Targeted analysis of Ubiquitin-Specific Peptidase (USP8) in a population of Iranian people with Cushing's disease and a systematic review of the literature.

OBJECTIVE: Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs. METHODS: Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases. RESULTS: In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas. CONCLUSION: Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies.

COMPARISON OF CABERGOLINE VERSUS RALOXIFENE ADD-ON THERAPY TO LONG-ACTING SOMATOSTATIN ANALOGUE IN PATIENTS WITH INADEQUATELY CONTROLLED ACROMEGALY: A RANDOMIZED OPEN LABEL CLINICAL TRIAL.

OBJECTIVE: The present study aimed to evaluate the efficacy of add-on therapy of cabergoline versus raloxifene to long-acting somatostatin analogues (SAs) in patients with inadequately controlled acromegaly. METHODS: This was a prospective, randomized open label clinical trial. Forty-four patients (22 per group) completed the study; where participants received either cabergoline (3 mg/week) or raloxifene (60 mg twice daily) add-on therapy for 12 weeks in a parallel manner. The primary outcome was the rate of reduction in serum insulin-like growth factor 1 (IGF-1) from baseline. Secondary outcomes comprised normalization of serum IGF-1 for age and sex. RESULTS: Serum IGF-1 was significantly decreased in both the cabergoline (40.3 ± 25.6%, P<.001) and raloxifene (31.5 ± 24.6%, P<.001) groups, with no significant difference between arms ( P>.05). Normalization in serum IGF-1 values occurred in 40.9% of patients who were on cabergoline compared to 45.5% of those receiving raloxifene ( P = .76). The subsequent logistic regression analysis highlighted baseline IGF-1 as a significant predictor of IGF-1 normalization (odds ratio, 0.995; 95% confidence interval, 0.990-0.999; P = .02). Using the receiver operating characteristic (ROC) curve analysis for the entire group, the baseline IGF-1 value of 1.47 the upper limit of normal (ULN) was the best cut-off point to identify patients with normal IGF-1 at the end of the study (sensitivity: 52.6%, specificity: 84.0%, Yoden's index: 0.366). Full biochemical control of acromegaly was achieved in 22.7% of patients in the cabergoline group compared to 13.6% of those in the raloxifene group ( P = .43). CONCLUSION: Cabergoline and raloxifene add-on therapy could effectively decrease serum IGF-1 level in patients with inadequately controlled acromegaly. The efficacy profiles of both drugs are comparable. ABBREVIATIONS: DA = dopamine agonist; FBG = fasting blood glucose; GH = growth hormone; IGF1 = insulin-like growth factor-1; IQR = interquartile range; OR = odds ratio; ROC = receiver operating characteristic; SA = somatostatin analogue; SERM = selective estrogen modulator receptor; ULN = upper limit of normal.