The effects of cabergoline in the presurgical and recurrence periods of Cushing's disease patients.

BACKGROUND: The dopaminergic agonist cabergoline (CAB) has been used in the pharmacological treatment of Cushing's disease (CD). The effect is attributed to the frequent expression of the dopamine receptor subtype 2 in corticotroph tumors. However, in vivo studies have demonstrated the normalization of 24-h urinary cortisol (24-h UC) in approximately 30-40% of patients over the long term, mainly after surgical failure. OBJECTIVE: To evaluate the effect of CAB as monotherapy in the early preoperative period and on the recurrence of CD. METHODS: A single-center retrospective study was conducted in a tertiary referral center. Twenty-one patients with confirmed CD were included. The median age was 32 years (13-70), 86% were female, 10 had microadenomas, and 11 had macroadenomas. They were diagnosed from 1986 to 2016 and used CAB as monotherapy either in the preoperative period (n=7, CABi) or upon recurrence before any other treatment (n=14, CABr). A 'complete response' was considered 24-h UC normalization and a 'partial response' was considered a 24-h UC reduction of >50%. UC was obtained at the last follow-up evaluation. The normalization of late-night salivary cortisol (LNSC) after CAB use was evaluated in most patients, as well as the tumor diameter by pituitary MRI, before and after CAB treatment. RESULTS: Complete response was achieved in 29% (6/21) of subjects after 14.9±16.4 months of treatment, with an average dose of 2.2±1.0 mg/week. Partial response occurred in 9.5% (2/21). LNSC normalized in 35% (6/17) of patients, and no variation in tumor diameter before and after CAB use was observed (n=13): 6.8±6.8 vs. 7.2±7.1 mm. There was no normalization of 24-h-UC in the CABi subgroup at the end of the treatment, whereas 43% (6/14) of patients in the CABr subgroup reached complete response. The CABi subgroup was treated for 4.7±1.9 months, and the CABr subgroup was treated for 20.1±18.1 months. Both groups were administered similar doses of CAB (CABi 2.1±0.9 and CABr 2.3±1.1 mg/week). Interestingly, the difference between the subgroups' complete response was evident early on in the three months of treatment: no patients in the CABi subgroup vs. 6/10 (60%) in the CABr subgroup (p=0.035), despite a lower dose in the CABr subgroup (1.1 vs. 1.6; p=0.008). The normalization of LNSC occurred in 20% of the CABi subgroup and in 42% of the CABr subgroup. CONCLUSIONS: The normalization of 24-h UC and LNSC occurred in approximately 30% of all patients, mainly in those who used CAB for the recurrence of CD. Despite the small number of subjects in the CABi subgroup, the absence of hormone control in this subgroup discourages the use of this medication as primary therapy or as a preoperative treatment option.

Cabergoline in the Management of Residual Nonfunctioning Pituitary Adenoma: A Single-Center, Open-Label, 2-Year Randomized Clinical Trial.

BACKGROUND: Complete tumor removal by transsphenoidal surgery is usually difficult for large nonfunctioning pituitary adenomas (NFPAs). A validated medical treatment may be useful for their management. This study evaluates the clinical efficacy of the dopaminergic agonist cabergoline for residual NFPA. DESIGN, SETTING, AND PARTICIPANTS: We conducted a randomized, parallel, open-label clinical trial that compared cabergoline with nonintervention in patients with residual NFPA after transsphenoidal surgery over 2 years. The primary outcome was clinical efficacy (tumor reduction). The secondary outcome was the relationship between tumor dopamine D2 receptor (D2R) expression and clinical responsiveness. Tumor measurements and clinical evaluations were performed every 6 months. RESULTS: In total, 59 and 57 individuals were randomly assigned to the study and control groups, respectively. At the end of the study, residual tumor shrinkage, stabilization, and enlargement were observed in 28.8%, 66.1%, and 5.1% of patients, respectively, in the medical-therapy group and in 10.5%, 73.7%, and 15.8% of patients, respectively, in the control group (P=0.01). The progression-free survival rate was 23.2 and 20.8 months for the study and control groups, respectively (P=0.01). D2R was not associated with cabergoline responsiveness. No major side effects were related to cabergoline use. CONCLUSIONS: Cabergoline was an effective drug for treating residual NFPA, and its use was associated with a high rate of tumor shrinkage (ClinicalTrials.gov NCT03271918).

Differential gene expression of sirtuins between somatotropinomas and nonfunctioning pituitary adenomas.

Sirtuins 1-7 (SIRT) are a highly conserved family of histone deacetylases involved in the regulation of longevity that have a considerable impact in transcription, DNA repair regulation, telomeric stability, cell senescence and apoptosis. In the present study, SIRT1-7 mRNA levels were evaluated in 37 somatotropinomas and 31 nonfunctioning pituitary adenomas (NFPAs) using qPCR and relation to tumor size, invasiveness and Ki-67 proliferative index was made. Overexpression of SIRT1 was observed in 86.5% of somatotropinomas versus 41.9% of NFPAs (P < 0.01). SIRT3 was more underexpressed in NFPAs than somatotropinomas (77.4 and 40.5%, respectively, P < 0.01) as well as SIRT4 and SIRT7. Despite the lack of association between sirtuins and invasiveness or Ki-67 index, SIRT1 and SIRT3 expressions were related to tumor size. Mean of the largest diameter was smaller in adenomas with SIRT1 overexpression than with normal expression (P < 0.01) and SIRT3 underexpression was associated with larger tumors (P < 0.01). In conclusion, a pronounced difference in sirtuins expression was identified between pituitary adenomas, suggesting that these genes are potential markers of pituitary adenomas and could be employed in the characterization of somatotropinomas and NFPAs. The role of sirtuins in pathogenesis of pituitary tumors merits further investigation and possibly will provide new molecular insight about their progression.

PROP1 overexpression in corticotrophinomas: evidence for the role of PROP1 in the maintenance of cells committed to corticotrophic differentiation.

OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n=10), somatotrophinomas (n=8), and nonfunctioning adenomas (n=6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r=0.49, p=0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation.

PROP1 overexpression in corticotrophinomas: evidence for the role of PROP1 in the maintenance of cells committed to corticotrophic differentiation

OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n = 10), somatotrophinomas (n = 8), and nonfunctioning adenomas (n = 6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r = 0.49, p = 0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation. .

iASPP: a novel protein involved in pituitary tumorigenesis?

Pituitary tumors can be morphologically classified as microadenomas (diameter<1 cm) or macroadenomas (>1 cm), which can be enclosed, invasive and/or expansive. Functionally, they are classified as secreting tumors and clinically non-secreting or 'non-functioning' tumors. Several molecular mechanisms have been studied acting in uncontrolled cell proliferation and the acquisition of resistance to apoptosis. A potential mechanism related to apoptosis control has been found following the isolation and characterization of the ASPP proteins family. All these proteins share sequence similarities in their C-termini, which contains their signature sequences of Ankyrin repeats, SH3 domain and proline-rich region. Recent investigations reported that the expression of iASPP mRNA and protein was increased in non-transformed cells induced to undergo apoptosis and inhibition of iASPP expression in these cells by siRNA reduced apoptosis. Thus, modulation of iASPP expression seems to be an integral part of the apoptotic response. The ASPP proteins family binds to proteins that are key players in controlling apoptosis (P53 and NFkappaB p65 subunit). It has been speculated that the iASPP protein product induces apoptosis by blocking NFkappaB or inhibits apoptosis by blocking P53. By either mechanism, the gene could influence the survival of precancerous lesions.

Does partial surgical tumour removal influence the response to octreotide-LAR in acromegalic patients previously resistant to the somatostatin analogue?

OBJECTIVE: To compare the intrapatient response to the same dose of slow-release octreotide (OCT-LAR) before and after noncurative surgery in acromegalic patients who did not attain disease control after primary treatment with OCT-LAR. DESIGN: Prospective clinical study. PATIENTS: Eleven acromegalic patients (eight men, aged 42.45 +/- 11.15 years, 10 macroadenomas) received OCT-LAR (20 mg, n = 1; 30 mg, n = 10) every 28 days as the primary treatment (1stOCT-LAR) for 11.3 +/- 4.2 months, without IGF-I normalization. They were subsequently submitted to surgery without cure and were then treated with the same dose of OCT-LAR for 8.0 +/- 6.5 months (2ndOCT-LAR). MEASUREMENTS: GH and IGF-I serum concentrations were obtained under basal conditions as well as during treatment. Pituitary tumour volume was assessed by magnetic resonance imaging (MRI) of the sella. IGF-I was also expressed as a percentage of the upper limit of the normal age- and sex-matched range (%ULNR IGF-I). RESULTS: After 1stOCT-LAR, there was a decrease in GH levels (P = 0.003) and %ULNR IGF-I (P = 0.009) compared to baseline (B), but no IGF-I normalization. Tumour shrinkage was observed in eight of 10 patients with macroadenomas (median 63.7%, range 24.5-75.5%). After surgery, mean levels of GH and %ULNR IGF-I were lower than those at baseline (P = 0.0004 and P = 0.003, respectively), but not when compared to values during 1stOCT-LAR (P = 1.000 and P = 0.957, respectively). MRI confirmed surgical tumour removal (median 64%, range 4.9-96.6%) in eight of the 10 patients. Comparing the 2ndOCT-LAR results with postsurgical results, there were no significant decrease in %ULNR IGF-I (P = 0.061) and GH levels (P = 0.414). Nine patients (82%) achieved IGF-I normalization. The degree of surgical tumour reduction did not correlate with IGF-I normalization (P = 0.794). When comparing the results between 1stOCT-LAR and 2ndOCT-LAR, there was a decrease, albeit not statistically significant, in serum GH levels (P = 0.059) and a significant decrease in %ULNR IGF-I (P = 0.011). CONCLUSIONS: Using strict criteria (same patient, same drug, same dose) our results strongly suggest that the surgical reduction of tumour mass can improve the outcome of OCT-LAR treatment in acromegalic patients resistant to primary therapy with SA.

Preservation of the olfactory tract in bifrontal craniotomy.

The bifrontal craniotomy approach used to be associated with a high percentage of olfactory tract damage. We present our experience with this technique, that was used with excellent results in a series of 11 patients that underwent the surgical approach described in this paper. We support the idea that bilateral subfrontal craniotomy allows a wide operative exposure as well as the complete anatomic and functional preservation of the olfactory tracts bilaterally.

Preservation of the olfactory tract in bifrontal craniotomy

The bifrontal craniotomy approach used to be associated with a high percentage of olfactory tract damage. We present our experience with this technique, that was used with excellent results in a series of 11 patients that underwent the surgical approach described in this paper. We support the idea that bilateral subfrontal craniotomy allows a wide operative exposure as well as the complete anatomic and functional preservation of the olfactory tracts bilaterally