Completion Thyroidectomy is Less Common Following Updated 2015 American Thyroid Association Guidelines.

BACKGROUND: The 2015 American Thyroid Association (ATA) guidelines recommended that low-risk, differentiated thyroid cancers (DTC) between 1 and 4 cm may be treated with thyroid lobectomy alone. We sought to determine the effect of these guideline changes on the rate of completion thyroidectomy (CT) for low-risk DTC and factors influencing surgical decision-making. METHODS: All patients from 2014 to 2018 who received an initial thyroid lobectomy at our institution with final pathology demonstrating DTC were included. Patients were divided into "pre" and "post" guideline cohorts (2014-2015 and 2016-2018, respectively). The rate of CT was compared between the two cohorts. Patient demographics and tumor characteristics were examined for association with CT. RESULTS: A total of 163 patients met study criteria: 63 patients in the 2014-2015 ("pre") and 100 in the 2016-2018 ("post") group. In the "pre" period, 41 (65.1%) patients received CT compared with 43 (43.0%) in the "post" period (p < 0.01)-a 34% decrease in the rate of completion surgery (p < 0.01). Of low-risk patients with DTC between 1 and 4 cm in size, 17 of 35 (48.6%) received CT in the "pre" period compared with 15 of 60 (25.0%) in the post period-a 48.6% decrease in the rate of completion surgery (p = 0.02). Greater tumor size, capsular invasion, and multifocality were associated with CT in low-risk "post" guideline patients (p < 0.05 for all). CONCLUSIONS: The rate of CT decreased significantly by 48.6% for low-risk patients with DTC between 1 and 4 cm, demonstrating recognition of the 2015 ATA guidelines. However, 25% of these patients underwent CT, suggesting additional factors influencing the decision for further treatment.

Effect of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) on Malignancy Rates in Thyroid Nodules: How to Counsel Patients on Extent of Surgery.

PURPOSE: To investigate the impact of the nomenclature change to "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) on reported malignancy rates following thyroidectomy. METHODS: Retrospective cohort study of patients with thyroid nodules sampled preoperatively with fine-needle aspiration (FNA) and subsequently removed at one tertiary-care hospital from 4/2016 to 2/2017. Surgical procedure, anatomic pathology, thyroid cytopathology classification, and demographic characteristics were recorded. RESULTS: Thyroidectomy was performed in 353 patients. Twenty-six patients (7.3%) had NIFTP on anatomic pathology. Preoperative FNA demonstrated atypia of undetermined significance (AUS/Bethesda III) in 13 (50%), suspicious for malignancy (SUS/Bethesda V) in 6 (23%), suspicious for follicular neoplasm (SFN/Bethesda IV) in 4 (15%), benign/Bethesda I in 2 (8%), and malignant/Bethesda VI in 1 (4%). Invasive malignancy rates across cytologic categories changed as follows: benign (n = 74) from 4 to 1%, AUS (n = 85) from 33 to 18% (p < 0.05), SFN (n = 58) from 29 to 22%, SUS (n = 33) from 91 to 73% (p < 0.05), and malignant (n = 99) from 99 to 98%. Overall decrease in invasive malignancy was 7.3% for the entire population and 13.1% for indeterminate preoperative FNA cytology (Bethesda III-V). Among 26 NIFTP patients, 17 had thyroid lobectomy (TL) and 9 underwent total thyroidectomy (TT). Eight of the nine patients with TT could have been definitively treated with TL, an 89% decrease. CONCLUSIONS: The NIFTP nomenclature change led to an overall decrease in the malignancy rate at our institution, especially for Bethesda III-V categories. Patients may be counseled toward more conservative surgical options if NIFTP is in the differential.

The Posterior Adiposity Index: A Quantitative Selection Tool for Adrenalectomy Approach.

BACKGROUND: Objective criteria are lacking to determine whether a laparoscopic transabdominal (LA) or retroperitoneoscopic (RP) approach to adrenalectomy is optimal. We hypothesized that imaging characteristics could predict patients for whom RP adrenalectomy is the optimal approach. MATERIALS AND METHODS: Retrospective cohort study of all patients undergoing minimally invasive adrenalectomy between 2014 and 2016 (n = 113) at one institution. Imaging measurements included distances between the skin and Gerota's fascia (S-GF), upper borders of adrenal and kidney (A-K), adrenal and 12th rib (A-R), 12th rib and iliac crest (R-IC), and perinephric fat (PNF). These characteristics plus patient body mass index, gender, age, tumor size, and diagnosis were compared with operative time and estimated blood loss using Pearson's correlation or ANOVA. Multivariable linear regression also identified independent predictors of operative time. RESULTS: Half of patients underwent LA (n = 57) and RP adrenalectomy (n = 56). Median age was 57 y; 60% were female. Mean tumor size was 3.2 cm. Higher body mass index patients were more likely to undergo LA (P = 0.03). Increasing lesion size modestly correlated with longer operative time (r = 0.341). On bivariate analysis, S-GF and PNF distances moderately correlated with operative time (r = 0.464 and 0.494) for RP procedures. The sum of S-GF and PNF generated a Posterior Adiposity Index (PAI). The PAI strongly correlated with operative time for RP (r = 0.590). Nothing was significantly associated with estimated blood loss. Multivariate analysis revealed larger lesions (P = 0.025) and increasing PAI (P = 0.019) were predictive of longer operative time, with PAI ≥9 conferring the greatest risk (P = 0.004). CONCLUSIONS: Smaller tumors and PAI <9 are associated with shorter operative times in RP adrenalectomy. Surgeons can utilize preoperative images to calculate the PAI and determine whether an RP approach would be favorable.

4D-CT is Superior to Ultrasound and Sestamibi for Localizing Recurrent Parathyroid Disease.

BACKGROUND: Recurrent primary hyperparathyroidism (PHPT) presents a diagnostic challenge in localizing a hyperfunctioning gland. Although several imaging modalities are available for preoperative localization, 4D-CT is increasingly utilized for its ability to locate both smaller and previously unlocalized lesions. Currently, there is a paucity of data evaluating the utility of 4D-CT in the reoperative setting compared with ultrasound (US) and sestamibi. We aimed to determine the sensitivity of 4D-CT in localizing parathyroid adenomas in recurrent or persistent PHPT. METHODS: We performed a retrospective review of prospectively collected data from a tertiary-care hospital, and identified 58 patients who received preoperative 4D-CT with US and/or sestamibi between May 2008 and March 2016. Data regarding the size, shape, and number of parathyroid lesions were collected for each patient. RESULTS: A total of 62 lesions were identified intraoperatively among the 58 patients (6 with multigland disease) included in this investigation. 4D-CT missed 13 lesions identified intraoperatively, compared with 32 and 22 lesions missed by US and sestamibi, respectively. Sensitivity for correct lateralization of culprit lesions was 77.4% for 4D-CT, 38.5% for US, and 46% for sestamibi. 4D-CT was superior in lateralizing adenomas (49/62) compared with US (20/52; p < 0.001) and sestamibi (18/47; p < 0.001). The overall cure rate (6-month postoperative calcium < 10.7 mg/dL) was 89.7%. All patients with lesions correctly lateralized by 4D-CT were cured at 6 months. CONCLUSION: 4D-CT localized parathyroid adenomas with higher sensitivity among patients with recurrent or persistent PHPT compared with sestamibi or US-based imaging.

Reasons Associated with Total Thyroidectomy as Initial Surgical Management of an Indeterminate Thyroid Nodule.

BACKGROUND: Diagnostic hemithyroidectomy (HT) is the most widely recommended surgical procedure for a nodule with indeterminate cytology; however, additional details may make initial total thyroidectomy (TT) preferable. We sought to identify patient-specific factors (PSFs) associated with initial TT in patients with indeterminate thyroid nodules. METHODS: Retrospective analysis of all patients with a thyroid nodule ≥ 1 cm and initial cytology of atypia of undetermined significance or suspicious for follicular neoplasm between 2012 and 2015 who underwent thyroidectomy. Medical records were reviewed for patient demographics, neck symptoms, nodule size, cytology, molecular test results, final histopathology, and additional PSFs influencing surgical management. Variables were analyzed to determine associations with the use of initial TT. Logistic regression analyses were performed to identify independent associations. RESULTS: Of 325 included patients, 182/325 (56.0%) had HT and 143/325 (44.0%) had TT. While patient age and sex, nodule size, and cytology result were not associated with initial treatment, five PSFs were associated with initial TT (p < 0.0001). These included contralateral nodules, hypothyroidism, fluorodeoxyglucose avidity on positron emission tomography scan, family history of thyroid cancer, and increased surgical risk. At least one PSF was present in 126/143 (88.1%) TT patients versus 47/182 (25.8%) HT patients (p < 0.0001). Multivariate logistic regression analysis demonstrated that these variables were the strongest independent predictor of TT (odds ratio 45.93, 95% confidence interval 18.80-112.23, p < 0.001). CONCLUSIONS: When surgical management of an indeterminate cytology thyroid nodule was performed, several PSFs were associated with a preference by surgeons and patients for initial TT, which may be useful to consider in making decisions on initial operative extent.

The variable phenotype and low-risk nature of RAS-positive thyroid nodules.

BACKGROUND: Oncogenic mutations are common in thyroid cancers. While the frequently detected RAS-oncogene mutations have been studied for diagnostic use in cytologically indeterminate thyroid nodules, no investigation has studied such mutations in an unselected population of thyroid nodules. No long-term study of RAS-positive thyroid nodules has been performed. METHODS: We performed a prospective, blinded cohort study in 362 consecutive patients presenting with clinically relevant (>1 cm) thyroid nodules. Fine needle aspiration cytology and mutational testing were obtained for all nodules. Post-operative histopathology was obtained for malignant or indeterminate nodules, and benign nodules were sonographically followed. Histopathological features were compared between RAS- and BRAF-positive malignancies. RAS-positive benign nodules were analyzed for growth or cellular change from prior aspirations. RESULTS: Overall, 17 of 362 nodules were RAS-positive. Nine separate nodules were BRAF-positive, of which eight underwent surgery and all proved malignant (100%). Out of the 17 RAS-positive nodules, ten underwent surgery, of which eight proved malignant (47%). All RAS-positive malignancies were low risk - all follicular variants of papillary carcinoma, without extrathyroidal extension, metastases, or lymphovascular invasion. RAS-positivity was associated with malignancy in younger patients (P = 0.028). Of the nine RAS-positive benign nodules, five had long-term prospective sonographic follow-up (mean 8.3 years) showing no growth or signs of malignancy. Four of these nodules also had previous aspirations (mean 5.8 years prior), all with similar benign results. CONCLUSIONS: While RAS-oncogene mutations increase malignancy risk, these data demonstrate a low-risk phenotype for most RAS-positive cancers. Furthermore, cytologically benign, yet RAS-positive nodules behave in an indolent fashion over years. RAS-positivity alone should therefore not dictate clinical decisions.

False negative cytology in large thyroid nodules.

BACKGROUND: Controversy exists regarding the accuracy of fine-needle aspiration (FNA) in large thyroid nodules. Recent surgical series have documented false-negative rates ranging from 0.7 to 13 %. We examined the accuracy of benign FNA cytology in patients with thyroid nodules ≥3 cm who underwent surgical resection and identified features characteristic of false-negative results. METHODS: We retrospectively studied all thyroidectomy specimens between January 2009 and October 2011 and identified nodules ≥3 cm with corresponding benign preoperative FNA cytology. We collected clinical information regarding patient demographics, nodule size, symptoms, sonographic features, FNA results, and final surgical pathology. For comparison, we analyzed nodules <3 cm from this cohort also with benign FNA cytology. RESULTS: A total of 323 nodules with benign preoperative cytology were identified. Eighty-three nodules were <3 cm, 94 nodules were 3-3.9 cm, and 146 nodules were ≥4 cm in size. The false-negative rate was 11.7 % for all nodules ≥3 cm and 4.8 % for nodules <3 cm (p = 0.03). Subgroup analysis of nodules ≥3 cm revealed a false-negative rate of 12.8 % for nodules 3-3.9 cm and 11 % for nodules ≥4 cm. Age ≥55 years and asymptomatic clinical status were the only patient characteristics that reached statistical significance as risk factors. Final pathology of the false-negative specimens consisted mainly of follicular variant of papillary thyroid cancer and follicular thyroid cancer. CONCLUSIONS: When referred for thyroidectomy, patients with large thyroid nodules demonstrate a modest, yet significant, false-negative rate despite initial benign aspiration cytology. Therefore, thyroid nodules ≥3 cm may be considered for removal even when referred with benign preoperative cytology.

How are childhood thyroid nodules discovered: opportunities for improving early detection.

In a retrospective analysis of childhood thyroid nodules, 18% were radiographic incidentalomas and 41% were discovered by a clinician's palpation; 40% were discovered by patients' families. The latter group had the largest nodules and highest rates of thyroid cancer metastasis, suggesting opportunities for earlier detection through annual well-child visits.

Surgeons and patients disagree on the potential consequences from hypoparathyroidism.

OBJECTIVE: To test the hypothesis that surgeons and their patients underestimate the potential negative impact that permanent hypoparathyroidism has on quality of life (QOL). METHODS: We used a modified SF-36 assessment tool to compare the perceptions of patients with permanent hypoparathyroidism to the perceptions of control subjects who were given a standardized preoperative statement about the complications of hypoparathyroidism. We also elicited the perceptions of endocrine surgeons regarding the QOL impacts of hypoparathyroidism using a subset of questions from the modified SF-36. RESULTS: A total of 340 postsurgical patients with permanent hypoparathyroidism, 200 controls, and 102 surgeons participated in the study. Both surgeons and controls underestimated the negative impact of hypoparathyroidism on QOL when compared to patients living with permanent hypoparathyroidism. Forty-seven percent of hypoparathyroid patients believed that their health was "much worse" than before surgery, compared with 16% of surgeons (P<.001) and 7% of controls (P<.001). Postoperative hypoparathyroid patients also reported far more negative effects on QOL, from interference with social activities, paresthesias, muscle cramping, and medications than were anticipated by surgeons or controls (P<.05 for all comparisons). In each of the 8 dimensions of QOL, including physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy/fatigue, emotional well-being, social functioning, pain, and general health, hypoparathyroid patients reported a significantly lower mean score compared to the control group (P<.001 for all comparisons). CONCLUSION: The impact of postoperative hypoparathyroidism on patient QOL is consistently and significantly underestimated by surgeons and subjects receiving surgical consultation.

Bilateral neck exploration decreases operative time compared to minimally invasive parathyroidectomy in patients with discordant imaging.

BACKGROUND: Unilateral parathyroidectomy for primary hyperparathyroidism (PHPT) has a high success rate in patients with concordant imaging by sestamibi and ultrasound. However, the optimal procedure when imaging is discordant remains controversial; therefore we compared unilateral exploration with intraoperative parathyroid hormone (IOPTH) monitoring to bilateral neck exploration without IOPTH monitoring in patients with discordant localization studies. METHODS: We conducted a retrospective study of 324 consecutive patients with PHPT treated at our institution from October 2005 to September 2009. We collected information regarding imaging, localization site, procedure performed, operative time, and calcium/PTH measurements. RESULTS: Of the 324 patients in the study, 79 (24 %) had discordant imaging by sestamibi and ultrasound. Of these, 62 patients (78 %) underwent bilateral neck exploration without IOPTH monitoring, and 14 patients (18 %) had unilateral exploration with IOPTH monitoring. IOPTH monitoring during unilateral exploration correctly predicted removal of single adenomas in 10/14 patients (71 %) and altered operative management in 4/14 cases (29 %), resulting in conversion to bilateral neck exploration. Operative time for unilateral exploration with IOPTH [median time: 96 min (range: 51-153 min)] was significantly increased relative to bilateral exploration [median time: 52 min (range: 28-149 min)]; p = 0.0027. We identified single-gland disease in 53/76 patients (70 %), double adenomas in 13/76 patients (17 %), and multiglandular hyperplasia in 10/76 patients (13 %). There was no difference in cure rate between these two surgical approaches (p = 1.0) CONCLUSIONS: In contrast with prior studies, we found that operative time for unilateral exploration with IOPTH was significantly increased compared to bilateral neck exploration. In patients with discordant imaging, IOPTH is a useful adjunct in limiting exploration to a single side despite a high false negative rate.

Identification of the target self-antigens in reperfusion injury.

Reperfusion injury (RI), a potential life-threatening disorder, represents an acute inflammatory response after periods of ischemia resulting from myocardial infarction, stroke, surgery, or trauma. The recent identification of a monoclonal natural IgM that initiates RI led to the identification of nonmuscle myosin heavy chain type II A and C as the self-targets in two different tissues. These results identify a novel pathway in which the innate response to a highly conserved self-antigen expressed as a result of hypoxic stress results in tissue destruction.

Global tyrosine kinome profiling of human thyroid tumors identifies Src as a promising target for invasive cancers.

BACKGROUND: Novel therapies are needed for the treatment of invasive thyroid cancers. Aberrant activation of tyrosine kinases plays an important role in thyroid oncogenesis. Because current targeted therapies are biased toward a small subset of tyrosine kinases, we conducted a study to reveal novel therapeutic targets for thyroid cancer using a bead-based, high-throughput system. METHODS: Thyroid tumors and matched normal tissues were harvested from twenty-six patients in the operating room. Protein lysates were analyzed using the Luminex immunosandwich, a bead-based kinase phosphorylation assay. Data was analyzed using GenePattern 3.0 software and clustered according to histology, demographic factors, and tumor status regarding capsular invasion, size, lymphovascular invasion, and extrathyroidal extension. Survival and invasion assays were performed to determine the effect of Src inhibition in papillary thyroid cancer (PTC) cells. RESULTS: Tyrosine kinome profiling demonstrated upregulation of nine tyrosine kinases in tumors relative to matched normal thyroid tissue: EGFR, PTK6, BTK, HCK, ABL1, TNK1, GRB2, ERK, and SRC. Supervised clustering of well-differentiated tumors by histology, gender, age, or size did not reveal significant differences in tyrosine kinase activity. However, supervised clustering by the presence of invasive disease showed increased Src activity in invasive tumors relative to non-invasive tumors (60% v. 0%, p<0.05). In vitro, we found that Src inhibition in PTC cells decreased cell invasion and proliferation. CONCLUSION: Global kinome analysis enables the discovery of novel targets for thyroid cancer therapy. Further investigation of Src targeted therapy for advanced thyroid cancer is warranted.

The inflammatory response after an epidermal burn depends on the activities of mouse mast cell proteases 4 and 5.

A second-degree epidermal scald burn in mice elicits an inflammatory response mediated by natural IgM directed to nonmuscle myosin with complement activation that results in ulceration and scarring. We find that such burn injury is associated with early mast cell (MC) degranulation and is absent in WBB6F1-Kit(W)/Kit(Wv) mice, which lack MCs in a context of other defects due to a mutation of the Kit receptor. To address further an MC role, we used transgenic strains with normal lineage development and a deficiency in a specific secretory granule component. Mouse strains lacking the MC-restricted chymase, mouse MC protease (mMCP)-4, or elastase, mMCP-5, show decreased injury after a second-degree scald burn, whereas mice lacking the MC-restricted tryptases, mMCP-6 and mMCP-7, or MC-specific carboxypeptidase A3 activity are not protected. Histologic sections showed some disruption of the epidermis at the scald site in the protected strains suggesting the possibility of topical reconstitution of full injury. Topical application of recombinant mMCP-5 or human neutrophil elastase to the scalded area increases epidermal injury with subsequent ulceration and scarring, both clinically and morphologically, in mMCP-5-deficient mice. Restoration of injury requires that topical administration of recombinant mMCP-5 occurs within the first hour postburn. Importantly, topical application of human MC chymase restores burn injury to scalded mMCP-4-deficient mice but not to mMCP-5-deficient mice revealing nonredundant actions for these two MC proteases in a model of innate inflammatory injury with remodeling.

Inhibition of rat gut reperfusion injury with an agent developed for the mouse. Evidence that amplification of injury by innate immunity is conserved between two animal species.

Murine reperfusion injury follows binding of specific IgM natural antibodies to neo-antigens exposed in ischemic tissue. Peptides that mimic the site of antibody binding in the injury prevent IgM binding when administered intravenously before reperfusion. To determine whether this pathogenic sequence is restricted to mice, we have tested the ability of the peptide to prevent reperfusion injury in a dissimilar species, the rat. Sprague-Dawley rats were subjected to 40 min of mesenteric ischemia followed by 180 min of reperfusion. The peptide mimic was administered intravenously prior to reperfusion. Gut injury was quantified using a scoring system based on the hematoxylin-and-eosin section. (125)I-labeled albumin was used to assess local (gut) and remote (lung) injury. The macroscopic appearance of bowel from peptide-treated animals was less edematous and hemorrhagic. Microscopic analysis showed a significantly reduced injury score in peptide-treated animals. Permeability data indicated a significant reduction in local and remote injury in peptide-treated animals. The data demonstrate attenuation of rat gut microvillus injury, of gut edema, and of remote injury following mesenteric ischemia-reperfusion due to administration of an intravenous peptide mimic of a murine ischemia neo-antigen, indicating a second species uses a similar ischemia neo-antigen and corresponding natural antibody specificity to amplify reperfusion injury to the point of necrosis. This mechanism of inflammation is potentially applicable to higher species.

Galectin-3 regulates apoptosis and doxorubicin chemoresistance in papillary thyroid cancer cells.

A subset of patients with papillary thyroid cancer (PTC) present with aggressive disease that is refractory to conventional treatment. Novel therapies are needed to treat this group of patients. Galectin-3 (Gal-3) is a beta-galactoside-binding protein with anti-apoptotic activity. Over 30 studies in the last 3 years have reported that Gal-3 is highly expressed in PTC relative to normal thyrocytes. In this study, we show that Gal-3 silencing with RNA interference stimulates apoptosis, while Gal-3 overexpression protects against both TRAIL- and doxorubicin-induced apoptosis in PTC cells. The anti-apoptotic activity and chemoresistance related to Gal-3 function can be partially reversed through the inhibition of the PI3K-Akt pathway, suggesting that Gal-3 acts, at least in part, on the PI3K-Akt axis. These observations support further evaluation of Gal-3 as a potential therapeutic target in patients with aggressive PTC.

Differences in Thyroid Nodule Cytology and Malignancy Risk Between Children and Adults.

Background: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) is used to interpret fine-needle aspiration (FNA) cytology of thyroid nodules in children and adults. Nodule management is guided by the implied malignancy risk of each cytological category, which has been derived from adult populations. Whether these implied risks are applicable to pediatric thyroid nodules remains uncertain. We compared malignancy rates between pediatric and adult thyroid nodules within each cytological category. Methods: We evaluated consecutive thyroid nodules ≥1 cm that underwent FNA at the Boston Children's Hospital and Brigham and Women's Hospital from 1998 to 2016. All cytology was interpreted by a single cytopathology group according to the BSRTC. Malignancy rates were compared between pediatric (<19 years) and adult (≥19 years) patients. Results: Four hundred thirty pediatric thyroid nodules and 13,415 adult nodules were analyzed. Pediatric nodules were more likely to be malignant than adult nodules (19% vs. 12%, p = 0.0002). Within cytological categories, malignancy rates were higher in pediatric nodules than in adult nodules that were cytologically nondiagnostic (11% vs. 4%, p = 0.03), atypia of undetermined significance (AUS; 44% vs. 22%, p = 0.004), or suspicious for follicular neoplasm (SFN; 71% vs. 28%, p = 0.001). There were no significant differences between children and adults in the types of thyroid cancers diagnosed in these cytological categories. Among cytologically benign nodules, the difference in malignancy rates was statistically significant but clinically minimal (0.7% vs. 1%, p = 0.001). Malignancy rates did not differ between children and adults among nodules with cytology suspicious for papillary carcinoma (73% vs. 68%, p = 0.67) or positive for malignancy (97% vs. 95%, p = 1). Among the subset of nodules that were resected, the malignancy rate was higher in children than in adults only in nodules that were SFN (71% vs. 36%, p = 0.007). Conclusions: Among thyroid nodules that are cytologically AUS, SFN, or nondiagnostic, malignancy rates are higher in children than in adults. These discrepancies likely represent true differences in malignancy risk between pediatric and adult patients, rather than differences in cytological interpretation. Our findings provide pediatric-specific data to inform the optimal management of thyroid nodules in children, which may differ from that of adult nodules with equivalent cytology.

A Cohort Analysis of Clinical and Ultrasound Variables Predicting Cancer Risk in 20,001 Consecutive Thyroid Nodules.

CONTEXT: Assessing thyroid nodules for malignancy is complex. The impact of patient and nodule factors on cancer evaluation is uncertain. OBJECTIVES: To determine precise estimates of cancer risk associated with clinical and sonographic variables obtained during thyroid nodule assessment. DESIGN: Analysis of consecutive adult patients evaluated with ultrasound-guided fine-needle aspiration for a thyroid nodule ≥1 cm between 1995 and 2017. Demographics, nodule sonographic appearance, and pathologic findings were collected. MAIN OUTCOME MEASURES: Estimated risk for thyroid nodule malignancy for patient and sonographic variables using mixed-effect logistic regression. RESULTS: In 9967 patients [84% women, median age 53 years (range 18 to 95)], thyroid cancer was confirmed in 1974 of 20,001 thyroid nodules (9.9%). Significant ORs for malignancy were demonstrated for patient age <52 years [OR: 1.82, 95% CI (1.63 to 2.05), P < 0.0001], male sex [OR: 1.68 (1.45 to 1.93), P < 0.0001], nodule size [OR: 1.30 (1.14 to 1.49) for 20 to 19 mm, OR: 1.59 (1.34 to 1.88) for 30 to 39 mm, and OR: 1.71 (1.43 to 2.04) for ≥40 mm compared with 10 to 19 mm, P < 0.0001 for all], cystic content [OR: 0.43 (0.37 to 0.50) for 25% to 75% cystic and OR: 0.21 (0.15 to 0.28) for >75% compared with predominantly solid, P < 0.0001 for both], and the presence of additional nodules ≥1 cm [OR: 0.69 (0.60 to 0.79) for two nodules, OR: 0.41 (0.34 to 0.49) for three nodules, and OR: 0.19 (0.16 to 0.22) for greater than or equal to four nodules compared with one nodule, P < 0.0001 for all]. A free online calculator was constructed to provide malignancy-risk estimates based on these variables. CONCLUSIONS: Patient and nodule characteristics enable more precise thyroid nodule risk assessment. These variables are obtained during routine initial thyroid nodule evaluation and provide new insights into individualized thyroid nodule care.

Genomic Correlates of Response to Everolimus in Aggressive Radioiodine-refractory Thyroid Cancer: A Phase II Study.

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine-refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3-18.5) with a 2-year PFS of 23.6% (95% CI, 10.5-39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8-85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt-mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546-53. ©2018 AACR.

Quantitative Analysis of the Benefits and Risk of Thyroid Nodule Evaluation in Patients ≥70 Years Old.

BACKGROUND: In older patients, thyroid nodules are frequently detected and referred for evaluation, though usually prove to be benign disease or low-risk cancer. Therefore, management should be guided not solely by malignancy risk, but also by the relative risks of any intervention. Unfortunately, few such data are available for patients ≥70 years old. METHODS: All consecutive patients ≥70 years old assessed by ultrasound (US) and fine-needle aspiration (FNA) between 1995 and 2015 were analyzed. Clinical, US, and histologic data, including patient comorbidities and outcomes, were obtained. Imaging and cytology results from initial evaluation were reviewed to detect significant-risk thyroid cancer (SRTC), which was defined as anaplastic, medullary, or poorly differentiated carcinoma, or the presence of distant metastases. Overall survival analyses were then performed to assist with risk-to-benefit assessment. RESULTS: A total of 1129 patients ≥70 years old with 2527 nodules ≥1 cm were evaluated. FNA was safe in all, and cytology proved benign in 67.3% of patients. However, FNA led to surgery in 208 patients, of whom 93 (44.7%) had benign histopathology. Among all patients who underwent FNA, only 17 (1.5%) SRTC were identified, all of which were preoperatively identifiable by imaging and/or cytology. These SRTC were responsible for all (n = 10; 0.9%) thyroid cancer deaths. Among all other patients (n = 1112), 160 deaths (14.4%) were confirmed during a median follow-up of four years. None of these were thyroid cancer related. Survival analysis for these 1112 patients demonstrated that a separate non-thyroidal malignancy or coronary artery disease at the time of nodule evaluation was associated with increased mortality compared to those without these diagnoses (hazard ratio = 2.32 [confidence interval 1.66-3.26]; p < 0.01), confirming these are important variables to identify prior to thyroid nodule evaluation. CONCLUSIONS: For patients ≥70 years old, US and FNA are safe and prove helpful in identifying SRTC and benign cytology. However, the surgical management of patients ≥70 years old presenting without high-risk findings should be tempered, especially when comorbid illness is identified.

Predicting future staffing needs at teaching hospitals: use of an analytical program with multiple variables.

OBJECTIVE: To develop a model to predict future staffing for the surgery service at a teaching hospital. SETTING: Tertiary hospital. INTERVENTIONS: A computer model with potential future variables was constructed. Some of the variables were distribution of resident staff, fellows, and physician extenders; salary/wages; work hours; educational value of rotations; work units, inpatient wards, and clinics; future volume growth; and efficiency savings. Outcomes Number of staff to be hired, staffing expense, and educational impact. RESULTS: On a busy general surgery service, we estimated the impact of changes in resident work hours, service growth, and workflow efficiency in the next 5 years. Projecting a reduction in resident duty hours to 60 hours per week will require the hiring of 10 physician assistants at a cost of $1 134 000, a cost that is increased by $441 000 when hiring hospitalists instead. Implementing a day of didactic and simulator time (10 hours) will further increase the costs by $568 000. A 10% improvement in the efficiency of floor care, as might be gained by advanced information technology capability or by regionalization of patients, can mitigate these expenses by as much as 21%. On the other hand, a modest annual growth of 2% will increase the costs by $715 000 to $2 417 000. CONCLUSIONS: To simply replace residents with alternative providers requires large amounts of human and fiscal capital. The potential for simple efficiencies to mitigate some of this expense suggests that traditional patterns of care in teaching hospitals will have to change in response to educational mandates.