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Free access

Mortality in Cushing's syndrome: data from 386 patients from a single tertiary referral center

Maria Yaneva, Krassimir Kalinov, and Sabina Zacharieva

Objective

Data on the incidence, mortality, and causes of death in patients with Cushing's syndrome (CS) are scarce, due to the rarity of CS. The aim of the study was to analyze mortality in a large cohort of patients of all etiologies and to determine the cause of death.

Design

This was a retrospective study of patients with CS, treated over a period of 45 years in the main tertiary referral center in Bulgaria.

Methods

Three hundred and eighty-six patients with CS of all etiologies were included. The main outcome measures were the standardized mortality ratio (SMR) and the cause of death.

Results

Mean (±s.d.) age at diagnosis was 38±13 years; 84% of patients were women; mean follow-up was 85 months (range: 0–494 months). The SMR in the CS cohort was 4.05 (95% CI 2.50–5.80) (P<0.0001). The following subgroups did not have a significantly increased SMR: patients with Cushing's disease SMR – 1.88 (95% CI 0.69–4.08), adrenal adenomas 1.67 (95% CI 0.20–6.02), and ACTH-independent bilateral adrenal hyperplasia 1.14 (95% CI 0.21–6.34). Patients with adrenal carcinomas, ectopic CS, and those with CS of undetermined etiology had significantly increased SMR: 48.00 (95% CI 30.75–71.42), 13.33 (95% CI 0.00–24.59), and 4.00 (95% CI 0.48–14.45) respectively (P<0.0001). The significant predictors for mortality were active disease at death, age, male sex, etiology of the disease, and the overall duration of active disease. The major causes of death were vascular events (40%) – cardiovascular 29%, and cerebrovascular 11% – followed by infections (12%).

Conclusions

Patients with CS have increased mortality due to vascular events and infections.

Free access

Increased prevalence of subclinical cardiac valve fibrosis in patients with prolactinomas on long-term bromocriptine and cabergoline treatment

Atanaska Elenkova, Rabhat Shabani, Krassimir Kalinov, and Sabina Zacharieva

Background

In contrast to cabergoline, evidence-based information about a possible profibrotic effect of bromocriptine in prolactinoma patients is extremely limited.

Objective

To assess the prevalence of valvular lesions among patients on long-term bromocriptine or cabergoline therapy.

Design

Case–control study.

Methods

A transthoracic echocardiographic evaluation was performed in 334 subjects divided into four groups: 103 cabergoline treated, 55 bromocriptine treated, 74 naïve patients, and 102 controls.

Results

Clinically relevant valve regurgitations were equally prevalent in all investigated groups whereas subclinical valve fibrosis was significantly more frequent in both bromocriptine- and cabergoline-treated patients (40 vs 43.6 vs 21.6 vs 23.5%; P=0.004). The odds ratio (OR) for developing valvular fibrosis was 2.27 (95% CI 1.17–4.41; P=0.016) for cabergoline and 2.66 (95% CI 1.22–5.78; P=0.014) for bromocriptine groups compared with subjects not exposed to dopamine agonists (DAs). A significantly higher pulmonary arterial pressure corresponding to the longer treatment duration was observed among patients taking bromocriptine compared with cabergoline-treated subjects.

Conclusions

Long-term treatment with cabergoline and bromocriptine seems not to be associated with an increased risk of clinically significant valve disease but possible subclinical lesions should be expected. An echocardiographic examination is recommended at the beginning and periodically during therapy with DAs acting as full or partial agonists of 5-hydroxytrytamine 2B receptors (cabergoline and bromocriptine). Bromocriptine seems not to be a safe alternative for patients receiving cabergoline treatment who have preexisting or diagnosed abnormalities suggesting valvular, interstitial myocardial, or pulmonary fibrosis. Further studies are needed to investigate the possible impact of DA treatment on pulmonary arterial pressure.

Free access

Transforming growth factor β1 is not a reliable biomarker for valvular fibrosis but could be a potential serum marker for invasiveness of prolactinomas (pilot study)

Atanaska Elenkova, Iliana Atanassova, Georgi Kirilov, Vladimir Vasilev, Krassimir Kalinov, and Sabina Zacharieva

Background

Transforming growth factor β1 (TGFβ1) signaling pathway is crucial for both human fibrogenesis and tumorigenesis.

Objective

This study aimed to investigate the usefulness of TGFβ1 and matrix metalloproteinase 2 (MMP2) as potential circulating markers for fibrotic valvular heart disease (FVHD) and invasiveness as well as of Fetuin A as a marker for calcification in patients with prolactinomas.

Design

The study population consisted of 147 subjects divided into four groups: 30 dopamine agonist (DA)-treated prolactinoma patients with proven FVHD and three control groups with normal echocardiograms: 43 DA-treated patients, 26 naïve patients, and 48 healthy subjects.

Results

We observed significantly higher serum TGFβ1 levels in all three patient groups than in the healthy subjects (21.4±8.86 vs 19.1±9.03 vs 20.7±11.5 vs 15.8±7.2 ng/ml; P=0.032). Moreover, TGFβ1 levels were significantly higher in patients with macroprolactinomas and invasive prolactinomas than in those with microprolactinomas and noninvasive tumors respectively. In addition, a strong positive linear relationship between TGFβ1 levels and invasiveness score (ρ=0.924; P<0.001) and a moderate correlation between TGFβ1 levels and tumor volume (r=0.546; P<0.002) were observed in patients with invasive prolactinomas. By contrast, prolactin (PRL) levels exhibited a better correlation with tumor volume (r=0.721; P<0.001) than with invasiveness score (ρ=0.436; P<0.020). No significant difference was observed in Fetuin A levels between patients with FVHD and healthy controls. Results concerning MMP2 were unclear.

Conclusions

TGFβ1, MMP2, and Fetuin A are not reliable biomarkers for valvular fibrosis and calcification in DA-treated patients with prolactinomas, but TGFβ1 may represent a useful serum marker for tumor invasiveness. The simultaneous determination of TGFβ1 and PRL levels could improve the noninvasive assessment of prolactinoma behavior.

Free access

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Silvia Vandeva, Adrian F Daly, Patrick Petrossians, Sabina Zacharieva, and Albert Beckers

Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

Free access

Could different treatment approaches in acromegaly influence life expectancy? A comparative study between Bulgaria and Campania (Italy)

Annamaria Colao, Silvia Vandeva, Rosario Pivonello, Ludovica Francesca Stella Grasso, Emil Nachev, Renata S Auriemma, Krasimir Kalinov, and Sabina Zacharieva

Background

Mortality in acromegaly strictly depends on optimal control of GH and IGF1 levels. Modern medical therapy with somatostatin analogs (SSAs) and GH receptor antagonists (GHRAs) is not available in many countries due to funding restrictions. This retrospective, comparative, cohort study investigated the impact of different treatment modalities on disease control (GH and IGF1) and mortality in acromegaly patients.

Methods

Two cohorts of patients with acromegaly from Bulgaria (n=407) and Campania, Italy (n=220), were compared, and mortality rates were evaluated during a 10-year period (1999–2008).

Results

The major difference in treatment approach between cohorts was the higher utilization of SSAs and GHRAs in Italy, leading to a decreased requirement for radiotherapy. Significantly more Italian than Bulgarian patients had achieved disease control (50.1 vs 39.1%, P=0.005) at the last follow-up. Compared with the general population, the Bulgarian cohort had a decreased life expectancy with a standardized mortality ratio (SMR) of 2.0 (95% CI 1.54–2.47) that was restored to normal in patients with disease control – SMR 1.25 (95% CI 0.68–1.81). Irradiated patients had a higher cerebrovascular mortality – SMR 7.15 (95% CI 2.92–11.37). Internal analysis revealed an independent role of age at diagnosis and last GH value on all-cause mortality and radiotherapy on cerebrovascular mortality. Normal survival rates were observed in the Italian cohort: SMR 0.66 (95% CI 0.27–1.36).

Conclusions

Suboptimal biochemical control was associated with a higher mortality in the Bulgarian cohort. Modern treatment options that induce a strict biochemical control and reduce the necessity of radiotherapy might influence the life expectancy. Other factors, possibly management of comorbidities, could contribute to survival rates.

Free access

MANAGEMENT OF ENDOCRINE DISEASE: Pituitary ‘incidentaloma’: neuroradiological assessment and differential diagnosis

Vladimir Vasilev, Liliya Rostomyan, Adrian F Daly, Iulia Potorac, Sabina Zacharieva, Jean-François Bonneville, and Albert Beckers

Pituitary incidentalomas are a by-product of modern imaging technology. The term ‘incidentaloma’ is neither a distinct diagnosis nor a pathological entity. Rather, it is a collective designation for different entities that are discovered fortuitously, requiring a working diagnosis based on the input of the radiologist, endocrinologist and often a neurosurgeon. In addition to pathological conditions affecting the pituitary gland, a thorough knowledge of the radiological characteristics of normal variants and technical artifacts is required to arrive at an accurate differential diagnosis. After careful radiological and hormonal evaluation, the vast majority of pituitary incidentalomas turn out to be non-functioning pituitary microadenomas and Rathke’s cleft cysts (RCCs). Based on the low growth potential of non-functioning pituitary microadenomas and RCCs, periodic MRI surveillance is currently considered the optimal management strategy. Stricter follow-up is required for macroadenomas, as increases in size occur more frequently.

Open access

Levoketoconazole treatment in endogenous Cushing’s syndrome: extended evaluation of clinical, biochemical, and radiologic outcomes

Maria Fleseriu, Richard J Auchus, Yona Greenman, Sabina Zacharieva, Eliza B Geer, Roberto Salvatori, Rosario Pivonello, Ulla Feldt-Rasmussen, Laurence Kennedy, Michael Buchfelder, Beverly MK Biller, Fredric Cohen, and Anthony P Heaney

Objective

This extended evaluation (EE) of the SONICS study assessed the effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing’s syndrome.

Design/Methods

SONICS included dose-titration (150–600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at months 9 and 12 (relative to the start of maintenance). For pituitary MRI in patients with Cushing’s disease, a threshold of ≥2 mm denoted change from baseline in the largest tumor diameter.

Results

Sixty patients entered EE at month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, BMI, abdominal girth, hirsutism, CushingQoL, and Beck Depression Inventory-II scores improved from the study baseline at months 9 and 12. Forty-six patients completed month 12; four (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced alanine aminotransferase or aspartate aminotransferase >3× upper limit of normal, Fridericia-corrected QT interval >460 ms, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and month 12 or follow-up, the largest tumor diameter was stable in 27 (87%) patients, decreased in one, and increased in three (largest increase 4 mm).

Conclusion

In the first long-term levoketoconazole study, continued treatment through a 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects.

Free access

The European Registry on Cushing's syndrome: 2-year experience. Baseline demographic and clinical characteristics

Elena Valassi, Alicia Santos, Maria Yaneva, Miklós Tóth, Christian J Strasburger, Philippe Chanson, John A H Wass, Olivier Chabre, Marija Pfeifer, Richard A Feelders, Stylianos Tsagarakis, Peter J Trainer, Holger Franz, Kathrin Zopf, Sabina Zacharieva, Steven W J Lamberts, Antoine Tabarin, and Susan M Webb

Objective

The European Registry on Cushing's syndrome (ERCUSYN) is designed to collect prospective and follow-up data at EU level on Cushing's syndrome (CS).

Design and methods

Baseline data on 481 CS patients (390 females, 91 males; mean age (±s.d.): 44±14 years) collected from 36 centres in 23 countries, including new patients from 2008 and retrospective cases since 2000. Patients were divided into four major aetiologic groups: pituitary-dependent CS (PIT-CS) (66%), adrenal-dependent CS (ADR-CS) (27%), CS from an ectopic source (ECT-CS) (5%) and CS from other aetiologies (2%).

Results

Proportion of men in the ECT-CS group was higher than in the other groups (P<0.05). The ADR-CS group was older than the PIT-CS (P<0.05). Prevalence of hirsutism (92%) and diabetes (74%) in ECT-CS was higher than in the other groups (P<0.05 and P<0.01 respectively). PIT-CS had more skin alterations, menstrual irregularities and hirsutism than ADR-CS (P<0.01). Reduced libido was more prevalent in men than women (P<0.01). Prevalence of spine osteoporosis was higher in men than women (P<0.05), and males had more vertebral and rib fractures than females (52 vs 18% for vertebrae; P<0.001 and 34 vs 23% for ribs; P<0.05). ECT-CS consulted a diabetologist more frequently than ADR-CS (P<0.05), while a gynaecologist was consulted more often by women with PIT-CS or ADR-CS than with ECT-CS (P<0.05). Overall, weight gain was more common in women than men (P<0.01). CushingQoL and EuroQoL visual analogue scale scores did not differ between the groups.

Conclusions

The ERCUSYN project demonstrates a heterogeneous clinical presentation of CS at a European level, depending on gender and aetiology.

Free access

High mortality within 90 days of diagnosis in patients with Cushing’s syndrome: results from the ERCUSYN registry

Elena Valassi, Antoine Tabarin, Thierry Brue, Richard A Feelders, Martin Reincke, Romana Netea-Maier, Miklós Tóth, Sabina Zacharieva, Susan M Webb, Stylianos Tsagarakis, Philippe Chanson, Marija Pfeiffer, Michael Droste, Irina Komerdus, Darko Kastelan, Dominique Maiter, Olivier Chabre, Holger Franz, Alicia Santos, Christian J Strasburger, Peter J Trainer, John Newell-Price, Oskar Ragnarsson, and the ERCUSYN Study Group

Objective

Patients with Cushing’s syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality.

Methods

In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2–5.5) years.

Results

Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment.

Conclusion

Mortality rate was highest in patients with ectopic CS. Infectious diseases were the commonest cause of death soon after diagnosis, emphasizing the need for careful clinical vigilance at that time, especially in patients presenting with concomitant diabetes mellitus.