Radu Mihai

Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: International standards guideline statement

Intraoperative neural monitoring (IONM) during thyroid and parathyroid surgery has gained widespread acceptance as an adjunct to the gold standard of visual nerve identification. Despite the increasing use of IONM, review of the literature and clinical experience confirms there is little uniformity in application of and results from nerve monitoring across different centers. We provide a review of the literature and cumulative experience of the multidisciplinary International Neural Monitoring Study Group with IONM spanning nearly 15 years. The study group focused its initial work on formulation of standards in IONM as it relates to important areas: 1) standards of equipment setup/endotracheal tube placement and 2) standards of loss of signal evaluation/intraoperative problem‐solving algorithm. The use of standardized methods and reporting will provide greater uniformity in application of IONM. In addition, this report clarifies the limitations of IONM and helps identify areas where additional research is necessary. This guideline is, at its forefront, quality driven; it is intended to improve the quality of neural monitoring, to translate the best available evidence into clinical practice to promote best practices. We hope this work will minimize inappropriate variations in monitoring rather than to dictate practice options. Laryngoscope, 121:S1–S16, 2011

Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status

Germline mutations in the FH gene encoding the Krebs cycle enzyme fumarate hydratase predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. FH‐deficient cells and tissues accumulate high levels of fumarate, which may act as an oncometabolite and contribute to tumourigenesis. A recently proposed role for fumarate in the covalent modification of cysteine residues to S‐(2‐succinyl) cysteine (2SC) (termed protein succination) prompted us to assess 2SC levels in our existing models of HLRCC. Herein, using a previously characterized antibody against 2SC, we show that genetic ablation of FH causes high levels of protein succination. We next hypothesized that immunohistochemistry for 2SC would serve as a metabolic biomarker for the in situ detection of FH‐deficient tissues. Robust detection of 2SC was observed in Fh1 (murine FH)‐deficient renal cysts and in a retrospective series of HLRCC tumours (n = 16) with established FH mutations. Importantly, 2SC was undetectable in normal tissues (n = 200) and tumour types not associated with HLRCC (n = 1342). In a prospective evaluation of cases referred for genetic testing for HLRCC, the presence of 2SC‐modified proteins (2SCP) correctly predicted genetic alterations in FH in every case. In two series of unselected type II papillary renal cancer (PRCC), prospectively analysed by 2SCP staining followed by genetic analysis, the biomarker accurately identified previously unsuspected FH mutations (2/33 and 1/36). The investigation of whether metabolites in other tumour types produce protein modification signature(s) that can be assayed using similar strategies will be of interest in future studies of cancer. Copyright

External branch of the superior laryngeal nerve monitoring during thyroid and parathyroid surgery: International Neural Monitoring Study Group standards guideline statement.

Intraoperative neural monitoring (IONM) during thyroid surgery has gained widespread acceptance as an adjunct to the gold standard of visual identification of the recurrent laryngeal nerve (RLN). Contrary to routine dissection of the RLN, most surgeons tend to avoid rather than routinely expose and identify the external branch of the superior laryngeal nerve (EBSLN) during thyroidectomy or parathyroidectomy. IONM has the potential to be utilized for identification of the EBSLN and functional assessment of its integrity; therefore, IONM might contribute to voice preservation following thyroidectomy or parathyroidectomy. We reviewed the literature and the cumulative experience of the multidisciplinary International Neural Monitoring Study Group (INMSG) with IONM of the EBSLN. A systematic search of the MEDLINE database (from 1950 to the present) with predefined search terms (EBSLN, superior laryngeal nerve, stimulation, neuromonitoring, identification) was undertaken and supplemented by personal communication between members of the INMSG to identify relevant publications in the field. The hypothesis explored in this review is that the use of a standardized approach to the functional preservation of the EBSLN can be facilitated by application of IONM resulting in improved preservation of voice following thyroidectomy or parathyroidectomy. These guidelines are intended to improve the practice of neural monitoring of the EBSLN during thyroidectomy or parathyroidectomy and to optimize clinical utility of this technique based on available evidence and consensus of experts.

Negative imaging studies for primary hyperparathyroidism are unavoidable: correlation of sestamibi and high-resolution ultrasound scanning with histological analysis in 150 patients.

Preoperative localization studies with Tc99m-sestamibi have become an integral step in the preoperative assessment of patients with primary hyperparathyroidism (PHPT). This enables scan-directed minimally invasive parathyroidectomy (MIP) to be the preferred treatment for PHPT in many units. This study aimed to identify factors that lead to negative imaging studies in patients with PHPT. Over a 3-year period consecutive unselected patients with PHPT underwent Tc99m-sestamibi scanning and high-resolution ultrasound (US) scanning by the same radiologist. When localization studies were concordant, patients underwent MIP. Those patients with negative imaging studies underwent bilateral neck exploration. Histology slides were independently reviewed and the proportion of chief cells and oxyphil cells within each adenoma was estimated. One hundred and fifty-eight patients underwent localization studies (38 men and120 women, aged 61.8 ± 15.2 years). Sestamibi scans were negative in 52 (32%) and positive in 106 (68%) patients. There was a higher incidence of hyperplasia in the group of patients with negative sestamibi scans (4 out of 52 vs. 4 out of 103, P < 0.05, χ2 test). In patients with negative sestamibi scans the majority of adenomas were formed predominantly from chief cells (26 out of 36) while the majority of patients with adenomas composed predominantly of oxyphil cells had positive scans (21 out of 23) (P < 0.05, χ2 test). The weight of parathyroid adenomas was higher when sestamibi scans were positive (median: 1,180 vs. 517 mg, P < 0.05, Student’s t-test). Successful preoperative localization of parathyroid adenomas using Tc99m-sestamibi scanning is influenced by the cytological predominance of individual tumors. Negative scans might therefore be unavoidable in a subgroup of patients.

Imaging for primary hyperparathyroidism—an evidence-based analysis

ObjectiveImaging in patients with primary hyperparathyroidism has been proven difficult. During the last decade, sestamibi scintigraphy and ultrasound (US) have been used with various success. The importance of these procedures has risen since minimal invasive parathyroid (MIP) surgery also has developed, and it is claimed that preoperative localization usually is needed before embarking on such a procedure.MethodsWe have scanned the most recent literature in this matter in order to identify evidence, using commonly accepted grading, and also concluded a number of recommendations.Results and conclusionsWe found evidence at level III leading to recommendations at grade B, that sestamibi scintigraphy is a recommended first test, but that US by an experienced investigator may be an alternative. MIP may be performed when both tests are concordant, and in case of only one test being positive, unilateral exploration and use of intraoperative PTH measurements are recommended. Bilateral neck exploration is used when both tests are negative. For reoperative procedures, repeat investigations are recommended, but also to use US-guided fine needle aspiration and PTH measurements as well as venous sampling. However, for reoperative procedures, the level of evidence is weaker—level IV, but recommendations still at grade B.

Minimally invasive parathyroidectomy without intraoperative parathyroid hormone monitoring in patients with primary hyperparathyroidism

Minimally invasive parathyroidectomy (MIP) is the preferred operation for patients with primary hyperparathyroidism (HPT) and positive preoperative imaging. This non‐randomized case series assessed the long‐term results of MIP performed without the use of intraoperative parathyroid hormone (ioPTH) monitoring.

Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24

Five single nucleotide polymorphisms (SNPs) associated with thyroid cancer (TC) risk have been reported: rs2910164 (5q24); rs6983267 (8q24); rs965513 and rs1867277 (9q22); and rs944289 (14q13). Most of these associations have not been replicated in independent populations and the combined effects of the SNPs on risk have not been examined. This study genotyped the five TC SNPs in 781 patients recruited through the TCUKIN study. Genotype data from 6122 controls were obtained from the CORGI and Wellcome Trust Case-Control Consortium studies. Significant associations were detected between TC and rs965513A (p=6.35×10−34), rs1867277A (p=5.90×10−24), rs944289T (p=6.95×10−7), and rs6983267G (p=0.016). rs6983267 was most strongly associated under a recessive model (PGG vs GT + TT=0.004), in contrast to the association of this SNP with other cancer types. However, no evidence was found of an association between rs2910164 and disease under any risk model (p>0.7). The rs1867277 association remained significant (p=0.008) after accounting for genotypes at the nearby rs965513 (p=2.3×10−13) and these SNPs did not tag a single high risk haplotype. The four validated TC SNPs accounted for a relatively large proportion (∼11%) of the sibling relative risk of TC, principally owing to the large effect size of rs965513 (OR 1.74).

Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2

Heterozygous mutations of GATA3, which encodes a dual zinc-finger transcription factor, cause hypoparathyroidism with sensorineural deafness and renal dysplasia. Here, we have investigated the role of GATA3 in parathyroid function by challenging Gata3+/- mice with a diet low in calcium and vitamin D so as to expose any defects in parathyroid function. This led to a higher mortality among Gata3+/- mice compared with Gata3+/+ mice. Compared with their wild-type littermates, Gata3+/- mice had lower plasma concentrations of calcium and parathyroid hormone (PTH) and smaller parathyroid glands with a reduced Ki-67 proliferation rate. At E11.5, Gata3+/- embryos had smaller parathyroid-thymus primordia with fewer cells expressing the parathyroid-specific gene glial cells missing 2 (Gcm2), the homolog of human GCMB. In contrast, E11.5 Gata3-/- embryos had no Gcm2 expression and by E12.5 had gross defects in the third and fourth pharyngeal pouches, including absent parathyroid-thymus primordia. Electrophoretic mobility shift, luciferase reporter, and chromatin immunoprecipitation assays showed that GATA3 binds specifically to a functional double-GATA motif within the GCMB promoter. Thus, GATA3 is critical for the differentiation and survival of parathyroid progenitor cells and, with GCM2/B, forms part of a transcriptional cascade in parathyroid development and function.

One in Four Patients with Follicular Thyroid Cytology (THY3) Has a Thyroid Carcinoma

BACKGROUND Fine-needle aspiration (FNA) biopsy is the cornerstone of assessment of thyroid nodules. Cytological criteria for benign (THY2) and malignant (THY5) aspirates are well established and reliable. When cytology suggests a follicular neoplasm (THY3), only formal histological assessment can differentiate between benign and malignant lesions. The objective of this study was to determine the factors predictive of malignancy in thyroid nodules when cytological assessment is restricted to euthyroid patients living in an area without endemic goiter who undergo routine diagnostic lobectomy once the FNA raises the suspicion of a follicular neoplasm. METHOD Retrospective review of histological and clinical data in a cohort of patients with a palpable thyroid nodule and THY3 cytology. RESULTS Between January 2000 and December 2007, 1981 patients (346 males and 1635 females) underwent 2809 thyroid FNAs. There were 201 THY3 reports (9%). Histology demonstrated thyroid carcinomas in 57 patients (31 follicular carcinomas, 11 Hurthle cell carcinomas, 11 papillary carcinomas, 1 medullary thyroid carcinoma, 1 poorly differentiated thyroid cancer, 1 lymphoma, and 1 metastatic renal carcinoma). Benign tumors were found in 144 patients with follicular adenomas (n = 76), Hurthle cell adenomas (n = 33), multinodular goiter (n = 13), adenomatoid nodules (n = 15), colloid nodules (n = 4), and thyroiditis (n = 3). THY3 cytology was more predictive of malignancy in men (13/34 male symbol vs. 44/167 female symbol, p < 0.001, chi(2) test). The risk for malignancy was 1:4 for the entire group and 1:3 for patients under 30 years and over 60 years. About 17/46 nodules over 40 mm in diameter were carcinomas, compared with only 35/140 in nodules under 40 mm (p < 0.01, chi2 test). CONCLUSION One in four patients with cytological features of a follicular neoplasm has a thyroid carcinoma. A large nodule (>4 cm) with THY3 cytology has a high likelihood of being a cancer, and arguably such patients could be offered total thyroidectomy rather than diagnostic lobectomy.

Surgical strategy for sporadic primary hyperparathyroidism an evidence-based approach to surgical strategy, patient selection, surgical access, and reoperations

PurposeProgress in parathyroid imaging has brought substantial changes in the surgical strategy to approach patients with sporadic primary hyperparathyroidism (pHPT). The present review is focused on the safety and efficacy of limited parathyroid exploration.Materials and methodsReview of the literature focused on studies dealing with unilateral (two-gland exploration) or selective parathyroidectomy (one-gland exploration) in selected patients with pHPT and on the classification of published reports according to the degree of evidence.ResultsParathyroid exploration limited to a solitary parathyroid adenoma can be considered a minimally invasive procedure that can be performed by the minicervicotomy, video-assisted, or endoscopic approaches. In properly selected patients, it affords results comparable to those of four-gland bilateral exploration in terms of cure and recurrence. It causes less postoperative hypocalcemia.ConclusionsSelective parathyroidectomy is an option for patients with positive preoperative localization tests undergoing first-time surgery who have no family history of pHPT, no goiter for which surgical therapy is proposed, and are not on lithium therapy.