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Thyroid dysfunction during tyrosine kinase inhibitor (TKI) cancer treatment is common, but predisposing risk factors have not been determined. Recommendations for monitoring patients treated with one or multiple TKI and in conjunction with other relevant cancer therapies could be improved. The study objective was to assess the risk factors for new thyroid dysfunction in TKI-treated previously euthyroid cancer patients.A retrospective cohort study of patients with advanced nonthyroidal cancer treated with TKI from 2000 to 2017, having available thyroid function tests showing initial euthyroid status, excluding patients with preexisting thyroid disease or lack of follow-up thyroid function tests. During TKI treatment, patients were classified as euthyroid (thyrotropin [TSH] normal), subclinical hypothyroidism (TSH 5-10 mIU/L, or higher TSH if free thyroxine normal), or overt hypothyroidism (TSH10 mIU/L, low free thyroxine, or requiring thyroid hormone replacement). The timing of thyroid dysfunction and TKI used were assessed. Risk factors for incident hypothyroidism were evaluated using multivariate models.In 538 adult patients included, subclinical hypothyroidism occurred in 71 (13.2%) and overt hypothyroidism occurred in 144 (26.8%) patients with TKI therapy, following a median cumulative TKI exposure of 196 days (interquartile range [IQR] 63.5-518.5 days). The odds of hypothyroidism were greatest during the first six months on a TKI. Median exposure time on the TKI concurrent with thyroid dysfunction in patients treated with only one TKI was 85 days (IQR 38-293.5 days) and was similar to the 74 days (IQR 38-133.3 days) in patients treated previously with other TKI (p = 0.41). Patients who developed hypothyroidism compared to those who remained euthyroid had greater odds of being female (odds ratio = 1.99 [confidence interval 1.35-2.93], p 0.01), but greater cumulative TKI exposure and greater number of TKI received were not associated with thyroid dysfunction.Thyroid dysfunction occurred in 40% of euthyroid patients. Monitoring thyroid function in TKI-treated patients is recommended, with particular attention to female patients and within the first six months of exposure to a new TKI.

Tyrosine kinase inhibitor (TKI)-induced thyroid dysfunction is recognized as a common adverse effect of treatment, but the importance of incident hypothyroidism during TKI therapy remains unclear. This study analyzed the prognostic significance of hypothyroidism during TKI therapy in cancer patients.This was a retrospective cohort study of adult patients with advanced nonthyroidal cancer treated with TKI and available thyroid function testing at three affiliated academic hospitals from 2000 to 2017. Patients with preexisting thyroid disease were excluded. Demographic, clinical, and cancer treatment data were collected. Thyroid status with TKI treatment was determined from thyroid function testing and initiation of thyroid medication, and classified as euthyroid (thyrotropin [TSH] normal), subclinical hypothyroidism (SCH; TSH 5-10 mIU/L, or higher TSH if free thyroxine normal), or overt hypothyroidism (OH; TSH10 mIU/L, low free thyroxine, or requiring replacement). Multivariate models were used to evaluate the effect of TKI-related hypothyroidism on overall survival (OS).Of 1120 initial patients, 538 remained after exclusion criteria. SCH occurred in 72 (13%) and OH in 144 (27%) patients with TKI therapy. Patients with hypothyroidism had significantly longer OS, with median OS in euthyroid patients of 685 days [confidence interval (CI) 523-851] compared to 1005 days [CI 634-1528] in SCH and 1643 days [CI 1215-1991] in OH patients (p 0.0001). After adjustment for age, sex, race/ethnicity, cancer type, cancer stage, ECOG performance status, and checkpoint inhibitor therapy, OH remained significantly associated with OS (hazard ratio = 0.561; p 0.0001), whereas SCH did not (hazard ratio = 0.796; p = 0.165). Analysis of hypothyroid patients (SCH and OH) with TSH5 and10 mIU/L stratified by hormone replacement status showed improved survival associated with hormone replacement.New hypothyroidism in cancer patients treated with TKI is associated with significantly improved OS, should not necessitate TKI dose reduction or discontinuation, and may provide independent prognostic information.

Background VEGF signaling pathway inhibitor (anti-VEGF) therapy is associated with hypertension, but little is known about predisposing clinical characteristics. This study describes the real-world association between baseline clinical characteristics, blood pressure (BP) response, and survival in patients prescribed anti-VEGF therapies. Methods Clinical data from Partners HealthCare in Massachusetts was obtained from adults treated with anti-VEGF therapies (2002-2013). Treatment-induced hypertensive response was defined as worsening of preexisting hypertension or new diagnosis of hypertension (if no prior hypertension history). Results Data from 1120 patients with renal cell carcinoma (32.2%), hepatocellular carcinoma (11.6%), gastrointestinal stromal tumors (12.5%), and other sarcomas (15.3%) were analyzed. Most patients received sunitinib (52%), sorafenib (25.9%), or pazopanib (18%). A treatment-induced hypertensive response was identified in 49.7% of treated patients. Preexisting hypertension, present in 65.4%, was an independent risk factor for BP elevation (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.27-1.92); other risk factors included age ≥60 years (OR, 1.26; 95% CI, 1.06-1.52), and body mass index (BMI) ≥25 kg/m(2) (OR, 1.26; 95% CI, 1.04-1.53). Race, sex, anti-VEGF therapy prescribed, and baseline antihypertensive class were not significant risk factors. The absolute observed mean increase in BP was 21 mm Hg (systolic)/15 mm Hg (diastolic), both in patients with and without preexisting hypertension. The development of hypertension predicted improved survival (hazard ratio, 0.76; 95% CI, 0.65-0.89). Conclusions Preexisting hypertension, age, and BMI identify patients at risk for significant anti-VEGF therapy-induced BP elevation. Hypertension appears to be a clinical biomarker of efficacy of anti-VEGF therapies in a broad range of malignancies.

Objective To study the day-night variation of omentin-1 levels and assess whether leptin, and/or short-and long-term energy deprivation alter circulating omentin-1 levels via cytokines. Design and Methods Omentin-1 levels were measured hourly in serum samples from six healthy men to evaluate for day-night variation. To study effects of acute energy deprivation and of leptin administration, eight healthy subjects were studied in the fasting state for 72 hours with administration of either placebo or metreleptin in physiological replacement doses. We evaluated the effect of leptin in pharmacological doses on serum omentin-1 and cytokine levels, as well as on omentin-1 levels in ex vivo omental adipose tissue, in fifteen healthy volunteers. To study the effect of chronic energy deprivation and weight loss on omentin-1 levels we followed eighteen obese subjects for 12 months who underwent bariatric surgery. Results There is no day-night variation in omentin-1 levels. Short-term and chronic energy deprivation as well as ex vivo leptin administration and physiological replacement doses of leptin do not alter omentin-1 levels, whereas pharmacologic doses of metreleptin reduce omentin-1 levels whereas levels of TNF-α receptor II and IL-6 tend to increase. Conclusions Omentin-1 levels are reduced by pharmacological doses of metreleptin independent of effects on cytokine levels.

Objective Undercarboxylated osteocalcin (ucOC) is a bone marker with potent metabolic effects. Leptin regulates Esp gene expression and osteocalcin carboxylation in animal models. We aim to elucidate day/night patterns of ucOC levels, whether short-term and/or chronic energy deprivation alters ucOC levels, and whether leptin may mediate these changes in humans. Design and Methods Twelve healthy males and females were studied for 72 h in the fed state to study day/night pattern of ucOC. The six female subjects were also studied in a crossover interventional study in the fasting state for 72 h with administration of either placebo or metreleptin in physiological doses. Blood samples were obtained hourly from 0800 a.m. on day 3 until 0800 a.m. on day 4. In a separate study, eleven obese subjects who underwent bariatric surgery were followed for 24 weeks to examine the effects of postsurgery weight loss on ucOC levels. Results Males have higher ucOC levels compared to females. There is no day/night variation pattern of circulating ucOC in humans. Short-term and chronic energy deprivation or leptin administrations do not alter ucOC levels. Conclusions The hypothesis that ucOC plays a role in energy homeostasis or of leptin in regulating ucOC in humans is not supported.

Obesity is associated with chronic low-grade inflammation leading to insulin resistance and diabetes. Adiponectin is an adipokine that regulates inflammatory responses. The aim of our study was to investigate whether any effects of adiponectin against obesity and insulin-resistance may depend on the adaptive immune system.We treated high-fat-diet fed Rag1-/- mice lacking mature lymphocytes with adiponectin over 7weeks and investigated alterations in their metabolic outcome and inflammatory state.Adiponectin protects from weight gain despite a small compensatory stimulation of energy intake in mice lacking an adaptive immune system. Additionally, adiponectin protects from dysglycemia. Minor alterations in the macrophage phenotype, but not in the circulating cytokine levels, may contribute to the protective role of adiponectin against hyperglycemia and diabetes.Adiponectin or agents increasing adiponectin may be a promising therapeutic option against obesity and hyperglycemia in immune-deficient populations.

The spectrum of lipid-induced changes in the secretion of hormones important in energy homeostasis has not yet been fully elucidated.To identify potential incretin-like effects in response to lipid administration, we examined the short-term effect of iv vs oral lipids on key molecules regulating energy homeostasis. Design, Intervention, and Participants: After a 10-hour overnight fast, 26 subjects were randomized to receive an oral lipid load, a 10% iv lipid emulsion, a 20% iv lipid emulsion, or an iv saline infusion. We obtained blood samples at 30-minute intervals for the first 2 hours and hourly thereafter for a total of 6 hours.Circulating levels of insulin, glucose, c-peptide, free fatty acids, incretins (glucagon-like peptide-1, gastric inhibitory polypeptide), glucagon, peptide YY, ghrelin, fibroblast growth factor 21, fetuin A, irisin, omentin, and adiponectin were measured.Oral lipid ingestion resulted in higher glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, and peptide YY levels, compared with the other three groups (incremental area under the curve P = .003, P.001, P.001, P.001, respectively). The 20% lipid emulsion, leading to higher free fatty acid levels, resulted in greater insulin, c-peptide, and fibroblast growth factor 21 responses compared with placebo and the other two groups (incremental area under the curve P = .002, P = .005, P.001, P.001, respectively). Omentin, adiponectin, fetuin A, and irisin levels were not affected by either mode of lipid administration.Metabolic responses to lipids depend on the route of administration. Only iv lipids trigger a dose-dependent fibroblast growth factor 21 secretion, which is nonglucagon mediated. Intravenous lipids also induce hyperinsulinemia without concurrent decreases in glucose, a phenomenon observed in insulin-resistant states. Orally administered lipids mostly affect gastrointestinal tract-secreted molecules important in glucose and energy homeostasis such as glucagon, incretins, and peptide YY.

Leptin, a peptide hormone secreted by adipocytes in proportion of the amount of energy stored in fat, plays a central role in regulating human energy homeostasis. In addition, leptin plays a significant permissive role in the physiological regulation of several neuroendocrine axes, including the hypothalamic-pituitary-gonadal, -thyroid, -growth hormone, and -adrenal axes. Decreased levels of leptin, also known as hypoleptinemia, signal to the brain a state of energy deprivation. Hypoleptinemia can be a congenital or acquired condition, and is associated with alterations of the aforementioned axes aimed at promoting survival. More specifically, gonadotropin levels decrease and become less pulsatile under conditions of energy deprivation, and these changes can be at least partially reversed through leptin administration in physiological replacement doses. Similarly, leptin deficiency is associated with thyroid axis abnormalities including abnormal levels of thyrotropin-releasing hormone, and leptin administration may at least partially attenuate this effect. Leptin deficiency results in decreased insulin-like growth factor 1 levels which can be partially ameliorated through leptin administration, and leptin appears to have a much more pronounced effect on the growth of rodents than that of humans. Similarly, adrenal axis function is regulated more tightly by low leptin in rodents than in humans. In addition to congenital leptin deficiency, conditions that may be associated with decreased leptin levels include hypothalamic amenorrhea, anorexia nervosa, and congenital or acquired lipodystrophy syndromes. Accumulating evidence from proof of concept studies suggests that leptin administration, in replacement doses, may ameliorate neuroendocrine abnormalities in individuals who suffer from these conditions.

We examined the relationship between serum levels of leptin-binding protein (soluble leptin receptor [sOB-R]) and leptin with metabolic parameters at baseline and prospectively at 2-year follow-up in young healthy men. A total of 916 eighteen-year-old men were examined at baseline, with a subgroup of 91 participants examined again 2 years later. Anthropometric and metabolic measurements were performed at baseline and at follow-up. In the cross-sectional study, levels of sOB-R were significantly inversely correlated with all baseline measures of obesity and metabolic risk factors (blood pressure, total and low-density lipoprotein cholesterol, and fasting glucose), and significantly positively correlated with high-density lipoprotein cholesterol. After correcting for age, smoking status, and waist-to-hip ratio, the inverse correlation remained statistically significant for all measures of adiposity, fasting glucose, and the metabolic syndrome score. Correlations for leptin were similar in magnitude but opposite in direction to correlations for sOB-R. In prospective analyses, baseline levels of sOB-R were predictive at 2-year follow-up of fasting glucose, the metabolic syndrome score, and measures of adiposity in both unadjusted and adjusted models. Similarly, leptin was predictive of fasting glucose, the metabolic syndrome score, adiposity, and systolic blood pressure. We confirm correlations of leptin and sOB-R levels with measures of adiposity and metabolic risk factors at baseline, and demonstrate for the first time prospectively the role of sOB-R as an independent, although weak, predictor of metabolic syndrome and fasting glucose in young men. (C) 2011 Elsevier Inc. All rights reserved.

Lymphocytic hypophysitis—an inflammatory condition of presumed autoimmune etiology—is characterized by an enlargement of the pituitary gland, resulting in its dysfunction. Although found generally in peripartum women, this Case Study of a 29-year-old man, who was referred to a neurosurgical clinic for evaluation of a suprasellar mass and diabetes insipidus, illustrates the need to consider this disorder in men. Background. A 29-year-old man was referred to a multidisciplinary pituitary clinic with a 3.5-year history of central diabetes insipidus, initially presumed to be idiopathic based on a normal MRI scan of the pituitary gland. Subsequent scanning revealed a suprasellar mass, which demonstrated progressive enlargement on serial imaging. He also developed hypogonadotropic hypogonadism. Investigations. Measurement of levels of serum morning fasting cortisol, adrenocorticotropic hormone, total testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin, insulin-like growth factor 1, TSH and free T4, MRI of the pituitary gland and a transsphenoidal biopsy of a pituitary mass were performed. Diagnosis. Lymphocytic hypophysitis presenting with diabetes insipidus, with development of hypogonadotropic hypogonadism and a suprasellar mass. Management. The patient was treated with intranasal desmopressin and transdermal testosterone. The underlying lymphocytic hypophysitis was initially managed conservatively with serial MRI and visual field testing. No immunosuppressant medication was given and, aside from the diagnostic transsphenoidal biopsy, no surgical intervention was required. He subsequently developed secondary hypothyroidism, secondary adrenal insufficiency and growth hormone deficiency. These disorders were managed with levothyroxine and prednisone.

Objective To comparatively evaluate traditional liver tests and fetuin A as predictors of cardiometabolic risk, we studied associations between serum alanine transaminase (ALT), γ-glutamyl transferase (GGT), aspartate aminotransferase (AST) and fetuin-A and anthropometric, metabolic, and cardiovascular parameters cross-sectionally at baseline, and prospectively, after 2-years of follow-up. Research Design and Methods 616 randomly enrolled young healthy participants in the Cyprus Metabolism Study, including all 93 subjects who participated in the follow-up study 2 years after baseline assessment, were included in this study. Results In the cross-sectional study, serum ALT and GGT were strongly correlated with anthropometric, cardiovascular, and metabolic variables, while serum AST was only correlated with waist circumference and waist-to-hip ratio. Fetuin-A was correlated with anthropometric variables, systolic blood pressure (SBP), insulin, and homeostasis model of assessment-insulin resistance (HOMA-IR) in the unadjusted model. In the fully adjusted model, both serum ALT and GGT levels remained positively correlated with total and low-density lipoprotein (LDL) cholesterol. GGT levels also remained correlated with triglycerides. ALT levels remained strongly positively correlated with insulin (r = 0.17, p

Leptin is an adipocyte-secreted hormone that has been proposed to regulate energy homeostasis as well as metabolic, reproductive, neuroendocrine, and immune functions. In the context of open-label uncontrolled studies, leptin administration has demonstrated insulin-sensitizing effects in patients with congenital lipodystrophy associated with relative leptin deficiency. Leptin administration has also been shown to decrease central fat mass and improve insulin sensitivity and fasting insulin and glucose levels in HIV-infected patients with highly active antiretroviral therapy (HAART)-induced lipodystrophy, insulin resistance, and leptin deficiency. On the contrary, the effects of leptin treatment in leptin-replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. Similarly, experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients with nonalcoholic fatty liver disease. In this review, we present a description of leptin biology and signaling; we summarize leptin's contribution to glucose metabolism in animals and humans in vitro, ex vivo, and in vivo; and we provide insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy and/or diabetes.

The study was supported by the Cyprus Research Promotion Foundation (EP gamma E Xi/0205/10). The Mantzoros Lab is supported by a discretionary grant from Beth Israel Deaconess Medical Center. Objective: Lipocalin 2 (LCN2 or NGAL), a protein derived from neutrophils, macrophages, adipocytes, and other cells, has been proposed to be a link between obesity and insulin resistance (IR), but animal and cross-sectional human studies have revealed conflicting results. We studied the association of serum lipocalin 2 with anthropometric, metabolic, and cardiovascular risk markers in young healthy men cross-sectionally and, for the first time, prospectively after 2 years of follow-up, with and without adjustment for potential confounders including serum creatinine. Design: Two hundred and seventy-two participants were randomly selected from the Cyprus Metabolism Study (1056 men, 18 years), of whom 93 subjects participated in the follow-up study 2 years after baseline assessment. Associations were also explored between total and free leptin levels (to serve as positive controls) and anthropometric metabolic variables. Results: In the cross-sectional study, lipocalin 2 levels were marginally correlated in the unadjusted model with central fat distribution but not with body weight or total body fat mass. After adjusting for age, smoking, activity, body mass index, fat percentage, waist-to-hip ratio, and serum creatinine, no correlation was found with any cardiovascular risk factor. There was no correlation with the homeostasis model assessment of IR (HOMA-IR) at baseline. In the prospective analyses, baseline levels of lipocalin 2 were not predictive of any variables in unadjusted or adjusted models. As expected, total and free leptin were associated with anthropometric and metabolic variables both cross-sectionally and prospectively. Conclusions: We demonstrate that lipocalin 2 is not an independent predictor of metabolic and cardiovascular risk factors in young men cross-sectionally or prospectively. Cyprus Research Promotion Foundation [EPgammaEXi/0205/10], Beth Israel Deaconess Medical Center

Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics.

There is growing evidence that patients with type 2 diabetes mellitus have increased cancer risk. We examined the association between diabetes, cancer, and cancer-related mortality and hypothesized that insulin sensitizers lower cancer-related mortality. Participants in the Diabetes Cardiovascular Risk and Evaluation: Targets and Essential Data for Commitment of Treatment study, a nationwide cross-sectional and prospective epidemiological study, were recruited from German primary care practices. In the cross-sectional study, subjects with type 2 diabetes mellitus had a higher prevalence of malignancies (66/1308, 5.1%) compared to nondiabetic subjects (185/6211, 3.0%) (odds ratio, 1.64; 95% confidence interval, 1.12-2.41) before and after adjustment for age, sex, hemoglobin A(1c), smoking status, and body mass index. Patients on metformin had a lower prevalence of malignancies, comparable with that among nondiabetic patients, whereas those on any other oral combination treatment had a 2-fold higher risk for malignancies even after adjusting for possible confounders; inclusion of metformin in these regimens decreased the prevalence of malignancies. In the prospective analyses, diabetic patients in general and diabetic patients treated with insulin (either as monotherapy or in combination with other treatments) had a 2- and 4-fold, respectively, higher mortality rate than nondiabetic patients, even after adjustment for potential confounders (incidence of cancer deaths in patients with type 2 diabetes mellitus [2.6%] vs the incidence of cancer deaths in patients without type 2 diabetes mellitus [1.2%]). Our results suggest that diabetes and medications for diabetes, with the exception of the insulin sensitizer metformin, increase cancer risk and mortality.

Objective Craniopharyngioma (CP) is a benign tumour of the suprasellar region that is associated with increased morbidity and mortality in comparison with other causes of hypopituitarism. We aimed to establish the rate and causes of mortality and morbidity in patients with CP who attended our centre. Design We performed a retrospective case note audit of patients with CP who were managed by our service. We established the standardized mortality ratio (SMR) for patients with CP. We compared obesity prevalence with two other hypopituitary groups who are managed by our service. Patients We identified 70 patients with CP, 97% of whom had undergone surgery and 42% radiotherapy. We compared the prevalence of obesity with that of 89 patients with hypopituitarism secondary to surgery for nonfunctioning pituitary adenoma and 29 patients with post-traumatic hypopituitarism (PTHP). Measurements Standardized mortality ratio for patients with CP was 8.75 (95% CI of 5.4-13.3); SMR for women was 10.51 (95% CI 5.04-19.3) and 7.55 (95% CI 3.77-13.52) for men. The rates of growth hormone (GH), gonadotrophin, adrenocorticotrophic hormone (ACTH) and TSH deficiencies were 91%, 93.5%, 92% and 86%, respectively. The rate of diabetes insipidus (DI) was 81%; 7.1% had adipsic DI. Dyslipidaemia was present in 46.9% and diabetes mellitus in 11.5%. Obesity affected 66% of patients with CP, 47% of patients with nonfunctioning adenoma and 31% of those with PTHP (P Conclusions Patients with CP suffer from high rates of mortality and morbidity. The underlying causes for mortality and for obesity in this population remain poorly understood.