Alberto M. Pereira

Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma.

OBJECTIVE Treatment options for patients with radioactive iodine (RaI) refractory metastases of differentiated thyroid carcinoma (DTC) are limited. We studied the effects of the multitarget tyrosine kinase inhibitor sorafenib on the reinduction of RaI uptake and tumor progression. DESIGN Open, single center, single arm 26-week prospective phase II study with open-ended extension. METHODS We treated 31 patients with progressive metastatic or locally advanced RaI refractory DTC with sorafenib 400 mg b.i.d. The primary endpoint was reinduction of RaI uptake at 26 weeks. Additional endpoints were the radiological response and the influence of bone metastases. RESULTS At 26 weeks of sorafenib therapy, no reinduction of RaI uptake at metastatic sites was observed, but 19 patients (59%) had a clinical beneficial response, eight of whom had a partial response (25%) and 11 had stable disease (34%). Seven patients had progressive disease (22%). Sorafenib was significantly less effective in patients with bone metastases. The estimated median progression free survival was 58 weeks (95% confidence interval, CI, 47-68). In general, thyroglobulin (Tg) response (both unstimulated and TSH stimulated) reflected radiological responses. The median time of the nadir of Tg levels was 3 months. Responses were not influenced by histological subtype, mutational status or other variables. No unusual side effects were observed. CONCLUSIONS Sorafenib has a beneficial effect on tumor progression in patients with metastatic DTC, but was less effective in patients with bone metastases. Diagnostic whole body scintigraphy did not reveal an effect of sorafenib on the reinduction of RaI uptake.

Treatment and Follow-Up of Clinically Nonfunctioning Pituitary Macroadenomas

CONTEXT Although the majority of pituitary macroadenomas are clinically nonfunctioning, treatments as well as follow-up strategy for this condition lack evidence from randomized studies. EVIDENCE ACQUISITION We evaluated the evidence of treatment and follow-up strategies for clinically nonfunctioning adenomas. PubMed was searched for articles on nonfunctioning adenomas in November 2007, and references of selected articles were assessed for potentially relevant articles. EVIDENCE SYNTHESIS All evidence for treatment and follow-up for nonfunctioning adenomas is based on observational studies. The most effective treatment is transsphenoidal surgery, indicated in patients with visual field defects. A wait-and-see approach may be considered in nonfunctioning macroadenomas not reaching to the optic chiasm. Some of these tumors ( approximately 10%) will show spontaneous regression, whereas in approximately 50% there will be progression within 5 yr observation. Postoperative radiotherapy should not be applied to all patients after surgery but can be considered in patients with large postoperative remnants of the tumor. During follow-up careful assessment and replacement of pituitary insufficiencies should be performed. Magnetic resonance imaging is advised with intervals of 1-3 yr and evaluation of visual fields when appropriate. Recurrence rates are reported to be 6-46% after transsphenoidal surgery, whereas after postoperative radiotherapy, recurrence rates of 0-36% are reported. Long-term sequelae of nonfunctioning macroadenomas are hypopituitarism, persistent visual field defects, and decreased quality of life. Whether nonfunctioning macroadenomas are associated with an increased mortality is still a matter of debate. CONCLUSION Clinically nonfunctioning pituitary macroadenomas, although benign in nature, need individualized treatment and lifelong radiological and endocrinological follow-up.

Multisystem Morbidity and Mortality in Cushing's Syndrome: A Cohort Study

CONTEXT Cushings syndrome (CS) is associated with hypercoagulability, insulin resistance, hypertension, bone loss, and immunosuppression. To date, no adequately large cohort study has been performed to assess the multisystem effects of CS. OBJECTIVE We aimed to examine the risks for mortality, cardiovascular disease, fractures, peptic ulcers, and infections in CS patients before and after treatment. DESIGN Population-based cohort study. SETTING Source population was the entire population of Denmark (1980 to 2010). Data were obtained from the Danish National Registry of Patients and the Danish Civil Registration System. PATIENTS Benign CS of adrenal or pituitary origin and a matched population comparison cohort were included. OUTCOME MEASURES We used Cox regression, and computed hazard ratios (HR) with 95% confidence intervals (95% CI). Morbidity was investigated in the 3 years before diagnosis; morbidity and mortality were assessed during complete follow-up after diagnosis and treatment. RESULTS Included were 343 CS patients and 34 300 controls. Mortality was twice as high in CS patients (HR 2.3, 95%CI 1.8-2.9) compared with controls. Patients with CS were at increased risk for venous thromboembolism (HR 2.6, 95%CI 1.5-4.7), myocardial infarction (HR 3.7, 95%CI 2.4-5.5), stroke (HR 2.0, 95%CI 1.3-3.2), peptic ulcers (HR 2.0, 95%CI 1.1-3.6), fractures (HR 1.4, 95%CI 1.0-1.9), and infections (HR 4.9, 95%CI 3.7-6.4). This increased multimorbidity risk was present before diagnosis. Mortality and risk of myocardial infarction remained elevated during long-term follow-up. Mortality and risks for acute myocardial infarction, venous thromboembolism, stroke, and infections were similarly increased in adrenal and pituitary CS. CONCLUSIONS Despite the apparently benign character of the disease, CS is associated with clearly increased mortality and multisystem morbidity, even before diagnosis and treatment.

High prevalence of long‐term cardiovascular, neurological and psychosocial morbidity after treatment for craniopharyngioma

Introduction  The treatment of craniopharyngiomas is associated with long‐term morbidity.

Disease-specific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas

Objective  Quality of life (QoL) is impaired in patients treated for pituitary adenomas. However, differences in age and gender distributions hamper a proper comparison of QoL. Therefore, we compared age‐ and gender‐specific standard deviations (SD) scores (Z‐scores) of QoL parameters in patients treated for pituitary adenomas.

Aortic valve calcification and mild tricuspid regurgitation but no clinical heart disease after 8 years of dopamine agonist therapy for prolactinoma

OBJECTIVE Treatment with ergot-derived dopamine agonists, pergolide, and cabergoline has been associated with an increased frequency of valvular heart disease in Parkinsons disease. The aim of the present study was to assess the prevalence of valvular heart disease in patients treated with dopamine agonists for prolactinomas. DESIGN This was a cross-sectional study. PATIENTS We performed two-dimensional and Doppler echocardiography in 78 consecutive patients with prolactinoma (mean age 47 +/- 1.4 yr, 26% male, 31% macroprolactinoma) treated with dopamine agonists for at least 1 yr (mean 8 +/- 0.6 yr) and 78 control subjects. Patients were classified according to treatment: patients treated with cabergoline (group 1: n = 47) and patients not treated with cabergoline (group 2: n = 31). RESULTS Clinically relevant valvular heart disease was present in 12% of patients (nine of 78) vs. 17% of controls (13 of 78) (P = 0.141) and 17% (eight of 47) of patients treated with cabergoline vs. 3% (one of 31) of patients not treated with cabergoline (P = 0.062). Mild tricuspid regurgitation was present in 41% of patients vs. 26% of controls (P = 0.042), and aortic valve calcification was present in 40% of patients, compared with 18% of controls (P = 0.003). There was no relation between the cumulative dose of cabergoline and the presence of mild, moderate, or severe valve regurgitation. CONCLUSION Several years of dopamine agonist treatment in patients with prolactinomas is associated with increased prevalence of aortic valve calcification and mild tricuspid regurgitation but not with clinically relevant valvular heart disease. Therefore, additional studies on the adverse cardiac effects of dopaminergic drugs in prolactinoma are warranted, especially in patients with much longer use of these drugs.

Recurrence of Hyperprolactinemia after Withdrawal of Dopamine Agonists: Systematic Review and Meta-Analysis

CONTEXT Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear in all details. OBJECTIVE The aim of the study was to assess the effect of dopamine agonist withdrawal in patients with idiopathic hyperprolactinemia and prolactinomas. DATA SOURCES PubMed, the Cochrane Library, the Web of Science, and EMBASE were searched electronically. No restriction was made with respect to language. STUDY SELECTION Studies reporting the proportion of normoprolactinemic patients after withdrawal of dopamine agonist or studies in which this proportion could be calculated were eligible. Both observational studies and clinical trials were eligible. Nineteen studies were included in the meta-analysis, with a total of 743 patients. DATA EXTRACTION Data extraction was performed by two reviewers independently. DATA SYNTHESIS The pooled proportion of patients with persisting normoprolactinemia after dopamine agonist withdrawal was 21% in a random effects model [95% confidence interval (CI), 14-30%; I(2) 81%). Stratified analysis showed higher proportions of treatment success in idiopathic hyperprolactinemia (32%; 95% CI, 5-80%), compared with both microprolactinomas (21%; 95% CI, 10-37%), and macroprolactinomas (16%; 95% CI, 6-36%). In a random effects meta-regression adjusting for cause of hyperprolactinemia, a longer treatment duration was associated with treatment success (P = 0.015), whereas the use of cabergoline showed a trend of effect (P = 0.07). CONCLUSIONS This meta-analysis showed that hyperprolactinemia will recur after dopamine agonist withdrawal in a considerable proportion of patients. The probability of treatment success was highest when cabergoline was used for at least 2 yr.

Coexpression of Dopamine and Somatostatin Receptor Subtypes in Corticotroph Adenomas

CONTEXT Previous studies have demonstrated the expression of somatostatin receptor subtypes (mainly sst(5)) and dopamine (DA) receptor subtypes (mainly D(2)) in smaller series of human corticotroph adenomas. In line with these findings, sst(5) and D(2)-targeting agents have already been used clinically in patients with Cushings disease (CD) and have shown promising results in subsets of patients. To what extent these receptor subtypes are coexpressed within individual adenomas, is not known however. OBJECTIVE The aim of the study was to investigate the (co-)expression of both sst and DA receptors in a large series of human corticotroph adenomas. DESIGN We performed in vitro analysis of corticotroph adenoma tissue obtained via transsphenoidal adenomectomy. SETTING The study was conducted at two university medical centers. PATIENTS Adenoma tissue from 30 patients with CD was analyzed in this study. RESULTS Analyzed by quantitative RT-PCR, D(2) and sst(5) were significantly (co-) expressed in the majority (60%) of adenomas, whereas 23% of adenomas only expressed D(2), but not sst(5). The remaining 17% of adenomas did not significantly express either sst(5) or D(2). Overall, expression of sst(1-4) and D(4) was low to nondetectable. Corticotroph adenomas with invasive growth invariably showed loss of sst(5) and D(2) expression. Autoradiography revealed clear D(2) and/or SS-14 binding in a subset of cases, which correlated well with their respective mRNA data. CONCLUSIONS Sst(5) and especially D(2) are highly expressed in the majority of human corticotroph adenomas, with coexpression of sst(5) and D(2) being a common phenomenon. These findings support the current studies with sst(5) and D(2)-targeting agents in patients with CD and highlight the rationale behind sst(5)-D(2) combination therapy.

Increased Prevalence of Psychopathology and Maladaptive Personality Traits after Long-Term Cure of Cushing’s Disease

CONTEXT AND OBJECTIVE Psychopathology and maladaptive personality traits are often observed during the active phase of Cushings disease (CD). We hypothesized that patients with long-term cure of CD show persistent psychopathology and maladaptive personality traits. DESIGN Four questionnaires on frequently occurring psychopathology in somatic illnesses were used, including the Apathy Scale, Irritability Scale, Hospital Anxiety and Depression Scale, and Mood and Anxiety Symptoms Questionnaire short-form. Personality was assessed using the Dimensional Assessment of Personality Pathology short-form (DAPPs). PATIENTS AND CONTROL SUBJECTS We included 51 patients cured of CD (16% men, 53 ± 13 yr) and 51 matched controls. In addition, we included 55 patients treated for nonfunctioning pituitary macroadenomas (55% men, 62 ± 10 yr), and 55 matched controls. RESULTS Mean duration of remission was 11 yr (range 1-32 yr). Compared with matched controls, patients cured from CD scored significantly worse on virtually all questionnaires. Compared with nonfunctioning pituitary macroadenoma patients, patients treated for CD scored worse on apathy (P < 0.001), irritability (P < 0.001), anxiety (P < 0.001), negative affect and lack of positive affect (P < 0.001 on both scales), somatic arousal (P < 0.001), and 11 of 18 subscales of the Dimensional Assessment of Personality Pathology short-form (P < 0.05). CONCLUSIONS Patients with long-term cured CD show an increased prevalence of psychopathology and maladaptive personality traits. These observations suggest irreversible effects of previous glucocorticoid excess on the central nervous system rather than an effect of pituitary tumors and/or their treatment in general. This may also be of relevance for patients treated with high doses of exogenous glucocorticoids.

Subtle Cognitive Impairments in Patients with Long-Term Cure of Cushing’s Disease

CONTEXT AND OBJECTIVE Active Cushings disease is associated with cognitive impairments. We hypothesized that previous hypercortisolism in patients with Cushings disease results in irreversible impairments in cognitive functioning. Therefore, our aim was to assess cognitive functioning after long-term cure of Cushings disease. DESIGN Cognitive assessment consisted of 11 tests, which evaluated global cognitive functioning, memory, and executive functioning. PATIENTS AND CONTROL SUBJECTS We included 74 patients cured of Cushings disease and 74 controls matched for age, gender, and education. Furthermore, we included 54 patients previously treated for nonfunctioning pituitary macroadenomas (NFMA) and 54 controls matched for age, gender, and education. RESULTS Compared with NFMA patients, patients cured from Cushings disease had lower scores on the Mini Mental State Examination (P = 0.001), and on the memory quotient of the Wechsler Memory Scale (P = 0.050). Furthermore, patients cured from Cushings disease tended to recall fewer words on the imprinting (P = 0.013), immediate recall (P = 0.012), and delayed recall (P = 0.003) trials of the Verbal Learning Test of Rey. On the Rey Complex Figure Test, patients cured from Cushings disease had lower scores on both trials (P = 0.002 and P = 0.007) compared with NFMA patients. Patients cured from Cushings disease also made fewer correct substitutions on the Letter-Digit Substitution Test (P = 0.039) and came up with fewer correct patterns on the Figure Fluency Test (P = 0.003) compared with treated NFMA patients. CONCLUSIONS Cognitive function, reflecting memory and executive functions, is impaired in patients despite long-term cure of Cushings disease. These observations indicate irreversible effects of previous hypercortisolism on cognitive function and, thus, on the central nervous system. These observations may also be of relevance for patients treated with high-dose exogenous glucocorticoids.