Machine Learning May Be An Alternative To BIPSS In The Differential Diagnosis Of ACTH-Dependent Cushing's Syndrome.

OBJECTIVE: This study aimed to develop machine learning (ML) algorithms for the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) based on biochemical and radiological features. METHODS: Logistic regression algorithms were used for ML, and the area under the receiver operating characteristics curve (AUROC) was used to measure performance. We used Shapley Contributed Comments (SHAP) values, which help explain the results of the ML models to identify the meaning of each feature and facilitate interpretation. RESULTS: A total of 106 patients, 80 with Cushing's disease (CD) and 26 with ectopic ACTH syndrome (EAS), were enrolled in the study. The ML task was created to classify patients with ACTH-dependent CS into CD and EAS. The average AUROC value obtained in the cross-validation of the logistic regression model created for the classification task was 0.850. The diagnostic accuracy of the algorithm was 86%. The SHAP values indicated that the most important determinants for the model were the 2-day 2-mg dexamethasone suppression test, the > 50% suppression in the 8-mg high-dose dexamethasone test, late-night salivary cortisol, and the diameter of the pituitary adenoma. We have also made our algorithm available to all clinicians via a user-friendly interface. CONCLUSION: ML algorithms have the potential to serve as an alternative decision support tool to invasive procedures in the differential diagnosis of ACTH-dependent CS.

The Effect of Metformin Treatment on Disease Control in Patients with Acromegaly.

BACKGROUND: The increase in portal insulin levels has been shown to upregulate growth hormone receptor expression in the liver, leading to increased insulin-like growth hormone- 1 levels. Metformin inhibits hepatic gluconeogenesis and reduces fasting insulin. OBJECTIVE: We evaluated the effect of metformin treatment in patients with acromegaly on growth hormone, insulin-like growth hormone-1, and pituitary adenoma size. METHODS: Patients who were followed up with the diagnosis of acromegaly in Istanbul University- Cerrahpasa, Cerrahpasa Medical Faculty were evaluated. The patients were divided into three groups after pituitary adenectomy as those who received somatostatin receptor ligand and metformin treatment (group A), somatostatin receptor ligand treatment only (group B), and those who received metformin treatment only (group C). Groups A and B were compared with each other, and patients in group C were compared among themselves. RESULTS: While the median insulin-like growth factor-1 level decreased to 170 ng/ml in Group A after the treatment, the median insulin-like growth factor-1 level decreased to 229 ng/ml in Group B, and a statistically significant difference was found between the two groups (p =0.020). There was no significant difference in post-treatment growth hormone levels and residual adenoma sizes between groups A and B (p >0.005). In group C, there was no significant difference in growth hormone values pre-and post-metformin treatment (p =0.078); however, the median insulin-like growth factor-1 level decreased from 205 ng/ml to 168 ng/ml during metformin treatment and was found to be statistically significant (p =0.027). CONCLUSION: Due to the effect of metformin treatment on insulin-like growth factor-1 values in patients with acromegaly, it can be used in disease control, as well as diabetes treatment.

Is There A Connection Between Primary Hypophysitis and Celiac Disease?

AIM: To investigate the autoimmune and genetic relationship between primary hypophysitis (PH) and celiac disease (CD). METHODS: The study was retrospective and patients with PH followed in our clinic between 2007 and 2022 were evaluated. Clinical, endocrinologic, pathologic, and radiologic findings and treatment modalities were assessed. Patients diagnosed with CD in the Gastroenterology outpatient clinic in 2020-2022 were included in the study as a control group. Information such as sociodemographic data, year of diagnosis, human leukocyte antigen (HLA) DQ2/8 information, CD-specific antibody levels, pathologic results of duodenal biopsy, treatment received, follow-up status, additional diseases, hormone use, and surgical history was obtained from patient records at PH.In patients diagnosed with PH, a duodenal biopsy was obtained, and the tissue was examined for CD by experienced pathologists. Anti-pituitary antibody (APA) and anti-arginine-vasopressin (AAVP) antibody levels of individuals with PH and CD were measured. RESULTS: The study included 19 patients with lymphocytic hypophysitis, 30 celiac patients, and 30 healthy controls. When patients diagnosed with lymphocytic hypophysitis were examined by duodenal biopsy, no evidence of CD was found in the pathologic findings. The detection rate of HLA-DQ2/8 was 80% in celiac patients and 42% in PH (p=0.044). (APA and AAVP antibodies associated with PH were tested in two separate groups of patients and in the control group. APA and anti-arginine vasopressin (AAVP) levels in PH, CD and healthy controls, respectively M [IQR]: 542 [178-607];164 [125-243]; 82 [74-107] ng/dL (p=0.001), 174 [52-218]; 60 [47-82]; 59 [48-76] ng/dL (p=0.008) were detected. The presence of an HLA-DQ2/8 haplotype correlates with posterior hypophysitis and panhypophysitis (r=0.598, p=0.04 and r=0.657, p=0.02, respectively). CONCLUSION: Although patients with PH were found to have significant levels of HLA-DQ2/8, no CD was found in the tissue. Higher levels of pituitary antibodies were detected in celiac patients compared with healthy controls, but no hypophysitis clinic was observed at follow-up. Although these findings suggest that the two diseases may share a common genetic and autoimmune basis, the development of the disease may be partially explained by exposure to environmental factors.

The Association between Serum 25-Hydroxyvitamin D3 Levels and Pro-Inflammatory Markers in New-Onset Type 2 Diabetes Mellitus and Prediabetes.

In this study, we aimed to reveal the pro-inflammatory effects of serum 25-hydroxyvitamin D3 (Vit D) deficiency and insufficiency in new-onset type 2 diabetes mellitus (T2DM) and prediabetes. We recruited 84 prediabetes patients, 94 new-onset T2DM patients and 113 healthy participants. We measured the levels of C-reactive protein (CRP), fibrinogen, ferritin, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) in the serum of the participants. ANOVA Bonferroni and Kruskal-Wallis Dunn tests were used to compare the inflammation markers and vitamin D levels between the groups. Based on covariance analysis with age, gender and BMI, the Vit D levels of the T2DM group were significantly lower (p < 0.003). Pro-inflammatory markers and CRP were significantly higher in prediabetic and diabetic subjects. In the prediabetes group, IL-1ß, IL-6, IL-8, TNF-α and MAPK were significantly higher in those with Vit D insufficiency and deficiency groups. In the T2DM group, IL-1ß, IL-6, IL-8, TNF-α, NF-κB, MAPK and CRP were significantly higher in those with Vit D insufficiency and deficiency. Our study emphasizes the pro-inflammatory effects of Vit D deficiency and insufficiency in new-onset type 2 diabetes mellitus and prediabetes.

The effect of radioiodine therapy on blood cell count in patients with differentiated thyroid cancer.

PURPOSE: This study aimed to investigate the long-term effects of radioiodine treatment (RAI) on blood cell counts in patients with differentiated thyroid cancer (DTC) and to describe the characteristics of patients at high risk for blood cell count abnormalities. METHODS: The study included patients with DTC who underwent RAI treatment between 2007 and 2017. Patients with regular complete blood counts for at least 5 years were included, while those with diseases or treatments that could influence blood count parameters were excluded. Blood cell count abnormalities were defined according to the Common Terminology Criteria for Adverse Events version 5.0, and factors influencing these abnormalities were examined. RESULTS: A total of 225 patients were analyzed. The mean age at diagnosis was 45.8 ± 13.9 years, and 76.5% of patients were female. In the first year after RAI, leukocyte, neutrophil, and lymphocyte counts were significantly reduced compared with baseline values. The leukocyte and neutrophil counts returned to baseline values by the third year, while the decrease in lymphocytes continued until the fifth year. Blood cell count abnormalities developed in 16 patients (7.1%) within the first year after RAI. Risk factors for blood cell count abnormalities within the first year after RAI included male sex, older age, T4, N1, and M1 disease, as well as higher RAI doses. In logistic regression analysis, only RAI dose remained independently associated with blood cell count abnormalities. CONCLUSION: These results suggest an association between RAI dose and blood cell count abnormalities, characterized by mild lymphopenia, and indicate that the risk of mild lymphopenia persists over time. Careful consideration should be given when planning high-dose RAI for patients at a high risk of blood cell count abnormalities, such as males with metastatic disease and of advanced age.

Risk of impulse control disorders in patients with Cushing's disease: do not blame cabergoline but do not give up caution.

PURPOSE: To asses risk of new-onset impulse control disorders (ICDs) in patients with Cushing's disease (CD) who initiated cabergoline (CBG) and to determine frequency of ICDs in CBG-treated patients with CD. METHODS: This naturalistic observational study had prospective and cross-sectional arms which included patients at five referral centers based in Istanbul. Patients who were scheduled for CBG were assigned to prospective arm. These patients underwent neuropsychological tests (Barratt Impulsiveness Scale, Minnesota Impulsive Disorders Interview, Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale, Go/No-Go Task, Iowa Gambling Task, and Short Penn Continuous Performance Test) for assessment of impulsivity and psychiatric evaluations at baseline, 3, 6, and 12 months of CBG treatment. Impulsivity and new-onset ICDs were prospectively assessed. Patients with CD with current CBG treatment for ≥ 3 months and matched CBG-naïve patients with CD were included in cross-sectional arm. These patients underwent the same neuropsychological and psychiatric assessments. The impulsivity and frequency of ICDs were compared between CBG-treated and CBG-naïve patients with CD. RESULTS: The follow-up duration of prospective cohort (n = 14) was 7.3 ± 2.3 months. One patient developed major depressive episode and another patient developed compulsive gambling after CBG. We observed no significant changes in impulsivity scores during follow-up. In cross-sectional arm, CBG-treated (n = 34) and CBG-naïve patients (n = 34) were similar in impulsivity scores and frequency of ICDs [3 patients (8.8%) vs. 2 patients (5.9%) respectively, p = 1.0]. CONCLUSION: CBG-treated patients with CD appeared to have a low risk of ICDs, suggesting that CBG still holds promise as a safe agent in CD.

The Combination of Dopamine Agonist Treatment and Surgery May Be the Best Option in Challenging Prolactinoma Cases: A Single-Centre Experience.

OBJECTIVE: To investigate the initial and long-term remission rates, factors related to remission, secondary treatments, and outcomes for patients with prolactinoma who underwent endoscopic transsphenoidal surgery (ETSS). METHODS: The medical files of the 45 prolactinoma patients who underwent ETSS between 2015 and 2022 were retrospectively reviewed. Relevant demographic and clinical data were obtained. RESULTS: Twenty-one (46.7%) patients were female. The median age of patients at ETSS was 35 (interquartile range, 22.5-50) years. The median clinical follow-up of patients was 28 (interquartile range 12-44) months. The initial surgical remission rate was 60%. Recurrence was detected in 7 patients (25.9%). Postoperative dopamine agonists were used in 25 patients, radiosurgery in 2, and second ETSS in 4 patients. After these secondary treatments, the long-term biochemical remission rate was 91.1%. The factors associated with failure in surgical remission are: male gender, older age, higher tumor size, advanced Knosp and Hardy stage, and elevated prolactin level at diagnosis. A prolactin level of <19 ng/mL in the first postoperative week predicted surgical remission with a sensitivity of 77.8% and a specificity of 70.6% in patients who received preoperative dopamine agonist treatment. CONCLUSIONS: In macro adenomas and/or giant adenomas with cavernous sinus invasion, and significant suprasellar extension, which constitutes the difficult part of prolactinoma treatment, neither surgery nor medical treatment alone may be effective enough. Both treatment modalities should be carried out together by a team of neurosurgery and endocrinology in the management of these patients.

Altered thalamic volume in patients with mild autonomous cortisol secretion: a structural brain MRI study.

PURPOSE: To compare thalamic volume and cognitive functions of patients with mild autonomous cortisol secretion (MACS) with control subjects and patients with overt Cushing's syndrome (CS). METHODS: In this cross-sectional study, volumes of regions of interest were assessed using 3 T magnetic resonance imaging and a voxel-based morphometry approach in 23 patients with MACS, 21 patients with active CS, 27 patients with CS in remission, and 21 control subjects. Cognitive functions were assessed using validated questionnaires. RESULTS: Patients with MACS had smaller left thalamic (F = 3.8, p = 0.023), left posterior thalamic (F = 4.9, p = 0.01), left medial thalamic (F = 4.7, p = 0.028), and right lateral thalamic (F = 4.1, p = 0.025) volumes than control subjects. Patients with active CS also had smaller left thalamic (F = 3.8, p = 0.044), left posterior thalamic (F = 4.9, p = 0.007), left medial thalamic (F = 4.7, p = 0.006), and right lateral thalamic (F = 4.1, p = 0.042) volumes compared to controls. Patients with CS in remission had smaller left medial (F = 4.7, p = 0.030) and right lateral thalamic (F = 4.1, p = 0.028) volumes than controls. Neuropsychological tests showed no difference between the groups. CONCLUSION: MACS may decrease thalamic volume.

Do not forget the kidney in graves' disease.

PURPOSE: To investigate the prevalence of microalbuminuria and factors associated with microalbuminuria in Graves' Disease (GD). METHODS: This cross-sectional and single-center study included 99 patients with GD and 47 healthy controls (HC). Exclusion criteria such as active infection, uncontrolled diabetes, and chronic kidney disease were applied to the participants. The participants' clinical findings, comorbidities, drug use, laboratory tests, and thyroid antibody levels were recorded. Spot urine samples were collected and stored at - 80 â„ƒ to analyze the presence of microalbuminuria. RESULTS: The prevalence of microalbuminuria in patients with GD was 12.1%. The median microalbumin/creatinine ratio in spot urine (UACR) in patients with GD (9.49 mg/g [5.09-18.10]) was higher than in the HC group (7.99 mg/g [3.48-12.88], p = 0.033). UACR was correlated with thyroid-stimulating hormone receptor antibody (TRAb), thyroid-stimulating hormone (TSH), and free triiodothyronine (FT3) levels (p = 0.020, p = 0.006, p = 0.009 respectively). In the regression analysis, only the relationship between TRAb level and UACR remained (p = 0.040). CONCLUSION: This study demonstrates an increased prevalence of microalbuminuria in patients with GD. There was a significant correlation between microalbuminuria and TRAb level in patients with GD. This relationship suggests that one of the underlying mechanisms of microalbuminuria seen in patients with GD may be autoimmunity.

Does the Association of Hashimoto's Thyroiditis with Differentiated Thyroid Cancer Really Have a Protective Role?

The study is an investigation of aggressive tumor features, prognosis, and disease-specific mortality rates of differentiated thyroid cancer (DTC) in the presence of concomitant Hashimoto's Thyroiditis (HT). The data of patients with DTC followed in our tertiary care center between 2000-2022 were analyzed. Variables such as patient age, gender, preoperative serum autoantibody levels, tumor characteristics, and treatment modalities were obtained from medical records. The diagnosis of HT was based either on the presence of a positive result in the pathological examination and/or on antibody positivity. A total of 637 patients [mean±SD age, 44.9±13.5 years; 485 women [76.1%)] were included in the analysis. The overall prevalence of coexistent HT was 22.9% (n=146). The disease-specific mortality associated with DTC was 2.9%. DTC patients with HT compared to those without; have more positive lymphovascular invasion (p<0.001), and lymph node metastases (p<0.001). According to the Kaplan-Meier curves, disease-specific survival rates among DTC patients without HT were significantly higher than patients with HT (log-rank p=0.002). The disease-specific mortality rate was 4.79% in DTC patients with HT, it was 1.43% in those without HT. Hashimoto thyroiditis was not associated with a 10-year recurrence-free survival (p=0.059). Differentiated thyroid cancers with concomitant HT are associated with some aggressive tumor features (such as lymphovascular invasion and nodal metastasis) and lower survival. In staging systems based on tumor risk factors, it may be useful to evaluate the presence of concomitant HT as a prognostic factor.

Visceral Adiposity Index as an Indicator of Cardiometabolic Risk in Patients with Congenital Adrenal Hyperplasia.

Aim: To evaluate the cardiometabolic risk in patients with CAH (21 (OH) enzyme deficiency) on the basis of the visceral adiposity index (VAI), which indicates dysfunction of the visceral adipose tissue (VAT). Materials and Methods: A total of 41 patients and 38 body mass index (BMI), age, and gender-matched healthy controls (HC) were included. The patients' and HCs' age, gender, waist circumference (WC), BMI information and total cholesterol (TC), high-density lipoprotein (HDL), triglyceride (TG) values, smoking, and medication history were obtained from medical charts. Weight, height, WC, and blood pressure levels were measured. Patients' and HCs' BMI, Framingham risk scores (FRS), VAI and Ferriman-Gallwey scores were calculated. The patients' and HCs' age, gender TC, HDL, and TG, androstenedione, dehydroepiandrosterone sulfate (DHEASO4), 17 hydroxyprogesterone (17(OH)P) values, smoking, and medication history were obtained from medical charts. Body fat and muscle mass levels were measured with Tanita T 6360. Results: Gender distribution, mean age, and BMI of patients with CAH were 34/7, 30 ± 8, 27 ± 5.4; HC subjects 30/8, 30 ± 6, 27 ± 3.8 (P = 0.9, 0.6, 0.9, respectively). The VAI values of patients with a diagnosis of CAH 3.7 (2.3-6.9) were found to be significantly higher than those of HC patients 2.5 (1.8-3.9; P = 0.02). The mean glucocorticoid doses of the patients were 17 ± 9 mg/day. The glucocorticoid dose level was determined as independent risk factor on the FRS (P = 0.03, ß = 0.04) and VAI (P = 0.018, ß = 0.17). Conclusion: Glucocorticoid dose optimization should be done more carefully to improve metabolic and cardiovascular outcomes in CAH patients.

A Genetic Assessment of Dopamine Agonist-Induced Impulse Control Disorder in Patients With Prolactinoma.

CONTEXT: Dopamine agonist (DA)-induced impulse control disorder (ICD) represents a group of behavioral disorders that are increasingly recognized in patients with prolactinoma. OBJECTIVE: We aimed to examine the genetic component of the underlying mechanism of DA-induced ICD. METHODS: Patients with prolactinoma receiving dopamine agonist (cabergoline) treatment were included in the study. These patients were divided into 2 groups: patients who developed ICD due to DA and patients who did not. Patients were evaluated for polymorphisms of the DRD1, DRD3, COMT, DDC, GRIN2B, TPH2, OPRK1, OPRM1, SLC6A4, SLC6A3, HTR2A genes. RESULTS: Of the 72 patients with prolactinoma using cabergoline, 20 were diagnosed with ICD. When patients with and without ICD were compared according to genotype frequencies, OPRK1/rs702764, DRD3/rs6280, HTR2A/rs6313, SLC6A4/rs7224199, GRIN2B/rs7301328, TPH2/rs7305115, COMT/rs4680, DRD1/rs4532 polymorphisms significantly increased in patients with DA-induced ICD. CONCLUSION: Our results show that multiple neurotransmission systems affect DA-induced ICD in patients with prolactinoma.

Problem-solving therapy can reduce psychological distress in patients with Cushing's disease: a randomized controlled trial.

OBJECTIVE: To evaluate the effects of online group problem-solving therapy (PST) for reducing negative problem orientation (NPO), psychological distress, and increasing quality of life in patients with Cushing's disease (CD). METHODS: In this randomized trial, we allocated 55 eligible patients to either PST (n = 28) or treatment as usual (TAU) (n = 27) groups. The analyses primarily relied on intent-to-treat (ITT) principle and were repeated with intervention completers (per-protocol analyses). Social problem-solving inventory-revised short form, Beck Depression Inventory (BDI), General Health Questionnaire-12 (GHQ-12), Perceived Stress Scale (PSS), The Satisfaction with Life Scale, and Cushing's Quality of Life scale were used. Pre-test, post-test, and follow-up measures were obtained. Linear mixed models were used to compare PST and treatment as usual (TAU) groups across time. RESULTS: Of the total 55 patients with CD, the mean age was 46 ± 12 years, 49 patients (89%) were female, and 41 patients (74.5%) were in remission. The patients within the PST and TAU groups were similar in terms of age, sex, and disease activity. ITT analyses showed a greater reduction of NPO scores in patients who received PST as compared to patients who received usual care (df = 45.9, p = 0.029, Cohen's d = 0.47). The decrease in NPO was sustained at follow-up (mean difference: - 2.2, p = 0.007). Results of the ITT analyses revealed no superior benefits of the intervention for psychological distress. However, per-protocol analyses demonstrated that PST provided a greater decrease in BDI, PSS, and GHQ-12 scores. CONCLUSION: PST may decrease NPO and improve the psychological well-being of patients with CD.

Pasireotide treatment in Cushing's disease: A single tertiary center's experience.

BACKGROUND: Patients who were followed up for CD and treated with pasireotide between 2014-2020 at Cerrahpasa Medical Faculty, were evaluated retrospectively. The efficacy and adverse effects of pasireotide were evaluated in this study. METHODS: Thirty-two patients were evaluated. The mean duration of treatment was 26.5 [range, 12.0-37.0] months. The 24-h urinary free cortisol (UFC) decreased 46% during the treatment and normalized in 37.5% of patients. A significant decrement was found between pretreatment and last follow-up UFC (p = 0.001). Plasma ACTH decreased by 21%. A significant decrement was found between pre-treatment and the 3rd month, 6th month, and last follow-up ACTH levels (p = 0.014, p = 0.017, and p = 0.017, respectively). Serum cortisol levels decreased by 18% and a significant decrement was found between pretreatment and the 3rd month, and between pretreatment and the last follow-up (p = 0.034 and p = 0.013, respectively). While fasting blood glucose at the 3rd month was significantly higher than pretreatment fasting blood glucose, no significant difference was found between pretreatment fasting blood glucose and 6th month and last follow-up fasting blood glucose. Although there was a significant difference between pretreatment HbA1c levels and the HbA1c levels at the 3rd month (5.9% vs. 6.6% p = 0.007), 6th month (5.9% vs. 6.7% p = 0.003), and the last follow-up (5.9% vs. 7.1% p = 0.001), in the last follow-up, the majority (77%) of patients had adequate glycemic control (HbA1c ≤ 7.0 %). The authors declare that there is no conflict of interest. DISCUSSION: Pasireotide treatment is an alternative treatment in CD, remission is obtained in the first months of treatment, and continues for an extended period. Although hyperglycemia is the most common adverse effect, it can be successfully controlled.

Effect of metformin on thyroid cancer risk in patients with acromegaly: A preliminary observational study.

PURPOSE: To evaluate the role of metformin on thyroid cancer risk in patients with acromegaly. METHODS: Medical charts of 534 patients with acromegaly that were followed-up between 1983 and 2019 were reviewed. Patients with follow-up duration at least 6 months were included. Cohort entry was defined as first visit date. The date of each case's thyroid cancer diagnosis was defined as index date. Patients were followed until the index date, death, or last visit date, whichever came first. Nested case-control study design was selected to evaluate the association between metformin and the thyroid cancer risk in patients with acromegaly. RESULTS: 291 patients with acromegaly were included into final analysis. The mean age at acromegaly diagnosis was 42.3 ± 1.3 years. The median follow-up duration was 76 [34-132] months. Among 291 patients, 13 patients (4.5%) had thyroid cancer. Thirty-one percent (n = 92) of the patients used metformin for 6 months or longer. One standard deviation (SD) increase in average growth hormone increased the odds of having thyroid cancer by 1.164 folds (p = 0.017). One SD increase of the average insulin-like growth factor 1 to upper limit of normal ratio increased the odds of having thyroid cancer by 1.201 folds (p = 0.004). If a patient used metformin for at least 6 months, the odds to have thyroid cancer was decreased, multiplied by 0.62 with a 95% confidence interval of [0.47, 0.83] (p = 0.0013). The risk of thyroid cancer decreased with increasing duration of metformin use. CONCLUSION: Metformin may decrease the thyroid cancer risk in patients with acromegaly.

Machine learning as a clinical decision support tool for patients with acromegaly.

OBJECTIVE: To develop machine learning (ML) models that predict postoperative remission, remission at last visit, and resistance to somatostatin receptor ligands (SRL) in patients with acromegaly and to determine the clinical features associated with the prognosis. METHODS: We studied outcomes using the area under the receiver operating characteristics (AUROC) values, which were reported as the performance metric. To determine the importance of each feature and easy interpretation, Shapley Additive explanations (SHAP) values, which help explain the outputs of ML models, are used. RESULTS: One-hundred fifty-two patients with acromegaly were included in the final analysis. The mean AUROC values resulting from 100 independent replications were 0.728 for postoperative 3 months remission status classification, 0.879 for remission at last visit classification, and 0.753 for SRL resistance status classification. Extreme gradient boosting model demonstrated that preoperative growth hormone (GH) level, age at operation, and preoperative tumor size were the most important predictors for early remission; resistance to SRL and preoperative tumor size represented the most important predictors of remission at last visit, and postoperative 3-month insulin-like growth factor 1 (IGF1) and GH levels (random and nadir) together with the sparsely granulated somatotroph adenoma subtype served as the most important predictors of SRL resistance. CONCLUSIONS: ML models may serve as valuable tools in the prediction of remission and SRL resistance.

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.

Assessment of Neuroendocrine Changes and Hypothalamo-Pituitary Autoimmunity in Patients with COVID-19.

SARS-CoV-2 may affect the hypothalamic-pituitary axis and pituitary dysfunction may occur. Therefore, we investigated neuroendocrine changes, in particular, secondary adrenal insufficiency, using a dynamic test and the role of autoimmunity in pituitary dysfunction in patients with COVID-19. The single-center, prospective, case-control study included patients with polymerase chain reaction (PCR)-confirmed COVID-19 and healthy controls. Basal hormone levels were measured, and the adrenocorticotropic hormone (ACTH) stimulation test was performed. Antipituitary (APA) and antihypothalamic antibodies (AHA) were also determined. We examined a total of 49 patients with COVID-19 and 28 healthy controls. The frequency of adrenal insufficiency in patients with COVID-19 was found as 8.2%. Patients with COVID-19 had lower free T3, IGF-1, and total testosterone levels, and higher cortisol and prolactin levels when compared with controls. We also demonstrated the presence of APA in three and AHA in one of four patients with adrenal insufficiency. In conclusion, COVID-19 may result in adrenal insufficiency, thus routine screening of adrenal functions in these patients is needed. Endocrine disturbances in COVID-19 are similar to those seen in acute stressful conditions or infections. Pituitary or hypothalamic autoimmunity may play a role in neuroendocrine abnormalities in COVID-19.

Discrimination between non-functioning pituitary adenomas and hypophysitis using machine learning methods based on magnetic resonance imaging­derived texture features.

PURPOSE: Hypophysitis is a heterogeneous condition that includes inflammation of the pituitary gland and infundibulum, and it can cause symptoms related to mass effects and hormonal deficiencies. We aimed to evaluate the potential role of machine learning methods in differentiating hypophysitis from non-functioning pituitary adenomas. METHODS: The radiomic parameters obtained from T1A-C images were used. Among the radiomic parameters, parameters capable of distinguishing between hypophysitis and non-functioning pituitary adenomas were selected. In order to avoid the effects of confounding factors and to improve the performance of the classifiers, parameters with high correlation with each other were eliminated. Machine learning algorithms were performed with the combination of gray-level run-length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray-level co-occurrence entropy. RESULTS: A total of 34 patients were included, 17 of whom had hypophysitis and 17 had non-functioning pituitary adenomas. Among the 38 radiomics parameters obtained from post-contrast T1-weighted images, 10 tissue features that could differentiate the lesions were selected. Machine learning algorithms were performed using three selected parameters; gray level run length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray level co-occurrence entropy. Error matrices were calculated by using the machine learning algorithm and it was seen that support vector machines showed the best performance in distinguishing the two lesion types. CONCLUSIONS: Our analysis reported that support vector machines showed the best performance in distinguishing hypophysitis from non-functioning pituitary adenomas, emphasizing the importance of machine learning in differentiating the two lesions.

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.