Long-term efficacy and safety of subcutaneous pasireotide alone or in combination with cabergoline in Cushing's disease.

Objective: This study evaluated short- and long-term efficacy and safety of the second-generation somatostatin receptor ligand pasireotide alone or in combination with dopamine agonist cabergoline in patients with Cushing's disease (CD). Study design: This is an open-label, multicenter, non-comparative, Phase II study comprising 35-week core phase and an optional extension phase. All patients started with pasireotide, and cabergoline was added if cortisol remained elevated. Eligible patients had active CD, with or without prior surgery, were pasireotide naïve at screening or had discontinued pasireotide for reasons other than safety. Primary endpoint was proportion of patients with a mean urinary free cortisol (mUFC) level not exceeding the upper limit of normal (ULN) at week 35 with missing data imputed using last available post-baseline assessments. Results: Of 68 patients enrolled, 26 (38.2%) received pasireotide monotherapy and 42 (61.8%) received pasireotide plus cabergoline during the core phase. Thirty-four patients (50.0%; 95% CI 37.6-62.4) achieved the primary endpoint, of whom 17 (50.0%) received pasireotide monotherapy and 17 (50.0%) received combination therapy. Proportion of patients with mUFC control remained stable during the extension phase up to week 99. Treatment with either mono or combination therapy provided sustained improvements in clinical symptoms of hypercortisolism up to week 99. Hyperglycemia and nausea (51.5% each), diarrhea (44.1%) and cholelithiasis (33.8%) were the most frequent adverse events. Conclusion: Addition of cabergoline in patients with persistently elevated mUFC on maximum tolerated doses of pasireotide is an effective and well-tolerated long-term strategy for enhancing control of hypercortisolism in some CD patients. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT01915303, identifier NCT01915303.

Capillary microarchitectural changes are independent of disease activity in acromegaly.

OBJECTIVE: Although atherosclerosis-related macrovascular complications are well known in acromegaly, studies on endothelial function and arteriolar level are contradictory. In order to test the hypothesis, microvascular changes associated with macrovascular changes in acromegaly, we aimed to evaluate microvascular changes in nailfold capillaries and carotid intima-media thickness (CIMT) in patients with acromegaly. DESIGN: In this cross-sectional observation study, of total 70 patients with acromegaly [ten (14.3 %) were active acromegaly (AA), 60 (85.7 %) were controlled acromegaly (CA)] and 74 healthy controls were enrolled. Microvascular structure was evaluated using the nailfold video capillaroscopy, and CIMT was measured using ultrasonography. RESULTS: The median number of capillaries was less [10 no./mm (min-max: 5-16) vs. 11 no./mm (min-max: 9-15); p = 0.001] in the acromegaly group than in the controls. Capillaries below 6-8 per/mm was more common in the acromegaly patients [six (8.6 %) vs. one (1.4 %); p = 0.046]. All capillaroscopic parameters were similar among the patients with CA or AA. CIMT levels were higher in the acromegaly group than in the control group [0.60 mm (0.43-0.86) vs. 0.38 mm (0.27-0.59); p < 0.001], and AA patients had higher CIMT than CA patients (p = 0.037). None of the clinical or laboratory parameters including growth hormone and IGF-1 were related to capillaroscopic parameters or CIMT. CONCLUSION: Decreased capillary number was the major capillaroscopic finding in acromegaly and there was no significant difference between active and controlled cases, but CIMT was found to be higher in the active group. Increased CIMT levels in acromegaly were not associated with capillary changes. Large-scale, prospective studies are needed to make a definite conclusion about the effect of the disease activity on nailfold capillaries and its association with macrovascular changes.

Morbid obesity leads to increased skin autofluorescence independent of metabolic syndrome components.

BACKGROUND: Obesity, diabetes mellitus, and metabolic syndrome (MetS) are associated with increased accumulated skin advanced glycation end products. We aimed to evaluate the association of MetS components with skin autofluorescence (SAF) in patients with morbid obesity. METHODS: Eight hundred and one patients with morbid obesity and 94 age-matched controls with normal body mass index (BMI) and normal glucose metabolism were included. Advanced glycation end products (AGEs) were measured using SAF in the forearm, with an AGE reader. RESULTS: The prevalence of MetS in patients with morbid obesity was 65.5% (n = 525). Type 2 diabetes mellitus (type 2 DM) and hypertension were present in 40.9% (n = 328) and 43.7% (n = 357). Patients with morbid obesity and those with MetS had higher SAF measurements compared with the control group, 1.85 ± 0.44 arbitrary unit (AU) and 1.86 ± 0.43 AU vs. 1.72 ± 0.30 AU, respectively (p = 0.016). There was no difference in SAF levels between patients with and without MetS. SAF measurements of patients without MetS were not statistically different from the control group (p = 0.076). Patients with five MetS criteria had higher SAF measurements compared with patients with fewer MetS components (p = 0.019). There was no difference in SAF levels between patients with type 2 DM, impaired glucose metabolism, and patients with normal glucose metabolism (p = 0.513). DISCUSSION: Although MetS and type 2 DM are known as factors related to increased SAF levels, obesity can cause elevated SAF measurements in different ways independent of concomitant comorbid diseases. Larger studies with longer follow-ups are needed to enlighten the underlying mechanism.

Vitamin D receptor and estrogen receptor gene polymorphisms in men with type 2 diabetes: Effects on Bone Metabolism.

Purpose: There is an increased fracture risk in type 2 diabetes mellitus [DM] patients independent of bone mineral density [BMD], both in men and women. Estrogen receptor [ER]-alpha and vitamin D receptor [VDR] gene polymorphisms may predispose patients to increased osteoporosis and fracture risk. This study aims to analyze the relationship of the ER-alpha gene and VDR gene polymorphisms with indicators of bone turnover and BMD in male type 2 diabetic patients. Methods: Type 2 diabetic men diagnosed with diabetes for at least one year and healthy controls were included in this cross-sectional study. BMD was measured by dual X ray absorptiometry. Gene polymorphisms were evaluated with polymerase chain reaction-restriction length polymorphism. Serum iPTH, calcium, beta-CrossLaps (cTx), osteocalcin, and free testosterone levels were also evaluated. Results: Participants were 141 type 2 diabetic men [55 ± 8 years] and 100 healthy controls [53 ± 7 years]. BMD measurements were not statistically different between the groups. While iPTH [p < 0.05] and serum calcium levels [p = 0.03] were higher in men with type 2 DM; beta-CrossLaps [p = 0.0001], osteocalcin [p = 0.005], and free testosterone [p = 0.04] were lower than controls. The differences in terms of the frequencies of VDR Apa, Taq, Bsm, Fok and ER-alpha polymorphisms were not statistically significant between the groups. No relationship was observed between polymorphisms and BMD in both groups. Conclusions: VDR and ER-alpha gene polymorphisms seem to have no effect on BMD and bone turnover in men with DM.

Effect of denosumab treatment on bone mineral density and bone turnover markers in osteoporotic patients: real-life experience 2-year follow-up.

Denosumab leads to improvements in BMD levels and is a well-tolerated agent according to results of randomized controlled studies but results in real-life setting are important to evaluate drug adherence and real-life efficiency. In this study, we present the results of 305 patients that were treated with denosumab in our clinic. INTRODUCTION: The long-term efficacy of anti-osteoclastic drugs in treatment of osteoporosis is well known. Denosumab, a novel human monoclonal antibody, is an anti-osteoclastic agent that has been shown to lead to reductions in vertebral, nonvertebral, and hip fracture risk in randomized and observational studies. Real-life data of this agent is increasing. In this study, we presented our real-life data about the 2-year follow-up of patients under denosumab treatment. METHODS: Osteoporotic patients who were treated with at least one denosumab injection between 2014 and 2020 years were included. Clinical and demographic data, bone turnover markers, and radiological reports (bone mineral densitometry (BMD), vertebral x-ray) were obtained from patient files retrospectively. RESULTS: A total of 305 patients (f/m: 275/30, 68.1 ± 11.05 years) were included. The median injection number was 4 (1-10). Two hundred seventy-three patients (89.8%) were persistent on treatment at the 12th month; 175 patients (57.3%) were persistent at 24th month. Sixty-eight patients (22%) were not using denosumab anymore, 55 of the patients were not continuing by doctor desicion and 13 were not continuing due to patient-related causes. Median BMD levels significantly increased from 0.809 (0.2-1.601, IQR: 0.136) to 0.861 (0.517-1.607, IQR: 0.14) in L1-L4 and from 0.702 (0.349-0.997, IQR: 0.125) to 0.745 (0.508-1.008, IQR: 0.137) in femur area at the 24th month of treatment. An improvement of 8.04% in L1-L4 BMD and 4.5% in femur neck BMD levels at the 24th month of treatment was observed. There was a significant decrease in bone turnover markers at the 24th month of treatment. CONCLUSION: In our group of patients under denosumab treatment, 53% of persistence was found at 24 months and associated with improvement in BMD levels without any significant side effects except one case with urticarial reaction. Denosumab leads to improvements in BMD levels and is a well-tolerated agent in a real-life setting comparable to results of randomized controlled studies in patients with different comorbidities.

Assesment of attainment of recommended TSH levels and levothyroxine compliance in differentiated thyroid cancer patients.

OBJECTIVE: Thyroid-stimulating hormone (TSH) suppression treatment can induce signs and symptoms of hyperthyroidism and hypothyroidism due to inappropriate treatment or poor compliance to the treatment. The current study aimed to investigate TSH levels, frequency of being on target TSH, adherence to levothyroxine (LT4) suppression treatment in differentiated thyroid cancer (DTC) patients after surgery in a multicentric setting. DESIGN AND PATIENTS: This multicentric cross-sectional study was conducted at 21 medical centres from 12 cities in Turkey. DTC patients followed at least one year in the same center included in the study. Clinical data, serum TSH, free thyroxine (FT4), thyroglobulin (Tg) and anti-Tg levels were recorded during the most recent visit. Body mass index, systolic and diastolic blood pressures, pulse rate were measured. LT4 doses were recorded and doses per kilogram of bodyweight were calculated. Pill ingestion habits recorded and adherence to the therapy were evaluated using the Morisky Medication Adherence Scale and categorized as good, moderate or poor compliant based on their scores. Risk stratification forpredicting the disease persistance and/or reccurence was assessed using the American Joint Committee on Cancer-7th edition thyroid cancer staging calculator. TSH serum concentrations were classified as severe suppression (TSH < 0.01 mU/L), moderate suppression (TSH: 0.01-0.1 mU/L), mild suppression (TSHL 0.1-0.5 mU/L), euthyroid (TSH: 0.5-4 mU/L) and hypothyroid (TSH > 4 mU/L). TSH levels can also be classified as on being on target, under the target, or beyond over the target, according to the American Thyroid Association recommendations. RESULTS: A group of 1125 patients (F/M: 941/184, 50.7 ± 11.7 years) were included in the study. The mean LT4 daily dosage was 132.4 ± 39.6 mcg/day. TSH levels showed severe suppression in 99 (%8.8) patients, moderate suppression in 277 (%24.6) patients and mild suppression in 315 (%28) patients and euthyroid range in 332 (%29.5) patients and hypothyroid range in 97 (8.6%). TSH levels were in target in 29.2% of the patients 20.4% of the patients were undertreated, 50.4% overtreated. The daily LT4 dose and LT4 dose/kg were significantly higher in the severe suppression group (p < .001, p < .001). According to the Morisky scale, 564 patients (50.1%) were good compliant, 368 patients (32.7%) were moderate compliant, and 193 patients (17.1%) were noncompliant. Patients with poor compliance need a higher dose of LT4 compared to the good compliance group (p < .001). TSH levels of patients with good compliance were 0.67 ± 1.96 mU/L and TSH with poor compliance was 2.74 ± 7.47 mU/L (p < .001). TSH levels were similar in patients on fixed and alternating dosages. CONCLUSION: In 29.2% of the DTC patients, serum TSH levels were at target levels. Remaining of the study group have TSH levels under or over treatment range, exposing the patient to medication side effects. Majorty of the study group 82.8% have good or moderate adherence to LT4 therapy. Reaching TSH targets requires simplified and applicable guidelines and following the guideline recommendations.

When do we need to suspect maturity onset diabetes of the young in patients with type 2 diabetes mellitus?

ABSTRACT Objetivo: Maturity onset diabetes of the young (MODY) patients have clinical heterogeneity as shown by many studies. Thus, often it is misdiagnosed to type 1 or type 2 diabetes(T2DM). The aim of this study is to evaluate MODY mutations in adult T2DM patients suspicious in terms of MODY, and to show clinical and laboratory differences between these two situations. Subjects and methods: In this study, we analyzed 72 type 2 diabetic patients and their relatives (35F/37M) who had been suspected for MODY and referred to genetic department for mutation analysis. The gene mutations for MODY have been assessed in the laboratory of Marmara University genetics. Totally 67 (32F/35M; median age 36.1) diabetic patients were analyzed for 7 MODY mutations. Twelve patients who have uncertain mutation (VUS) were excluded from study for further evaluation. MODY(+) (n:30) patients and T2DM patients (n:25) were compared for clinical and laboratory parameters. Results: In MODY(+) subjects, mutations in GCK (MODY 2) (n:12; 40%) were the most common followed by HNF4A (MODY 1) (n:4; 13.3%). Diabetes diagnosis age was younger in MODY(+) group but not statistically significant. Sixty-six percent of MODY(+) subjects had diabetes history at 3-consecutive generations in their family compared with 28% of T2DM patients statistically significant (p:0.006). Gender, BMI, C-peptide, HbA1c, lipid parameters, creatinine, GFR, microalbuminuria, vitamin D and calcium were not statistically different between the groups. Conclusion: According to present study results, MODY mutation positivity is most probable in young autoantibody (-) diabetic patients diagnosed before 30 years of age, who have first degree family history of diabetes.

When do we need to suspect maturity onset diabetes of the young in patients with type 2 diabetes mellitus?

OBJECTIVE: Maturity onset diabetes of the young (MODY) patients have clinical heterogeneity as shown by many studies. Thus, often it is misdiagnosed to type 1 or type 2 diabetes(T2DM). The aim of this study is to evaluate MODY mutations in adult T2DM patients suspicious in terms of MODY, and to show clinical and laboratory differences between these two situations. METHODS: In this study, we analyzed 72 type 2 diabetic patients and their relatives (35F/37M) who had been suspected for MODY and referred to genetic department for mutation analysis. The gene mutations for MODY have been assessed in the laboratory of Marmara University genetics. Totally 67 (32F/35M; median age 36.1) diabetic patients were analyzed for 7 MODY mutations. Twelve patients who have uncertain mutation (VUS) were excluded from study for further evaluation. MODY(+) (n:30) patients and T2DM patients (n:25) were compared for clinical and laboratory parameters. RESULTS: In MODY(+) subjects, mutations in GCK (MODY 2) (n:12; 40%) were the most common followed by HNF4A (MODY 1) (n:4; 13.3%). Diabetes diagnosis age was younger in MODY(+) group but not statistically significant. Sixty-six percent of MODY(+) subjects had diabetes history at 3-consecutive generations in their family compared with 28% of T2DM patients statistically significant (p:0.006). Gender, BMI, C-peptide, HbA1c, lipid parameters, creatinine, GFR, microalbuminuria, vitamin D and calcium were not statistically different between the groups. CONCLUSION: According to present study results, MODY mutation positivity is most probable in young autoantibody (-) diabetic patients diagnosed before 30 years of age, who have first degree family history of diabetes.

Skin autofluorescence Is associated With low bone mineral density in type 2 diabetic patients.

Although the risk of bone fracture is increased in type 2 diabetes (T2DM), bone mineral density (BMD) is increased rather than decreased. Accumulation of advanced glycation end products (AGEs) adversely influences the fracture resistance of bone in T2DM. We hypothesized that SAF is also associated with BMD levels in type 2 diabetic patients and aimed to evaluate the association of SAF with BMD and the presence of osteoporosis. This cross-sectional case-control study included 237 patients with T2DM (F/M: 133/104, 56.2±11.9 yrs) and 100 age- and sex-matched controls (F/M: 70/30, 54.8±8.8 yrs). Skin autofluorescence, a validated non-invasive measure of tissue AGEs, is used to detect the accumulation of AGEs in skin collagen using AGE Reader (DiagnOptics B.V., Groningen, The Netherlands). In addition, BMD was measured with DEXA (Lunar DPX-L). Patients with T2DM had higher SAF values compared to control group (2.21±0.53 AU vs. 1.79±0.33 AU, p < 0.001). Male subjects had higher SAF compared to women (2.34±0.53 AU vs. 2.11±0.50 AU, p < 0.001). Subjects with below -2.5 femoral neck or lumbar T scores had higher SAF measurements compared to subjects with normal T scores (2.46±0.53 AU vs. 2.18±0.52 AU, p = 0.006). Femoral neck BMD was lower in subjects with T2DM (0.946±0.345 g/cm2 vs. 1.005±0.298 g/cm2, p = 0.002). There was a negative correlation between SAF and femoral neck BMD (r=-0.24, p < 0.001), femoral neck T scores (r=-0.24, p < 0.001), L1-4 BMD (r=-0.10, p = 0.005), L1-4 T score (r=-0.16, p=0.001) and a positive correlation between SAF and age (r=0.44, p < 0.001), body mass index (r:0.16, p = 0.002) and HbA1c (r=0.37, p < 0.001). Accumulation of skin AGEs was increased, and BMD levels were decreased in diabetic patients. A negative association between SAF and BMD was detected, indicating a relationship between higher AGE accumulation and low BMD and osteoporosis in diabetic patients. Long-term prospective studies are needed to identify the practical use of SAF measurement in diabetic bone disease.

The current situation in the approach to osteoporosis in older adults in Turkey: areas in need of improvement with a model for other populations.

PURPOSE: The total number of older adults in Turkey is striking, amounting to around 8 million, and this translates into considerably higher numbers of cases of osteoporosis (OP) and fractures in older adults. In this article, we outlined the current situation of OP in older adults in Turkey and investigated the differences between Turkey and a representative developed European country (Belgium), in terms of the screening, diagnosis, and treatment of OP. Our intention in this regard was to identify areas in need of improvement and subsequently to make a clear call for action to address these issues. METHODS: Herein, considering the steps related to the OP approach, we made a complete review of the studies conducted in Turkey and compared with the literature recommendations. RESULTS: There is a need for a national osteoporotic fracture registry; measures should be taken to improve the screening and treatment of OP in older males, such as educational activities; technicians involved in dual-energy X-ray absorptiometry (DXA) scanning should undergo routine periodic training; all DXA centers should identify center-specific least significant change values; all older adults should be considered for routine lateral dorsolumbar X-ray imaging for the screening of vertebral fractures while ordering DXA scans; the inclusion of vertebral fracture assessment (VFA) software in DXA assessments should be considered; screening using a fracture risk assessment tool (FRAX) algorithm that is specific to Turkey should be integrated; the fortification of foods with vitamin D is required; the high fracture risk by country-specific FRAX algorithm and the presence of falls/high fall risk should be integrated in reimbursement terms; and finally, more "fracture liaison services" should be established. CONCLUSION: We suggest that the practical consideration of our suggestions will provide considerable support to the efforts for combating with the adverse consequences of OP in society. This approach can be subsequently modeled for other populations to improve the management of OP globally.

Biochemical characteristics and calcium and PTH levels of patients with high normal and elevated serum 25(OH)D levels in Turkey: DeVIT-TOX survey.

Vitamin D intake over the recommended dose is usually associated with high serum 25(OH)D levels and generally not associated with symptoms of hypercalcemia. High doses of cholecalciferol need to be avoided to protect against vitamin D toxicity and related complications. Strict adherence to the clinical guidelines for treating vitamin D deficiency can ensure safe and effective treatment. PURPOSE: We observed a tendency to use high doses of cholecalciferol for vitamin D deficiency treatment or vitamin D supplementation. We aimed to determine the biochemical characteristics of patients with high normal and elevated serum 25(OH)D levels. METHODS: An online invitation was sent to all tertiary endocrinology clinics in Turkey to complete an online retrospective survey (DeVIT-TOX Survey) for patients diagnosed with high serum 25(OH)D levels (> 88 ng/mL) between January 2019 and December 2019. The patients were evaluated according to the presence of signs and symptoms of hypercalcemia and doses of vitamin D intake, evaluated into the following three groups according to their 25(OH)D levels: group 1, > 150 ng/mL; group 2, 149-100 ng/mL; and group 3, 99-88 ng/mL. RESULTS: A total of 253 patients were included in the final analysis (female/male: 215/38; mean age, 51.5 ± 15.6 years). The average serum 25(OH)D level was 119.9 ± 33 (range, 88-455) ng/mL, and the average serum calcium level was 9.8 ± 0.7 (range, 8.1-13.1) mg/dL. Most (n = 201; 75.4%) patients were asymptomatic despite having high serum 25(OH)D and calcium levels. The serum 25(OH)D level was significantly higher in the symptomatic groups than in the asymptomatic groups (138.6 ± 64 ng/mL vs. 117.7 ± 31 ng/mL, p < 0.05). The most common cause (73.5%) associated with high serum 25(OH)D levels was the inappropriate prescription of a high dose of oral vitamin D (600.000-1.500.000 IU) for treating vitamin D deficiency/insufficiency in a short time (1-3 months). The cut-off value of 25 (OH) D level in patients with hypercalcemia was found to be 89 ng/mL [median 116.5 (89-216)]. CONCLUSIONS: High dose of vitamin D intake is associated with a high serum 25 OH D level, without symptoms of hypercalcemia. Inappropriate prescription of vitamin D is the primary cause for elevated 25(OH) D levels and related hypercalcemia. Hypercalcemia may not be observed in every patient at very high 25(OH) D levels. Adherence to the recommendation of guidelines is essential to ensure safe and effective treatment of vitamin D deficiency.

Effects of concomitant obesity and diabetes on the aggressiveness and outcomes of differentiated thyroid cancer patients

ABSTRACT Objective: Obesity and diabetes are the risk factors for cancer development including differentiated thyroid cancer (DTC). Contradictory accumulated data indicates the possible negative effects of obesity and hyperglyceamia as a factor for aggressiveness of DTC. The aim of the present study is to investigate the association of high body mass index (BMI) and presence of type 2 diabetes mellitus (T2DM) on the histological aggressiveness and clinical outcomes in DTC patients followed for over 4 years in a single center. Materials and methods: Consequative 526 DTC patients who had undergone total thyroidectomy and/or radioactive iodine (RAI) ablation were reviewed retrospectively. Patients were divided into groups based on their BMI: normal weight, overweight, obese and also were evalauted in 3 groups presence of diabetes, prediabetes and nomoglyceamia. Histological aggressiveness of DTC at the time of diagnosis and clinical response at the time of last clinical visit were reassessed according to the criteria suggested by ATA 2015 guideline. Results: No differences in histopathologic features, risk of recurrence, cumulative dose of RAI ablation and prevalence of 131I avid metastatic disease were demonstrated among the groups both classified according to BMI and hyperglycemia. Mean of 3.4 year follow-up also showed no differences in the clinial repsonse to therapy and percentage of nonthyroid primary cancer in DTC patients. Conclusion: In this retrospective study we demonstrated that obesity and T2DM have no additive effect on DTC aggressiveness and response to therapy. DTC patients with obesity and diabetes can be treated according to present guidelines without requirement for spesific attention.

Prevalence of vertebral fractures and serum sclerostin levels in acromegaly.

OBJECTIVE: An increased prevalence of vertebral fractures (VFs) has been reported in previous studies. The aim of this study was to evaluate the association between bone mineral density (BMD), bone turnover markers, serum sclerostin levels, and vertebral fractures (VFs) in acromegaly patients. We also evaluated the effects of gonadal status, disease activity, treatment modality, age, sex, and body mass index (BMI) on skeletal endpoints. DESIGN: Case-control study. PATIENTS AND MEASUREMENTS: Seventy acromegaly patients (M/F:36/34, mean age 45.5 ± 11.9 years) and 70 controls (M/F:31/39; mean age 45.66 ± 11.9 years) were included. VFs, BMD, calcium metabolism, markers of bone turnover, and sclerostin levels were evaluated. BMD was measured by dual-energy X-ray absorptiometry (Hologic QDR 4500). Conventional lateral radiography of the spine was performed and the Genant method was used for the assessment of fractures of T4-L5 vertebrae. RESULTS: The prevalence of vertebral fractures was higher in acromegalic patients as compared with the control group (72.9 vs. 20%; p < 0.001). Serum phosphate (P) levels (3.46 ± 0.59 mg/dl vs. 3.11 ± 0.44 mg/dl; p < 0.001) and b-cross laps (CTx) levels (0.47 µg/l, range 0.04-2.38 vs. 0.28 µg/l, range 0.11-0.80; p < 0.001) were significantly higher in acromegaly patients than control subjects. Serum sclerostin levels were similar between either acromegaly patients and control subjects or acromegaly patients with VF and without VF. In the means of treatment modality, VFs were more frequent in patients treated with adjuvant gamma knife radiosurgery (GKS) (p = 0.07). In the binary logistic regression analysis, the age of the acromegaly patients, the presence of hypogonadism, and GKS treatment were the factors significantly correlated with the occurrence of spinal fractures. CONCLUSIONS: The prevalence of VFs in patients with acromegaly is higher than in control subjects. Since advanced age, the presence of hypogonadism and GKS treatment were the factors predicting VFs in acromegaly; radiological evaluations should be considered as an emerging tool especially in those patients. Although markers of bone turnover elevated in acromegaly, they were not useful for the prediction of fractures. Serum sclerostin levels showed no discrepancy between the two groups and further studies are required for assessment of sclerostin role in this form of secondary osteoporosis.

Effects of concomitant obesity and diabetes on the aggressiveness and outcomes of differentiated thyroid cancer patients.

OBJECTIVE: Obesity and diabetes are the risk factors for cancer development including differentiated thyroid cancer (DTC). Contradictory accumulated data indicates the possible negative effects of obesity and hyperglyceamia as a factor for aggressiveness of DTC. The aim of the present study is to investigate the association of high body mass index (BMI) and presence of type 2 diabetes mellitus (T2DM) on the histological aggressiveness and clinical outcomes in DTC patients followed for over 4 years in a single center. METHODS: Consequative 526 DTC patients who had undergone total thyroidectomy and/or radioactive iodine (RAI) ablation were reviewed retrospectively. Patients were divided into groups based on their BMI: normal weight, overweight, obese and also were evalauted in 3 groups presence of diabetes, prediabetes and nomoglyceamia. Histological aggressiveness of DTC at the time of diagnosis and clinical response at the time of last clinical visit were reassessed according to the criteria suggested by ATA 2015 guideline. RESULTS: No differences in histopathologic features, risk of recurrence, cumulative dose of RAI ablation and prevalence of 131I avid metastatic disease were demonstrated among the groups both classified according to BMI and hyperglycemia. Mean of 3.4 year follow-up also showed no differences in the clinial repsonse to therapy and percentage of nonthyroid primary cancer in DTC patients. CONCLUSION: In this retrospective study we demonstrated that obesity and T2DM have no additive effect on DTC aggressiveness and response to therapy. DTC patients with obesity and diabetes can be treated according to present guidelines without requirement for spesific attention.

Low bone density, vertebral fracture and FRAX score in kidney transplant recipients: A cross-sectional cohort study.

BACKGROUND: Kidney transplantation (KT) recipients are at increased risk of low bone density (LBD) and fractures. In this retrospective study, we investigated bone mineral density (BMD), vertebral fractures, calculated risk for major osteoporotic fractures (MOF), and hip fractures in the KT recipients. PATIENTS-METHOD: Patients who completed at least one year after KT were included in the analysis. Demographic, clinical, and laboratory data were recorded. Measurements of BMD were performed by dual-energy X-ray absorptiometry. Vertebral fractures were assessed using semi-quantitative criteria with conventional radiography. The ten-year risk for MOF and hip fracture were calculated using the FRAX@ tool with BMD. RESULTS: One hundred fifty-three KT recipients were included in the study. The population included 77 women. The mean age at evaluation was 46,5±11,9 years. Seventy-eight (50.9%) patients had normal femoral neck BMD while osteoporosis and osteopenia at the femoral neck were present in 12 (7.8%) and 63 (41.1%) of the patients, respectively. Age at evaluation was the risk factor for LBD (OR 1.057; 95% CI 1.024-1.091; p = 0.001). In female KT recipients, LBD was principally affected by menopausal status whereas in males, mammalian target of rapamycin (mTOR) inhibitor use and lower BMI levels were the risk factors. The prevalent vertebral fracture was found in 43.4% of patients. In multivariate analysis, only steroid use (OR 0.121; 95% CI 0.015-0.988; p = 0.049) was found to be associated with prevalent fracture. Among all KT recipients, 1.9% had a high MOF probability (≥20% risk of fracture), and 23.5% had high hip fracture probability (≥3% risk of hip fracture) according to FRAX. CONCLUSION: Exploring the prevalence of LBD and vertebral fracture and the risk factors would help clinicians to modify long-term follow-up strategies. Furthermore, the high hip fracture risk probability in our cohort suggested that there is a need for longitudinal studies to confirm the validity of the FRAX tool in the transplant population.

Early detection of neuropathy in patients with type 2 diabetes with or without microalbuminuria in the absence of peripheral neuropathy and retinopathy.

PURPOSE: Our goal is early detection of neuropathy in patients with type 2 diabetes with or without microalbuminuria in the absence of diabetic retinopathy and peripheral neuropathy by using in vivo corneal confocal microscopy (IVCCM). METHODS: A total of 60 type-2 diabetic patients, assigned to either a diabetes mellitus (DM) with microalbuminuria group (DM/MA+, n=30) or a DM without microalbuminuria group (DM/MA-, n=30), and 30 age-matched control subjects were enrolled in this study. All cases underwent evaluation of blood glucose level, HbA1c, lipid fractions, body mass index (BMI), and corneal sensitivity (CS). Corneal nerve fiber length (NFL), nerve fiber density (NFD), nerve branch density (NBD), and tortuosity coefficient (TC) were quantified by IVCCM. None of the patients had peripheral neuropathy or retinopathy. RESULTS: Compared with the healthy subjects, NFL and NFD were reduced in both diabetic groups (P<0.0001), while NBD was significantly reduced in the DM/MA+ group. Between the diabetic groups, NFL, NFD, and NBD were significantly higher in the DM/MA- group (all P's<0.001). CS was significantly lower in DM/MA+ compared with DM/MA- and controls (both P's<0.0001). NFD and NFL were inversely correlated with age, triglyceride level, and BMI. CONCLUSION: These results indicate that significant damage to small nerves, quantified using IVCCM, can be detected in the absence of retinopathy, peripheral neuropathy or microalbuminuria in type 2 diabetic patients. The severity of corneal nerve involvement may further increase in the presence of nephropathy. This feature may also be valuable for early detection of microvascular complications of DM, allowing for the prevention of progression of life threatening microvascular complications.

Determinants of High-Dose Insulin Usage and Upper Extremity Muscle Strength in Adult Patients With Type 2 Diabetes.

OBJECTIVES: In this study, we aimed to determine the association between upper extremity muscle strength and insulin dose in patients with type 2 diabetes. METHODS: A total of 236 patients with type 2 diabetes under insulin treatment for at least 1 year were included in this cross-sectional study. Patients were divided into 3 groups based on their total daily insulin dose (TDID): group 1, TDID >2 U/kg/day or >200 units/day; group 2, TDID 1 to 2 U/kg/day or 51 to 199 U/day; and group 3, TDID <0.5 U/kg/day or 50 U/day. High-dose insulin use was defined as total daily insulin dose >2 U/kg or >200 U/day. Muscle strength was measured using a handgrip dynamometer. RESULTS: High-dose insulin users were younger and had higher measures of generalized and central obesity and glycated hemoglobin. There was no significant difference in muscle strength between the groups. Low muscle strength was seen in 26.7% of all patients. Patients with low muscle strength were older, had lower insulin dose treatment and had better glycemic control than patients with normal muscle strength. Handgrip strength was inversely correlated with age, body mass index and duration of diabetes, but not with TDID. CONCLUSIONS: Patients with type 2 diabetes with high-dose insulin use had similar upper extremity muscle strength measurements with standard-dose insulin users. Studies with more patients are needed to determine the relationship between muscle mass, muscle strength and high-dose insulin use.

Seven cases of parathyroid carcinoma and review of the literature.

Parathyroid cancer is a rare malignancy and an uncommon cause of hyperparathyroidism. In the present study, we present seven cases of parathyroid carcinoma. The female ratio was 5/7 (71.4%). Median age at diagnosis was 47 years, and median follow-up duration was 60 months (IQR 29-75). Mean calcium level at diagnosis was 12.7 mg/dL (range, 11.3-13.9), and mean parathormone level was 1115 ng/L (IQR 287-1470). Two patients (28.5%) had a palpable neck mass. Coexisting brown tumor was present in three patients (42.8%), and nephrolithiasis was found in one patient (14.2). Average tumor size was 29 mm (IQR 28-40). Capsular and vascular invasion were detected in six patients (85.7%), intrathyroidal spread was observed in two patients (28.5%), and soft tissue invasion was seen in three patients (42.8%). Parathyroid adenoma was present in one patient and parathyroid gland hyperplasia in another patient. Adjuvant radiotherapy was given to four patients (57.1%). There was no metastatic disease or death. At the last visit, two patients had increased parathormone levels and no additional focus could be detected in either. Patients with markedly elevated parathormone and calcium levels and a palpable larger mass on the neck should be evaluated for parathyroid cancer. En bloc resection is the mainstay treatment. Despite contradictory results, adjuvant radiotherapy to the neck may help to reduce the risk of local recurrence in patients with microscopic residual parathyroid carcinoma.

Long-term endocrinological outcomes of gamma knife radiosurgery in acromegaly patients.

Gamma knife radiosurgery (GKS) is a treatment option for recurrent or persistent disease in patients with acromegaly. OBJECTIVE: We aimed to retrospectively evaluate acromegaly patients who had undergone GKS in terms of pituitary hormone status, efficacy of GKS, and prognostic factors. METHOD: One-hundred and ten acromegaly patients who underwent GKS, and who were referred to our outpatient endocrinology clinic between 2007 and 2017, were included in the study. Anterior pituitary hormones and radiology imaging during follow-up were recorded. Remission for acromegaly was defined as a normal insulin-like growth factor 1 (IGF-1) level adjusted for age and gender, and a random growth hormone (GH) level < 1 ng/ml. Endocrine control was defined as normal GH and IGF-1 levels under medication. RESULTS: After a mean follow-up of 6.5 ±â€¯4.7 years; remission, endocrine control, and uncontrolled status was observed in 16.4%, 60%, and 23.6% of patients; respectively. Adenoma volume was decreased after GKS (P < .0001). Remnant adenoma diameter was higher in the uncontrolled group compared to the remission and endocrine control group. The presence of tumor extension was associated with disease status (P = .03) and higher initial GH and IGF-1 levels. The mean time after GKS to remission was 26.5 months. Six (5.4%) patients had new-onset pituitary deficiency after GKS. In the multivariate analysis, pre-GKS IGF-1 levels and patient's age were associated with disease status. CONCLUSION: GKS is an effective adjuvant treatment with minimal side effects to control GH and IGF-1 levels, increase remission rates, endocrine control, and reduce tumor diameter in persistent acromegaly patients after surgery.