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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.

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.

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 peri...

Afirma Gene Expression ClassifierWe 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.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%.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.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.

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

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. (Endocr Pract. 2014;20:364-369)

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. (Endocr Pract. 2006;12:179-182)

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 meta-static 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.

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.

Hypothesis Specimen mammography is not beneficial in the management or outcome of patients undergoing image-guided needle-localized breast biopsies. Design A retrospective study of consecutive patients who underwent needle/dye-localized breast biopsies between January 1, 1993, and December 31, 1995. Setting National Cancer Institute (Bethesda, Md)–designated comprehensive cancer center. Patients One hundred sixty-four patients underwent 165 needle/dye-localized breast biopsies for suspicious mammographic abnormalities. Results In only 3 (1.8%) of 165 patients did the patient clearly benefit from specimen mammography. In no patient was a malignant neoplasm missed. The mean time for the specimen mammogram was 20 minutes, adding an additional 55 hours of operating room time. Specimen mammography cost an additional $60,522 and was incorrect in 41 (24.8%) of 165 patients. Conclusion Specimen mammography added little to patient care, as only 3 (1.8%) of 165 patients benefited from the information.

Background: Continuous thoracic epidural analgesia is considered by many the gold standard for post-thoracotomy pain control but is associated with its own complications. In this study we compare continuous paravertebral extrapleural to epidural infusion for post-thoracotomy pain control. Methods: In a prospective fashion, 50 patients were randomized to receive either paravertebral or epidural infusion for post-thoracotomy pain control. The anesthesia department placed epidurals, and the operative surgeon placed unilateral paravertebral catheters. Patients were evaluated for analgesic efficacy and postoperative complications. Results: We found that both methods of analgesia provide adequate postoperative pain control. Epidural infusion demonstrated an improved efficacy early in the postoperative course but provided statistically similar analgesia to paravertebral by postoperative day 2. Neither group demonstrated a greater number of pain-related complications. Narcotic-induced complications such as pruritus, nausea/vomiting, and postural hypotension/mental status changes/respiratory depression were seen with statistically similar frequency in both epidural and paravertebral arms. Urinary retention, however, was noted to be significantly more frequent in patients with epidural catheters. Drug toxicity was not observed with either epidural or paravertebral infusion. Conclusions: We recommend continuous paravertebral infusion as an improved method of post-thoracotomy analgesia that can be placed and managed by the surgeon. (Surgery 1999;126:650-7.)

Molecular chaperones influence the process of protein folding and, under conditions of stress, recognize non-native proteins to ensure that misfolded proteins neither appear nor accumulate. BAG-1, identified as an Hsp70 associated protein, was shown to have the unique properties of a negative regulator of Hsp70. Here, we demonstrate that BAG-1 inhibits the in vitro protein refolding activity of Hsp70 by forming stable ternary complexes with non-native substrates that do not release even in the presence of nucleotide and the co-chaperone, Hdj-1. However, the substrate in the BAG-1-containing ternary complex does not aggregate and remains in a soluble intermediate folded state, indistinguishable from the refolding-competent substrate-Hsp70 complex. BAG-1 neither inhibits the Hsp70 ATPase, nor has the properties of a nucleotide exchange factor; instead, it stimulates ATPase activity, similar to that observed for Hdj-1, but with opposite consequences. In the presence of BAG-1, the conformation of Hsp70 is altered such that the substrate binding domain becomes less accessible to protease digestion, even in the presence of nucleotide and Hdj-1. These results suggest a mechanistic basis for BAG-1 as a negative regulator of the Hsp70-Hdj-1 chaperone cycle.

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.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.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.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.

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.

The 70 kDa heat shock family of molecular chaperones is essential to a variety of cellular processes, yet it is unclear how these proteins are regulated in vivo. We present evidence that the protein BAG-1 is a potential modulator of the molecular chaperones, Hsp70 and Hsc70. BAG-1 binds to the ATPase domain of Hsp70 and Hsc70, without requirement for their carboxy-terminal peptide-binding domain, and can be co-immunoprecipitated with Hsp/Hsc70 from cell lysates. Purified BAG-1 and Hsp/Hsc70 efficiently form heteromeric complexes in vitro. BAG-1 inhibits Hsp/Hsc70-mediated in vitro refolding of an unfolded protein substrate, whereas BAG-1 mutants that fail to bind Hsp/Hsc70 do not affect chaperone activity. The binding of BAG-1 to one of its known cellular targets, Bcl-2, in cell lysates was found to be dependent on ATP, consistent with the possible involvement of Hsp/Hsc70 in complex formation. Overexpression of BAG-1 also protected certain cell lines from heat shock-induced cell death. The identification of Hsp/Hsc70 as a partner protein for BAG-1 may explain the diverse interactions observed between BAG-1 and several other proteins, including Raf-1, steroid hormone receptors and certain tyrosine kinase growth factor receptors. The inhibitory effects of BAG-1 on Hsp/Hsc70 chaperone activity suggest that BAG-1 represents a novel type of chaperone regulatory proteins and thus suggest a link between cell signaling, cell death and the stress response.