEC in our practice environment was 89.6%. CONCLUSION: In a practice with a high incidence of thyroid cancer in patients with indeterminate FNAs (33% for our practice), the NPV of the Afirma GEC test may not be as robust as suggested in the existing literature.

Challenges in Risk Stratification of Solid Atypical Mixed Echogenicity Thyroid Nodules.

Background: To determine the prevalence and risk of malignancy (ROM) in solid atypical mixed echogenicity thyroid nodules (SAMENs) with sonographic patterns not classifiable by the 2015 American Thyroid Association Ultrasound Risk Stratification System (NC ATA). Methods: We searched our prospectively collected endocrine surgery thyroid nodule (TN) database, with particular attention to those solid nodules that were NC ATA. An algorithm assigned each into one of the five ATA risk groups per the 2015 American Thyroid Association Ultrasound Risk Stratification System (ATA USRSS). TNs that the algorithm could not assign to a risk group were deemed NC ATA and were subsequently analyzed. Additionally, we categorized this group using an algorithm based on the 2017 American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS). We were specifically interested in the characteristics that resulted in non-classification by the 2015 ATA USRSS and the fine needle aspiration biopsy (FNAB) cytology and surgical pathology results from the group. Results: We evaluated data from 5,040 nodules, of which 1,772 had surgical pathology. There were 150 solid nodules not classified by 2015 ATA USRSS, all of which demonstrated atypical features along with iso-, hetero-, hyper-and mixed echogenicity (solid atypical mixed echogenicity nodules-SAMENs). Sixty of these nodules were excised and sent for surgical pathology, while 90 were followed without surgical excision. Out of the 90 that did not undergo surgery, 82 underwent FNAB with cytologic evaluation. Of our 150 SAMENs, 40 were malignant by surgical histology and six were likely malignant by cytology (total SAMEN ROM without noninvasive follicular thyroid neoplasm with papillary-l ike nuclear features 31%). The most common sonographic pattern present in our SAMEN group consisted of an isoechoic solid component with microcalcifications (28/40-70% of all excised malignant nodules). In our excised malignant SAMENs, 50% demonstrated follicular-patterned neoplastic architecture while 48% displayed papillary architecture. Conclusion: Our study demonstrates that SAMENs with at least one suspicious sonographic feature: including (1) microcalcifications; (2) irregular or other suspicious margins,;opulation, and a higher ROM (31%) than the intermediate-risk group of the 2015 ATA USRSS (10-20%).

NEOADJUVANT LENVATINIB IN ADVANCED UNRESECTABLE MEDULLARY THYROID CARCINOMA: A CASE REPORT.

OBJECTIVE: Medullary thyroid carcinoma, a rare form of thyroid cancer, is typically managed with surgical excision. However, in patients with locally-invasive tumors, an aggressive surgical attempt may result in unnecessary morbidity. Neoadjuvant tyrosine kinase inhibition has been utilized to downstage tumors prior to surgical excision but its role in thyroid cancer treatment is not well-established. We describe the potential role that lenvatinib, a tyrosine kinase inhibitor, may have as a neoadjuvant agent in advanced locoregional medullary thyroid carcinoma. METHODS: Our patient presented with a large left thyroid mass and bulky left lateral neck lymphadenopathy. Imaging studies revealed a hypervascular and locally-invasive tumor with metastatic central and left lateral lymphadenopathy. A lymph node biopsy cytologic evaluation and plasma calcitonin concentration of 32,926 pg/mL were consistent with medullary thyroid carcinoma. Rearranged during transfection germline mutation testing was negative. A multidisciplinary team of physicians deemed the patient a poor surgical candidate and recommended 4 months of neoadjuvant lenvatinib therapy to reduce tumor burden with a subsequent reassessment of resectability. Given the tumor's hypervascularity, lenvatinib was chosen due its potent vascular endothelial growth factor receptor inhibition, as well as its availability at our institution. RESULTS: Lenvatinib therapy resulted in rapid regression of tumor volume (approximately 70% reduction) as documented by computed tomography and ultrasound. Surgery after 4 months of treatment resulted in a 99% reduction in serum calcitonin and imaging studies 6 months later showed no residual disease. CONCLUSION: Lenvatinib has potential as a neoadjuvant agent in advanced medullary thyroid carcinoma, and permitted tumor resection in this previously inoperable patient.

Noninvasive Encapsulated Follicular Variant of Papillary Thyroid Cancer: Clinical Lessons from a Community-Based Endocrine Surgical Practice.

Objective. Retrospective studies have found that noninvasive encapsulated follicular variant of papillary thyroid cancer (EFVPTC) exhibits highly indolent clinical behavior. We studied the clinical features of our patients with noninvasive EFVPTC tumors culled from a community endocrine surgical practice registry over the past four years. Methods. We interrogated the Memorial Center for Integrative Endocrine Surgery (MCIES) Registry for all recorded encapsulated follicular variant of papillary cancer pathologic diagnoses. We identified a subgroup of patients without capsular or vascular invasion and studied their clinical characteristics. Results. Thirty-seven patients met inclusion and exclusion criteria. The typical patient was young and female. Nodules averaged 3.1 cm in greatest dimension by ultrasound evaluation. Thirteen patients were found to have synchronous malignancies elsewhere in the thyroid (35%). At the time of this writing, we have not seen a clinical recurrence in any of our 37 noninvasive EFVPTC patients. Conclusions. Early clinical follow-up data suggests that the majority of noninvasive EFVPTC tumors exhibit indolent behavior, but clinical decision-making with regard to completion thyroidectomy, central lymph node dissection, and adjunctive radioiodine therapy often depends on the amount and type of synchronous thyroid cancer detected elsewhere in the thyroid gland and the central neck.

Nonequivalent results of tetrofosmin and sestamibi imaging of parathyroid tumors.

OBJECTIVE: To report the case of a patient with a large parathyroid carcinoma missed by dual-phase technetium Tc 99m tetrofosmin (TETRO) parathyroid scanning. METHODS: We present the clinical findings, laboratory results, imaging studies, and surgical pathology report in a man with parathyroid carcinoma and review the literature regarding the use of TETRO scintigraphy in patients with hyperparathyroidism. RESULTS: In an 83-year-old man with hyperparathyroidism, severe hypercalcemia developed in the context of nephrolithiasis. An in-office ultrasonographic evaluation of the neck revealed a partially calcified mass (2.3 by 1.3 by 1.6 cm) at the inferoposterior border of the left thyroid lobe. Technetium Tc 99m sestamibi (MIBI) scanning was requested and reported as "negative." In fact, TETRO scanning had been substituted for MIBI scanning by the management of the nuclear medicine facility. Before neck exploration, performance of dual-phase MIBI parathyroid scintigraphy revealed radionuclide retention in the left lower neck area at 120 minutes, in the same site as the ultrasonographically visualized mass. A limited left inferior parathyroidectomy was performed, and intraoperative parathyroid hormone levels declined from 254 pg/mL to 28 pg/mL 10 minutes after near-complete resection of the mass. Pathology evaluation of the surgical specimen revealed a 2,000-mg parathyroid carcinoma. CONCLUSION: Although both agents incorporate the same technetium Tc 99m radionuclide, TETRO and MIBI parathyroid scanning are not equivalent in the detection of parathyroid tumors with use of the dual-phase technique. We do not recommend substitution of TETRO for MIBI as a cost-control measure in the evaluation of hyperparathyroidism.

Full-thickness chest wall resection for recurrent breast carcinoma: an institutional review and meta-analysis.

Locoregional recurrence of breast cancer can occur in up to 30 per cent of patients and has often been considered to indicate a poor prognosis. We reviewed our experience with full-thickness chest wall resection for recurrent breast cancer and conducted a meta-analysis of the English literature to determine patient characteristics and outcomes. Twenty-two women with isolated chest wall recurrence of breast cancer were treated between 1970 and 2000 at our institution. We reviewed their preoperative demographics, operative management and outcome, and combined our results with seven other English language studies. A majority of women (90%) underwent a mastectomy as initial management of their breast cancer. Only 18 per cent of patients had metastatic disease at the time of chest wall resection, and 71 per cent of patients had an R0 resection. The 5-year disease-free survival at City of Hope National Medical Center (COH) was 67 per cent and was 45 per cent for the entire group of 400 patients. The 5-year overall survival was 71 per cent for the COH group and 45 per cent for the entire group. Several studies reported prognostic factors, the most common being a better prognosis in patients with a disease-free interval greater than 24 months. Full-thickness chest wall resection for patients with isolated local recurrence of breast cancer can provide long-term palliation and even cure in some patients.

Optimization of minimally invasive radio-guided parathyroidectomy: the importance of neck ultrasonography and intraoperative parathyroid hormone assay.

OBJECTIVE: To determine whether close collaboration between a neck ultrasound-certified endocrinologist and a skilled endocrine surgeon can optimize minimally invasive radio-guided parathyroidectomy (MIRP) surgical outcomes. METHODS: Outcome data were collected on patients with primary hyperparathyroidism whom we intended to treat with MIRP at the induction of anesthesia between October 1, 2005, and December 31, 2007. Patients underwent preoperative gamma camera sestamibi scanning (GCSS), intraoperative gamma probe sestamibi scanning (IOSS), and preoperative neck ultrasonography. Intraoperative parathyroid hormone (PTH) monitoring was performed. Postoperative surgical success was defined as a serum calcium concentration between 8.0 and 10.4 mg/dL within 4 weeks of surgery. RESULTS: During the study period, MIRP was planned for 46 patients. Of the 46 patients, 39 had preoperative neck ultrasonography; 7 underwent evaluation by an endocrinologist or internist who was not ultrasound certified and they therefore did not undergo preoperative ultrasonography. IOSS correctly identified 1 adenomatous gland in 38 of 46 patients (83%), while GCSS correctly localized 1 adenomatous gland in 30 of 46 patients (65%). In 11 GCSS-negative patients, IOSS identified the abnormal gland in 7 (64%), while ultrasonography identified the abnormal gland in 8 (73%). The surgical approach was converted to traditional parathyroidectomy in 3 patients. Every patient exhibited at least a 51% drop in intraoperative PTH levels with resection of the final adenoma; average decrement for the entire group was 79 +/- 8% from the highest baseline level. Forty-five patients (98%) demonstrated sustained normalization of serum calcium within several days of surgery. CONCLUSION: A collaborative endocrinology and surgical endocrine oncology practice arrangement, emphasizing careful preoperative physician-supervised neck ultrasonography and the use of intraoperative PTH measurement, optimizes MIRP outcomes.

Arginine residues 47 and 70 of human flap endonuclease-1 are involved in DNA substrate interactions and cleavage site determination.

Flap endonuclease-1 (FEN-1) is a critical enzyme for DNA replication and repair. Intensive studies have been carried out on its structure-specific nuclease activities and biological functions in yeast cells. However, its specific interactions with DNA substrates as an initial step of catalysis are not defined. An understanding of the ability of FEN-1 to recognize and bind a flap DNA substrate is critical for the elucidation of its molecular mechanism and for the explanation of possible pathological consequences resulting from its failure to bind DNA. Using human FEN-1 in this study, we identified two positively charged amino acid residues, Arg-47 and Arg-70 in human FEN-1, as candidates responsible for substrate binding. Mutation of the Arg-70 significantly reduced flap endonuclease activity and eliminated exonuclease activity. Mutation or protonation of Arg-47 shifted cleavage sites with flap substrate and significantly reduced the exonuclease activity. We revealed that these alterations are due to the defects in DNA-protein interactions. Although the effect of the single Arg-47 mutation on binding activities is not as severe as R70A, its double mutation with Asp-181 had a synergistic effect. Furthermore the possible interaction sites of these positively charged residues with DNA substrates were discussed based on FEN-1 cleavage patterns using different substrates. Finally data were provided to indicate that the observed negative effects of a high concentration of Mg(2+) on enzymatic activity are probably due to the competition between the arginine residues and metal ions with DNA substrate since mutants were found to be less tolerant.