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D A Vassiliadi and S Tsagarakis

Transsphenoidal surgery (TSS) is the treatment of choice in Cushing’s disease. However, recurrence rates are substantial and currently there are no robust predictors of late prognosis. As accumulating evidence challenge the accuracy of the traditionally used early postoperative cortisol values, alternative tests are required. The study of Cambos et al., published in a recent issue of the European Journal of Endocrinology, adds to the existing data that support a role of the desmopressin test as an early and reliable predictive marker in successfully TSS-treated patients. However, despite these promising data, the use of this test is hampered by the fact that it can be applied only in patients with a documented preoperative positive test. Moreover, the lack of robust criteria to define positive postoperative responses represents another major limitation.

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NC Thalassinos, S Tsagarakis, G Ioannides, I Tzavara and C Papavasiliou

Radiotherapy (RT) has long been used in the treatment of acromegaly, but confusion regarding the definition of biochemical cure has hampered interpretation of previous reports on the outcome of this treatment. In the present study we present additional data using the currently accepted criteria of biochemical cure in a large group of patients followed up by our department. Forty-six acromegalic patients were treated with external beam megavoltage RT and followed up for a mean of 7.6 years (range 2-22 years). Only four patients had had previous surgical treatment by either transsphenoidal or transfrontal routes. Following RT, mean basal GH levels decreased from 30.9 ng/ml (5-96 ng/ml) to 11.5 ng/ml (1-36 ng/ml) at 10 years of follow up with a further fall to 6.1 ng/ml (1-29 ng/ml) in those patients followed up for more than 10 years. As a result, although mean GH levels of less than 5 ng/ml were achieved in 9/28 (30.1%) at 5 years, 6/19 (31.6%) at 10 years, and in 6/11 (54.5%) of those patients followed up for more than 10 years post-RT, only 0/28 (0%), 7/28 (25%), 4/19 (21%) and 1/11 (1%) achieved GH levels of <2.5 ng/ml at 2, 5. 10 and >10 years following RT. Thus, in the whole series only 10/48 (20.8%) patients showed a decrease of GH level to less than 2.5 ng/ml at their latest follow up. Hypopituitarism as a result of RT was only infrequently observed in this series; gonadal deficiency developed in 12 (26.6%) patients, thyrotrophin (TSH) deficiency in 3 (6.6%) and adrenocorticotrophin deficiency in 2 (4.4%). In conclusion, megavoltage RT is an effective treatment for the control of GH hypersecretion in acromegaly, with a continuing lowering effect for several years following RT but seldom leads to safe GH levels.

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I Perogamvros, D A Vassiliadi, O Karapanou, E Botoula, M Tzanela and S Tsagarakis

Objective

The treatment of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas (AI) is debatable. We aimed to compare the biochemical and clinical outcome of unilateral adrenalectomy vs a conservative approach in these patients.

Design

Retrospective study.

Methods

The study included 33 patients with bilateral AI; 14 patients underwent unilateral adrenalectomy of the largest lesion (surgical group), whereas 19 patients were followed up (follow-up group). At baseline and at each follow-up visit, we measured 0800 h plasma ACTH, midnight serum cortisol (MSF), 24-h urinary-free cortisol (UFC) and serum cortisol following a standard 2-day low-dose-dexamethasone-suppression test (LDDST). We evaluated the following comorbidities: arterial hypertension, impaired glucose tolerance or diabetes mellitus, dyslipidemia and osteoporosis.

Results

Baseline demographic, clinical characteristics and the duration of follow-up (53.9±21.3 vs 51.8±20.1 months, for the surgical vs the follow-up group) were similar between groups. At the last follow-up visit the surgical group had a significant reduction in post-LDDST cortisol (2.4±1.6 vs 6.7±3.9 μg/dl, P=0.002), MSF (4.3±2 vs 8.8±4.6 μg/dl, P=0.006) and 24-h UFC (50.1±21.1 vs 117.9±42.4 μg/24 h, P=0.0007) and a significant rise in mean±s.d. morning plasma ACTH levels (22.2±9.6 vs 6.9±4.8 pg/ml, P=0.002). Improvement in co-morbidities was seen only in the surgical group, whereas no changes were noted in the follow-up group.

Conclusions

Our early results show that removal of the largest lesion offers significant improvement both to cortisol excess and its metabolic consequences, without the debilitating effects of bilateral adrenalectomy. A larger number of patients, as well as a longer follow-up, are required before drawing solid conclusions.

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G Ntali, A Asimakopoulou, T Siamatras, J Komninos, D Vassiliadi, M Tzanela, S Tsagarakis, A B Grossman, J A H Wass and N Karavitaki

Objective

In this study, we aim to assess the long-term survival and causes of death in a retrospective cohort study on patients with all aetiologies of endogenous Cushing's syndrome (CS) (except adrenal cancer), presenting to two large tertiary endocrine referral centres, and to identify variables predicting mortality.

Subjects and methods

The records of all patients presenting with endogenous CS in the Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK and the Department of Endocrinology, ‘Evangelismos’ General Hospital, Athens, Greece between 1967–2009 (Oxford series) and 1962–2009 (Athens series) were reviewed. The standardised mortality ratio (SMR) was calculated for the Oxford series.

Results

In total, 418 subjects were identified (311 with Cushing's disease (CD), 74 with adrenal Cushing's (AC) and 33 with ectopic Cushing's (EC)). In CD, the probability of 10-year survival was 95.3% with 71.4% of the deaths attributed to cardiovascular causes or infection/sepsis. SMRs were significantly high overall (SMR 9.3; 95% CI, 6.2–13.4, P<0.001), as well as in all subgroups of patients irrespective of their remission status. In AC, the probability of 10-year survival was 95.5% and the SMR was 5.3 (95% CI, 0.3–26.0) with P=0.2. Patients with EC had the worst outcome with 77.6% probability of 5-year survival.

Conclusions

In this large series of patients with CS and long-term follow-up, we report that in CD the mortality is significantly affected, even after apparently successful treatment. The SMR of patients with AC was high, but this was not statistically significant. The implicated pathophysiological mechanisms for these findings need to be further elucidated aiming to improve the long-term outcome.

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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.

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Elena Valassi, Holger Franz, Thierry Brue, Richard A Feelders, Romana Netea-Maier, Stylianos Tsagarakis, Susan M Webb, Maria Yaneva, Martin Reincke, Michael Droste, Irina Komerdus, Dominique Maiter, Darko Kastelan, Philippe Chanson, Marija Pfeifer, Christian J Strasburger, Miklós Tóth, Olivier Chabre, Michal Krsek, Carmen Fajardo, Marek Bolanowski, Alicia Santos, Peter J Trainer, John A H Wass, Antoine Tabarin and for the ERCUSYN Study Group

Background

Surgery is the definitive treatment of Cushing’s syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial.

Objective

(1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS).

Patients and methods

1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS).

Results

Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups.

Conclusions

PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results.