Circulating brain injury biomarkers increase after endoscopic surgery for pituitary tumors.

Pituitary tumors and subsequent treatment with endoscopic transsphenoidal surgery (ETSS) may cause injury to suprasellar structures, causing long-term fatigue and neurocognitive impairment. A method to quantify brain injury after ETSS is not available. In this prospective, exploratory study of patients undergoing ETSS for pituitary tumors, a novel approach to detect possible neuronal damage is presented. Plasma concentrations of brain injury biomarkers (glial fibrillary acidic protein [GFAP], tau, and neurofilament light [NFL]) were measured the day before surgery, immediately after surgery, at day 1 and 5, and at 6 and 12 months after surgery, using enzyme-linked immunosorbent assays. The association between the increase of biomarkers with preoperative tumor extension and postoperative patient-perceived fatigue was evaluated. Suprasellar tumor extension was assessed from MRI scans, and self-perceived fatigue was assessed using the Multidimensional Fatigue Inventory before and 6 months after surgery. Thirty-five patients were included in the analysis. Compared to baseline, GFAP showed a maximal increase at day 1 after surgery (p = 0.0005), tau peaked postoperatively on the day of surgery (p = 0.019), and NFL reached its maximum at day 5 after surgery (p < 0.0001). The increase in GFAP correlated with preoperative chiasmal compression (p = 0.020). The increase in tau was correlated with preoperative chiasmal (p = 0.011) and hypothalamus compression (p = 0.016), and fatigue score 6 months after surgery (p = 0.016). In conclusion, the concentrations of brain injury biomarkers in blood increased after ETSS for pituitary tumors. The results indicate that postoperative plasma GFAP and tau might reflect astroglial and neuronal damage after ETSS.

MCM7 as a marker of postsurgical progression in non-functioning pituitary adenomas.

OBJECTIVE: Current markers predicting tumour progression of pituitary adenomas after surgery are insufficient. Our objective was to investigate if minichromosome maintenance protein 7 (MCM7) expression predicts tumour progression in non-functioning pituitary adenomas (NFPAs). METHODS: In a cohort study of surgically treated NFPAs, two groups with distinctly different behaviour of a residual tumour were selected: one group requiring reintervention due to tumour progression (reintervention group, n = 57) and one with residual tumours without progression (radiologically stable group, n = 40). MCM7, Ki-67, oestrogen receptor-α expression, mitotic index and tumour subtype were assessed by immunohistochemistry, and their association with tumour progression requiring reintervention was analysed. RESULTS: Median (IQR) MCM7 expression was 7.4% (2.4-15.2) in the reintervention group compared with 2.0% (0.6-5.3) in the radiologically stable group (P <0.0001). Cox regression analysis showed an association between high (>13%) MCM7 expression and reintervention (HR: 3.1; 95% CI:1.7-5.4; P = 0.00012). The probability for reintervention within 6 years for patients with high MCM7 was 93%. Ki-67 expression >3% (P = 0.00062), age ≤55 years (P = 0.00034) and mitotic index≥1 (P = 0.024) were also associated with reintervention. Using a receiver operating characteristics curve, a predictive model for reintervention with all the above predictors yielded an area under the curve of 82%. All eight patients with both high MCM7 and high Ki-67 needed reintervention. CONCLUSION: This cohort study shows that expression of MCM7 is a predictor for clinically significant postoperative tumour progression. Together with age, Ki-67 and mitotic index, MCM7 might be of added value as a predictive marker when managing patients with NFPA after surgery.

Body Composition and Bone Mineral Density in Craniopharyngioma Patients: A Longitudinal Study Over 10 Years.

CONTEXT: Patients with craniopharyngioma suffer from obesity and impaired bone health. Little is known about longitudinal changes in body composition and bone mineral density (BMD). OBJECTIVE: To describe body composition and BMD (change). DESIGN: Retrospective longitudinal study. SETTING: Two Dutch/Swedish referral centers. PATIENTS: Patients with craniopharyngioma (n = 112) with a dual X-ray absorptiometry (DXA) scan available (2 DXA scans, n = 86; median Δtime 10.0 years; range 0.4-23.3) at age ≥ 18 years (58 [52%] male, 50 [45%] childhood onset). MAIN OUTCOME MEASURES: Longitudinal changes of body composition and BMD, and associated factors of ΔZ-score (sex and age standardized). RESULTS: BMI (from 28.8 ±â€…4.9 to 31.2 ±â€…5.1 kg/m2, P < .001), fat mass index (FMI) (from 10.5 ±â€…3.6 to 11.9 ±â€…3.8 kg/m2, P = .001), and fat free mass index (FFMI) (from 18.3 ±â€…3.2 to 19.1 ±â€…3.2 kg/m2, P < .001) were high at baseline and increased. Fat percentage and Z-scores of body composition did not increase, except for FFMI Z-scores (from 0.26 ±â€…1.62 to 1.06 ±â€…2.22, P < .001). Z-scores of total body, L2-L4, femur neck increased (mean difference 0.61 ± 1.12, P < .001; 0.74 ± 1.73, P < .001; 0.51 ±â€…1.85, P = .02). Linear regression models for ΔZ-score were positively associated with growth hormone replacement therapy (GHRT) (femur neck: beta 1.45 [95% CI 0.51-2.39]); and negatively with radiotherapy (femur neck: beta -0.79 [-1.49 to -0.09]), glucocorticoid dose (total body: beta -0.06 [-0.09 to -0.02]), and medication to improve BMD (L2-L4: beta -1.06 [-1.84 to -0.28]). CONCLUSIONS: Z-scores of BMI, fat percentage, and FMI remained stable in patients with craniopharyngioma over time, while Z-scores of FFMI and BMD increased. Higher glucocorticoid dose and radiotherapy were associated with BMD loss and GHRT with increase.

Fractures, Bone Mineral Density, and Final Height in Craniopharyngioma Patients with a Follow-up of 16 Years.

CONTEXT: Pituitary hormonal deficiencies in patients with craniopharyngioma may impair their bone health. OBJECTIVE: To investigate bone health in patients with craniopharyngioma. DESIGN: Retrospective cross-sectional study. SETTING: Dutch and Swedish referral centers. PATIENTS: Patients with craniopharyngioma (n = 177) with available data on bone health after a median follow-up of 16 years (range, 1-62) were included (106 [60%] Dutch, 93 [53%] male, 84 [48%] childhood-onset disease). MAIN OUTCOME MEASURES: Fractures, dual X-ray absorptiometry-derived bone mineral density (BMD), and final height were evaluated. Low BMD was defined as T- or Z-score ≤-1 and very low BMD as ≤-2.5 or ≤-2.0, respectively. RESULTS: Fractures occurred in 31 patients (18%) and were more frequent in men than in women (26% vs. 8%, P = .002). Mean BMD was normal (Z-score total body 0.1 [range, -4.1 to 3.5]) but T- or Z-score ≤-1 occurred in 47 (50%) patients and T-score ≤-2.5 or Z-score ≤-2.0 in 22 (24%) patients. Men received less often treatment for low BMD than women (7% vs. 18%, P = .02). Female sex (OR 0.3, P = .004) and surgery (odds ratio [OR], 0.2; P = .01) were both independent protective factors for fractures, whereas antiepileptic medication was a risk factor (OR, 3.6; P = .03), whereas T-score ≤-2.5 or Z-score ≤-2.0 was not (OR, 2.1; P = .21). Mean final height was normal and did not differ between men and women, or adulthood and childhood-onset patients. CONCLUSIONS: Men with craniopharyngioma are at higher risk than women for fractures. In patients with craniopharyngioma, a very low BMD (T-score ≤-2.5 or Z-score ≤-2.0) seems not to be a good predictor for fracture risk.

Diagnosing metabolic syndrome in craniopharyngioma patients: body composition versus BMI.

OBJECTIVE: Craniopharyngioma patients often have poor metabolic profiles due to hypothalamic-pituitary damage. Previously, using BMI as obesity marker, the occurrence of the metabolic syndrome in these patients was estimated at 46%. Our aim was to determine if dual X-ray absorptiometry (DXA) scan in evaluation of obesity and metabolic syndrome would be superior. DESIGN: Retrospective study of craniopharyngioma patients for whom DXA scan results were available. METHODS: BMI, fat percentage and fat mass index were used to evaluate obesity and as components for obesity in metabolic syndrome. RESULTS: Ninety-five craniopharyngioma patients were included (51% female, 49% childhood-onset disease). Metabolic syndrome occurred in 34-53 (45-51%) subjects (depending on the definition of obesity, although all definitions occurred in higher frequency than in the general population). Metabolic syndrome frequency was higher if obesity was defined by fat percentage (52 vs 42%) or fat mass index (51 vs 43%) compared to BMI. Misclassification appeared in 9% (fat percentage vs BMI) and 7% (fat mass index vs BMI) for metabolic syndrome and 29 and 13% for obesity itself, respectively. For metabolic syndrome, almost perfect agreement was found for BMI compared with fat percentage or fat mass index. For obesity, agreement was fair to moderate (BMI vs fat percentage). CONCLUSION: Using BMI to evaluate obesity underestimates the true prevalence of metabolic syndrome in patients with craniopharyngioma. Furthermore, fat percentage contributes to a better evaluation of obesity than BMI. The contribution of DXA scan might be limited for identification of the metabolic syndrome.

Comorbidities in patients with non-functioning pituitary adenoma: influence of long-term growth hormone replacement

Background: Patients with hypopituitarism have an increased mortality. The aim of this study was to investigate comorbidities including cerebral infarction, type 2 diabetes mellitus (T2DM) and malignant tumors in patients with non-functioning pituitary adenomas (NFPA) with and without growth hormone replacement therapy (GHRT). Methods: Observational cohort study in patients with NFPA within the western region of Sweden. Subjects were identified through the National Patient Registry and followed between 1987 and 2014. Patient records were reviewed and standardized incidence ratios (SIRs) with 95% CIs for comorbidities were calculated. Results: In total, 426 patients were included, 206 with GHRT and 219 without. Median (range) follow-up time for patients with and without GHRT was 12.2 (0­24) and 8.2 (0­27) years, respectively. Mean ± s.d. BMI was 28.5 ± 4.5 and 26.5 ± 4.4 for patients with and without GHRT, respectively (P < 0.001). Incidence of cerebral infarction was increased (SIR: 1.39; 95% CI: 1.03­1.84; P = 0.032), with no difference between patients with and without GHRT. SIR for T2DM in patients not receiving GHRT was increased (1.65; 1.06­2.46; P = 0.018), whereas the incidence in patients receiving GHRT was not (0.99; 0.55­1.63; P = 0.99). The incidence of malignant tumors was not increased, either in patients with or without GHRT. Conclusion: The incidence of cerebral infarction is increased in patients with NFPA irrespective of GHRT. Patients without GHRT had an increased risk of T2DM, whereas patients with GHRT had a normal incidence of T2DM, despite having higher BMI. Incidence of malignant tumors was not increased. Thus, long-term GHRT seems to be safe regarding risk of comorbidities.

Excess morbidity and mortality in patients with craniopharyngioma: a hospital-based retrospective cohort study.

OBJECTIVE: Most studies in patients with craniopharyngioma did not investigate morbidity and mortality relative to the general population nor evaluated risk factors for excess morbidity and mortality. Therefore, the objective of this study was to examine excess morbidity and mortality, as well as their determinants in patients with craniopharyngioma. DESIGN: Hospital-based retrospective cohort study conducted between 1987 and 2014. METHODS: We included 144 Dutch and 80 Swedish patients with craniopharyngioma identified by a computer-based search in the medical records (105 females (47%), 112 patients with childhood-onset craniopharyngioma (50%), 3153 person-years of follow-up). Excess morbidity and mortality were analysed using standardized incidence and mortality ratios (SIRs and SMRs). Risk factors were evaluated univariably by comparing SIRs and SMRs between non-overlapping subgroups. RESULTS: Patients with craniopharyngioma experienced excess morbidity due to type 2 diabetes mellitus (T2DM) (SIR: 4.4, 95% confidence interval (CI): 2.8-6.8) and cerebral infarction (SIR: 4.9, 95% CI: 3.1-8.0) compared to the general population. Risks for malignant neoplasms, myocardial infarctions and fractures were not increased. Patients with craniopharyngioma also had excessive total mortality (SMR: 2.7, 95% CI: 2.0-3.8), and mortality due to circulatory (SMR: 2.3, 95% CI: 1.1-4.5) and respiratory (SMR: 6.0, 95% CI: 2.5-14.5) diseases. Female sex, childhood-onset craniopharyngioma, hydrocephalus and tumour recurrence were identified as risk factors for excess T2DM, cerebral infarction and total mortality. CONCLUSIONS: Patients with craniopharyngioma are at an increased risk for T2DM, cerebral infarction, total mortality and mortality due to circulatory and respiratory diseases. Female sex, childhood-onset craniopharyngioma, hydrocephalus and tumour recurrence are important risk factors.

The metabolic syndrome and its components in 178 patients treated for craniopharyngioma after 16 years of follow-up.

OBJECTIVE: Patients with craniopharyngioma are at an increased risk for cardio- and cerebrovascular mortality. The metabolic syndrome (MetS) is an important cardiometabolic risk factor, but barely studied in patients with craniopharyngioma. We aimed to investigate the prevalence of and risk factors for the MetS and its components in patients with craniopharyngioma. DESIGN: Cross-sectional study with retrospective data. METHODS: We studied the prevalence of and risk factors for the MetS and its components in 110 Dutch (median age 47 years, range 18-92) and 68 Swedish (median age 50 years, range 20-81) patients with craniopharyngioma with ≥3 years of follow-up (90 females (51%); 83 patients with childhood-onset craniopharyngioma (47%); median follow-up after craniopharyngioma diagnosis 16 years (range 3-62)). In Dutch patients aged 30-70 years and Swedish patients aged 45-69 years, we examined the prevalence of the MetS and its components relative to the general population. RESULTS: Sixty-nine (46%) of 149 patients with complete data demonstrated the MetS. Prevalence of the MetS was significantly higher in patients with craniopharyngioma compared with the general population (40% vs 26% (P < 0.05) for Dutch patients; 52% vs 15% (P < 0.05) for Swedish patients). Multivariable logistic regression analysis identified visual impairment as a borderline significant predictor of the MetS (OR 2.54, 95% CI 0.95-6.81; P = 0.06) after adjustment for glucocorticoid replacement therapy and follow-up duration. Age, female sex, tumor location, radiological hypothalamic damage, 90Yttrium brachytherapy, glucocorticoid replacement therapy and follow-up duration significantly predicted components of the MetS. CONCLUSIONS: Patients with craniopharyngioma are at an increased risk for the MetS, especially patients with visual impairment.

Higher glucocorticoid replacement doses are associated with increased mortality in patients with pituitary adenoma.

OBJECTIVE: Patients with secondary adrenal insufficiency (AI) have an excess mortality. The objective was to investigate the impact of the daily glucocorticoid replacement dose on mortality in patients with hypopituitarism due to non-functioning pituitary adenoma (NFPA). METHODS: Patients with NFPA were followed between years 1997 and 2014 and cross-referenced with the National Swedish Death Register. Standardized mortality ratio (SMR) was calculated with the general population as reference and Cox-regression was used to analyse the mortality. RESULTS: The analysis included 392 patients (140 women) with NFPA. Mean ± s.d. age at diagnosis was 58.7 ± 14.6 years and mean follow-up was 12.7 ± 7.2 years. AI was present in 193 patients, receiving a mean daily hydrocortisone equivalent (HCeq) dose of 20 ± 6 mg. SMR (95% confidence interval (CI)) for patients with AI was similar to that for patients without, 0.88 (0.68-1.12) and 0.87 (0.63-1.18) respectively. SMR was higher for patients with a daily HCeq dose of >20 mg (1.42 (0.88-2.17)) than that in patients with a daily HCeq dose of 20 mg (0.71 (0.49-0.99)), P = 0.017. In a Cox-regression analysis, a daily HCeq dose of >20 mg was independently associated with a higher mortality (HR: 1.88 (1.06-3.33)). Patients with daily HCeq doses of ≤20 mg had a mortality risk comparable to patients without glucocorticoid replacement and to the general population. CONCLUSION: Patients with NFPA and AI receiving more than 20 mg HCeq per day have an increased mortality. Our data also show that mortality in patients substituted with 20 mg HCeq per day or less is not increased.

Incidence of malignant tumours in patients with a non-functioning pituitary adenoma.

Whether patients with non-functioning pituitary adenoma (NFPA) are at increased risk of developing malignant tumours has been sparsely studied and is a matter of debate. In this study, we have investigated the incidence of malignant tumours in a large and unselected group of patients with NFPA. The study was nationwide and included all patients diagnosed with NFPA between 1987 and 2011 (n = 2795) in Sweden, identified in the National Patient Register. Malignant tumours, occurring after the NFPA diagnosis, were identified in the Swedish Cancer Register between 1987 and 2014. Standardised incidence ratios (SIRs) for malignant tumours with 95% confidence intervals (CI) were calculated using the Swedish population as reference. In total, 448 malignant tumours were detected in 386 patients with NFPA, as compared to 368 expected malignancies in the general population (SIR 1.22 (95% CI 1.11-1.33)). The incidence of neoplasms of the brain was increased (SIR 5.83 (95% CI 4.03-8.14)). When analysing the total incidence of malignancies excluding neoplasms of the brain, the overall SIR was still increased (SIR 1.14 (95% CI 1.03-1.26)). The incidence of malignant neoplasm of skin other than malignant melanoma (SIR 1.99 (95% CI 1.55-2.52)) and malignant melanoma (SIR 1.62 (95% CI 1.04-2.38)) were increased, whereas the incidence of breast cancer (SIR 0.65 (95% CI 0.42-0.97)) was decreased. The incidence of other types of malignancies did not differ significantly from the expected incidence in the general population. In conclusion, patients with NFPA have an increased overall risk of developing malignancies. To what extent these findings are due to more frequent medical surveillance, genetic predisposition or endocrine changes, remains unknown.