Disease-free survival and the prognostic factors affecting disease-free survival in patients with medullary thyroid carcinoma: a multicenter cohort study.

PURPOSE: Despite several factors that may have been associated with poor disease-free survival (DFS) in patients with medullary thyroid carcinoma (MTC), only a few studies have evaluated the prognostic factors affecting DFS in MTC patients. Therefore, this study evaluated the prognostic factors affecting DFS, in a large number of patients with MTC. METHODS: Patients treated for MTC were retrospectively analyzed. Patients were stratified as having persistent/recurrent disease and no evidence of disease (NOD) at the last follow-up. The factors affecting DFS after the initial therapy and during the follow-up period were investigated. RESULTS: This study comprised 257 patients [females 160 (62.3%), hereditary disease 48 (18.7%), with a mean follow-up time of 66.8 ± 48.5 months]. Persistent/recurrent disease and NOD were observed in 131 (51%) and 126 (49%) patients, respectively. In multivariate analysis, age > 55 (HR: 1.65, p = 0.033), distant metastasis (HR: 2.41, p = 0.035), CTN doubling time (HR: 2.7, p = 0.031), and stage III vs. stage II disease (HR 3.02, p = 0.048) were independent predictors of persistent/recurrent disease. Although 9 (8%) patients with an excellent response after the initial therapy experienced a structural recurrence, the absence of an excellent response was the strongest predictor of persistent/recurrent disease (HR: 5.74, p < 0.001). CONCLUSIONS: The absence of an excellent response after initial therapy is the strongest predictor of a worse DFS. However, a significant proportion of patients who achieve an excellent response could experience a structural recurrence. Therefore, careful follow-up of patients, including those achieving an excellent response is essential.

Ubiquitin-specific Protease 8 Gene Expression in Sporadic Pituitary Adenomas.

OBJECTIVES: In sporadic pituitary adenomas, the role of Ubiquitin-specific protease 8 (USP8) is not clearly defined. Mutations in USP8 gene are known to influence formation of the corticotroph adenomas. However, it has not been clarified whether changes in expression of USP8 have an impact on other pituitary adenomas or not. In this study we addressed the changes in USP8 gene expression levels in pituitary adenomas (PA) relative to non-adenomatous brain tissue. MATERIAL AND METHODS: USP8 gene expression analysis was performed on a total of 43 tissue samples from human pituitary adenomas and on 16 tissue samples from non-pituitary brain tissues (control group). Adenomatous tissues and control tissues were assessed for quantification of RNA expression of USP8.The levels of USP8 gene expression were determined relative to those in control group. RESULTS: Overall, the USP8 gene expression levels in PA were 3.7 times higher than the control brain tissues (CBT) (p=0.002). However, after stratification, only the USP8 in the secretory PA were higher than CBT(p=0.002). CONCLUSIONS: Present findings support that USP8 gene expression levels may contribute to pitutary tumorigenesis and hormonogenesis..

Do neurosteroids have impact on depression and cognitive functions in cases with acromegaly?

OBJECTIVE: Neurosteroids (NSs) are a distinct hormone group and, they are known for their contribution into the status of mood and cognitive functions. Whether they are also involved in the mood disturbances and cognition in acromegaly is not known. Herein we aimed to evaluate the relation of mood status and cognitive functions with the NS levels in cases with acromegaly. DESIGN: A total of 33 cases with acromegaly composed the acromegaly group (AG) and, 30 age and gender-matched cases without acromegaly composed the control group (CG). The levels of Allopregnanolone (AP), pregnenolone (PRG), 24S-hydroxycholesterol (24OHC), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androsterone (ADT), GH and IGF-1 were measured in each group. Beck Depression Inventory (BDI) was used to assess depressive symptoms, whereas an extensive neuropsychological assessment with several neurocognitive tests were carried out for each subject by an experienced psychologist. RESULTS: Cases with acromegaly had lower 24OHC and DHEA levels (p = 0.002 and p = 0.007, respectively) in comparison to CG. Of the cognitive functions time to complete 1 s Series was significantly higher and, the scores on Switching Verbal Fluency Test, Boston Naming Test (BNT)-semantic and BNT-phonological, the highest learning point of Oktem Verbal Memory Processes Test (VMPT) were significantly lower in cases with acromegaly in comparison to those in controls (p = 0.004, p = 0.01, p < 0.001, p = 0.02 and p = 0.05, respectively). KAS-perseveration errors were higher in CG (p = 0.03). In AG the levels of AP were negatively correlated with the scores on Months backward Test (MBT), Animal Naming Test, Construction, BNT-spontaneous and positively correlated with BNT-incorrect answers; PRG was positively correlated with VMPT-retention scores, ADT was negatively correlated with MBT and 3 s Series scores, DHEAS was positively correlated with VMPT-the highest learning point whereas it was negatively correlated with MBT scores. Additionally, the scores on BDI were positively correlated with DHEA levels in AG. CONCLUSION: Cognitive changes may be encountered in acromegaly and, neurosteroids may contribute to the changes in certain cognitive functions.

Acromegaly might not negatively affect microvascular circulation.

BACKGROUND: Endothelial dysfunction and atherosclerosis are well known complications of acromegaly. However, current data on microvascular circulation are limited. AIMS: To evaluate microvascular circulation in patients with acromegaly. METHODS: This comparative study included a total of 21 patients with acromegaly and 20 age- and sex-matched healthy subjects. A stereomicroscope under ×100 magnification was used by a single rheumatologist to evaluate the capillary dimensions (capillary loop length, capillary width) and capillary/mm count in the capillaries of subjects. Statistical data analysis was conducted using the SPSS 15.0 package program. RESULTS: The mean number of capillaries per millilitre (normal ≥8/mL) in the acromegaly group (AG) and healthy controls (HC) was 7.67 ± 1.88 and 8.67 ± 0.65, respectively (P = 0.04). In the AG and the HC, the number of tortuous capillaries, the mean capillary loop length and the mean capillary width were not different. Although the median number of capillaries in the AG was lower than in the HC, it was still within normal limits. CONCLUSION: Although the number of capillaries was statistically lower in patients with acromegaly, they were within a normal range and the difference was not clinically significant. Moreover, there was no difference in morphological characteristics between the groups. While endothelial dysfunction is the earliest known marker of the atherosclerotic process and is considered to be one of the complications of acromegaly, the disease may not result in impairment of microvasculature of those people afflicted by it.

Increased mitochondrial common deletion in platelets from patients with type 2 diabetes is not associated with abnormal platelet activity or mitochondrial function.

The present study examined the presence and frequency of the 4,977­base pair mitochondrial (mt)DNA (mtDNA4977) deletion in blood platelets, and whether increased mtDNA4977 deletion was associated with abnormal mitochondrial and platelet function in type 2 diabetes mellitus. A total of 66 patients with type 2 diabetes mellitus and 23 healthy subjects were included in the present study. Patients were divided into three subgroups according to glycemic control, and the presence or absence of chronic diabetic complications: i) Good glycemic control [glycated hemoglobin (HbA1c) <7] without complications; ii) poor glycemic control (HbA1c ≥7) without complications; and iii) poor glycemic control (HbA1c ≥7) with complications. mtDNA4977 deletion, mtDNA copy number, adenine nucleotides, mitochondrial membrane potential and P­selectin expression levels were analyzed in platelets. Although the frequency of mtDNA4977 deletion in platelets of the patient (96.9%) and control groups (95.6%) was extremely similar, the deletion level significantly increased in all the diabetic groups, compared with the healthy control group. However, the data from the present study revealed that an increased deletion frequency in platelets was not associated with disease severity, although there was clear interindividual variability. Furthermore, all other parameters were not significantly different among the groups, and there were no correlations between mtDNA4977 deletion frequency and all other studied parameters for any of the case groups. The results indicated that the mtDNA4977 deletion occurred in platelets, and increased deletion in patients with type 2 diabetes did not have a marked influence on mitochondrial and/or platelet dysfunction, when compared with the non­diabetic subjects. Further research is required to elucidate the sources of inter­individual variability observed in certain parameters.

Serum survivin increases in prolactinoma.

BACKGROUND: Prolactinoma is the most common adult pituitary adenoma. Survivin is a member of the family of inhibitors of apoptosis proteins. Its expression is observed in many tumors. Survivin expression has shown in prolactinoma tissue before but no study exists showing serum survivin level. The aim of the present study was to investigate serum survivin levels in patients with prolactinoma and demonstrate its value in diagnosis of the disease. METHODS: The group of patients consisted of 25 women, aged from 17 to 51 years. As a control group, 21 healthy women, aged from 22 to 45 years were included. Twenty patients had microprolactinoma, while five patients had macroprolactinoma. All patients had received dopamine agonist treatment. Serum survivin levels were measured in all of the groups. RESULTS: Survivin levels were significantly higher in prolactinoma patients compared to controls (19.04 (10 - 38) pg/mL; 15.05 (8 - 22) pg/mL; P = 0.042). There was no difference between microadenoma and macroadenoma patients in survivin levels (19.22 (10 - 38) pg/mL; 18.40 (16 - 22) pg/mL; P = 0.914). In correlation analysis, survivin was not correlated with other parameters. CONCLUSIONS: We consider that higher survivin levels might be a molecular marker predicting the presence of prolactinoma and may be useful for the diagnosis. But large-scale research is needed to clarify its role in diagnosis of prolactinoma patients.

Acromegaly and aging: a comparative cross-sectional study.

OBJECTIVE: Cognitive and functional geriatric assessment may change in acromegaly. Herein we aimed to determine at which points geriatric assessment of the cases with acromegaly differs from that of general elderly population. DESIGN: In this comparative cross-sectional study, a total of 30 cases with acromegaly (controlled n = 14, uncontrolled n = 16) and 30 gender and body-mass index-matched cases without acromegaly (control group, CG) above 60 years old were included. Cognitive functions were evaluated on the basis of the mini-mental state exam (MMSE). Affective status was determined using the geriatric depression scale. Activities of daily living (ADL) were ranked according to the Barthel index while instrumental activities of daily living (IADL) were graded on the basis of the Lawton scale. Nutritional status was evaluated using the mini-nutritional assessment (MNA). Body composition was measured through bioimpedance analysis. Functional mobility was determined using the Timed Up and Go test (TUG) and muscle strength with the handgrip strength test. RESULTS: Scores on the MMSE were significantly lower in the elderly cases with acromegaly than in the cases without acromegaly (p < 0.001). Dementia was more frequent in the acromegaly group than in the CG (p = 0.04). Total MNA scores were significantly lower in cases with acromegaly than in the CG (p = 0.006). More subjects in the acromegaly group (33%) were at greater risk of malnutrition than in the CG (3%) (p = 0.003). There was greater moderate functional impairment based on Barthel ADL in the acromegaly group than in the CG (p = 0.04). CONCLUSION: Acromegaly may impair cognitive functions, functional mobility and instrumental daily living activities in the geriatric population. With acromegaly, the risk of malnutrition may also increase.

Physical and cardiovascular performance in cases with acromegaly after regular short-term exercise.

OBJECTIVE: Impaired physical performance is a disturbing complication of acromegaly. We aimed to evaluate the role of regular exercise in amelioration of the impaired physical performance in acromegaly. METHODS: Patients with acromegaly were divided into two groups according to their participation in a prescheduled programme of exercise. Participants in the study group were exercised 3 days a week for 3 consecutive months. Exercise tolerance was evaluated by maximal oxygen consumption (VO2 max) and time (T) taken to complete the Bruce protocol, muscle flexibility by the sit and reach test (SRT) and muscle strength by the hand grip strength test (HGST). Concomitantly, anthropometric assessment was performed using body mass index (BMI), waist-to-hip ratio (WHR), skinfold measurements from 8 points, percentage body fat (PBF), fat mass (FM) and lean body mass (LBM). RESULTS: After 3 months of exercise, VO2 max and T were higher in cases that exercised than in cases that did not (P = 0.004 and P = 0.001). Over 3 months, within the exercise group, VO2 max and T of the Bruce protocol increased (P = 0.003 and P = 0.004) and heart rate during warming decreased (P = 0.04). SRT increased within the exercise group after 3 months (P = 0.004). HGSRT did not change significantly (right P = 0.06 and left P = 0.2). The sum of skinfolds, BMI, WHR and LBM remained stable over the study period (P = 0.1, P = 0.08, P = 0.3 and P = 0.09). PBF decreased slightly and FM decreased significantly over 3 months (P = 0.05 and P = 0.03). CONCLUSION: Even short-term exercise may improve impaired physical performance, muscle activity and disturbed body fat composition in acromegaly.

A rare case of solitary subcutaneous scalp metastasis from follicular thyroid carcinoma revealed with positron emission tomography/computed tomography: a case report and review.

Differentiated thyroid cancer frequently metastasizes to regional cervical lymph nodes and in advanced cases metastases can be seen in the lungs and skeleton. Metastases to the skin or subcutaneous tissue are rare. Here we present a 49-year-old female patient with solitary scalp metastasis from follicular thyroid carcinoma FTC which was revealed with positron emission tomography (PET)/computed tomography (CT) imaging. PET showed flourodeoxiglucose avid lesion in the left vertex scalp. Scalp lesion was removed totally and histopathological examination revealed well-differentiated thyroid cancer metastasis.

Association of PARP-1, NF-κB, NF-κBIA and IL-6, IL-1ß and TNF-α with Graves Disease and Graves Ophthalmopathy.

BACKGROUND: Graves Disease (GD) is an autoimmune disorder affected by an interaction of multiple genes such as Nuclear Factor-κB (NF-κB), Nuclear Factor-κB Inhibitor (NF-κBIA), Poly (ADP-ribose) polymerase-1 (PARP-1) and cytokines like Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) and mostly accompanied by an ocular disorder, Graves Ophthalmopathy (GO). We hypothesize that there is a relationship between GD, GO, polymorphisms of inflammatory related genes and their association with cytokines, which may play important roles in autoimmune and inflammatory processes. SUBJECTS AND METHODS: To confirm our hypothesis, we studied the polymorphisms and cytokine levels of 120 patients with GD and GO using PCR-RFLP and ELISA methods, respectively. RESULTS: We found that patients with GG genotype and carriers of G allele of PARP-1 G1672A polymorphism are at risk in the group having GD (p=0.0007) while having GA genotype may be protective against the disease. PARP-1 C410T polymorphism was found to be associated with GO by increasing the risk by 1.7 times (p=0.004). Another risk factor for development of GO was the polymorphism of del/ins of NFkB1 gene (p=0.032) that increases the risk by 39%. Levels of cytokines were also elevated in patients with GD, but no association was found between levels of cytokines and the development of GO as there was no change in levels of cytokines. CONCLUSIONS: We suggest that, PARP-1 and NFkB1 gene polymorphisms may be risk factors for developing Graves Disease and Ophthalmopathy.

Association of three SNPs in the PARP-1 gene with Hashimoto's thyroiditis.

Poly(ADP-ribose) polymerase-1 (PARP-1) has a vital role in the progression of the inflammatory response, and its inhibition confers protection in various models of inflammatory disorders. Therefore, we investigated the effect of promoter and exon variations of the PARP-1 gene on the risk for the inflammatory disease Hashimoto's thyroiditis (HT). This case-control association study was comprised of 141 HT patients and 150 controls from a group of women in a Turkish population. Two polymorphisms in the promoter region of the PARP-1 gene, rs2793378 and rs7527192, were analyzed using the PCR-RFLP method. In addition, single nucleotide polymorphism (SNP) rs1136410, which is located at codon 762, was analyzed using bidirectional sequencing. The combined genotype and haplotype analyses of these polymorphisms were performed using SPSS 18 and Haploview 4.2. The results were statistically analyzed by calculating the odds ratios and 95% confidence interval using Pearson's χ (2)-test and Fisher's exact test (two-sided). Although we had a number of significant results, the associations became nonsignificant following a Bonferroni correction for multiple comparisons. Nonetheless, a protective factor against HT was still observed for the heterozygous genotype (TC) of SNP rs1136410 (P=0.001), even following Bonferroni correction, and according to the rs2793378-rs7527192 combined analysis, the occurrence of the TT/GA combined genotype was significantly higher in the controls (P=0.007). These results prove that the heterozygosity of SNP rs1136410 provides a protective effect against HT disease in a group of women in a Turkish population.

Familial acromegaly due to aryl hydrocarbon receptor-interacting protein (AIP) gene mutation in a Turkish cohort.

Aryl hydrocarbon receptor-interacting protein (AIP) is associated with 15-20% of familial isolated pituitary adenomas and 50-80% of cases with AIP mutation exhibit a somatotropinoma. Herein we report clinical characteristics of a large family where AIP R304X variants have been identified. AIP mutation analysis was performed on a large (n = 52) Turkish family across six generations. Sella MRIs of 30 family members were obtained. Basal pituitary hormone levels were evaluated in 13 family members harboring an AIP mutation. Thirteen of 52 family members (25%) were found to have a heterozygous nonsense germline R304X mutation in the AIP gene. Seven of the 13 mutation carriers (53.8%) had current or previous history of pituitary adenoma. Of these 7 mutation carriers, all but one had somatotropinoma/somatolactotropinoma (85.7% of the pituitary adenomas). Of the 6 acromegaly patients with AIP mutation (F/M: 3/3) the mean age at diagnosis of acromegaly was 32 ± 10.3 years while the mean age of symptom onset was 24.8 ± 9.9 years. Three of the six (50%) acromegaly cases with AIP mutation within the family presented with a macroadenoma and none presented with gigantism. Biochemical disease control was achieved in 66.6% (4/6) of the mutation carriers with acromegaly after a mean follow-up period of 18.6 ± 17.6 years. Common phenotypic characteristics of familial pituitary adenoma or somatotropinoma due to AIP mutation vary between families or even between individuals within a family.

Impact of exercise on quality of life and body-self perception of patients with acromegaly.

In acromegaly the impact of therapy on well-being and self-perception of patients is not clearly defined. The data existing on the effect of treatment on health-related quality of life in patients with acromegaly is inconclusive. In this study we addressed the effect of exercise on health-related quality of life, symptoms of depression and perception of body image in patients with acromegaly. Patients with acromegaly were stratified into two groups according to their participation in a prescheduled program of exercise. Participants in the study group performed exercise for 75 min a day for 3 days a week during cosecutive 3 months. Warming, cardio, strength, balance and stretching moves applied in every course. Both the exercise group and control group were asked to complete a questionnaire on quality of life, symptoms of depression and self-perception of body image. Each questionnaire was answered by both groups before the beginning of the exercise program (at month-0) and after the completion of the program (at month-3). In exercise group after the completion of exercise period there was a tendency towards decreament in body mass index and IGF-I, although not statistically significant (p = 0.08 and p = 0.09). Self-assessment of body image improved significantly after participation in the exercise program (p = 0.01). Present findings support that exercise may be an adjunctive method for patients with acromegaly to improve self esteem and perception.

Acromegaly is not associated with irritable bowel syndrome: a pilot study.

BACKGROUND: In acromegaly, the gastrointestinal system is under the influence of excessive growth hormone (GH) and insulin like growth factor-1 (IGF-I). Increased bowel length and delayed transit time may cause functional disturbance of the bowel. The objective of the current study is to evaluate the frequency of irritable bowel syndrome (IBS) in cases with acromegaly. PATIENTS AND METHODS: Twenty-three active cases with acromegaly newly diagnosed between 2010-2011 were included in the study. The control group consisted of ninety gender and age-matched healthy controls (HC). All cases were questioned for presence of IBS using Rome III criteria. Abdominal ultrasonography and colonoscopy results of acromegalic patients were obtained. In addition, cases with acromegaly were evaluated for their quality of life and status of depression by using the Acromegaly Quality of Life Questionnaire (AcroQoL) and Beck Depression Inventory (BDI), respectively. RESULTS: The median GH and IGF-1 levels of cases with acromegaly were 5.72 [IQR: 2.2-34] ng/ml and 753 [IQR: 503-1050] ng/ml, respectively. The median AcroQoL score of patients with acromegaly was 56 [IQR: 43-71.5] and the median BDI score was 16 [IQR: 11-21]. Rome III diagnostic criteria were positive in 2 of 23 acromegaly patients and in 3 of 90 HC (p=0.26). IBS was present in 1 of 23 of the acromegaly patients compared to 3 of 90 HC (p=0.81). CONCLUSION: Although acromegaly and IBS may cause similar gastrointestinal symptoms, acromegaly is not associated with a greater incidence of true IBS.

Iatrogenic Cushing's syndrome with inhaled steroid plus antidepressant drugs.

Current guidelines recommend the use of inhaled corticosteroids (ICS) for suppression of airway inflammation in patients with asthma. Although it is well known that ICS cause dose-related adrenocortical suppression, it is less known that they can lead to iatrogenic Cushing's syndrome (CS). Fluticasone propionate (FP) is an ICS more potent than beclomethasone and budesonide. FP is metabolized as mediated by cytochrome P450 3A4 in the liver and the gut. Systemic bioactivity of FP can increase with the use of drugs that affect the cytochrome P450. Herein, we report the rapid development of iatrogenic CS in a patient receiving paroxetine and mirtazepine for 12 weeks in addition to inhaled FP.