Effects of SGLT2 inhibitors on patients with diabetic kidney disease: A preliminary study on the basis of podocyturia.

BACKGROUND: The aim of this study was to investigate the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on the glomerulus through the evaluation of podocyturia in patients with diabetic kidney disease (DKD). METHODS: The study population was composed of 40 male patients with type 2 diabetes mellitus; 22 of them received SGLT2i (SGLT2i group), and the others who did not were the control. The DKD-related parameters of patients were monitored before SGLT2i initiation, and then in the third and sixth month of the follow-up period. Patients' demographic, clinical, laboratory, and follow-up data were obtained from medical charts. Microalbuminuria was measured in 24-h urine. The number of podocytes in the urine was determined by immunocytochemical staining of two different markers, namely podocalyxin (podx) and synaptopodin (synpo). Concentrations of urine stromal cell-derived factor 1a and vascular endothelial growth factor cytokines were quantified with an enzyme-linked immunosorbent assay kit. RESULTS: At the end of the follow-up period, decreases in glycosylated hemoglobin, glucose, systolic and diastolic blood pressure, uric acid level, and microalbuminuria, and improvement in body mass index level and weight loss were significant for the SGLT2i group. On the other hand, there was no significant difference in terms of these parameters in the control group. The excretion of synaptopodin-positive (synpo+ ) and podocalyxin-positive (podx+ ) cells was significantly reduced at the end of the follow-up period for the SGLT2i group, while there was no significant change for the control. CONCLUSIONS: At the end of the follow-up period, male patients receiving SGLT2i had better DKD-related parameters and podocyturia levels compared to baseline and the control group. Our data support the notion that SGLT2i might have structural benefits for glomerular health.

Fibroblast Growth Factor Receptor-4 Expression in Pituitary Adenomas is Associated with Aggressive Tumor Features.

PURPOSE: To investigate the relationship of Fibroblast Growth Factor Receptor-4 (FGFR-4) expression with radiologic, pathologic, and clinical parameters in pituitary adenomas. METHODS: Among 307 patients who underwent pituitary surgery for a pituitary adenoma between 2000 and 2015, we included 161 patients (53 gonadotroph, 26 corticotroph, 25 null cell, 22 lactotroph, 13 somatotroph, 8 adenomas with unusual combination, 7 Pit-1 positive adenomas, and 7 lactosomatotroph) based on availability of pathology specimens. Patients' radiologic, pathologic, and clinical parameters were determined. FGFR-4 immunostaining was evaluated using a semi-quantitative histologic score (H-score). RESULTS: The mean follow-up period was 61 (IQR=32-84) months. The median H-scores for FGFR-4 were higher in patients without remission, those with residual lesion, and T2-hyperintense adenoma (p<0.05). Ki-67 level was higher in patients without remission compared to those in remission (p<0.05). The mean Ki-67 levels did not differ between patients with and without residual lesion or T2-hyperintense tumor (p>0.05). There was no significant difference (p>0.05) when the H-score and Ki-67 levels were assessed in terms of sex, sellar-dural invasion, Knosp and a grading system for superior, inferior, parasellar, anterior and posterior tumor extension Classification, tumor function or presence of poor subtype. Adenomas with Ki-67 expression ≥3% had higher FGFR4 expression levels than those with <3% expression (p=0.002). There was a weak positive correlation between H-score and Ki-67 (p=0.011; r=0.201). CONCLUSIONS: Higher levels of FGFR-4 in pituitary adenomas could be use a marker for more aggressive tumor behavior.

Primary hypophysitis: Experience of a Single Tertiary Center.

PURPOSE: The authors review the clinical outcomes of patients with primary hypophysitis (PH). METHODS: Patients with PH who were followed up between 2007 and 2018 at our clinic were evaluated. Clinical, endocrinologic, pathologic, radiologic findings and treatment modalities were assessed. RESULTS: Seventeen patients with PH were assessed. The median follow-up was 24 (range, 6-84) months. Histologic confirmation was available in 8 patients (6 lymphocytic hypophysitis, 1 lymphocytic-granulomatous hypophysitis, 1 xanthomatous hypophysitis). None of the cases were diagnosed after pregnancy. Two patients had an autoimmune disease. The most commonly seen symptom was headache. The most common anterior pituitary deficiencies were hypocortisolemia and hypothyroidism. The radiologic findings of the patients at the time of diagnosis revealed various results including space-occupying lesion (41.2%), loss of posterior hypophysis bright spot (47.1%), pituitary stalk thickening (41.2%), uniform contrast enhancement (17.6%), partially empty sella (11.8%), optic chiasm compression (11.8%). The most frequent initial treatment modality was observation. Ten patients who were followed up conservatively had no endocrinologic deterioration; additional treatment was not needed in 8 of these 10 patients. The second most frequent initial treatment modality was pituitary surgery. Five patients received steroid treatment. We found serious adverse effects during steroid treatment in 3 of 5 (60%) patients; unilateral avascular necrosis of the femoral head (n=2), diabetes mellitus(n=1). CONCLUSION: Correctly diagnosing PH and giving appropriate treatment is challenging. It is unclear whether active treatment with steroids improves clinical outcomes. The serious adverse effects of steroids are also taken into account. Observation, surgery and/or radiotherapy can be appropriate treatment modalities for selected patients.

SNPs of miR-23b, miR-107 and HMGA2 and their Relations with the Response to Medical Treatment in Acromegaly Patients.

INTRODUCTION: Acromegaly is a chronic disease of increased growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels induced by a pituitary adenoma. HMGA2 (high mobility group A2) and AIP (aryl hydrocarbon receptor-interacting protein) expression levels are related to GH-secreting adenomas, and also a response to Somatostatin Analogs (SSAs). We studied SNPs in miR-107 and miR-23b that related with AIP and HMGA2 genes respectively and control their expression, and also SNP in the 3'UTR of HMGA2 gene. Our aim was to investigate genotype distributions of the studied SNPs, as well as the possible relationship between disease and/or response to SSAs treatment in patients with acromegaly. MATERIAL AND METHODS: Genotypes were determined by qRT-PCR method from DNA materials obtained blood samples of acromegaly patients (141) and healthy individuals (99). The genotype distributions of patients and healthy groups, as well as the relationship between the clinical data of the disease and genotypes were statistically compared. RESULTS: In acromegaly patients with T-allele, p53 expression (p=0.049) was significantly higher. In patients with CT+TT genotype and T-allele who were responder to SSA-treatment Ki-67 index (respectively p=0.019, p=0.020 respectively) was higher. We did not observe the genotypes for miR-23b and miR-107 polymorphisms in the patients and control group of Turkish population. CONCLUSION: The genetic variations of the miRNAs genes related with HMGA2 and AIP genes were not seen in our study. Although there is no relationship between HMGA2-rs1351394 polymorphism and acromegaly disease, T allele was associated with some clinical features related to adenoma in patients with acromegaly.

Effectiveness of Cabergoline Treatment in Patients with Acromegaly Uncontrolled with SSAs: Experience of a Single Tertiary Center.

PURPOSE: To evaluate the effectiveness of cabergoline and the parameters affecting cabergoline response as add-on treatment to somatostatin analaogues (SSA) in patients with acromegaly uncontrolled with SSAs. MATERIAL AND METHOD: One hundred and twenty-nine acromegalic patients uncontrolled with SSA who had cabergoline added to their treatment were included in this retrospective study. Patients were divided into the SSAs + cabergoline-responsive (group 1) and non-responsive groups (group 2), and biochemical, pathologic, and radiologic parameters were assessed. RESULTS: IGF-1 normalization was achieved in 75 of 129 patients (58%) when cabergoline was added to the SSA treatment. Female patients were significantly higher in group 1 compared to group 2 (p=0.006). Group 1 had significantly smaller pre- and post-cabergoline tumor size (p=0.011, p=0.007 respectively), lower levels of IGF-1 in pre-and post-operative period (p=0.040, p=0.001), and lower levels of IGF-1 in pre- and post-cabergoline treatment (p<0.001). Cavernous invasion on sellar magnetic resonance imaging, dural invasion in pathologic examination were not significantly different between the groups. Sellar invasion in pathologic examination was significantly higher in group 1 (p=0.011). No significant difference was found in proliferation indices between two groups. The presence of fibrous bodies was significantly lower in group 1 (p=0.010). CONCLUSION: Cabergoline can be added to the treatment of acromegalic patients uncontrolled with SSAs due to its ease of use and low economic cost, especially in patients with acromegaly who have small adenomas and no fibrous bodies.

Patients with acromegaly might not be at higher risk for dopamine agonist-induced impulse control disorders than those with prolactinomas.

OBJECTIVE: To evaluate the prevalence of impulse control disorders (ICD) and psychiatric symptoms in patients with acromegaly receiving dopamine agonists (DA) in comparison with those with prolactinoma, nonfunctioning pituitary adenomas (NFA), and healthy controls (HC). DESIGN: Forty patients with acromegaly, 40 with prolactinoma, 38 with NFA, and 32 HCs were included. All patients and controls were evaluated using the revised version of the Minnesota Impulsive Disorders Interview (MIDI-R), Symptom Check List (SCL-90-R) questionnaire, Barratt Impulsiveness Scale (BIS-11), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). RESULTS: We detected ICD associated with DAs in two patients with acromegaly (5%) and three patients (7.5%) with prolactinoma. All patients' symptoms resolved after discontinuation of the drug. While the mean DA dose was higher in patients with acromegaly than prolactinomas (p < 0.05), no difference was detected in terms of ICD prevalence between two groups (p > 0.05). SCL-90 depression and interpersonal sensitivity subscale positivity was higher in patients with NFA than HCs. Patients with prolactinoma had higher obsession and interpersonal sensitivity positivity and those with NFA had higher somatization, interpersonal sensitivity, and depression positivity as compared to patients with acromegaly (p < 0.05 for all). CONCLUSIONS: Although DA dose was significantly higher in patients with acromegaly, there was no significant difference in the prevalence of DA-related ICD. The higher prevalence of positive screening in SCL-90 in patients with NFA in comparison to HCs supports the hypothesis that the presence of a pituitary adenoma per se might cause significant psychiatric symptoms.

Clinicopathologic Characteristics and Surgical Treatment of Plurihormonal Pituitary Adenomas.

OBJECTIVE: Plurihormonal pituitary adenomas (PPAs) have recently been divided into 2 subtypes: pituitary specific transcription factor 1-positive plurihormonal pituitary adenomas (PIT-1+ PPAs) and plurihormonal adenomas with unusual immunohistochemical combinations (PAwUIC). The purpose of this study was to review patients with PPAs, elucidate their clinicopathologic characteristics, and present the surgical results. METHODS: Records were analyzed for 665 patients who underwent endoscopic endonasal transsphenoidal surgery for pituitary adenomas between 2007 and 2018. Data were reviewed for 27 patients who met the definition of PPAs and delineated regarding clinical, radiologic, pathologic features, and surgical outcomes. RESULTS: Of the 27 patients, 18 had PAwUIC, and 9 patients were diagnosed with PIT-1+ PPAs. Twenty-four patients (88.8%) had macroadenomas, including 6 giant adenomas (≥4 cm) (22.2%). Cavernous sinus invasion was found in 12 patients (44.4%). Pathologic examinations showed high aggressivity in nearly half of the patients. Most patients with PAwUIC (77.8%) had features of nonfunctioning pituitary adenomas, and only 4 had features of hormone-secreting pituitary adenomas. Gross total resection rates were 57.1% for PAwUIC and 77.8% for PIT-1+ PPAs. The remission rate for hormone-secreting pituitary adenomas was 100% in this case series. Mean follow-up was 74.4 ± 33 months (range, 6-121 months) for overall groups. CONCLUSIONS: To our knowledge, this is the first study to describe the clinicopathologic features of newly classified PPAs, which are characterized by aggressive behavior with higher values of percentage of cavernous sinus invasion. Relevant pathologic diagnosis of PPAs is crucial for appropriate management and follow-up.