Influence of Daily Variations in Individual Surgeon's Operative Time on Patient Outcomes.

BACKGROUND: Evidence is lacking regarding the potential association between daily variation in individual surgeon's operative time, procedure after procedure, and risk of patient complication. We assumed that surgeon deviation from the expected procedure duration may be harmful for patient. METHOD: All patients who underwent a thyroidectomy undertaken in five hospitals during a 1-year period were included prospectively. For each thyroidectomy, we estimated the expected operative time from a multilevel linear regression considering the attending surgeon who performed the operation, the patient preoperative risk, and the procedure complexity. Three groups of thyroidectomies were identified according to whether the observed duration is: slower than expected, as expected, or faster than expected. Rates of permanent recurrent laryngeal nerve palsy and hypoparathyroidism at 6 months were then compared between these groups. RESULTS: A total of 3102 patients who underwent a thyroidectomy undertaken by 22 surgeons were considered. Risk of laryngeal nerve palsy was higher in the "slow" group than in the "normal" group (OR = 4.63, 95% confidence interval 2.21-9.70), as was that of hypoparathyroidism (OR = 2.43, 95% confidence interval 1.21-4.88). There was no significant difference between "fast" and "normal" groups for either complication. Deviation from expected procedure duration was more frequent at the end than at the beginning of the daily operation schedule (29.4% vs. 18.3%, respectively, P < .001). CONCLUSION: Patients had a greater risk of complication when the surgeon performed thyroidectomy slower than expected. Surgeons avoiding excessive deviations from their expected procedures durations reflect safer practice.

Correction to: Does Surgery Without Lugol's Solution Pretreatment for Graves' Disease Increase Surgical Morbidity?

In the original article, Mathieu Bonal's last name was spelled incorrectly. It is correct as reflected here. The original article has also been updated.

Does Surgery Without Lugol's Solution Pretreatment for Graves' Disease Increase Surgical Morbidity?

BACKGROUND: Total thyroidectomy can be performed for Graves' disease after a euthyroid state is achieved using inhibitors of thyroid hormone synthesis (thioamides). However, hypervascularization of the thyroid gland is associated with increased hemorrhage risk, in addition to complicating identification of the recurrent laryngeal nerve and parathyroid gland. Saturated iodine solution (Lugol's solution) has been recommended to reduce thyroid gland hypervascularization and intraoperative blood loss, although this approach is not used at our center based on our experience that it induces thyroid firmness and potentially hypoparathyroidism. METHODS: This retrospective single-center study evaluated patients who underwent total thyroidectomy for Graves' disease between November 2010 and November 2015. The rates of various complications at our center were compared to those from the literature (e.g., cervical hematoma, hypocalcemia, and recurrent laryngeal nerve palsy). RESULTS: Three hundred and eighty consecutive patients underwent total thyroidectomy without preoperative Lugol's solution (311 women [81.84%] and 69 men [18.16%], mean age 43.41 years). No postoperative deaths were reported, although 30 patients (7.89%) experienced recurrent laryngeal nerve palsy and 9 patients experienced permanent injuries (2.37%). Hypoparathyroidism was experienced by 87 patients (25.53%) and 14 patients experienced permanent hypoparathyroidism (3.68%). Four patients required reoperation for cervical hematoma (1.05%; 2 deep and 2 superficial hematomas). CONCLUSION: Despite the recommendation of iodine pretreatment, few of our non-pretreated patients experienced permanent nerve injury (2.37%) or permanent hypoparathyroidism (3.68%). These results are comparable to the outcomes from the literature. Randomized controlled trials are needed to determine whether iodine pretreatment is necessary before surgery for Graves' disease.

[Not Available]. / Qualité en chirurgie thyroidienne: Critères d'évaluation et applications pratiques.

Evaluation and research of quality factors in surgery necessitates the consideration of 3 types of indicators: indicators of structures, indicators of processes and indicators of outcomes. We used these 3 types of indicators to assess the quality of thyroid surgery and to evaluate quality indicators. These studies allowed us to demonstrate the importance of a permanent monitoring of the outcomes of the thyroid surgery and the presence of human and organizational factors in the mechanisms of the surgical complications. This type of evaluation and research in quality of health care should be extended to all the surgical subspecialties.

Role of preoperative basal calcitonin levels in the timing of prophylactic thyroidectomy in patients with germline RET mutations.

BACKGROUND: The American Thyroid Association (ATA) published recommendations for the timing of prophylactic surgery for medullary thyroid carcinoma based on the specific mutation, patient age, family history, and serum calcitonin levels. The aim of this study was to assess the role of preoperative basal calcitonin (prebCt) levels in predicting the presence of medullary carcinoma of the thyroid in patients with RET mutations. METHODS: We conducted a retrospective study in two endocrine surgery departments. Between 1986 and 2012, a total of 32 patients with RET mutations underwent prophylactic thyroidectomy. The patients were stratified into four ATA risk levels: A, B, C, and D. RESULTS: All of the patients were biologically cured. Microcarcinoma was observed in the final pathology report for four of the 20 patients with normal prebCt (25 %) and for nine of the 12 patients with elevated prebCt (75 %). In the level A group, four patients with normal prebCt and one patient with elevated prebCt presented with microcarcinoma. In the level C group, one patient with normal prebCt and six of the seven patients with elevated prebCt (86 %) presented with microcarcinoma. CONCLUSIONS: PrebCt can predict the presence of microcarcinoma according to surgical pathological analysis. Patients with microcarcinoma can be biochemically and clinically cured using prophylactic thyroidectomy.

Is basal ultrasensitive measurement of calcitonin capable of substituting for the pentagastrin-stimulation test?

OBJECTIVE: To evaluate a second-generation assay for basal serum calcitonin (CT) measurements compared with the pentagastrin-stimulation test for the diagnosis of inherited medullary thyroid carcinoma (MTC) and the follow-up of patients with MTC after surgery. Recent American Thyroid Association recommendations suggest the use of basal CT alone to diagnose and assess follow-up of MTC as the pentagastrin (Pg) test is unavailable in many countries. DESIGN: Multicentric prospective study. PATIENTS: A total of 162 patients with basal CT <10 ng/l were included: 54 asymptomatic patients harboured noncysteine 'rearranged during transfection' (RET) proto-oncogene mutations and 108 patients had entered follow-up of MTC after surgery. MEASUREMENT: All patients underwent basal and Pg-stimulated CT measurements using a second-generation assay with 5-ng/l functional sensitivity. RESULTS: Ninety-five per cent of patients with basal CT ≥ 5 ng/l and 25% of patients with basal CT <5 ng/l had a positive Pg-stimulation test (Pg CT >10 ng/l). Compared with the reference Pg test, basal CT ≥ 5 ng/l had 99% specificity, a 95%-positive predictive value but only 35% sensitivity (P < 0.0001). Overall, there were 31% less false-negative results using a 5-ng/l threshold for basal CT instead of the previously used 10-ng/l threshold. CONCLUSION: The ultrasensitive CT assay reduces the false-negative rate of basal CT measurements when diagnosing familial MTC and in postoperative follow-up compared with previously used assays. However, its sensitivity to detect C-cell disease remains lower than that of the Pg-stimulation test.

[Prophylactic thyroidectomy in medullary thyroid cancer]. / La chirurgie prophylactique du cancer médullaire de la thyroïde.

Medullary thyroid cancer (MTC) is genetically determined in 30% to 35% of cases, notably through multiple mutations in the RET protooncogene located on chromosome 10, for which a genotype-phenotype relationship determines age of onset. There are three phenotypes: MEN 2 A and B, and isolated familial MTC. The type of mutation determines 3 levels of aggressiveness. Current guidelines recommend thyroidectomy during the first months of life for patients with very-high-risk (level 3) mutations and before 5 years of age for high-risk (level 2) mutations. There are no precise recommendations for lower-risk mutations, for which the surgical decision also depends on the calcitonin level and family history. We describe 18 patients who underwent prophylactic surgery. Regardless of the mutation, all patients with a normal preoperative calcitonin level were cured. However, surgery was performed later than recommended, for various reasons, including late genetic diagnosis and parents' opposition.

Safety Attitude of Operating Room Personnel Associated With Accurate Completion of a Surgical Checklist: A Cross-sectional Observational Study.

OBJECTIVE: How the checklist is executed in routine practice may reflect the teamwork and safety climate in the operating room (OR). This cross-sectional study aimed to identify whether the presence of a fully completed checklist in medical records was associated with teams' safety attitudes. METHODS: Data from 29 French hospitals, including 5677 operated patients and 834 OR professionals, were prospectively collected. The degree of checklist compliance was categorized for each patient in 1 of 4 ways: full, incomplete, inaccurate, and no checklist completed. The members of OR teams were invited to complete a questionnaire including teamwork climate measurement (Safety Attitudes Questionnaire) and their opinion regarding checklist use, checklist audibly reading, and communication change with checklist. Multilevel modeling was performed to investigate the effect of variables related to hospitals and professionals on checklist compliance, after adjustment for patient characteristics. RESULTS: A checklist was present for 83% of patients, but only 35% demonstrated full completion. Compared with no checklist, full completion was associated with higher safety attitude (high teamwork climate [adjusted odds ratio for full completion, 4.14; 95% confidence interval, 1.75-9.76]; communication change [1.31, 1.04-1.66]; checklist aloud reading [1.16, 1.02-1.32]) and was reinforced by the designation of a checklist coordinator (2.43, 1.06-5.55). Incomplete completion was also associated with enhanced safety attitude contrary to inaccurate completion. CONCLUSIONS: Compliance with checklists is associated with safer OR team practice and can be considered as an indicator of the extent of safety in OR practice.

Results of combined treatment of anaplastic thyroid carcinoma (ATC).

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies. It is associated with a high rate of local recurrence and with poor prognosis. METHODS: We retrospectively reviewed 44 consecutive patients treated between 1996 and 2010 at Leon Berard Cancer Centre, Lyon, France. The combined treatment strategy derived from the one developed at the Institut Gustave Roussy included total thyroidectomy and cervical lymph-node dissection, when feasible, combined with 2 cycles of doxorubicin (60 mg/m2) and cisplatin (100 mg/m2) Q3W, hyperfractionated (1.2 Gy twice daily) radiation to the neck and upper mediastinum (46-50 Gy), and then four cycles of doxorubicin-cisplatin. RESULTS: Thirty-five patients received the three-phase combined treatment. Complete response after treatment was achieved in 14/44 patients (31.8%). Eight patients had a partial response (18.2%). Twenty-two (50%) had progressive disease. All patients with metastases at diagnosis died shortly afterwards. Thirteen patients are still alive. The median survival of the entire population was 8 months. CONCLUSION: Despite the ultimately dismal prognosis of ATC, multimodality treatment significantly improves local control and appears to afford long-term survival in some patients. There is active ongoing research, and results obtained with new targeted systemic treatment appear encouraging.

Influence of intraoperative neuromonitoring on surgeons' technique during thyroidectomy.

BACKGROUND: When assessing the value of intraoperative nerve monitoring (IONM) during routine thyroidectomy, it is necessary to consider its influence on the surgeon's dissection technique. We investigated the effect of IONM on individual surgeon performance by determining the learning curve associated with this tool. METHODS: A one-year prospective study was conducted between May 2008 and April 2009 within a team of three experienced endocrine surgeons. The measure of surgical performance was based on the detection of immediate postoperative recurrent laryngeal nerve palsy by laryngoscopy. Individual learning curves associated with IONM acquisition were drawn with the cumulative sum (CUSUM) chart. Each surgeon was questioned about possible changes he had experienced in his own surgical technique after the introduction of IONM. RESULTS: A total of 475 consecutive patients who underwent thyroid surgery with IONM were included. The pattern of learning curves varied among surgeons and ranged from 35 to 304 procedures required for complete IONM acquisition. The surgeon with the longest learning curve also described a drastic modification of his technique related to nerve dissection. CONCLUSIONS: Intraoperative nerve monitoring can induce changes in surgical practice. The different learning curve patterns among surgeons may reflect the variable degree to which surgeons will modify their own dissection technique. Such an effect on learning must be considered when assessing the impact of using IONM on patient safety.

Long-Term Outcome of Lobectomy for Thyroid Cancer.

INTRODUCTION: Recent guidelines of the American Thyroid Association (ATA) suggest that a lobectomy may be sufficient to treat low- to intermediate-risk patients with thyroid tumors ≤40 mm, without extrathyroidal extension or lymph node metastases. The present study aimed to evaluate long-term recurrence after lobectomy for differentiated thyroid cancer and to analyze factors associated with recurrence. METHODS: In this retrospective cohort study, patients who underwent a lobectomy for thyroid cancer in a tertiary center between 1970 and 2010 were included. The outcome was the proportion of pathology-confirmed thyroid cancer recurrence, assessed in the whole cohort or in subgroups according to tumor size (≤ or >40 mm). RESULTS: A total of 295 patients were included, and these were followed-up for a mean (standard deviation, SD) 19.1 (7.8) years (5,649 patient-years); 61 (20.7%) were male and the mean (SD) age at diagnosis was 39.7 (12) years. Histological subtype was papillary in 263 (89.2%) patients and mean cancer size was 22.9 (16.9) mm. According to the 2015 ATA guidelines, 271 (91.9%) cancers had a low risk of recurrence and 24 (8.1%) an intermediate risk. A reoperation was performed in 54 patients (18.3%) and recurrence was confirmed in 40 (13.6%), diagnosed for 55% of cases more than 10 years after their initial surgery. Among recurrent patients, 14 (4.8% of the cohort) were operated for a contralateral papillary thyroid microcarcinoma and 26 (8.8% of the cohort) for a locoregional or metastatic recurrence. Non-suspicious nodular recurrences were monitored without reoperation in 53 (18.0%) patients. At the end of follow-up, 282 (95.6%) patients were in remission. Tumors with locoregional or metastatic recurrence were more frequent among tumors with aggressive histology (19.2 vs. 4.1%, p = 0.015) and of intermediate risk category (28.6 vs. 7.1%, p = 0.018). Tumors >40 mm, which would have been treated by thyroidectomy according to the 2015 ATA guidelines criteria, were found in 34 (11.5%) patients and were associated with a higher frequency of recurrence (20.6 vs. 7.3%, p = 0.024) and less remission (85.3 vs. 96.9%, p = 0.001). CONCLUSION: The outcome of thyroid cancer treated by lobectomy is very good, particularly for cancer ≤40 mm. A prolonged follow-up is required due to the risk of late recurrence.

Thyroglobulin measurement in fine-needle aspirates of lymph nodes in patients with differentiated thyroid cancer: a simple definition of the threshold value, with emphasis on potential pitfalls of the method.

BACKGROUND: Thyroglobulin measurements in fine-needle aspirate (FNA-Tg) is an accurate method for the diagnosis of lymph node metastasis in differentiated thyroid carcinoma. The goal of this study is to determine the most appropriate diagnostic threshold value for FNA-Tg. METHODS: Ultrasound-guided fine-needle aspiration-cytology (FNA-C) and FNA-Tg were performed on suspicious lymph nodes in 114 consecutive patients with thyroid cancer prior to thyroidectomy (n=13) or during follow-up (n=93), and in 16 control subjects. Functional sensitivity of the thyroglobulin assay was 0.7 ng/mL. Sensitivity and specificity of FNA-Tg and FNA-C were determined for different cut-off values within a range of 0.69-1.34 nanogram/punction (ng/p) using receiver operating characteristic curve analysis. RESULTS: The FNA-Tg cut-off value of 0.93 ng/p offers the best diagnostic performances: 94.2% sensitivity, 97.8% specificity. FNA-C showed 100% specificity in diagnostic samples, but low sensitivity of 71% due primarily to inadequate samples. Combining FNA-C and FNA-Tg resulted in 98% sensitivity and 100% specificity. CONCLUSIONS: A unique threshold of 0.93 ng/p gives high sensitivity and specificity, even in non-thyroidectomized patients. However, since false negative results may be observed in poorly differentiated thyroid cancer, FNA-C should remain combined to FNA-Tg.

Evaluation of gene expression profiles in thyroid nodule biopsy material to diagnose thyroid cancer.

CONTEXT: Detection of thyroid cancer among benign nodules on fine-needle aspiration biopsies (FNAB), which presently relies on cytological examination, is expected to be improved by new diagnostic tests set up from genomic data. OBJECTIVE: The aim of the study was to use a set of genes discriminating benign from malignant tumors, on the basis of their expression levels, to build tumor classifiers and evaluate their capacity to predict malignancy on FNAB. DESIGN: We analyzed the level of expression of 200 potentially informative genes in 56 thyroid tissue samples (benign or malignant tumors and paired normal tissue) using nylon macroarrays. Gene expression data were subjected to a weighted voting algorithm to generate tumor classifiers. The performances of the classifiers were evaluated on a series of 26 sham FNAB, i.e. FNAB carried out on thyroid nodules after surgical resection. RESULTS: A series of 19 genes with a similar expression in follicular adenomas and normal tissue and discriminating follicular adenomas+normal tissue from the following: 1) follicular thyroid carcinomas (FTCs), 2) papillary thyroid carcinomas (PTCs), or 3) both FTCs and PTCs. These were used to generate four classifiers, the FTCs, PTCs, common (FTC+PTCs), and global classifiers. In 23 of the 26 sham FNAB, the four classifiers yielded a diagnosis in agreement with the diagnosis of the pathologist used as reference; in the three other cases, the correct diagnosis was given by three of four classifiers. CONCLUSIONS: We developed a procedure of molecular diagnosis of benign vs. malignant tumors applicable to the material collected by FNAB. The molecular test complied with a preclinical validation stage; it must be now evaluated on ultrasound-guided FNAB in a large-scale prospective study.

Predictive factors of outcome in poorly differentiated thyroid carcinomas.

BACKGROUND: The prognosis of poorly differentiated thyroid carcinomas (PDTC) is heterogeneous though generally poor. The objectives of this study were to identify clinical and molecular factors of poor prognosis. METHODS: One hundred four consecutive patients treated for a PDTC between 01/01/2000 and 31/12/2010 were included in this study. A pathological review was done for all cases (blinded to clinical data and outcome). RESULTS: All patients underwent thyroidectomy. Adjuvant radioactive-iodine was administered in 95.2% of them. Tumours were pT3 or pT4 in 68.3% of cases and metastatic in 38.5% of patients. Extrathyroidal extension (ETE) was observed in 40% of patients. At the end of the initial treatment, only 37% of patients were considered in remission. Fifty-two patients (50%) became refractory to radioiodine during follow-up. The 5-year overall survival was 72.8% and the 5-year recurrence-free survival (RFS) was 45.3%. Remission after initial treatment was an independent factor of RFS (HR = 0.22; [0.10-0.49]). ETE was the only significant parameter influencing the overall survival in multivariate analysis. TERT promoter mutations at positions -124 (C228T) and -146 (C250T) were present in 38.1% of analysed patients and significantly associated with radioiodine resistance but not with overall survival. Half of TERT promoter mutant tumours harboured also RAS or BRAF mutations. CONCLUSION: PDTC form a heterogeneous group of patients with usual late-stage diagnosis, low radioactive iodine avidity and frequent metastatic spread. TERT promoter mutations could help to identify patients with high risk of radio-iodine refractoriness.

Can we consider immediate complications after thyroidectomy as a quality metric of operation?

BACKGROUND: Permanent recurrent laryngeal nerve palsy and hypoparathyroidism are 2 major complications after thyroid operation. Assuming that the rate of immediate complications can predict the permanent complication rate, some authors consider these complications as a valid metric for assessing the performance of individual surgeons. This study aimed to determine the correlation between rates of immediate and permanent complications after thyroidectomy at the surgeon level. METHODS: We conducted a prospective, cross-sectional study in 5 academic hospitals between April 2008 and December 2009. The correlation between the rates of immediate and permanent complications for each of the 22 participating surgeons was calculated using the Pearson correlation test (r). RESULTS: The study period included 3,605 patients. There was a fairly good correlation between rates of immediate and permanent recurrent laryngeal nerve palsy (r = 0.70, P = .004), but no correlation was found for immediate and permanent hypoparathyroidism (r = 0.18, P = .427). CONCLUSION: The immediate hypoparathyroidism rate does not reflect the permanent hypoparathyroidism rate. Consequently, immediate hypoparathyroidism should not be used to assess the quality of thyroidectomy or to monitor the performance of surgeons.

Predicting thyroid nodule malignancy at several prevalence values with a combined Bethesda-molecular test.

Investigation of thyroid nodules using fine-needle aspiration cytology (FNAC) gives indeterminate results in up to 30% of samples using the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). We present a combined Bethesda-molecular predictor of nodule malignancy to improve the accuracy of the preoperative diagnosis of thyroid nodules. To detect a molecular signature of thyroid nodule malignancy, a molecular test was performed on FNACs from 128 thyroid nodules from prospectively included patients, collected in a tertiary center. The test relied on a transcriptomic array of 20 genes selected from a previous study. An optimal set of seven genes was identified using a logistic regression model. Comparison between the combined predictor (TBSRTC + molecular) and TBSRTC alone used the area under the ROC curve (AUC). Performance of the combined predictor was calculated according to various malignancy prevalence values and benefit-to-harm ratios (B/Hr) (favoring sensitivity or specificity). In our population (36% malignancy prevalence) and with a B/Hr of 1, the combined predictor achieved 95% specificity and 76% sensitivity. The AUC was 93.5%; higher than that of TBSRTC (P = 0.004). Among indeterminate nodules (30% malignancy prevalence), sensitivity and specificity were 52.2% and 96.2%, respectively, with a B/Hr of 1, or 95.7% and 64.2% with a B/Hr of 4 (favoring sensitivity), allowing avoidance of 64% of unnecessary surgeries at the cost of only one false-positive result. In conclusion, this predictor could improve the detection of thyroid nodule malignancy, taking into account malignancy prevalence and B/Hr, and reduce the number of unnecessary thyroidectomies.

Determinants of operative time in thyroid surgery: A prospective multicenter study of 3454 thyroidectomies.

OBJECTIVE: To identify the determinants of operative time for thyroidectomy and quantify the relative influence of preoperative and intra-operative factors. BACKGROUND: Anticipation of operative time is key to avoid both waste of hospital resources and dissatisfaction of the surgical staff. Having an accurate and anticipated planning would allow a rationalized operating room use and may improve patient flow and staffing level. METHODS: We conducted a prospective, cross-sectional study between April 2008 and December 2009. The operative time of 3454 patients who underwent thyroidectomy performed by 28 surgeons in five academic hospitals was monitored. We used multilevel linear regression to model determinants of operative time while accounting for the interplay of characteristics specific to surgeons, patients, and surgical procedures. The relative impact of each variable on operative time was estimated. RESULTS: Overall, 86% (99% CI 83 to 89) of operative time variation was related to preoperative variables. Surgeon characteristics accounted for 32% (99% CI 29 to 35) of variation, center location for 29% (99% CI 25 to 33), and surgical procedure or patient variables for 24% (99% CI 20 to 27). Operative time was significantly lower among experienced surgeons having practiced from 5-19 years (-21.8 min, P<0.05), performing at least 300 thyroidectomies per year (-28.8 min, P<0.05), and with increasing number of thyroidectomies performed the same day (-11.7min, P<0.001). Conversely, operative time increased in cases of procedure supervision by a more experienced surgeon (+20.0 min, P<0.001). The remaining 13.0% of variability was attributable to unanticipated technical difficulties at the time of surgery. CONCLUSIONS: Variation in thyroidectomy duration is largely explained by preoperative factors, suggesting that it can be accurately anticipated. Prediction tools allowing better regulation of patient flow in operating rooms appears feasible for both working conditions and cost management.

Aldosterone-Producing Adenoma With a Somatic KCNJ5 Mutation Revealing APC-Dependent Familial Adenomatous Polyposis.

CONTEXT: Recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 have been identified in aldosterone-producing adenomas (APAs). The question as to whether they are responsible for both nodulation and aldosterone production is not solved. CASE DESCRIPTION: We describe the case of a young patient who was diagnosed with severe arterial hypertension due to primary aldosteronism at age 26 years, followed by hemorrhagic stroke 4 years later. Abdominal computed tomography showed bilateral macronodular adrenal hyperplasia. Identification of lateralized aldosterone secretion led to right adrenalectomy, followed by normalization of biochemical and hormonal parameters and amelioration of blood pressure. The resected adrenal showed three nodules, one of them expressing aldosterone synthase and harboring a somatic KNCJ5 mutation. A Weiss revisited index of 3 of the APA prompted us to perform a second 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography after surgery, which revealed abnormal rectal activity despite the absence of clinical symptoms. Gastrointestinal exploration showed multiple polyps with severe dysplasia, and the diagnosis of familial adenomatous polyposis was established in the presence of a germline heterozygous APC gene mutation. Sequencing of somatic DNA from the APA and a second adrenal nodule revealed biallelic APC inactivation due to loss of heterozygosity in both nodules. CONCLUSIONS: This case report underlines the need for establishing the frequency of germline APC variants in patients with primary aldosteronism and bilateral macronodular adrenal hyperplasia because their presence may predispose to APA development and severe hypertension well before the first familial adenomatous polyposis symptoms appear. From a mechanistic point of view, it supports a two-hit model for APA development, whereby the first hit drives increased cell proliferation whereas the second hit specifies the pattern of hormonal secretion.

Does Molecular Genotype Provide Useful Information in the Management of Radioiodine Refractory Thyroid Cancers? Results of a Retrospective Study.

INTRODUCTION: Whether mutation status should be used to guide therapy is an important issue in many cancers. We correlated mutation profile in radioiodine-refractory (RAIR) metastatic thyroid cancers (TCs) with patient outcome and response to tyrosine kinase inhibitors (TKIs), and discussed the results with other published data. MATERIALS AND METHODS: Outcome in 82 consecutive patients with metastatic RAIR thyroid carcinoma prospectively tested for BRAF, RAS and PI3KCA mutations was retrospectively analyzed, including 55 patients treated with multikinase inhibitors. RESULTS: Papillary thyroid carcinomas (PTCs) were the most frequent histological subtype (54.9 %), followed by poorly differentiated thyroid carcinoma [PDTC] (30.5 %) and follicular thyroid carcinoma [FTC] (14.6 %). A genetic mutation was identified in 23 patients (28 %) and BRAF was the most frequently mutated gene (23 %). Median progression-free survival (PFS) on first-line TKI treatment was 14.6 months (95% CI 9.9-18.4). BRAF mutation positively influenced median PFS, both in the entire TKI-treated cohort (median PFS 34.7 months versus 11.6 months; hazard ratio [HR] 0.29; 95% CI 0.09-0.98; p = 0.03) and in the TKI-treated PTC cohort (n = 22) [log-rank p = 0.086; HR 2.95; 95 % CI 0.81-10.70). However, in TKI-treated patients, PDTC histologic subtype was the only independent prognostic factor for PFS identified in the multivariate analysis (HR 2.36; 95% CI 1.01-5.54; p = 0.048). CONCLUSION: Patients with BRAF-mutant PTC had a significantly longer PFS than BRAF wild-type when treated with TKIs. However, due to the small number of BRAF-mutant patients, further investigations are required, especially to understand the potential positive effect of BRAF mutations in RAIR TC patients while having a negative prognostic impact in RAI-sensitive PTC patients.