Risk of second brain tumour after radiotherapy for pituitary adenoma or craniopharyngioma: a retrospective, multicentre, cohort study of 3679 patients with long-term imaging surveillance.

BACKGROUND: Radiotherapy is a valuable treatment in the management algorithm of pituitary adenomas and craniopharyngiomas. However, the risk of second brain tumour following radiotherapy is a major concern. We assessed this risk using non-irradiated patients with the same primary pathology and imaging surveillance as controls. METHODS: In this multicentre, retrospective cohort study, 4292 patients with pituitary adenoma or craniopharyngioma were identified from departmental registries at six adult endocrine centres (Birmingham, Oxford, Leeds, Leicester, and Bristol, UK and Ferrara, Italy). Patients with insufficient clinical data, known genetic predisposition to or history of brain tumour before study entry (n=532), and recipients of proton beam or stereotactic radiotherapy (n=81) were excluded. Data were analysed for 996 patients exposed to 2-dimensional radiotherapy, 3-dimensional conformal radiotherapy, or intensity-modulated radiotherapy, and compared with 2683 controls. FINDINGS: Over 45 246 patient-years, second brain tumours were reported in 61 patients (seven malignant [five radiotherapy, two controls], 54 benign [25 radiotherapy, 29 controls]). Radiotherapy exposure and older age at pituitary tumour detection were associated with increased risk of second brain tumour. Rate ratio for irradiated patients was 2·18 (95% CI 1·31-3·62, p<0·0001). Cumulative probability of second brain tumour was 4% for the irradiated and 2·1% for the controls at 20 years. INTERPRETATION: Irradiated adults with pituitary adenoma or craniopharyngioma are at increased risk of second brain tumours, although this risk is considerably lower than previously reported in studies using general population controls with no imaging surveillance. Our data clarify an important clinical question and guide clinicians when counselling patients with pituitary adenoma or craniopharyngioma on the risks and benefits of radiotherapy. FUNDING: Pfizer.

Medical therapy for non-functioning pituitary tumors-a critical approach.

Non-functioning pituitary adenomas (NFPAs) are the second most common variant of pituitary tumors. When symptomatic, primary therapy is surgery. Recurrence rates are high. Since many NFPAs express dopamine and somatostatin receptors, medical therapy has been used after surgery in order to prevent recurrence. So far, dopamine agonists have been more widely tested with some promise when introduced immediately after surgery but with less efficacy when introduced later upon tumor regrowth. Currently, the role of medical therapy to prevent tumor regrowth in NFPAs is limited by imprecisions as to final outcome and uncertainties concerning on patient selection, dosing, duration, and side effects.

Impact of menopause on outcomes in prolactinomas after dopamine agonist treatment withdrawal.

OBJECTIVE: Discontinuation of dopamine agonist (DA) treatment in women with prolactinoma after menopause is a potential approach; studies systematically assessing long-term outcomes are lacking. Our aim was to investigate the natural history of prolactinoma in this group. DESIGN/PATIENTS: Retrospective cohort study of women with prolactinoma diagnosed before menopause and who after menopause were not on DA. RESULTS: Thirty women were included. Twenty-eight received DA (median duration 18 years, median age at DA withdrawal 52 years). At last assessment (median follow-up 3 years) and compared with values 6-12 months after stopping DA, Prolactin (PRL) increased in 15%, decreased but not normalized in 33% and was normal in 52%; PRL levels or visible adenoma on imaging before DA withdrawal, treatment duration and presence of macro-/microadenoma at diagnosis were not predictors of normoprolactinaemia at last review, whereas PRL values 6-12 months after stopping DA were. Adenoma regrowth was detected in 2/27 patients (7%), who showed gradual increase in PRL. Comparison with 28 women who had DA withdrawal before their menopause revealed lower risk of hyperprolactinaemia recurrence in the postmenopausal group (HR:0.316, 95% CI: 0.101-0.985, P < .05). Two women with microprolactinoma diagnosed in perimenopausal period had not been offered DA; PRL decreased (but not normalized) during observation of 1 and 8 years. CONCLUSIONS: Prolactin normalized over time in nearly half of the women and serum PRL 6-12 months after DA withdrawal is useful predictor. Nonetheless, 7% of the patients demonstrated adenoma regrowth which, given the life expectancy postmenopause, necessitate regular monitoring of the cases with persistent hyperprolactinaemia.

Mortality in patients with non-functioning pituitary adenoma.

Non-functioning pituitary adenomas (NFA) are benign pituitary neoplasms not associated with clinical evidence of hormonal hypersecretion. A substantial number of patients with NFA have morbidities related to the tumor and possible recurrence(s), as well as to the treatments offered. Studies assessing the long-term mortality of patients with NFA are limited. Based on the published literature of the last two decades, overall, the standardized mortality ratios in this group suggest mortality higher than that of the general population with deaths attributed mainly to circulatory, respiratory and infectious causes. Women seem to have higher mortality ratios, and assessment of time trends suggests improvement over the years. There is no consensus on predictive factors of mortality but those most consistently identified are older age at diagnosis and high doses of glucocorticoid substitution therapy. Well designed and of adequate power studies are needed to establish the significance of factors compromising the survival of patients with NFA and to facilitate improvements in long-term prognosis.

Prolactinomas diagnosed in the postmenopausal period: Clinical phenotype and outcomes.

OBJECTIVE: Most prolactinomas in females are diagnosed during the reproductive age, and the majority are microadenomas. Prolactinomas detected in the postmenopausal period are less common with limited published data on their presentation and prognosis. Our objective was to assess the presenting clinical, biochemical and imaging findings, as well as the outcomes of women diagnosed with a prolactinoma in the postmenopausal period. DESIGN AND METHODS: We undertook a retrospective cohort study of women diagnosed with prolactinoma after menopause and followed up in a large UK pituitary centre. Information on presentation, management and outcomes was collected. RESULTS: Seventeen women with a median age at diagnosis of 63 years (range 52-78) were identified. Headaches and/or visual deterioration were the most commonly reported complaints at detection of the adenoma (47%). Acute pituitary apoplexy was diagnosed at presentation or during follow-up in 18% of the cases. The median serum prolactin was 12 364 mU/L (range 2533-238 479). Macroprolactinomas comprised 94% of the tumours, and 88% of them had supra/parasellar extension. All patients with macroprolactinoma were offered dopamine agonist, and normal prolactin was achieved in 94% of them (median follow-up 91.5 months). Adenoma shrinkage was observed in all women. Improvement or resolution of visual disturbances documented at presentation was observed in 86% of cases. CONCLUSIONS: The clinical phenotype of prolactinomas diagnosed in the postmenopausal period is characterized by dominance of macroadenomas, with frequent supra/parasellar extension and a relative high rate of acute pituitary apoplexy. In this group of patients, the response of the macroadenomas to dopamine agonists is good.

Outcome of Nonfunctioning Pituitary Adenomas That Regrow After Primary Treatment: A Study From Two Large UK Centers.

Context: Despite the major risk of regrowth of clinically nonfunctioning pituitary adenomas (CNFAs) after primary treatment, systematic data on the probability of further tumor progression and the effectiveness of management approaches are lacking. Objective: To assess the probability of further regrowth(s), predictive factors, and outcomes of management approaches in patients with CNFA diagnosed with adenoma regrowth after primary treatment. Patients, Design, and Setting: Retrospective cohort study of 237 patients with regrown CNFA managed in two UK centers. Results: Median follow-up was 5.9 years (range, 0.4 to 37.7 years). The 5-year second regrowth rate was 35.3% (36.2% after surgery; 12.5% after radiotherapy; 12.7% after surgery combined with radiotherapy; 63.4% with monitoring). Of those managed with monitoring, 34.8% eventually were offered intervention. Type of management and sex were risk factors for second regrowth. Among those with second adenoma regrowth, the 5-year third regrowth rate was 26.4% (24.4% after surgery; 0% after radiotherapy; 0% after surgery combined with radiotherapy; 48.3% with monitoring). Overall, patients with a CNFA regrowth had a 4.4% probability of a third regrowth at 5 years and a 10.0% probability at 10 years; type of management of the first regrowth was the only risk factor. Malignant transformation was diagnosed in two patients. Conclusions: Patients with regrown CNFA after primary treatment continue to carry considerable risk of tumor progression, necessitating long-term follow-up. Management approach to the regrowth was the major factor determining this risk; monitoring had >60% risk of progression at 5 years, and a substantial number of patients ultimately required intervention.

THERAPY OF ENDOCRINE DISEASE: Surgery in microprolactinomas: effectiveness and risks based on contemporary literature.

Microprolactinomas are the most common pituitary adenomas. In symptomatic patients, dopamine agonists are the first-line treatment of choice; when cabergoline is used, biochemical control rates between 85 and 93% have been reported. Long-term treatment is needed in most of the cases with compliance, patient convenience, and potential adverse effects representing areas requiring attention. Based on the literature published in the past 15 years, transsphenoidal surgery can lead to normal prolactin in the postoperative period in usually 71-100% of the cases with very low postoperative complication rates. Surgical expertise is the major determinant of the outcomes, and it may be a cost-effective option in young patients with life expectancy greater than 10 years (provided it is performed by experienced surgeons at high volume centers with confirmed optimal outcomes). Larger series of patients with adequate follow-up could further validate the place of transsphenoidal surgery (particularly through the endoscopic approach for which long-term results are currently limited) in the management algorithm of patients with microprolactinoma.

The association between adherence to the Mediterranean diet and adiponectin levels among healthy adults: the ATTICA study.

Adiponectin is thought to exert anti-inflammatory actions. The aim of the present work was to evaluate the association of long-term adherence to the Mediterranean diet with adiponectin levels, in a sample of cardiovascular disease-free adults. In a random sub-sample of "ATTICA" study, 532 men and women, serum adiponectin was measured. Among several sociodemographic, clinical and biological factors, adherence to the Mediterranean diet was assessed by a special diet score (MedDietSCore) that incorporated the inherent characteristics of this traditional diet. Unadjusted analysis revealed that participants who were in the highest tertile of the diet score had an average 41% higher adiponectin levels, as compared to those who were in the lowest tertile (P<.001). Multiadjusted data analysis showed that compared to the highest tertile of diet score, participants in the middle or the lowest one had an average 0.99+/-0.22 (P=.001) and 1.05+/-0.27 microg/ml (P=.001) lower adiponectin levels after adjusting for age, sex and various bioclinical factors. Adherence to the Mediterranean diet was associated with an increase on adiponectin levels. This finding may partially explain beneficial effects of this traditional healthy diet on the cardiovascular system.

Association Between Low-Grade Systemic Inflammation and Type 2 Diabetes Mellitus Among Men and Women from the ATTICA Study.

AIM: To investigate the relationship between low-grade inflammation and several glycemic indices in a population-based sample of men and women. METHODS: The ATTICA study is a population-based cohort that randomly enrolled 1514 men and 1528 women (aged >18 years old), stratified by age and gender, from the Greater Athens area, during 2001-2002. Among several characteristics, inflammation markers (high sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, homocysteine and amyloid A) and glycemic control indices (fasting blood glucose, insulin, HOMA) were measured in the participants. RESULTS: The prevalence of diabetes was 7.8% in men and 6.0% in women. The prevalence of impaired fasting glucose (IFG) was 21% in men and 12% in women. Diabetic subjects had 57% higher mean levels of C-reactive protein (p < 0.001), 22% higher mean levels of interleukin-6 (p < 0.001) and 60% higher levels of tumor necrosis factor-alpha (p < 0.001) compared to non-diabetic subjects. Homocysteine and serum amyloid A levels did not show significant differences among groups. CONCLUSION: Our study supports a positive association between low-grade inflammation and diabetes in a population-based sample of men and women without any evidence of cardiovascular disease, which is independent of demographic, clinical and lifestyle characteristics, including physical activity and dietary factors.