Telomere length and Wnt/ß-catenin pathway in adamantinomatous craniopharyngiomas.

Objectives: To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations. Design: Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions. Methods: Clinicopathological features were retrieved from the patient's charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths. Results: Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297-0.597vs 0.607, IQR: 0.445-0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs. Conclusions: CTNNB1: mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/ß-catenin pathway and telomere biology in the pathogenesis of aCPs.

gsp Mutation Is Not a Molecular Biomarker of Long-Term Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.

BACKGROUND: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. METHODS: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. RESULTS: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. CONCLUSIONS: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.

Machine Learning-based Prediction Model for Treatment of Acromegaly With First-generation Somatostatin Receptor Ligands.

CONTEXT: Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in the treatment of acromegaly. OBJECTIVE: To develop a prediction model of therapeutic response of acromegaly to fg-SRL. METHODS: Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) <1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP). RESULTS: A total of 153 patients were analyzed. Controlled patients were older (P = .002), had lower GH at diagnosis (P = .01), had lower pretreatment GH and IGF-I (P < .001), and more frequently harbored tumors that were densely granulated (P = .014) or highly expressed SST2 (P < .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%. CONCLUSION: We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.

Endoscopic endonasal transsphenoidal surgery in elderly patients with pituitary adenomas.

OBJECT: With the increase in the average life expectancy, medical care of elderly patients with symptomatic pituitary adenoma (PA) will continue to grow. Little information exists in the literature about the surgical treatment of these patients. The aim of this study was to present the results of a single pituitary center in the surgical treatment of PAs in patients > 70 years of age. METHODS: In this retrospective study, 55 consecutive elderly patients (age ≥ 70 years) with nonfunctioning PAs underwent endoscopic transsphenoidal surgery at the General Hospital of Fortaleza, Brazil, between May 2000 and December 2012. The clinical and radiological results in this group were compared with 2 groups of younger patients: < 60 years (n = 289) and 60-69 years old (n = 30). RESULTS: Fifty-five patients ≥ 70 years of age (average age 72.5 years, range 70-84 years) underwent endoscopic surgery for treatment of PAs. The mean follow-up period was 50 months (range 12-144 months). The most common symptoms were visual impairment in 38 (69%) patients, headache in 16 (29%) patients, and complete ophthalmoplegia in 6 (10.9%). Elderly patients presented a higher incidence of ophthalmoplegia (p = 0.032) and a lower frequency of pituitary apoplexy before surgery (p < 0.05). Tumors with cavernous sinus invasion were treated surgically less frequently than in younger patients. Although patients with an American Society of Anesthesiologists score of 3 were more common in the elderly group (p < 0.05), no significant difference regarding surgical time, extent of resection, and hospitalization were observed. Elderly patients presented with more complications than patients < 60 years (32.7% vs 10%, p < 0.05). Complications observed in the elderly group included 5 CSF leaks (9%), 2 permanent diabetes insipidus cases (3.6%), 4 postoperative refractory hypertension cases (7.2%), 1 myocardial ischemia (1.8%), and 1 death (1.8%). Postoperative new anterior pituitary deficit was more common in the younger group (< 60 years old: 17.7%) than in the elderly (≥ 70 years old: 12.7%); however, there was no statistical difference. CONCLUSIONS: Endoscopic transsphenoidal surgery for elderly patients with PAs may be associated with higher complication rates, especially secondary to early transitory complications, when compared with surgery performed in younger patients. Although the worst preoperative clinical status might be observed in this group, age alone is not associated with a worst final prognosis after endoscopic removal of nonfunctioning PAs.

Urinary calcium excretion and insulin resistance in patients with acromegaly.

BACKGROUND: Renal complications in acromegaly include glomerular hyperfiltration, insulin resistance, hypercalciuria and urolithiasis. The aim of this study was to investigate whether urinary calcium (U(Ca)) excretion is a direct consequence of growth hormone secretion or secondary to hyperfiltration and/or insulin resistance. METHODS: We performed a cross-sectional study of 58 patients diagnosed with acromegaly. Demographic data were obtained, serum analysis was performed, including insulin-like growth factor (IGF)-1, and 24-h urine collection, to measure urinary protein excretion, U(Ca) and phosphate excretion, as well as fractional excretion of sodium and potassium. We also calculated the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Patients were predominantly male (60.3%), and their mean age was 45.9 ± 14 years. Hypercalciuria was present in 24% of patients. Patients with higher HOMA-IR had higher IGF-1 levels, a trend toward higher body mass index and higher U(Ca) excretion. In univariate analysis, U(Ca) excretion was associated with HOMA-IR (r = 0.472, P = 0.001), phosphaturia (r = 0.457, P = 0.001), IGF-1 (r = 0.398, P = 0.002) and creatinine clearance (r = 0.394, P = 0.001). HOMA-IR and phosphaturia were independently associated with U(Ca) excretion. No independent associations were found between phosphaturia and HOMA-IR or IGF-1. CONCLUSIONS: The present study revealed an association between hypercalciuria and insulin resistance in patients with acromegaly. Further studies are required to fully understand the pathogenesis of these abnormalities in patients with acromegaly.