Lenvatinib Therapy for Advanced Thyroid Cancer: Real-Life Data on Safety, Efficacy, and Some Rare Side Effects.

Context: The SELECT trial led to the approval of lenvatinib for the treatment of advanced radioiodine-refractory differentiated thyroid carcinomas (DTCs) but also revealed an important adverse event (AE) profile which may limit its use in clinical practice. Objective: We aim to describe the efficacy and toxicity profiles of lenvatinib in real life. Methods: We included all patients who received lenvatinib for an advanced DTC at our institution, enrolling 27 patients. We reviewed retrospectively electronic medical records to assess efficacy and AEs. Results: Among the 24 patients with evaluation of tumor response during treatment, overall response rate (ORR) was 37.0% (95% CI, 19.4%-57.6%), and disease control rate was 85.2% (95% CI, 66.3%-95.8%). The median progression-free survival (PFS) was 12 months (95% CI, 7.5-16.5]. The most prevalent AEs were hypertension (77.8%), fatigue (55.6%), and weight loss (51.9%). At least one grade ≥ 3 AE was experienced by 25/27 patients (92.6%), mostly hypertension (59.3%). Lenvatinib was discontinued due to AEs in 13/27 patients (48.1%). Interestingly, 1 patient experienced a grade 4 posterior reversible encephalopathy syndrome, and another developed a Takotsubo cardiomyopathy. Conclusion: The safety profile of lenvatinib in our cohort was similar to that reported in the literature, with a predominance of hypertension. Rigorous blood pressure control is therefore essential to avoid discontinuing therapy. We also report 2 severe and rarely described AEs that physicians should watch for. As for efficacy, although less than in the SELECT trial, ORR and PFS were similar to other real-life studies.

Effect of caloric restriction with or without physical activity on body composition and epicardial fat in type 2 diabetic patients: A pilot randomized controlled trial.

BACKGROUND AND AIMS: There is debate over the independent and combined effects of caloric restriction (CR) and physical activity (PA) on reduction in fat mass and in epicardial fat thickness. We compared the impact of a similar energy deficit prescription by CR or by CR combined with PA on total fat mass, epicardial fat thickness, and cardiometabolic profile in individuals with type 2 diabetes. METHODS AND RESULTS: In this 16-week randomized controlled study, 73 individuals were randomly enrolled to receive: 1) a monthly motivational phone call (Control), 2) a caloric deficit of -700 kilocalories/day (CR), or 3) a caloric deficit of -500 kilocalories/day combined with a PA program of -200 kilocalories/day (CR&PA). Total fat mass, epicardial fat, and cardiometabolic profile were measured at baseline and after 16 weeks. While comparable weight loss occurred in both intervention groups (-3.9 ± 3.5 kg [CR], -5.1 ± 4.7 kg [CR&PA], -0.2 ± 2.9 kg [Control]), changes in total fat mass were significantly different between all groups (-2.4 ± 2.9 kg [CR], -4.5 ± 3.4 kg [CR&PA], +0.1 ± 2.1 kg [Control]; p < 0.05) as well as epicardial fat thickness (-0.4 ± 1.6 mm [CR], -1.4 ± 1.4 mm [CR&PA], +1.1 ± 1.3 mm [Control]; p < 0.05). There were no significant differences in trends for cardiometabolic parameters improvement between groups. CONCLUSIONS: For a similar energy deficit prescription and comparable weight loss, the combination of CR&PA provides a greater reduction in fat mass and epicardial fat thickness than CR alone in individuals with comparable weight loss and with a similar energy deficit prescription. These results, however, do not translate into significant improvements in cardiometabolic profiles. CLINICALTRIALS. GOV IDENTIFIER: NCT01186952.

Vitamin D3 supplementation among adult patients with cystic fibrosis.

BACKGROUND & AIMS: Vitamin D (Vit D) deficiency in cystic fibrosis (CF) is partially secondary to exocrine pancreatic insufficiency. Our aim was to establish a Vit D3 supplementation protocol that will increase 25(OH)D to the recommended level (30 ng/mL). METHODS: Retrospective study of 200 patients (≥18 years) conducted from February 2007 to June 2014 at the CF clinic of the Centre Hospitalier de l'Université de Montréal. Vit D3 supplementation protocol was 1600 IU/day or 10,000 IU/week during the summer (May 1st to October 31st) and 3200 IU/day or 20,000 IU/week during the winter (November 1st to April 30th), in addition to the 1200 IU/day included in multivitamins. RESULTS: Significant increase in serum 25(OH)D levels from baseline (25.9 ± 10.3 ng/mL) to follow-up (37.0 ± 11.4 ng/mL) (P ≤ 0.001). At follow-up, increased doses during the winter improved serum 25(OH)D levels to a degree comparable to the summer. CONCLUSIONS: This supplementation protocol is efficient and needs to be tested in other CF adult cohorts and correlated to potential health benefit measurements.

Treatment of Hypoglycemia in Adult Patients with Type 1 Diabetes: An Observational Study.

OBJECTIVES: 1) To characterize the nutritional treatment of hypoglycemia in adult patients with type 1 diabetes mellitus and 2) to compare the characteristics of participants who follow the recommendations with the characteristics of those who do not. METHODS: A total of 121 adults with type 1 diabetes were included in this cross-sectional analysis. Participants completed a food record and a glycemia and insulin doses logbook to collect data on mild to moderate hypoglycemic events (glycemia <4.0 mmol/L or 4.0 to 5.0 mmol/L with symptoms) and their treatments over a 2-day period. Participants were identified as overcorrecting if they consumed, within 15 minutes after the episode, >20g of carbohydrates for correction. Self-administered questionnaires about fear of hypoglycemia were completed, and cardiometabolic profile variables were measured (glycated hemoglobin, blood pressure, lipid profile and body mass indexes). RESULTS: Of the 121 participants, 94 (78%) reported at least 1 hypoglycemic event, for a total of 271 events (2.2±2.1 episodes per patient). Of these events, 64% were treated within 15 minutes, and they were treated primarily with fruit juice or sweet beverages (39%) or mixed snacks (29%). Average carbohydrate intake for treatment was 32±24 grams. Of the participants, 73% overtreated their episodes. They were significantly younger and had greater fear of hypoglycemia than those who treated the episodes adequately. No difference was observed for cardiometabolic variables. CONCLUSIONS: The majority of patients in our cohort overtreated their hypoglycemic episodes. These results suggest that hypoglycemia-correction education needs to be reinforced.

A pilot program for physical exercise promotion in adults with type 1 diabetes: the PEP-1 program.

Physical inactivity is highly common in adults with type 1 diabetes (T1D) as specific barriers (i.e., hypoglycemia) may prevent them from being active. The objective of this study was to examine the efficacy of the Physical Exercise Promotion program in type 1 diabetes (PEP-1) program, a group program of physical activity (PA) promotion (intervention) compared with an information leaflet (control), to improve total energy expenditure (TEE) in adults with T1D after 12 weeks. TEE was measured with a motion sensor over a 7-day period at inclusion, after the program (12 weeks) and 1-year after inclusion. The 12 weekly sessions of the program included a 30-min information session (glycemic control and PA) and 60 min of PA. A total of 48 adults, aged 18 to 65 years with a reported PA practice <150 min per week, were recruited (45.8% men; aged 44.6 ± 13.3 years; 8.0% ± 1.1% glycated hemoglobin (A1c)) and randomized in this pilot trial. Ninety percent of participants completed the program and 88% completed the 1-year follow-up. No change was observed for TEE and A1c in both groups. After the 12-week program, the mean peak oxygen uptake increased (14%; p = 0.003) in the intervention group; however, at the 1-year follow-up, it was no longer different from baseline. In the control group, no difference was observed for the peak oxygen uptake. These results suggest that the PEP-1 pilot program could increase cardiorespiratory fitness. However, this benefit is not sustained over a long-term period. The PEP-1 program did not increase TEE in patients with T1D and other strategies remain necessary to counteract physical inactivity in this population.

Reference range thyroid-stimulating hormone is associated with physical activity energy expenditure in overweight and obese postmenopausal women: a Montreal-Ottawa New Emerging Team Study.

Clinical and, to a lesser extent, subclinical hypothyroidism is associated with a variety of metabolic abnormalities, including increased body mass index, unfavorable lipoprotein profile, and increased biomarkers for atherosclerosis. Energy expenditure could act as a confounding factor in the association reported between thyroid-stimulating hormone (TSH) levels and cardiometabolic risk factors. The objective of the study was to investigate the relationship between reference range plasma TSH and energy expenditure as well as blood pressure, lipid, and inflammation parameters in women. One hundred four postmenopausal, overweight and obese, spontaneously euthyroid women were included in the study. We evaluated total energy expenditure by doubly labeled water, resting energy expenditure by indirect calorimetry, physical activity energy expenditure (PAEE = [total energy expenditure × 0.90] - resting metabolic rate), body weight, and percentage of fat mass by dual-energy x-ray absorptiometry. Blood pressure, plasma lipoproteins profile, and high-sensitivity C-reactive protein levels were also measured. Mean TSH was 2.39 ± 1.09 mIU/L. We observed that high-density lipoprotein cholesterol (r = -0.20, P ≤ .05) was negatively associated with TSH, whereas systolic blood pressure (r = 0.21, P ≤ .05) and apolipoprotein B (r = 0.22, P ≤ .05) were positively correlated with TSH. However, these correlations were no longer significant after controlling for PAEE. A significant negative correlation was found between TSH and PAEE (r = -0.23, P ≤ .05). Our results suggest that, although TSH in the reference range is associated with some cardiometabolic risk factors, this is in large part explained by lower PAEE. In turn, lower PAEE could increase the cardiometabolic risk.

Barriers to physical activity among patients with type 1 diabetes.

OBJECTIVE: To determine, in an adult population with type 1 diabetes, barriers to regular physical activity using a diabetes-specific barriers measure (the Barriers to Physical Activity in Diabetes [type 1] [BAPAD1] scale) and factors associated with these barriers. RESEARCH DESIGN AND METHODS: One hundred adults with type 1 diabetes answered a questionnaire assessing perceived barriers to physical activity and related factors. A1C was obtained from the medical chart of each individual. RESULTS: Fear of hypoglycemia was identified as being the strongest barrier to physical activity. Greater knowledge about insulin pharmacokinetics and using appropriate approaches to minimize exercise-induced hypoglycemia were factors associated with fewer perceived barriers. Greater barriers were positively correlated with A1C levels (r = 0.203; P = 0.042) and negatively with well-being (r = -0.45; P < 0.001). CONCLUSIONS: Fear of hypoglycemia is the strongest barrier to regular physical activity in adults with type 1 diabetes, who should therefore be informed and supported in hypoglycemia management.

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology.

The purpose of this study was to use the microarray technology to define expression profiles characteristic of thyroid autonomous adenomas and relate these findings to physiological mechanisms. Experiments were performed on a series of separated adenomas and their normal counterparts on Micromax cDNA microarrays covering 2400 genes (analysis I), and on a pool of adenomatous tissues and their corresponding normal counterparts using microarrays of 18,000 spots (analysis II). Results for genes present on the two arrays corroborated and several gene regulations previously determined by Northern blotting or microarrays in similar lesions were confirmed. Five overexpressed and 24 underexpressed genes were also confirmed by real-time RT-PCR in some of the samples used for microarray analysis, and in additional tumor specimens. Our results show: (1) a change in the cell populations of the tumor, with a marked decrease in lymphocytes and blood cells and an increase in endothelial cells. The latter increase would correspond to the establishment of a close relation between thyrocytes and endothelial cells and is related to increased N-cadherin expression. It explains the increased blood flow in the tumor; (2) a homogeneity of tumor samples correlating with their common physiopathological mechanism: the constitutive activation of the thyrotropin (TSH)/cAMP cascade; (3) a low proportion of regulated genes consistent with the concept of a minimal deviation tumor; (4) a higher expression of genes coding for specific functional proteins, consistent with the functional hyperactivity of the tumors; (5) an increase of phosphodiesterase gene expression which explains the relatively low cyclic AMP levels measured in these tumors; (6) an overexpression of antiapoptotic genes and underexpression of proapoptotic genes compatible with their low apoptosis rate; (7) an overexpression of N-cadherin and downregulation of caveolins, which casts doubt about the use of these expressions as markers for malignancy.

Gene expression profile in thyroid of transgenic mice overexpressing the adenosine receptor 2a.

Mutations of the TSH receptor leading to constitutive activation of the cAMP cascade are responsible for the development of hot nodules, if arising in a somatic cell, and nonautoimmune hyperthyroidism, when occurring in a germinal cell. An animal model of constitutive activation of the thyroid cAMP cascade has been obtained by generating transgenic mice expressing the adenosine receptor (Tg-A2aR) under the control of the thyroglobulin promoter. These mice develop huge goiters and die prematurely due to hyperthyroidism induced cardiac failure. To identify new genes involved in the tumorigenic pathway of the thyroid, we designed a protocol using microarray technology to study the differential expression, between normal and transgenic thyroid, of +/-13,000 genes. A total of 360 genes or expressed sequence tags showed a strong modulation with background corrected values of fluorescence superior to 2-fold change. The modulated genes were classified according to their proposed gene ontology functions. Approximately half of them were up-regulated. The function of the majority of these genes in thyroid physiology is still to be determined. Some of them, like IGF-I or IGF binding protein 3 or 5, may play an important role in the development of thyroid nodules through paracrine mechanisms. This study demonstrates the feasibility of sequentially following the cascade of events leading to the formation of benign tumors such as hot thyroid nodule or hyperfunctional goiter.

Identification and characterization of a novel activated RhoB binding protein containing a PDZ domain whose expression is specifically modulated in thyroid cells by cAMP.

In a search for genes regulated in response to cAMP we have identified a new protein, p76RBE, whose mRNA and protein expression is enhanced in thyrocytes following thyrotropin stimulation of the cAMP transduction cascade. This protein presents important similarities with Rhophilin and contains different protein-protein interaction motifs. The presence of HR1 and PDZ motifs as well as a potential PDZ binding domain motif suggests that p76RBE could be implicated in targeting or scaffolding processes. By yeast two-hybrid screenings and coimmunoprecipitation, we show here that p76RBE is a specific binding protein of RhoB and binds selectively to the GTP-bound form of this small GTPase. p76RBE also binds in vitro to components of the cytoskeleton, including cytokeratin 18. p76RBE is essentially cytoplasmic in transfected COS-7 mammalian cells and seems to be recruited to an endosomal compartment when coexpressed with the activated form of RhoB. p76RBE was shown to be mainly expressed in tissues with high secretion activity. Our data suggest that p76RBE could play a key role between RhoB and potential downstream elements needed under stimulation of the thyrotropin/cAMP pathway in thyrocytes and responsible for intracellular motile phenomena such as the endocytosis involved in the thyroid secretory process.