Assessment of the spectrum of depression and bipolarity in patients with type 1 diabetes.

AIMS: The aim of the study was to check the prevalence of unipolarity (depression), bipolarity, as well as the quality of sleep and temperament traits in patients with type 1 diabetes (T1DM) who are provided with optimal conditions of diabetes care and to identify possible risk factors connected with affective traits. MATERIALS AND METHODS: Out of the 107 T1DM patients, 78 (54 females, 24 males) were included for the analysis (HbA1c [%] 7.11 ± 1.0, BMI [kg/m2 ] 25.3 ± 5.6; Years of disease duration [N] 13.7 ± 8.3). The patients filled in a set of questionnaires during their regular visit to the outpatient clinic. Three patients from the whole group were on intensive insulin therapy with Multiple Daily Injections (MDI) and Self-Monitoring of Blood Glucose (SMBG), all the rest were on various types of personal insulin pumps (years on insulin pump [N] 9.1 ± 4.5). All the patients were on regular diabetologist care, with regular visits in a Centre for Advanced Technologies in Diabetes (at least every 6 months). RESULTS: In QIDS-S (full explanation and abbreviation 26 patients (33.8%) were screened positive for depression, in PHQ (full explanation and ab 57.7% of the patients (45 patients) had symptoms of depression (age was negatively correlated with PHQ score [r = -0.26; p = 0.023]). In CES-D 16 (20%) of the patients assessed their present affect as depressed. None of the analysed clinical variables correlated with depression scores. In the Mood Disorder Questionnaire (MDQ), 16 patients reported having symptoms of bipolarity (20.5% vs. 79.5%). Hypomania Checklist (HCL) analysis indicated 10 patients with bipolar traits (>14) (14.9% vs. 85.1%). None of the analysed clinical variables correlated with HCL results. 11.5% of patients were indicated to be of morning type. Morningness was more often seen in younger patients (r = 0.39; p = 0.001). As many as 46.6% declared that they had poor sleep quality. The temperament traits analysis correlated with clinical parameters: Cyclothymic temperament trait was negatively correlated with age (r = -0.30; p = 0.007) and positively with HbA1c level (r = 0.30; p = 0.025). Hyperthymic temperament was positively correlated with (BMI r = 0.28; p = 0.016). Quality of sleep was highly correlated with depressive symptoms CESD (r = 0.61, p = 0.001), PHQ Score (r = 0.62; p = 0.001), QISD (r = 0.68; p = 0.001) and bipolarity MDQ (p = 0.50, p = 0.001) and HCL (r = 0.42, p = 0.001). In addition, QIDS was shown to be correlated with the following features of temperament: depressive factor (r = 0.41; p = 0.001), irritable factor (r = 0.53; p = 0.001), cyclothymic factor (r = 0.59; p = 0.001), anxious factor (r = 0.58, p = 0.001). CONCLUSIONS: The prevalence of affective disorders and poor sleep quality in the examined T1DM patients was much higher than in the general population. Even if the patients have in general good glycaemic control, their mental health condition should not be neglected. Well organised cooperation between patients, diabetologists, psychiatrists and psychotherapists is needed (Clinical Trials Identifier: NCT04616391).

Pasireotide-a novel somatostatin receptor ligand after 20 years of use.

Pasireotide, a novel multireceptor-targeted somatostatin receptor ligand (SRL) is characterized by a higher affinity to somatostatin receptor type 5 than type 2, unlike first-generation SRLs. Because of the broader binding profile, pasireotide has been suggested to have a greater clinical efficacy in acromegaly than first-generation SRLs and to be efficacious in Cushing's disease. The consequence of this binding profile is the increased blood glucose level in some patients. This results from the inhibition of both insulin secretion and the incretin effect and only a modest suppression of glucagon. A monthly intramuscular formulation of long-acting release pasireotide has been approved for both acromegaly and Cushing's disease treatment. This review presents data on the efficacy and safety of pasireotide treatment mostly in patients with acromegaly and Cushing's disease. Moreover, other possible therapeutic applications of pasireotide are mentioned.

Managing pasireotide-associated hyperglycemia: a randomized, open-label, Phase IV study.

PURPOSE: Pasireotide is an effective treatment for acromegaly and Cushing's disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs. METHODS: Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤ 16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n = 190) or Cushing's disease (n = 59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥ 126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms. RESULTS: Eighty-one (32.5%) patients were randomized to incretin-based therapy (n = 38 received sitagliptin, n = 28 subsequently switched to liraglutide; n = 12 received insulin as rescue therapy) or insulin (n = 43). Adjusted mean change in HbA1c between treatment arms was - 0.28% (95% CI - 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n = 43)/other OAD (n = 3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized. CONCLUSION: Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed. ClinicalTrials.gov ID: NCT02060383.

Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushing's syndrome.

PURPOSE: The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushing's syndrome (CS) and baseline mean urinary free cortisol (mUFC) ≥ 1.5× ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript. METHODS: Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]). RESULTS: Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; ∆ - 1.9; P < 0.0001), end of Month 1 for acne (mean baseline score, 2.8; ∆ - 1.2; P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; ∆ - 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; ∆ + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; ∆ - 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms. CONCLUSIONS: Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551.

Changes in the clinical characteristics of women with gestational diabetes mellitus - a retrospective decade-long single center analysis.

AIMS: Gestational diabetes mellitus (GDM) is an emerging worldwide problem. Changes in clinical characteristics of women affected by GDM in a long-term perspective are still not properly investigated. We aimed to examine such changes over a decade in a retrospective single-center analysis. METHODS: The medical documentation from Department of Metabolic Diseases, Krakow, Poland was analyzed. We included 633 women consecutively diagnosed with GDM in one of three time intervals: 2007-2008 (N = 157), 2012-2013 (N = 272), 2016-2017 (N = 234). Statistical analyses were performed. RESULTS: Comparison of the three groups identified differences in the mean age of women at the GDM diagnosis (30.7 ± 5.0 years vs. 31.2 ± 4.7 vs. 32.5 ± 4.7, respectively, starting from the earliest 2007-2008 group), pregnancy week at GDM diagnosis (28.0 ± 5.3 wks. vs. 25.9 ± 4.9 vs. 23.4 ± 6.8), the proportion of women diagnosed before the 24th week of pregnancy (12.8% vs. 16.5% vs. 31.3%), and gestational weight gain (12.4 ± 5.0 kg vs. 10.4 ± 5.2 vs. 10.0 ± 5.7); (p = 0.001 or less for all comparisons). We also found differences for glucose values on fasting and at 2 hours with the highest (0 min) and lowest level (120 min) in the 2016-2017, respectively. Finally, a borderline difference for the weight, but not for BMI, was found (64.1 ± 14.1 kg vs. 66.2 ± 13.1 vs. 67.8 ± 15.6; p = 0.04). Differences were also identified in the post hoc analysis between cohorts. CONCLUSION: This retrospective analysis illustrates changes in characteristics of women with GDM occurring over the period of decade in Poland. They likely result from both epidemiological trends and modifications of the WHO criteria for the GDM diagnosis.

Ectopic Cushing's syndrome in light of modern diagnostic techniques and treatment options.

Ectopic adrenocorticotropic hormone secretion (EAS) is responsible for approximately 10-15% cases of Cushing's syndrome. EAS is associated with various tumors such as small cell lung cancer and well-differentiated bronchial or gastrointestinal neuroendocrine tumors. Hormonal diagnostics include assessments in basic conditions as well as dynamic tests, such as the high-dose dexamethasone suppression test and corticotrophin releasing hormone (CRH) stimulation test. Treatment selection depends on the type of tumor and its extent. In the case of neuroendocrine tumors, the main treatments are surgery and administration of somatostatin analogs that may be additionally radiolabeled for targeted radiotherapy. The tumor histology and the presence and control of hypercortisolemia and metastases are of major importance in prognosis. In this article we presented the principles of modern hormonal and imaging diagnostics techniques as well as the key issues associated with treatment of ACTH-dependent Cushing's syndrome due to EAS.

Case report: A challenging case of severe Cushing's syndrome in the course of metastatic thymic neuroendocrine carcinoma with a synchronous adrenal tumor.

Ectopic ACTH syndrome (EAS) remains one of the most demanding diagnostic and therapeutic challenges for endocrinologists. Thymic neuroendocrine tumors account for 5%-10% of all EAS cases. We report a unique case of a 31-year-old woman with severe EAS caused by primary metastatic combined large-cell neuroendocrine carcinoma and atypical carcinoid of the thymus. The patient presented with severe hypercortisolemia, which was successfully controlled with continuous etomidate infusion. Complex imaging initially failed to detect thymic lesion; however, it revealed a large, inhomogeneous, metabolically active left adrenal mass infiltrating the diaphragm, suspected of primary disease origin. The patient underwent unilateral adrenalectomy, which resulted in hypercortisolemia resolve. The pathology report showed an adenoma with adrenal infarction and necrosis. The thymic tumor was eventually revealed a few weeks later on follow-up imaging studies. Due to local invasion and rapid progression, only partial resection of the thymic tumor was possible, and the patient was started on radio- and chemotherapy.

Response to Osilodrostat Therapy in Adrenal Cushing's Syndrome.

Cushing's disease (CD) is the most common cause of endogenous hypercortisolism. Osilodrostat was demonstrated to be efficient in treating CD, and the mean average dose required for CD control was <11 mg/day. Potential differences in osilodrostat treatment between cortisol-producing adenoma (CPA) and CD have not been reported. The aim of this study was to present two patients with CPA in whom significant differences in the response to therapy compared to CD were found. We demonstrated a case of inverse response of cortisol levels with adrenal tumor progression during the initial dose escalation (Case 1). Simultaneously, severe exaggeration of hypercortisolism symptoms and life-threatening hypokalemia occurred. A further rapid dose increase resulted in the first noticeable cortisol response at a dose of 20 mg/day, and a full response at a dose of 45 mg/day. We also present a case that was initially resistant to therapy (Case 2). The doses required to achieve the first response and the full response were the same as those for Case 1. Our study demonstrated that osilodrostat therapy in patients with CPA may require a different approach than that in CD, with higher doses, faster dose escalation, and a possible initial inverse response or lack of response.

Prolactin-secreting pituitary adenomas: male-specific differences in pathogenesis, clinical presentation and treatment.

Prolactinomas (PRLomas) constitute approximately half of all pituitary adenomas and approximately one-fifth of them are diagnosed in males. The clinical presentation of PRLomas results from direct prolactin (PRL) action, duration and severity of hyperprolactinemia, and tumor mass effect. Male PRLomas, compared to females, tend to be larger and more invasive, are associated with higher PRL concentration at diagnosis, present higher proliferative potential, are more frequently resistant to standard pharmacotherapy, and thus may require multimodal approach, including surgical resection, radiotherapy, and alternative medical agents. Therefore, the management of PRLomas in men is challenging in many cases. Additionally, hyperprolactinemia is associated with a significant negative impact on men's health, including sexual function and fertility potential, bone health, cardiovascular and metabolic complications, leading to decreased quality of life. In this review, we highlight the differences in pathogenesis, clinical presentation and treatment of PRLomas concerning the male sex.

Pituitary apoplexy as the first manifestation of non­functioning pituitary neuroendocrine tumour.

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Ectopic ACTH syndrome in the course of ACTH-secreting pancreatic neuroendocrine tumour in a patient with a pituitary lesion - diagnostic challenges and individual approach.

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The Heart's Function as a Pump Assessed via Impedance Cardiography and the Autonomic System Balance in Patients with Early-Stage Acromegaly.

BACKGROUND: Acromegaly is a rare, chronic disease that involves structural and functional abnormalities of the cardiovascular system. Acromegaly likely affects interactions between the cardiovascular system and the autonomic nervous system (ANS). Therefore, assessing the relationship between sympathetic-parasympathetic balance by analyzing heart rate variability (HRV) and the hemodynamic profile via impedance cardiography (ICG) may be useful in learning the exact nature of interactions between the ANS and the cardiovascular system. The purpose of this study was to assess a possible association between HRV and ICG-based parameters of cardiac function in patients newly diagnosed with acromegaly. METHODS: This observational cohort study was conducted on 33 patients (18 men, mean age of 47 years) newly diagnosed with acromegaly and no significant comorbidities. A correlation analysis (Spearman's rank coefficient R) of the parameters assessed via ICG and the HRV assessed via 24 h ambulatory electrocardiography was performed. ICG assessments included the following parameters: stroke volume index (SI), cardiac index (CI), acceleration index (ACI), velocity index (VI), and Heather index (HI). The analysis of HRV included both time-domain parameters (pNN50, SDNN, SDSD, rMSSD) and frequency-domain parameters (total power (TP) and its individual frequency bands: low-frequency (LF day/night), high-frequency (HF day/night), and the LF/HF ratio (day/night)). RESULTS: Frequency-domain HRV analysis showed the following correlations: (1) lower nighttime LF values with higher ACI (R = -0.38; p = 0.027) and HI (R = -0.46; p = 0.007) values; (2) higher nighttime HF values with higher ACI (R = 0.39; p = 0.027) and HI (R = 0.43; p = 0.014) values; (3) lower nighttime LF/HF values with higher ACI (R = -0.36; p = 0.037) and HI (R = -0.42; p = 0.014) values; (4) higher nighttime TP values with higher SI values (R = 0.35; p = 0.049). Time-domain parameters of HRV showed a significant correlation only between the nighttime values of SDSD and SI (R = 0.35; p = 0.049) and between the daytime and nighttime values of SDNN and HR (R = -0.50; p = 0.003 and R = -0.35; p = 0.046). In multivariate regression, only ACI was revealed to be independently related to HRV. CONCLUSIONS: In patients newly diagnosed with acromegaly, the relationship between the sympathetic-parasympathetic balance assessed via HRV and the hemodynamic profile assessed via ICG was revealed. Better function of the left ventricle was associated with a parasympathetic shift in the autonomic balance.

Predictive factors and the management of hyperglycemia in patients with acromegaly and Cushing's disease receiving pasireotide treatment: post hoc analyses from the SOM230B2219 study.

Introduction: Pasireotide, a somatostatin receptor ligand, is approved for treating acromegaly and Cushing's disease (CD). Hyperglycemia during treatment can occur because of the drug's mechanism of action, although treatment discontinuation is rarely required. The prospective, randomized, Phase IV SOM230B2219 (NCT02060383) trial was designed to assess optimal management of pasireotide-associated hyperglycemia. Here, we investigated predictive factors for requiring antihyperglycemic medication during pasireotide treatment. Methods: Participants with acromegaly or CD initiated long-acting pasireotide 40 mg/28 days intramuscularly (acromegaly) or pasireotide 600 µg subcutaneously twice daily during pre-randomization (≤16 weeks). Those who did not need antihyperglycemic medication, were managed with metformin, or received insulin from baseline entered an observational arm ending at 16 weeks. Those who required additional/alternative antihyperglycemic medication to metformin were randomized to incretin-based therapy or insulin for an additional 16 weeks. Logistic-regression analyses evaluated quantitative and qualitative factors for requiring antihyperglycemic medication during pre-randomization. Results: Of 190 participants with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication; most were aged <40 years (acromegaly 62.5%, CD 86.7%), with baseline glycated hemoglobin (HbA1c) <6.5% (<48 mmol/mol; acromegaly 98.9%, CD 100%) and fasting plasma glucose (FPG) <100 mg/dL (<5.6 mmol/L; acromegaly 76.1%, CD 100%). By logistic regression, increasing baseline HbA1c (odds ratio [OR] 3.6; P=0.0162) and FPG (OR 1.0; P=0.0472) and history of diabetes/pre-diabetes (OR 3.0; P=0.0221) predicted receipt of antihyperglycemic medication in acromegaly participants; increasing baseline HbA1c (OR 12.6; P=0.0276) was also predictive in CD participants. Investigator-reported hyperglycemia-related adverse events were recorded in 47.9% and 54.2% of acromegaly and CD participants, respectively, mainly those with diabetes/pre-diabetes. Conclusion: Increasing age, HbA1c, and FPG and pre-diabetes/diabetes were associated with increased likelihood of requiring antihyperglycemic medication during pasireotide treatment. These risk factors may be used to identify those who need more vigilant monitoring to optimize outcomes during pasireotide treatment.

Obesity-Related Hemodynamic Alterations in Patients with Cushing's Disease.

Background: Cushing's disease (CD) is associated with a specific form of metabolic syndrome that includes visceral obesity, which may affect cardiovascular hemodynamics by stimulating hypercortisolism-related metabolic activity. The purpose of this study was to evaluate the relationship between obesity and the hemodynamic profile of patients with CD. Methods: This prospective clinical study involved a hemodynamic status assessment of 54 patients newly diagnosed with CD with no significant comorbidities (mean age of 41 years). The assessments included impedance cardiography (ICG) to assess such parameters as stroke index (SI), cardiac index (CI), velocity index (VI), acceleration index (ACI), Heather index (HI), systemic vascular resistance index (SVRI), and total arterial compliance index (TACI) as well as applanation tonometry to assess such parameters as central pulse pressure (CPP) and augmentation index (AI). These assessments were complemented by echocardiography to assess cardiac structure and function. Results: Compared with CD patients without obesity, individuals with CD and obesity (defined as a body mass index ≥ 30 kg/m2) exhibited significantly lower values of ICG parameters characterizing the pumping function of the heart (VI: 37.0 ± 9.5 vs. 47.2 ± 14.3 × 1*1000-1*s-1, p = 0.006; ACI: 58.7 ± 23.5 vs. 76.0 ± 23.5 × 1/100/s2, p = 0.005; HI: 11.1 ± 3.5 vs. 14.6 ± 5.5 × Ohm/s2, p = 0.01), whereas echocardiography in obese patients showed larger heart chamber sizes and a higher left ventricular mass index. No significant intergroup differences in blood pressure, heart rate, LVEF, GLS, TACI, CPP, or AI were noted. Conclusions: Hemodynamic changes associated with obesity already occur at an early stage of CD and manifest via significantly lower values of the ICG parameters illustrating the heart's function as a pump, despite the normal function of the left ventricle in echocardiography.

Relevance of mutations in protein deubiquitinases genes and TP53 in corticotroph pituitary tumors.

Introduction: Corticotroph pituitary neuroendocrine tumors (PitNETs) develop from ACTH-producing cells. They commonly cause Cushing's disease (CD), however, some remain clinically silent. Recurrent USP8, USP48, BRAF and TP53 mutations occur in corticotroph PitNETs. The aim of our study was to determine frequency and relevance of these mutations in a possibly large series of corticotroph PitNETs. Methods: Study included 147 patients (100 CD and 47 silent tumors) that were screened for hot-spot mutations in USP8, USP48 and BRAF with Sanger sequencing, while 128 of these patients were screened for TP53 mutations with next generation sequencing and immunohistochemistry. Results: USP8 mutations were found in 41% CD and 8,5% silent tumors, while USP48 mutations were found in 6% CD patients only. Both were more prevalent in women. They were related to higher rate of biochemical remission, non-invasive tumor growth, its smaller size and densely granulated histology, suggesting that these mutation may be favorable clinical features. Multivariate survival analyses did not confirm possible prognostic value of mutation in protein deubiquitinases. No BRAF mutations were found. Four TP53 mutations were identified (2 in CD, 2 in silent tumors) in tumors with size >10mm including 3 invasive ones. They were found in Crooke's cell and sparsely granulated tumors. Tumors with missense TP53 mutations had higher TP53 immunoreactivity score than wild-type tumors. Tumor with frameshift TP53 variant had low protein expression. TP53 mutation was a poor prognostic factor in CD according to uni- and multivariate survival analyses in spite of low mutations frequency. Conclusions: We confirmed high prevalence of USP8 mutations and low incidence of USP48 and TP53 mutations. Changes in protein deubiquitinases genes appear to be favorable prognostic factors in CD. TP53 mutations are rare, occur in both functioning and silent tumors and are related to poor clinical outcome in CD.

Assessment of real-world usage of lanreotide AUTOGEL 120 in Polish acromegalic patients - results from the prospective 12-month phase of Lanro-Study.

AIM OF THE STUDY: To assess resource utilization and costs of treatment with lanreotide AUTOGEL 120 mg (ATG120) administered as part of routine acromegaly care in Poland. MATERIAL AND METHODS: A multicentre, non-interventional, observational study on resource utilization in Polish acromegalic patients treated with ATG120 at 4 weeks or extended (> 4 weeks) dosing interval. The study recruited adult acromegalic patients treated medically for ≥ 1 year including at least 3 injections of ATG120. Data on dosing interval, aspects of administration, and resource utilization were collected prospectively during 12 months. Costs were calculated in PLN from the public health-care payer perspective for the year 2013. RESULTS: 139 patients were included in the analysis. Changes in dosing regimen were reported in 14 (9.4%) patients. Combined treatment was used in 11 (8%) patients. Seventy patients (50%) received ATG120 at an extended dosing interval; the mean number of days between injections was 35.56 (SD 8.4). ATG120 was predominantly administered in an out-patient setting (77%), by health-care professionals (94%). Mean time needed for preparation and administration was 4.33 and 1.58 min, respectively, mean product wastage - 0.13 mg. Patients were predominantly treated in an out-patient setting with 7.06 physician visits/patient/year. The most common control examinations were magnetic resonance imaging of brain and brain stem (1.36/patient/year), ultrasound of the neck (1.35/patient/year), GH (1.69/patient/year), glycaemia (1.12/patient/year), IGF-1 (0.84/patient/year), pituitary-thyroid axis hormone levels assessment (TSH-0.58/patient/year, T4-0.78/patient/year). There were 0.43 hospitalizations/patient/year. For direct medical costs estimated at PLN 50 692/patient/year the main item was the costs of ATG120 (PLN 4103.87/patient/month; 97%). The mean medical cost, excluding pharmacotherapy, was PLN 1445/patient/year (out-patient care - 49%, hospitalization - 23%, diagnostics/laboratory tests - 28%). CONCLUSIONS: These results represent the current use of ATG120 in the population of Polish acromegalic patients in a realistic clinical setting. Findings that 50% of patients could be treated with dose intervals of longer than 28 days support the potential of ATG120 to reduce the treatment burden.

Medical treatment of Cushing's disease with concurrent diabetes mellitus.

Cushing's disease (CD) is a severe endocrine disorder characterized by chronic hypercortisolaemia secondary to an overproduction of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. Cortisol excess impairs normal glucose homeostasis through many pathophysiological mechanisms. The varying degrees of glucose intolerance, including impaired fasting glucose, impaired glucose tolerance, and Diabetes Mellitus (DM) are commonly observed in patients with CD and contribute to significant morbidity and mortality. Although definitive surgical treatment of ACTH-secreting tumors remains the most effective therapy to control both cortisol levels and glucose metabolism, nearly one-third of patients present with persistent or recurrent disease and require additional treatments. In recent years, several medical therapies demonstrated prominent clinical efficacy in the management of patients with CD for whom surgery was non-curative or for those who are ineligible to undergo surgical treatment. Cortisol-lowering medications may have different effects on glucose metabolism, partially independent of their role in normalizing hypercortisolaemia. The expanding therapeutic landscape offers new opportunities for the tailored therapy of patients with CD who present with glucose intolerance or DM, however, additional clinical studies are needed to determine the optimal management strategies. In this article, we discuss the pathophysiology of impaired glucose metabolism caused by cortisol excess and review the clinical efficacy of medical therapies of CD, with particular emphasis on their effects on glucose homeostasis.

Progression of a corticotroph tumour during durable medical therapy with osilodrostat in a patient with persistent Cushing's disease.

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Cushing's Disease: Long-Term Effectiveness and Safety of Osilodrostat in a Polish Group of Patients with Persistent Hypercortisolemia in the Experience of a Single Center.

Osilodrostat is a potent oral steroidogenesis inhibitor that has emerged as the new medical agent for patients with Cushing's disease (CD) requiring long-term medical therapy for hypercortisolemia control. Its efficacy and safety have been assessed in clinical trials; however, real-world evidence is still scarce. This study aimed to investigate the long-term treatment (156 weeks) clinical and biochemical effect of osilodrostat in six patients with CD at a single center in Poland, initially participating in the LINC4 study. At week 36, all six patients met the key secondary endpoint of the LINC4 trial, achieving normalization of median urinary free cortisol. Osilodrostat treatment allowed for complete disease control in all patients and none of the patients was excluded due to the lack of treatment effectiveness in 156 weeks of follow-up. All patients demonstrated significant improvement from baseline on most metabolic and cardiovascular parameters, which was most evident at week 36 and sustained throughout the study period. This study supports and strengthens the role of osilodrostat as an effective long-term medical treatment in patients with CD. We also present three patient case histories in detail to highlight the clinical situations that endocrinologists might face during osilodrostat therapy.