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A re-named diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) likely impacts the prevalence of thyroid cancer and risk of malignancy in populations based on the established Bethesda System of Reporting Thyroid Cytopathology (TBSRTC). This study was done to investigate the prevalence and cytological distribution of NIFTP. PRISMA guided systematic review was done from a database search of Pubmed, EMBASE, and Medline using the search terms "non-invasive follicular thyroid neoplasm with papillary-like nuclear features", "non-invasive follicular variant of papillary carcinoma", "niftp", and "Bethesda" until November 2018. Original articles with surgically proven diagnoses of NIFTP using strict NIFTP criteria were included. Twenty-nine studies with 1563 cases of NIFTP were included. The pooled prevalence of NIFTP in cases which would be classified previously as the follicular variant of papillary thyroid cancer (FVPTC) and papillary thyroid cancer (PTC) were 43.5% (95% CI 33.5-54.0%) and 4.4% (95% CI 2.0-9.0%) respectively. The pooled TBSRTC distribution of cases diagnosed as NIFTP was: from the non-diagnostic category 3.6% (95% CI 2.4-5.3%), benign 10.0% (95% CI 7.2-13.6%), AUS/FLUS 34.2% (95% CI 28.2-40.8%), FN/SFN 22.7% (95% CI 17.2-29.4%), suspicious for malignancy 22.4% (95% CI 17.7-27.9%), and malignant 7.5% (95% CI 4.2-12.9%). While a significant reduction in FVPTC prevalence is anticipated, a modest reduction of PTC prevalence is also expected with adoption of the NIFTP terminology that would be distributed mainly among lesions classified as indeterminate thyroid nodules. Further studies are needed to identify unique clinical characteristics of these lesions preoperatively.

Whether molecular testing adds diagnostic value to the evaluation of thyroid nodules 4-cm or larger is unknown. The impact of molecular testing on cytopathologic-histopathologic diagnosis of neoplasm (adenoma or malignant), stratified by nodule size

Exercise hypogonadal male condition is a well-recognized condition in women but much less understood in men. The aim of this case report is to highlight exercise-induced hypogonadotropic hypogonadism in a male who recovered with lifestyle modifications.We report a case of an adolescent male who developed hypogonadotropic hypogonadism secondary to excessive exercise and malnutrition that was followed up for a year without exogenous testosterone supplementation. Informed consent was obtained from the patient for his information to be used in a manuscript submitted to a journal.An 18-yr-old adolescent male presented to the clinic with symptoms of fatigue and low endurance, low libido, and lack of morning erections. At the time of his presentation, he was running about 60 miles per week for school cross-country team in addition to cross training with kickboxing. Physical examination was remarkable for low body mass index of 19 kg·m but was otherwise normal. Biochemical workup confirmed hypogonadotropic hypogonadism and a mild pancytopenia. Other pituitary laboratory values and MRI of the brain were unremarkable. Bone marrow biopsy performed for anemia showed features consistent with malnutrition. With a working diagnosis of exercise hypogonadal male condition, he was advised to reduce the frequency and intensity of his exercise and increase calorie intake. Cell counts and testosterone levels normalized, and his symptoms resolved without any further interventions.Significant reversible hypogonadism can develop after intensive and prolonged exercise. One of the mechanisms of hypogonadism in endurance athletes performing intensive exercise could be relative malnutrition. Further studies to evaluate the role of nutrition and body mass index in male endurance athletes presenting with hypogonadism are needed to identify the underlying mechanism of this condition.

Molecular diagnostics increasingly direct the management of thyroid nodules with an indeterminate cytologic diagnosis. This study was undertaken to correlate cytomorphologic features with the molecular profiles in an effort to identify features predictive of molecular aberrations. One hundred eighty-nine thyroid nodules with an indeterminate thyroid cytology diagnosis (atypia of undetermined significance, suspicious for follicular lesion, and suspicious for malignancy) with an adequate sample submitted for targeted mutation detection by polymerase chain reaction or next-generation sequencing were assessed semiquantitatively for the following cytomorphologic parameters: cellularity, Hurthle cell changes, microfollicles, nuclear elongation, nuclear grooves, nuclear enlargement, nuclear atypia, extent of atypia, and colloid. Based on this evaluation, a cumulative cytomorphologic score (CCS) and a more simplified overall atypia score (OAS) were assigned to each case. Associations among mutational status and each of the aforementioned parameters, CCS, and OAS were determined. Of the 189 nodules with indeterminate cytology, 63 (33.3%) harbored at least 1 mutation. RAS and BRAF were the most common mutations, found in 34 (18.0%) and 13 (6.9%) cases, respectively. Both CCS and OAS were highly associated with the presence of all mutations (P < .0001) and with the presence of BRAF and RAS mutations in particular (all P < .01). Semiquantitative assessment of various cytomorphologic features in indeterminate thyroid cytology cases showed a strong association of higher OAS and CCS and incidence of BRAF and RAS mutations. Using a more objective approach to thyroid cytology can potentially decrease the overall number of indeterminate diagnoses, leading to fewer repeat procedures and unnecessary surgical procedures.

We describe an unusual case of a 55-year old female with a proinsulin secreting pancreatic endocrine adenoma. She presented with partial seizures, fasting hypoglycemia, and hypoglycemia unawareness. CT and MRI confirmed a hyper-enhancing lesion in the pancreatic body. She was effectively treated with prednisone and utilized a continuous glucose monitor (CGM) to identify and treat hypoglycemia while she awaited surgery. She underwent resection and the surgical specimen was neuroendocrine adenomatous tissue. This case has several important teaching points: [1] Fasting hypoglycemia requires a complete work up since proinsulinomas, although rare, can occur. [2] Whipple’s triad is not 100% sensitive in the work-up of hypoglycemia. Patients with persistent hypoglycemia may develop hypoglycemia unawareness. [3] Continuous glucose monitors (CGM) may provide an alternative or adjunct to standard medical therapy while patients await definitive surgery. Prednisone may also be an inexpensive and effective therapy. References1. Fadini GP MAVAea. Hypoglycemic Syndrome in a Patient with Proinsulin-Only Secreting Pancreatic Adenoma (Proinsulinoma). Case Reports in Medicine. 2011.2. Clark G, Sadur C, Puligandla B. Multiple proinsulin-secreting tumors of the pancreas treated by laparoscopic distal pancreatectomy and splenectomy. World Journal of Surgery. 2009;33(3):397-3993. F. J. Gomez-Perez DCRPAVCAASRMaJAR. Beta-cell adenomas without hyperinsulinemia with use of highly specific insulin radioimmunoassays: case report and review of literature. Endocrine Practice. 2010;16(4):660-663.4. Gury H, Rio F, Neamtu D, Boivin S. Insulinoma with hyperproinsulinemia: A two cases report. Annales d'Endocrinologie. 2002;63(3):240-242.5. Piovesan A, Pia A, Visconti G, al e. Proinsulin-secreting neuroendocrine tumor of the pancreas. Journal of Endocrinological Investigation. 2003;26(8):758-761.

Whether thyroid nodules 4 cm or larger with benign cytology carry a higher risk of malignancy, and should be managed differently than smaller nodules remains controversial. We aimed to evaluate the malignancy rate and benign cytology false-negative rate in thyroid nodules ≥4 cm compared with those

The re-naming of noninvasive follicular variant papillary thyroid cancer to the apparently non-malignant, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) impacts the prevalence of malignancy rates, thereby affecting mutation frequency in papillary thyroid cancer. Preoperative assessment of such nodules could affect management in the future. The original publications following the designation of the new nomenclature have been extensively reviewed. With the adoption of NIFTP terminology, a reduction in the follicular variant of papillary thyroid cancer (FVPTC) prevalence is anticipated, as is a modest reduction of papillary thyroid cancer (PTC) prevalence that would be distributed mainly across indeterminate thyroid nodules. Identifying NIFTP preoperatively remains challenging. RAS mutations are predominant but the presence of BRAF V600E mutation has been observed and could indicate inclusion of the classical PTC. The histological diagnosis of NIFTP to designate low-risk encapsulated follicular variant papillary thyroid cancers (EFVPTCs) would impact malignancy rates, thereby altering the mutation prevalence. The histopathologic criteria have recently been refined with an exclusion of well-formed papillae. The preoperative identification of NIFTP using cytomorphology and gene testing remains challenging.

Indeterminate thyroid fine-needle aspiration (FNA) cytology, including atypia of undetermined significance (AUS/FLUS) and suspicious for follicular neoplasm (SFN), continues to generate uncertainty about the presence of malignancy, resulting in repeated follow-up, repeat FNA, or diagnostic surgery. Mutational panel testing may improve the malignancy risk prediction in indeterminate nodules, but the general application of such testing has not been investigated extensively.A retrospective review was performed of all patients undergoing thyroidectomy at a tertiary care facility over a two-year period. Mutational panel test results, when present, were analyzed relative to FNA cytologic result and surgical histopathologic diagnosis. Malignancy rates, sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV) and positive and negative likelihood ratios (LR) were calculated.A total of 261 operated thyroid nodules had the following initial FNA cytology results: 2% non-diagnostic, 23% benign, 28% AUS/FLUS, 11% SFN, 9% suspicious for malignancy (SUSP), and 27% malignant. The histopathologic malignancy rate was 48%, subcategorized by cytology into benign 7%, AUS/FLUS 30%, SFN 38%, and SUSP 83%. Mutations were more frequent in indeterminate nodules that were histologically malignant versus benign (p 0.0001) or versus adenoma (p = 0.001). Mutational analysis in 44 AUS/FLUS nodules resulted in a malignancy detection sensitivity of 85%, a specificity of 65%, a PPV of 50%, a NPV of 91%, and a positive LR of 2.4. In 12 SFN nodules analyzed with ThyroSeq(®) testing, sensitivity was 100%, specificity 57%, PPV 63%, NPV 100%, and LR 2.3. Performance of the seven-gene mutational panel was not significantly different from the ThyroSeq(®) panel in the AUS/FLUS group. The malignancy yield, comparing the mutation positive AUS/FLUS group with the untested AUS/FLUS surgical cohort, did not reach statistical significance (p = 0.17).In a surgical cohort, a similar NPV but a lower PPV was found with the use of mutational panel testing compared to the published literature. Following the identification of a mutation, the prevalence of malignancy in the AUS/FLUS or SFN category was increased by nearly 15% to 45% and 53%, respectively. Further study is needed to confirm these results and to analyze clinical outcome subcategories relative to the utility of mutational testing.

Background The atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) category in the Bethesda System of reporting thyroid fine-needle aspiration (FNA) includes various cytological findings considered to have a low risk of malignancy. It is still unclear if any particular subset of the cytological findings within this category carries a higher risk for malignancy requiring a more aggressive treatment plan. Methods We reviewed 221 AUS/FLUS FNAs performed between January of 2006 and May of 2012. Histopathological data from surgery was available in 101 nodules and characteristics of these nodules were analyzed. We reviewed the initial cytology report and subclassified the nodules into one of four groups: architectural atypia (AA, includes abnormal follicular arrangement but no cellular abnormalities), cellular atypia (CA, atypical cellular findings) with or without AA, Hurthle cells Predominant and Others that included otherwise unspecified AUS categories. The surgical pathology confirmed malignancy rate for each group was calculated. Result Papillary thyroid carcinoma was the most common malignancy identified (26 of 29 or 90%). We found that in the AA only category, 2/21 (10%) nodules were malignant, whereas when CA with or without AA was present, 23/66 (35%) were malignant, significantly higher than the former group (P values of 0.025). Conclusion CA seen on initial AUS/FLUS had a higher malignancy rate compared to AA group. Further research is required to consider subclassification of this category to assign appropriate risk of malignancy for AUS nodules. Diagn. Cytopathol. 2016. © 2016 Wiley Periodicals, Inc.

Multiple gene mutations in thyroid nodules are rare. The presence of several oncogenic mutations could be associated with aggressive biological behavior of tumors.A 60-year-old female presented to her physician after she felt a lump in her neck. On ultrasound, she was found to have a 1.4 cm × 0.8 cm × 1.3 cm nodule in the isthmus and a 0.5 cm × 0.6 cm × 0.6 cm nodule with irregular margins and hypoechogenicity in the right thyroid lobe, warranting fine-needle aspiration (FNA). Cytological examination of the smaller nodule yielded a diagnosis of atypia of undetermined significance (AUS/FLUS, Bethesda Category III). The aspirate was submitted for molecular testing using the next-generation sequencing ThyroSeq(®) v2 panel. The test revealed four distinct mutations: BRAF (p.V600E), TERT (C228T), PIK3CA (p.H1047R), and AKT1 (p.E17K). Presence of multiple oncogenic mutations in the FNA specimen was highly indicative of cancer, and suggestive of a cancer with propensity toward more aggressive biological behavior. Four weeks after the FNA results were available, the patient underwent total thyroidectomy. This was followed by radioactive iodine ablation after the final pathology revealed a 0.5 cm papillary thyroid carcinoma (PTC) with extrathyroidal extension and positive resection margins (pT3 stage).Herein, the first case of four mutations preoperatively detected in a subcentimeter thyroid nodule that was confirmed to be a PTC with aggressive biological behavior is reported.The judicious indication of FNA and use of molecular screening can potentially help in predicting aggressive behavior of small-sized thyroid cancers and in identifying patients who may benefit from early and more extensive therapy.

Aim Although regular human U‐500 insulin (U‐500) is frequently used for insulin resistant type 2 diabetics, pharmacokinetic and pharmacodynamic studies in these individuals are lacking. We set out to determine the rate of onset, duration of action and total glucose lowering effect of two doses of U‐500 insulin in obese insulin resistant subjects with type 2 diabetes. Materials and Methods Randomized double‐blind crossover study was designed to study subjects who were administered either 100 or 200 units SQ of U‐500 insulin once and then were provided intravenous glucose as necessary to maintain euglycaemia. Results A total of 12 subjects were studied. The time during which intravenous glucose was required to maintain euglycaemia following a 200‐unit dose of U‐500 insulin was significantly greater than the time following a 100‐unit dose. No differences were found between doses in measures related to the rate of onset or in the total amount of intravenous glucose required to maintain euglycaemia for the duration of the study. Conclusions The duration of action of U‐500 increases when dose is increased from 100 to 200 units. Neither dose of U‐500 insulin has an onset of action before 2.5 hours after administration. This suggests that U‐500 should not be used as a premeal bolus insulin to lower glucose two hours after a meal and that dosing intervals might need to be extended as dose is increased to avoid hypoglycaemia.

Practitioners often consider using U500 regular insulin (U500) in obese patients with T2DM who take >100 units of insulin/day. To compare the pharmacodynamic effects of 2 doses of U500 in such patients, we did a randomized double blind cross over study in which 100 or 200 units (U) SQ of U500 was given once and IV glucose was then given as necessary to maintain euglycemia (EU). Subjects stopped their own insulin at least 12 hours before the U500 dose and were kept on an insulin drip overnight to target EU. Subjects were NPO for 8 hours before and 4 hours after U500 dosing. Meals with 30 gm of carbohydrate were given at hours 4, 9, 13, 26, 30. Rate of U500 onset was determined by measuring the area under the curve (AUC) of IV glucose given hours 0-4, the peak infusion rate achieved hours 0-4, and the time at which IV glucose was started. Duration of action was determined by measuring the time IV glucose was required to maintain EU. The effect of the each dose on glucose lowering was determined by measuring the AUC of the IV glucose given to maintain EU for the entire study. 3F, 9M completed the study (age 54 ± 5 years, BMI 36.0 ± 3.3 kg/m2, total daily insulin dose 174 ± 40 units, mean ± SD). We conclude the duration of action of U500 is longer following administration 200 vs. 100. However, no differences were found in rate of onset or total amount of glucose required to maintain EU. Future studies should examine the pharmacodynamics of repeated doses of U500 in similar subjects. {6E9A1FC8-900A-4232-972F-0B0D186440A8}Dose100 units U500200 units U500Total glucose given 0-4 hours after U500 dose (mg/kg)5.3 ± 6.54.7 ± 5.6Peak infusion rate achieved 0-4 hours after U500 (mg/kg/min)5.3 ± 3.84.2 ± 1.9Time following injection the glucose infusion was started to maintain EU (hours)2.6 ± 1.32.2 ± 1.0Duration of action (hours)11.0 ± 5.616.5 ± 6.4p=0.031Total glucose required to maintain euglycemia (mg/kg)18.5 ± 20.720.1± 13.3 Disclosure A. Kumar: None. R.T. Shrestha: None. A.S. Taddese: None. A. Moheet: None. A. Khowaja: None. E.A. Olawsky: None. L.E. Eberly: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc..

The interface between thyroid hormone action and neuropsychiatric function is intricate, and several mechanisms of thyroid hormone uptake into brain tissues, hormone activation, and influences on neurotransmitter generation have been identified. Symptoms of hypothyroidism are nonspecific, whereas those attributed to thyrotoxicosis may be more characteristic. Neuropsychiatric manifestations triggered by thyroid dysfunction likely respond well to reestablishment of the euthyroid state, although some patients have persistent complaints. The addition of LT3 to ongoing LT4 replacement has yet to be definitively shown to be advantageous. Treatment of euthyroid depression with LT3 in addition to antidepressant therapy lacks convincing evidence of superior outcomes.

The atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) category in the Bethesda System of reporting thyroid fine-needle aspiration (FNA) includes various cytological findings considered to have a low risk of malignancy. It is still unclear if any particular subset of the cytological findings within this category carries a higher risk for malignancy requiring a more aggressive treatment plan.We reviewed 221 AUS/FLUS FNAs performed between January of 2006 and May of 2012. Histopathological data from surgery was available in 101 nodules and characteristics of these nodules were analyzed. We reviewed the initial cytology report and subclassified the nodules into one of four groups: architectural atypia (AA, includes abnormal follicular arrangement but no cellular abnormalities), cellular atypia (CA, atypical cellular findings) with or without AA, Hurthle cells Predominant and Others that included otherwise unspecified AUS categories. The surgical pathology confirmed malignancy rate for each group was calculated.Papillary thyroid carcinoma was the most common malignancy identified (26 of 29 or 90%). We found that in the AA only category, 2/21 (10%) nodules were malignant, whereas when CA with or without AA was present, 23/66 (35%) were malignant, significantly higher than the former group (P values of 0.025).CA seen on initial AUS/FLUS had a higher malignancy rate compared to AA group. Further research is required to consider subclassification of this category to assign appropriate risk of malignancy for AUS nodules. Diagn. Cytopathol. 2016;44:492-498. © 2016 Wiley Periodicals, Inc.

Importance Biotinylated antibodies and analogues, with their strong binding to streptavidin, are used in many clinical laboratory tests. Excess biotin in blood due to supplemental biotin ingestion may affect biotin-streptavidin binding, leading to potential clinical misinterpretation. However, the degree of interference remains undefined in healthy adults. Objective To assess performance of specific biotinylated immunoassays after 7 days of ingesting 10 mg/d of biotin, a dose common in over-the-counter supplements for healthy adults. Design, Setting, and Participants Nonrandomized crossover trial involving 6 healthy adults who were treated at an academic medical center research laboratory Exposure Administration of 10 mg/d of biotin supplementation for 7 days. Main Outcomes and Measures Analyte concentrations were compared with baseline (day 0) measures on the seventh day of biotin treatment and 7 days after treatment had stopped (day 14). The 11 analytes included 9 hormones (ie, thyroid-stimulating hormone, total thyroxine, total triiodothyronine, free thyroxine, free triiodothyronine, parathyroid hormone, prolactin, N-terminal pro-brain natriuretic peptide, 25-hydroxyvitamin D) and 2 nonhormones (prostate-specific antigen and ferritin). A total of 37 immunoassays for the 11 analytes were evaluated on 4 diagnostic systems, including 23 assays that incorporated biotin and streptavidin components and 14 assays that did not include biotin and streptavidin components and served as negative controls. Results Among the 2 women and 4 men (mean age, 38 years [range, 31-45 years]) who took 10 mg/d of biotin for 7 days, biotin ingestion–associated interference was found in 9 of the 23 (39%) biotinylated assays compared with none of the 14 nonbiotinylated assays ( P = .007). Results from 5 of 8 biotinylated (63%) competitive immunoassays tested falsely high and results from 4 out of 15 (27%) biotinylated sandwich immunoassays tested falsely low. Conclusions and Relevance In this preliminary study of 6 healthy adult participants and 11 hormone and nonhormone analytes measured by 37 immunoassays, ingesting 10 mg/d of biotin for 1 week was associated with potentially clinically important assay interference in some but not all biotinylated assays studied. These findings should be considered for patients taking biotin supplements before ordering blood tests or when interpreting results. Trial Registration clinicaltrials.gov Identifier:NCT03034707