Repeat Fine Needle Aspiration Cytology Refines the Selection of Thyroid Nodules for Afirma Gene Expression Classifier Testing.

Background: Molecular testing (MT) refines risk stratification for thyroid nodules that are indeterminate for cancer by fine needle aspiration (FNA) cytology. Criteria for selecting nodules for MT vary and remain largely untested, raising questions about the best strategy for maximizing the usefulness of MT while minimizing the harms of overtesting. We used a unique data set to examine the effects of repeat FNA cytology-based criteria for MT on management decisions and nodule outcomes. Methods: This was a study of adults (age 25-90 years; 281 women and 72 men) with cytologically indeterminate (Bethesda III/IV) thyroid nodules who underwent repeat FNA biopsy and Afirma Gene Expression Classifier (GEC) testing (N = 363 nodules from 353 patients) between June 2013 and October 2017 at a single institution, with follow-up data collected until December 2019. Subgroup analysis was performed based on classification of repeat FNA cytology. Outcomes of GEC testing, clinical/sonographic surveillance of unresected nodules, and histopathologic diagnoses of thyroidectomies were compared between three testing approaches: (i) Reflex (MT sent on the basis of the initial Bethesda III/IV FNA), (ii) SemiRestrictive (MT sent if repeat FNA is Bethesda I-IV), and (iii) Restrictive (MT sent only if repeat FNA is Bethesda III/IV) testing approaches. Results: Restricting MT to nodules that remain Bethesda III/IV on repeat FNA would have missed 4 low-risk cancers and 3 noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) (collectively 2% of the test population) but would have avoided diagnostic surgery for 42 benign nodules (12% of the test population). The Restrictive testing strategy was more specific (delta 0.126 confidence interval [CI 0.093 to 0.159] and 0.129 [CI 0.097 to 0.161], respectively) but less sensitive (delta -0.339 [CI -0.424 to -0.253] and -0.340 [CI -0.425 to -0.255], respectively) than the Reflex and SemiRestrictive approaches for detecting NIFTP or cancer. Conclusions: Repeat FNA cytology can guide the selection of cytologically indeterminate thyroid nodules that warrant MT. The Restrictive model of performing Afirma GEC only on nodules with two separate biopsies showing Bethesda III/IV cytology would reduce the rate of diagnostic surgery for histologically benign nodules while missing only rare low-risk tumors. Given the low but nontrivial risks of thyroidectomy, the higher specificity of the Restrictive testing approach disproportionately outweighs the potential harms.

Optimizing calcium and vitamin D intake through diet and supplements.

Calcium, a key component of bone, is obtained through diet or supplements, or both, and vitamin D is necessary for normal calcium absorption. Controversy exists as to the efficacy and even the safety of calcium. Our opinion, backed by studies and guidelines, is that adequate amounts of calcium are a must for patients concerned about bone health, and cardiovascular safety is not a concern.

Enhanced Precision of the New Hologic Horizon Model Compared With the Old Discovery Model Is Less Evident When Fewer Vertebrae Are Included in the Analysis.

The International Society for Clinical Densitometry guidelines recommend using locally derived precision data for spine bone mineral densities (BMDs), but do not specify whether data derived from L1-L4 spines correctly reflect the precision for spines reporting fewer than 4 vertebrae. Our experience suggested that the decrease in precision with successively fewer vertebrae is progressive as more vertebrae are excluded and that the precision for the newer Horizon Hologic model might be better than that for the previous model, and we sought to quantify. Precision studies were performed on Hologic densitometers by acquiring spine BMD in fast array mode twice on 30 patients, according to International Society for Clinical Densitometry guidelines. This was done 10 different times on various Discovery densitometers, and once on a Horizon densitometer. When 1 vertebral body was excluded from analysis, there was no significant deterioration in precision. When 2 vertebrae were excluded, there was a nonsignificant trend to poorer precision, and when 3 vertebrae were excluded, there was significantly worse precision. When 3 or 4 vertebrae were reported, the precision of the spine BMD measurement was significantly better on the Hologic Horizon than on the Discovery, but the difference in precision between densitometers narrowed and was no longer significant when 1 or 2 vertebrae were reported. The results suggest that (1) the measurement of in vivo spine BMD on the new Hologic Horizon densitometer is significantly more precise than on the older Discovery model; (2) the difference in precision between the Horizon and Discovery models decreases as fewer vertebrae are included; (3) the measurement of spine BMD is less precise as more vertebrae are excluded, but still quite reasonable even when only 1 vertebral body is included; and (4) when 3 vertebrae are reported, L1-L4 precision data can reasonably be used to report significance of changes in BMD. When 1 or 2 vertebrae are reported, precision data for 1 or 2 vertebrae, respectively, should be used, because the exclusion of 2-3 vertebrae significantly worsens precision.

Successful Treatment of an Unusual Case of FPLD2: The Role of Roux-en-Y Gastric Bypass-Case Report and Literature Review.

Familial partial lipodystrophy type 2 (FPLD2) is a rare disorder associated with LMNA gene mutations. It is usually marked by loss of subcutaneous fat on the limbs and trunk and severe insulin resistance. Scattered reports have indicated that Roux-en-Y bypass helps to control the diabetes mellitus in these patients. We present here a very unusual patient with FPLD2 who had life-threatening retroperitoneal and renal fat accumulation accompanied by bilateral renal cancers. Following cryotherapy of one renal cancer and a contralateral nephrectomy with debulking of the retroperitoneal fat, Roux-en-Y gastric bypass (RYGB) has successfully controlled the disease for 3 years. The clinical presentations and causes of FPLD are reviewed and the role of RYGB is discussed.

Lorcaserin Administration Decreases Activation of Brain Centers in Response to Food Cues and These Emotion- and Salience-Related Changes Correlate With Weight Loss Effects: A 4-Week-Long Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

Lorcaserin is a serotonin 5-hydroxytryptamine 2c receptor agonist effective in treating obesity. Studies in rodents have shown that lorcaserin acts in the brain to exert its weight-reducing effects, but this has not yet been studied in humans. We performed a randomized, placebo-controlled, double-blind trial with 48 obese participants and used functional MRI to study the effects of lorcaserin on the brain. Subjects taking lorcaserin had decreased brain activations in the attention-related parietal and visual cortices in response to highly palatable food cues at 1 week in the fasting state and in the parietal cortex in response to any food cues at 4 weeks in the fed state. Decreases in emotion- and salience-related limbic activity, including the insula and amygdala, were attenuated at 4 weeks. Decreases in caloric intake, weight, and BMI correlated with activations in the amygdala, parietal, and visual cortices at baseline. These data suggest that lorcaserin exerts its weight-reducing effects by decreasing attention-related brain activations to food cues (parietal and visual cortices) and emotional and limbic activity (insula, amygdala). Results indicating that baseline activation of the amygdala relates to increased efficacy suggest that lorcaserin would be of particular benefit to emotional eaters.

Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia.

Leptin is an adipocyte-derived hormone that controls food intake and reproductive and immune functions in rodents. In uncontrolled human studies, low leptin levels are associated with impaired immune responses and reduced T-cell counts; however, the effects of leptin replacement on the adaptive immune system have not yet been reported in the context of randomized, controlled studies and/or in conditions of chronic acquired leptin deficiency. To address these questions, we performed a randomized, double-blinded, placebo-controlled trial of recombinant methionyl-human leptin (metreleptin) administration in replacement doses in women experiencing the female triad (hypothalamic amenorrhea) with acquired chronic hypoleptinemia induced by negative energy balance. Metreleptin restored both CD4(+) T-cell counts and their in vitro proliferative responses in these women. These changes were accompanied by a transcriptional signature in which genes relevant to cell survival and hormonal response were up-regulated, and apoptosis genes were down-regulated in circulating immune cells. We also observed that signaling pathways involved in cell growth/survival/proliferation, such as the STAT3, AMPK, mTOR, ERK1/2, and Akt pathways, were activated directly by acute in vivo metreleptin administration in peripheral blood mononuclear cells and CD4(+) T-cells both from subjects with chronic hypoleptinemia and from normoleptinemic, lean female subjects. Our data show that metreleptin administration, in doses that normalize circulating leptin levels, induces transcriptional changes, activates intracellular signaling pathways, and restores CD4(+) T-cell counts. Thus, metreleptin may prove to be a safe and effective therapy for selective CD4(+) T-cell immune reconstitution in hypoleptinemic states such as tuberculosis and HIV infection in which CD4(+) T cells are reduced.

Preadipocyte factor-1 levels are higher in women with hypothalamic amenorrhea and are associated with bone mineral content and bone mineral density through a mechanism independent of leptin.

CONTEXT: Preadipocyte factor 1 (pref-1) is increased in anorexia nervosa and is associated negatively with bone mineral density (BMD). No previous studies exist on pref-1 in women with exercise-induced hypothalamic amenorrhea (HA), which similar to anorexia nervosa, is an energy-deficiency state associated with hypoleptinemia. OBJECTIVE: Our objective was to evaluate whether pref-1 levels are also elevated and associated with low BMD and to assess whether leptin regulates pref-1 levels in women with HA. DESIGN: Study 1 was a double-blinded, placebo-controlled randomized clinical trial of metreleptin administration in women with HA. Study 2 was an open-label study of metreleptin administration in low physiological, supraphysiological, and pharmacological doses in healthy women volunteers. SETTING AND PATIENTS: At Beth Israel Deaconess Medical Center, 20 women with HA and leptin levels higher than 5 ng/ml and nine healthy control women participated in study 1, and five healthy women participated in study 2. INTERVENTION: For study 1, 20 HA subjects were randomized to receive either 0.08 mg/kg metreleptin (n = 11) or placebo (n = 9). For study 2, five healthy subjects received 0.01, 0.1, and 0.3 mg/kg metreleptin in both fed and fasting conditions for 1 and 3 d, respectively. MAIN OUTCOME MEASURES: Circulating pref-1 and leptin levels were measured. RESULTS: Pref-1 was significantly higher in HA subjects vs. controls (P = 0.035) and negatively associated with BMD (ρ = -0.38; P < 0.01) and bone mineral content (ρ = -0.32; P < 0.05). Metreleptin administration did not alter pref-1 levels in any study reported herein. CONCLUSIONS: Pref-1 is higher in HA subjects than controls. Metreleptin administration at low physiological, supraphysiological, and pharmacological doses does not affect pref-1 levels, suggesting that hypoleptinemia is not responsible for higher pref-1 levels and that leptin does not regulate pref-1.