Utility of Ultrasound Versus Gene Expression Classifier in Thyroid Nodules with Atypia of Undetermined Significance

Objective: Thyroid nodules with fine-needle aspiration (FNA) cytology categorized as atypia of undetermined significance (AUS) often undergo additional diagnostic analysis with the Afirma Gene Expression Classifier (GEC), which classifies these as either high probability of being benign (GEC-B) or suspicious for malignancy (GEC-S). Our goal was to assess the clinical validity and utility of GEC in the evaluation of AUS cytology and evaluate the performance of ultrasonography (USG) for predicting malignancy in this subset.Methods: We conducted a study with a retrospective cohort of patients from January 2012 to January 2014 who had FNA of thyroid nodules >1 cm in size with AUS cytology.Results: Cleveland Clinic Florida has an overall prevalence of AUS of 5%. A total of 119 cases with nodules >1 cm in size were reported as AUS. Forty-eight (40.3%) had a GEC performed after the first FNA (AUS-1), and 27 of these were GEC-S. Of those 27, 21 went for surgery and 14 (66.6%) had thyroid cancer on histopathology. The remaining 71 with AUS-1 were sent for a second FNA: 19 nodules were benign and did not undergo further evaluation, while the remaining 52 were reported as AUS for the second consecutive time (AUS-2). AUS-2 samples were sent for GEC. Of these 52 AUS-2, 38 (73.1%) were reported as GEC-S. Thirty-five went for surgery and 32 (91.4%) had confirmed malignancy on histopathology. Positive predictive value (PPV) was 91.4% for AUS-2 and 66.6% for AUS-1. Moreover, AUS-2 nodules that were hypoechoic and solid on USG showed a PPV of 92% for malignancy.Conclusion: In our practice, the diagnostic accuracy to predict malignancy with GEC for AUS-1 nodules was poor (PPV, 66.6%). The PPV of GEC testing was markedly higher at 91.4% performed after two consecutive AUS cytologies. AUS-2 nodules that were solid and hypoechoic on USG also had a high probability to be malignant (PPV, 92%). We recommend repeat FNA on AUS-1 nodules rather than proceeding directly to GEC testing. Also, we suggest that among AUS-2 nodules, surgery can be recommended when USG shows solid and hypoechoic features with GEC testing reserved for the remainder.Abbreviations:AUS = atypia of undetermined significanceFNA = fine-needle aspirationGEC = gene expression classifierGEC-B = GEC-benignGEC-S = GEC-suspicious for malignancyNPV = negative predictive valuePPV = positive predictive valueUSG = ultrasonography     

Community Endocrine Surgical Experience With False-Negative Afirma Gec® Results: 2011–2017

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

Statistical Comparison of Afirma Gsc and Afirma Gec Outcomes in a Community Endocrine Surgical Practice: Early Findings

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

Predictive Value of Somatic Mutations for the Development of Malignancy in Thyroid Nodules by Cytopathology

Objective: The purpose of our prospective longitudinal study was to evaluate the predictive efficacy of genetic testing for malignancies in fine-needle aspiration biopsy samples that are cytologically benign at the time of biopsy.Methods: A total of 779 aspirated cytological samples collected from thyroid nodules of 626 patients were included in a 3-year follow-up study. Consecutive patients with cytologically benign thyroid nodules by the Bethesda System for Reporting Thyroid Cytopathology were enrolled in the study. At enrollment, somatic 1-point nucleotide polymorphisms of BRAF and RAS family genes were tested by melting-point analysis, while RET/PTC and PAX8/PPAR-gamma rearrangements were examined by real-time polymerase chain reaction. The genetic test was considered to be positive if a somatic mutation was found. Malignant cytopathologic diagnoses were confirmed by histopathology.Results: In samples collected from 779 thyroid nodules, there were 39 BRAF, 33 RAS mutations, and 1 RET/PTC rearrangements found at the beginning of the study. No PAX8/PPAR-gamma rearrangement was identified. There were 52 malignant thyroid tumors removed during follow-up, out of which 24 contained a somatic mutation. The specificity of the presence of somatic mutations for malignancies was as high as 93.3%, and sensitivity was 46.2%. The negative predictive value of genetic testing reached 96.0%.Conclusion: Our results show that our set of genetic tests can predict the appearance of malignancy in benign thyroid nodules (at the beginning of follow-up) with high specificity and strong negative predictive value.Abbreviations:BRAF = v-raf murine sarcoma viral oncogene homolog B1FLUS = follicular lesion of undetermined significanceFNAB = fine-needle aspiration biopsyFTC = follicular thyroid carcinomaHRAS = homologous to the oncogene from the Harvey rat sarcoma virusKRAS = homologous to the oncogene from the Kirsten rat sarcoma virusNRAS = first isolated from a human neuroblastoma/neuroblastomaRAS = viral oncogene homologPAX8 = paired box 8PCR = polymerase chain reactionPPAR-gamma = peroxisome proliferator-activated receptor gammaPTC = papillary thyroid carcinomaRAS = rat sarcomaRET = rearranged during transfection tyrosine-kinase proto-oncogeneSM = somatic mutationSNP = single-nucleotide polymorphism     

Utility of Afirma Gene Expression Classifier for Evaluation of Indeterminate Thyroid Nodules and Correlation with Ultrasound Risk Assessment: Single Institutional Experience

Objective: We assessed our experience with Afirma gene expression classifier (GEC) combined with sono-graphic risk assessment, using both the American Thyroid Association (ATA) and the Thyroid Imaging Reporting and Data System (TI-RADS) in evaluating indeterminate thyroid nodules.Methods: We identified 98 patients with 101 nodules who had a second fine needle aspiration biopsy (FNA) between January 1, 2014, and September 30, 2017, and sent to Veracyte for cytopathology and subsequent Afirma GEC testing. A second FNA biopsy was performed if the initial cytopathology was either Bethesda III or IV (n = 94) or nondiagnostic (n = 7). We correlated cytopathology, histopathology, and Afirma GEC results with sonographic risk assessment using both the ATA system and TI-RADS.Results: The mean age of the cohort was 57.4 ± 12.3 years; 84% women and 60% white. Repeat FNA was benign in 51 of 101 nodules, and of the remaining 50 nodules, 18 (36%) were GEC-benign and 32 (64%) GEC-suspicious. Eighteen of the 32 GEC-suspicious nodules underwent surgery with the following results: 7 benign (39%), 1 follicular thyroid carcinoma (6%), 6 follicular variant of papillary thyroid cancer (33%), and 4 noninvasive follicular tumor with papillary-like nuclear features (22%). The malignancy rate among the surgical cohort was 39% (without noninvasive follicular tumor with papillary-like nuclear features [NIFTP]) and 61% (with NIFTP) and about 50% and 20% of this group scored in the high suspicion category by ATA and TR5 by TI-RADS, respectively.Conclusion: Afirma GEC was useful in avoiding surgery in one-third of indeterminate nodules and performed similarly to ATA and TI-RADS. However, the use of echogenicity in scoring may underestimate the risk of malignancy in patients with indeterminate nodules.Abbreviations:ATA = American Thyroid Association; AUS = Atypia of Undetermined Significance; FLUS = Follicular Lesion of Undetermined Significance; FN = follicular neoplasm; FNA = fine needle aspiration; FTC = follicular thyroid cancer; FVPTC = follicular variant of papillary thyroid cancer; GEC = Gene Expression Classifier; ND = nondiagnostic; NIFTP = noninvasive follicular tumor with papillary-like nuclear features; TI-RADS = Thyroid Imaging Reporting and Data System; TR = TI-RADS     

Surgical Utility of Afirma: Effects of High Cancer Prevalence and Oncocytic Cell Types in Patients with Indeterminate Thyroid Cytology

ObjectiveThe 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.MethodsWe 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.ResultsWe 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%.ConclusionIn 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)     

Same-Day Fine-Needle Aspiration Cytology Diagnosis for Thyroid Nodules Achieves Rapid Anxiety Decrease and High Diagnostic Accuracy

Objective: The time between the moment of referral for the diagnostic workup for thyroid nodules and the outcome can be worrisome for patients. In general, patients experience high levels of anxiety during the evaluation of a lesion suspicious for cancer. Therefore, the implementation of same-day fine-needle aspiration cytology (FNAC) diagnosis is becoming standard-of-care for many solid tumors. Our aim was to assess the feasibility of same-day FNAC diagnosis for thyroid nodules and to assess patient anxiety during the diagnostic process.Methods: For feasibility of same-day FNAC diagnosis, we assessed the proportion of patients receiving a diagnosis at the end of the visit. Accuracy was measured by comparing histology with the FNAC result. Patient anxiety was measured by the State Trait Anxiety Inventory at 6 moments during the diagnostic workup.Results: Of the 131 included patients, 112 (86%) were female, and the mean age was 53 years. All patients, except those with a nondiagnostic FNAC result (n = 26; 20%), had a diagnosis at the end of the day. There were only two discordant results. Anxiety levels at the beginning of the day were high throughout the group, State Trait Anxiety Inventory (STAI) score 43.1 (SD 2.0) and decreased significantly more in patients with a benign FNAC result (STAI score 30.2), compared to patients with a malignant or indeterminate result (STAI score 39.6).Conclusion: Distress of patients with a thyroid nodule undergoing same-day FNAC diagnostics was high. Same-day FNAC diagnosis is feasible and accurate for the evaluation of thyroid nodules. Therefore, same-day FNAC diagnosis seems a safer, more patient-friendly approach to diagnose thyroid nodules.Abbreviations:AUS = atypia of undetermined significanceCWS = Cancer Worry ScaleFNAC = fine-needle aspiration cytologySTAI = State Trait Anxiety InventoryTSH = thyroid-stimulating hormone     

Important Management Considerations In Patients With Pituitary Disorders During The Time Of The Covid-19 Pandemic

Objective: In December 2019, a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an outbreak of coronavirus disease 2019 (COVID-19) that resulted in a global pandemic with substantial morbidity and mortality. Currently, there is no specific treatment or approved vaccine against COVID-19. The underlying associated comorbidity and diminished immune function of some pituitary patients (whether caused by the disease and its sequelae or treatment with excess glucocorticoids) increases their risk of contracting and developing complications from COVID-19 infection.Methods: A review of studies in PubMed and Google Scholar published between January 2020 to the time of writing (May 1, 2020) was conducted using the search terms ‘pituitary,’ ‘coronavirus,’ ‘COVID-19’, ‘2019-nCoV’, ‘diabetes mellitus’, ‘obesity’, ‘adrenal,’ and ‘endocrine.’Results: Older age and pre-existing obesity, hypertension, cardiovascular disease, and diabetes mellitus increase the risk of hospitalization and death in COVID-19 patients. Men tend to be more severely affected than women; fortunately, most men, particularly of younger age, survive the infection. In addition to general comorbidities that may apply to many pituitary patients, they are also susceptible due to the following pituitary disorder–specific features: hypercortisolemia and adrenal suppression with Cushing disease, adrenal insufficiency and diabetes insipidus with hypopituitarism, and sleep-apnea syndrome and chest wall deformity with acromegaly.Conclusion: This review aims to focus on the impact of COVID-19 in patients with pituitary disorders. As most countries are implementing mobility restrictions, we also discuss how this pandemic has affected patient attitudes and impacted our decision-making on management recommendations for these patients.Abbreviations: ACE = angiotensin-converting enzyme; AI = adrenal insufficiency; ARB = angiotensin receptor blocker; ARDS = acute respiratory disease syndrome; COVID-19 = coronavirus disease 2019; CPAP = continuous positive airway pressure; DI = diabetes insipidus; DM = diabetes mellitus; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2     

Hypophosphatasia: Clinical Assessment and Management in the Adult Patient–A Narrative Review

Objective: To review literature and present a schematic approach to hypophosphatasia (HPP) evaluation and management applicable to practicing physicians to ease its recognition and diagnosis.Methods: Studies were obtained from online databases PubMed and MEDLINE using keyword ‘hypophosphatasia.’Results: HPP is a rare disease characterized by low serum alkaline phosphatase along with diverse musculoskeletal symptoms that mimic different disorders. To date, the prevalence of HPP and its impact on adults has been unrecognized. There is lack of evidence from larger and long-term studies examining the adult type of this condition.Conclusion: It is essential to increase awareness on the complexity of the pathophysiology and clinical features of HPP, which causes debilitating physical conditions that severely affects quality of life. A better comprehension of adult forms of HPP is essential to reduce a delay in diagnosis as well as ensure suitable management.Abbreviations: ALP = alkaline phosphatase; HPP = hypophosphatasia; PEA = phosphorethanolamine; PLP = pyridoxal-5-phosphate; PPi = inorganic pyrophosphate; TNSALP/TNAP = tissue-nonspecific alkaline phosphatase     

Effectiveness of Percutaneous Ethanol Injection in Nodular Diseases of the Thyroid Gland: 10-Year Follow-Up

Objective: Percutaneous ethanol injection (PEI) of thyroid cysts is not considered to be the standard of care in Kazakhstan, although thyroid nodules are highly prevalent. Patients with cystic nodules >3 cm typically undergo surgery with high rate of disability due to postsurgical hypothyroidism. Adoption of PEI as a standard of care will help reduce the number of unnecessary surgical interventions. The objective of this study was to assess effectiveness of PEI in patients with thyroid cysts and colloid nodules with 10 years of follow-up.Methods: A total of 257 patients were treated with PEI and have been followed for 10 ± 1.2 years. All patients had baseline labs (thyroid-stimulating hormone [TSH] and free thyroxine [FT4] levels) and ultrasonography prior to the procedure. The Short Form Health Survey (SF-36) assessing quality of life (QoL) was performed 12 months after the last PEI procedure.Results: At baseline, all patients had normal levels of FT4 and TSH that remained within normal limits throughout the follow-up period. Ultrasound evaluation performed over 3 months after PEI demonstrated significant volumetric reduction from 18.4 to 0.2 mL (P<.001) in cystic nodules and from 10.2 to 1.1 cm³ (P<.001) in colloid nodules. Patients who underwent the procedure had better SF-36 survey scores compared to their baseline QoL scores.Conclusion: PEI for cystic and colloid thyroid nodules could be considered as an effective and safe procedure. It enables up to a 100% reduction of nodule volume and has a low rate of adverse effects.Abbreviations: FT4 = free thyroxine; PEI = percutaneous ethanol injection; QoL = quality of life; SF-36 = Short Form Health Survey; TSH = thyroid-stimulating hormone; US = ultrasound; VRR = volume reduction rate     

Ablation of Cystic Thyroid Nodules With N-Butyl Cyanoacrylate: A Preliminary Study

Objective: Generally recommended treatment options for cystic nodules with compressive symptoms are simple aspiration, percutaneous ethanol injection, or surgery. N-butyl cyanoacrylate (NBCA) is a glue-like substance widely used in neurointerventions, mainly for treating arteriovenous malformations. It obstructs and attaches to the vessel walls, preventing recanalization. Our purpose was to investigate the efficacy and safety of NBCA in volume reduction of benign cystic thyroid nodules with compressive symptoms.Methods: Twenty patients with 21 benign pure or partially cystic nodules were enrolled. After simple cyst aspiration, NBCA/lipiodol mixture was injected within the cyst cavity. Success was defined as at least 50% volume reduction after the intervention. Pre- and postintervention longest diameter and volume (calculated with ultrasonography after measuring three dimensions) of the nodules were compared. Posttreatment measurements were made at the 9-month final visit.Results: Median largest diameter of the nodules measured before and after NBCA treatment was 4.8 cm (min-max, 3.1 and 6.3 cm) and 3.4 cm (min-max, 2.4 and 5.6 cm), respectively. Pre-NBCA treatment median volume was 24.8 mL (min-max, 10.9 and 46.1 mL), whereas post-treatment median volume was 5.5 mL (min-max, 2.1 and 29.6 mL). Median volume reduction was 72.6% (min-max, 21.0 and 95.4%). Intervention was successful in 20 of 21 nodules according to the predefined criteria. The changes in pre- and postintervention median longest diameter and volume were statistically significant.Conclusion: For large cystic thyroid nodules, ablation with NBCA may be an effective treatment choice, as it significantly reduces the cyst volume and prevents fluid re-accumulation. There is need for further studies with a larger number of patients and longer follow-up.Abbreviations: NBCA = N-butyl cyanoacrylate; PEI = percutaneous ethanol injection; US = ultrasonography     

Long-Term Outcomes of Radioiodine Therapy for Juvenile Graves Disease with Emphasis on Subsequently Detected Thyroid Nodules: A Single Institution Experience from Japan

Objective: To investigate the long-term outcomes of radioiodine therapy (RIT) for juvenile Graves disease (GD) and the ultrasonographic changes of the thyroid gland.Methods: All of 117 juvenile patients (25 males and 92 females, aged 10 to 18 &lsqb;median 16] years) who had undergone RIT for GD at our clinic between 1999 and 2018 were retrospectively reviewed. Each RIT session was delivered on an outpatient basis. The maximum ¹³¹I dose per treatment was 13.0 mCi, and the total ¹³¹I dose per patient was 3.6 to 29.8 mCi (median, 13.0 mCi). ¹³¹I administration was performed once in 89 patients, twice in 26, and three times in 2 patients. Ultrasonography of the thyroid gland was regularly performed after RIT. The duration of follow-up after the initial RIT ranged from 4 to 226 (median 95) months.Results: At the latest follow-up more than 12 months after RIT (n = 111), the patients' thyroid functions were overt hypothyroidism (91%), subclinical hypothyroidism (2%), normal (5%), or subclinical hyperthyroidism (2%). New thyroid nodules were detected in 9 patients, 4 to 17 years after initial RIT. Patients with newly detected thyroid nodules underwent RIT with lower doses of ¹³¹I and had larger residual thyroid volumes than those without nodules. None of the patients were diagnosed with thyroid cancer or other malignancies during the follow-up period.Conclusion: Over a median follow-up period of 95 months (range, 4 to 226 months), RIT was found to be effective and safe in juvenile GD. However, cumulative evidence from further studies is required to confirm the long-term safety of RIT for juvenile GD.Abbreviations: ATD = antithyroid drug; GD = Graves disease; KI = potassium iodide; LT4 = levothyroxine; MMI = methimazole; PTU = propylthiouracil; RAIU = radio-active iodine uptake; RIT = radioiodine therapy; ^99mTc = technetium-99m; TSH = thyrotropin     

Pituitary Dysfunction in Patients with Intracranial Germ Cell Tumors Treated with Radiotherapy

Objective:To evaluate the endocrine abnormalities in intracranial germ cell tumors (iGCTs) treated with radio-therapy (RT), and to discuss the effects of RT on pituitary functions.Methods: Seventy-seven patients diagnosed with iGCTs who had received RT and endocrine follow-up in Huashan Hospital between January 2010 and July 2017 were retrospectively analyzed, consisting of 49 germinomas and 28 NGGCTs. The median follow-up period was 50.0 months. Fifty-one patients had radiologically proved suprasellar/sellar lesions.Results: The male to female ratio was 62/15. The median endocrine follow-up period was 19 (4, 42) months. The median age at the last endocrine visit was 18 (16, 20) years old. The 5-year overall and recurrence-free survival were both 98.7%. The overall prevalence of central adrenal insufficiency (CAI), central hypothyroidism (CHT), central hypogonadism (CHG), hyperprolactinemia, and central diabetes insipidus (CDI) was 57.3%, 56%, 56.6%, 35.3%, and 52.1%, respectively, after RT. Patients having suprasellar/sellar lesions showed significantly higher post-therapeutic prevalence of hypopituitarism than those who didn’t. Compared to that before RT, CAI, CHT, and CHG weren’t significantly improved while the levels of prolactin and the prevalence of CDI declined significantly (P =.03 and.001). The radiation doses to pituitary and hypothalamus between those with and without CAI, CHT, and CHG weren’t significantly different.Conclusion: The prevalence of hypopituitarism was high in iGCTs, especially in those with suprasellar/sellar involvement. The levels of prolactin and the prevalence of CDI declined significantly after RT. The hypopituitarism in iGCTs was mainly induced by tumor effects, and RT showed no additional damage to pituitary functions in our study.Abbreviations: AFP = alpha-fetoprotein; CAI = central adrenal insufficiency; CDI = central diabetes insipidus; CHG = central hypogonadism; CHT = central hypothyroidism; CT = computed tomography; DA = dopamine; GH = growth hormone; βHCG = beta-human chorionic gonadotropin; HPA = hypothalamus-pituitary-adrenal; HPG = hypothalamus-pituitary-gonadal; HPL = hyperprolactinemia; HPT = hypothalamus-pituitary-thyroid; iGCT = intracranial germ cell tumor; IGF-1 = insulin-like growth factor 1; NGGCT = nongerminomatous germ cell tumors; OS = overall survival; PFS = progression-free survival; PRL = hypothalamus-pituitary-prolactin; RT = radiotherapy     

Additional Surgery for Occult Risk Factors After Lobectomy in Solitary Thyroid Nodules is Predicted by Cytopathology Classification and Tumor Size

Objective: Clinical practice for differentiated thyroid cancer is moving towards lobectomy rather than total thyroidectomy in patients at low risk of recurrence. However, recurrence risk assessment depends on post-operative findings, while the surgical decision is based on preoperative factors. We determined the preoperative predictors of occult higher-risk pathology and rates of completion thyroidectomy among surgical candidates with nonbenign thyroid nodules 10 to 40 mm and no evidence of extrathyroidal extension or metastasis on preoperative evaluation.Methods: Thyroid surgery cases at a single institution from 2005–2015 were reviewed to identify those meeting American Thyroid Association (ATA) criteria for lobectomy. ATA-based risk stratification from postoperative surgical pathology was compared to preoperative cytopathology, ultrasound, and clinical findings.Results: Of 1,995 thyroid surgeries performed for nonbenign thyroid nodules 10 to 40 mm, 349 met ATA criteria for lobectomy. Occult high-risk features such as tall cell variant, gross extrathyroidal invasion, or vascular invasion were found in 36 cases (10.7%), while intraoperative lymphadenopathy led to surgical upstaging in 13 (3.7%). Intermediate risk features such as moderate lymphadenopathy or minimal extrathyroidal extension were present in an additional 44 cases. Occult risk features were present twice as often in Bethesda class 6 cases (35%) as in lower categories (12 to 17%). In multivariable analysis, Bethesda class and nodule size, but not age, race, sex, or ultrasound features, were significant predictors of occult higher-risk pathology.Conclusion: Most solitary thyroid nodules less than 4 cm and with cytology findings including atypia of undetermined significance through suspicious for papillary thyroid cancer would be sufficiently treated by lobectomy.Abbreviations: ATA = American Thyroid Association; CND = central neck dissection; DTC = differentiated thyroid cancer; ETE = extrathyroidal extension; FNA = fine needle aspiration; FTC/HCC = follicular thyroid carcinoma/Hurthle cell carcinoma; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; OR = odds ratio; PTC = papillary thyroid cancer; US = ultrasound     

The Impact of Age in the Management of Hypothyroidism: Results of a Nationwide Survey

Objective: Evidence exists that thyroid-stimulating hormone (TSH) increases with age and lowering the TSH goal in older patients on thyroid hormone may cause over-treatment. Risks of overtreatment include cardiac and skeletal events. We assessed practice patterns regarding TSH goals and explored factors influencing physicians' decision making when managing hypothyroidism.Methods: Members of the American College of Physicians, the American Academy of Family Practice, and the Endocrine Society were surveyed to determine goal TSH when treating hypothyroidism.Results: Fifty-three percent of physicians reported factoring patient age into their decision making when managing hypothyroidism. Patient age was prioritized third (53%), following patient symptoms (69.2%) and cardiac arrhythmias (65.7%). In multivariable analysis, endocrinologists (P = .002), internists (P = .049), physicians in academic settings (P = .003), and high-volume physicians (P = .021) were more likely to consider patient age when determining goal TSH. When presented with scenarios differing in patient gender and age, 90% of physicians targeted a TSH ≤3.0 mIU/L in 30-year-old patients. Fifty-three percent of respondents targeted a TSH ≤3.0 mIU/L in octogenarians, but 90% targeted a TSH >1.5 mIU/L in this group. Regardless of gender, physician-reported TSH goal ranges (0.1 to 0.5, 0.6 to 1.5, 1.6 to 3.0, and 3.1 to 5.0 mIU/L) increased in a direct relationship to patient age (P<.001).Conclusion: Just over half of physicians consider patient age when determining TSH goal. When presented with scenarios differing in patient age and gender, physicians targeted a higher TSH goal in octogenarians. This may indicate an attempt to avoid overtreatment in this group. Consensus is needed among physicians regarding the role of patient age in hypothyroidism management.Abbreviations:TSH = thyroid-stimulating hormone     

Health-Related Quality of Life in Patients with Nonfunctioning Pituitary Adenomas Undergoing Postoperative Radiation Therapy: A Case-Control Study

Objective: Nonfunctioning pituitary adenomas (NFPAs) can be associated with significant morbidity including a compromised quality of life (QoL). Radiotherapy (RT) is listed as one of the contributing factors to QoL impairment in these patients, however the evidence supporting this association is scarce and conflicting. Here we evaluate health-related QoL (HRQoL) impairment in patients with NFPA and to what extent this is due to RT.Methods: HRQoL was evaluated with the short form-36 questionnaire (SF-36), which explores 8 domains pertaining physical, emotional, and mental well being. We assessed 50 patients with NFPA subjected to RT after pituitary surgery, and their results were compared to those from 127 subjects who had undergone surgery but not RT. Both groups were matched for age, sex, and metabolic and cardiovascular comorbidities. The SF-36 was applied a median of 72 months after RT in the group of cases and 78 months after the last surgical procedure in the control group.Results: Both groups scored equally low in the 8 areas explored by the survey. In a multiple linear regression model, age was significantly associated with worse physical health scores, whereas female sex was associated with worse general health perception and lower emotional role and physical role scores. The presence of a visual field defect was significantly associated with a worse social role functioning score.Conclusion: QoL in patients with NFPAs is significantly compromised in most scales evaluated by the SF-36 survey. However, RT itself does not affect QoL.Abbreviations:CI = confidence intervalGH = growth hormoneHRQoL = health-related quality of lifeIQR = interquartile rangeNFPA = nonfunctioning pituitary adenomaQoL = quality of lifeRT = radiotherapySF-36 = short form 36-item health surveyTSS = transsphenoidal surgeryXRT = external beam radiotherapy     

Clinical Outcomes in Adrenal Incidentaloma: Experience From one Center

Objective: To investigate the outcome in patients with adrenal incidentaloma (AI).Methods: A retrospective evaluation of 637 patients with AI referred to a tertiary center over 8 years. Radiologic and hormonal evaluations were performed at baseline. Follow-up imaging was carried out if necessary, and hormonal evaluation was performed at 24 months according to national guidelines.Results: The mean age was 62.7 ± 11.6 years, and the mean AI size was 25.3 ± 17.0 mm at presentation. Hormonal evaluation revealed that 85.4% of all tumors were nonfunctioning adenomas, 4.1% subclinical Cushing syndrome (SCS), 1.4% pheochromocytoma, 1.4% primary hyperaldosteronism, 0.8% Cushing syndrome, 0.6% adrenocortical carcinoma, 0.3% congenital adrenal hyperplasia, 2.2% metastasis to adrenals, and 3.8% other lesions of benign origin. Bilateral tumors were found in 11%, and compared to unilateral tumors, SCS was more prevalent. Only 2 cases were reclassified during follow-up, both as SCS, but neither had had a dexamethasone suppression test performed at initial work-up. In patients diagnosed with an adrenal metastasis, 92.9% were deceased within 2 years. Excluding those with malignant tumors, 12.9% of patients died during the study period of up to 11 years due to other causes than adrenal.Conclusion: Most AIs were benign, but a small fraction of tumors were functional and malignant. The prognosis of patients with adrenal metastasis was extremely poor, but otherwise, the mortality rate was similar to that for the general population. Follow-up of AIs <4 cm with an initial nonfunctional profile and benign radiologic appearance appears unwarranted, but screening for congenital adrenal hyperplasia should be considered.Abbreviations: 17OHP = 17-hydroxyprogesterone ACC = adrenal cortical carcinoma ACTH = adrenocorticotropic hormone AI = adrenal incidentaloma CAH = congenital adrenal hyperplasia CT = computed tomography CS = Cushing syndrome DST = dexamethasone suppression test HPA = hypothalamic-pituitary-adrenal axis MRI = magnetic resonance imaging SCS = subclinical Cushing syndrome T2DM = type 2 diabetes mellitus UFC = urinary free cortisol     

Treatment Intensification with Insulin Degludec/Insulin Aspart Twice Daily: Randomized Study to Compare Simple and Step-Wise Titration Algorithms

Objective: This 26-week, multicenter, randomized, open-label, parallel-group, treat-to-target trial in adults with type 2 diabetes compared the efficacy and safety of treatment intensification algorithms with twice-daily (BID) insulin degludec/insulin aspart (IDegAsp).Methods: Patients randomized 1:1 to IDegAsp BID used either a ‘Simple’ algorithm (twice-weekly dose adjustments based on a single prebreakfast and pre-evening meal self-monitored plasma glucose [SMPG] measurement; IDegAsp[BID_Simple], n = 136) or a ‘Stepwise’ algorithm (once-weekly dose adjustments based on the lowest of 3 pre-breakfast and 3 pre-evening meal SMPG values; IDegAsp[BID_Step-wise], n = 136).Results: After 26 weeks, mean change from baseline in glycated hemoglobin (HbA1c) with IDegAsp[BID_Simple] was noninferior to IDegAsp[BID_Step-wise] (-15 mmol/mol versus -14 mmol/mol; 95% confidence interval [CI] upper limit, <4 mmol/mol) (baseline HbA1c: 66.3 mmol/mol IDegAsp[BID_Simple] and 66.6 mmol/mol IDegAsp[BID_Step-wise]). The proportion of patients who achieved HbA1c <7.0% (<53 mmol/mol) at the end of the trial was 66.9% with IDegAsp[BID_Simple] and 62.5% with IDegAsp[BID_Step-wise]. Fasting plasma glucose levels were reduced with each titration algorithm (-1.51 mmol/L IDegAsp[BID_Simple] versus -1.95 mmol/L IDegAsp[BID_Step-wise]). Weight gain was 3.8 kg IDegAsp[BID_Simple] versus 2.6 kg IDegAsp[BID_Step-wise], and rates of overall confirmed hypoglycemia (5.16 episodes per patient-year of exposure [PYE] versus 8.93 PYE) and nocturnal confirmed hypoglycemia (0.78 PYE versus 1.33 PYE) were significantly lower with IDegAsp[BID_Step-wise] versus IDegAsp[BID_Simple]. There were no significant differences in insulin dose increments between groups.Conclusion: Treatment intensification with IDegAsp[BID_Simple] was noninferior to IDegAsp[BID_Step-wise]. Both titration algorithms were well tolerated; however, the more conservative step-wise algorithm led to less weight gain and fewer hypoglycemic episodes. Clinicaltrials.gov: NCT01680341Abbreviations:AEs = adverse eventsANOVA = analysis of varianceBID = twice-dailyBID_Simple = ‘Simple’ algorithm twice-weekly dose adjustments based on a single pre-breakfast and pre–evening meal self-monitored plasma glucose measurementBID_Step-wise = ‘Step-wise’ algorithm once-weekly dose adjustments based on the lowest of 3 prebreakfast and 3 pre–evening meal self-monitored plasma glucose valuesCI = confidence intervalETD = estimated mean treatment differenceFPG = fasting plasma glucoseHbA1c = glycated hemoglobinIAsp = insulin aspartIDeg = insulin degludecIDegAsp = insulin degludec/insulin aspartIGlar = insulin glargineOAD = oral antidiabetic drugPYE = patient-year of exposureSMPG = self-monitored plasma glucoseSU = sulfonylureaT2D = type 2 diabetes     

Adding VFA to DXA Identifies Fracture Risk in a Way Not Duplicated by Other Measures

Objective: Published studies have demonstrated that adding vertebral fracture assessment (VFA) to dual-energy X-ray absorptiometry (DXA) identifies more patients with increased fracture risk than DXA alone. But who needs VFA? This study attempts to determine if some test other than VFA could duplicate the additional information obtained by performing VFA on all first-time patients. This study looked at the Fracture Risk Assessment Tool (FRAX), height loss, age, documented back pain, and nonvertebral fragility fractures.Methods: VFA was performed on 1,259 (all) DXA patients at their first visit from March 2010 through September 2013. All DXA and VFA results were read by the same International Society for Clinical Densitometry–certified clinician.Results: By DXA alone, 44% were osteoporosis. Adding VFA increased clinical osteoporosis by 36% of the original total patients. Eighty-three “normal bone mineral density” patients were changed to clinical osteoporosis. FRAX identified 53% of the patients with diagnosis changes. Historical height loss was not reliable. Increasing age correlated only weakly with clinical osteoporosis.Conclusion: These are modest numbers from a nonacademic referral practice and may not be typical of other populations. Thirty-six percent of our patients were misclassified by DXA alone, with fragility fractures already taken into account for T-scores of -1.5 and lower. FRAX, height loss, age, back pain, and fragility fractures all failed to identify many of the patients identified by VFA. Seeing the lateral spine images obtained by VFA influenced patients and families. VFA on all first-time patients should be reconsidered.Abbreviations:BMD = bone mineral density; DXA = dual-energy X-ray absorptiometry; FRAX = Fracture Risk Assessment Tool; HL = height loss; ISCD = International Society for Clinical Densitometry; VF = vertebral fracture; VFA = vertebral fracture assessment