Pituitary Adenoma

Our study population (1725 subjects, Table 1) was recruited via the collaborative research network of the International FIPA Consortium (15 ). Pituitary adenoma patients were grouped into 11 clinical diagnostic categories (Supplemental Table 1). The diagnoses of acromegaly, acromegaly/prolactinoma, gigantism, gigantism/prolactinoma, and mild acromegaly (16 (link)) were grouped together under the category of GH excess for some analyses.
Between January 2007 and January 2014, we recruited patients from 35 countries from two different groups: either members of FIPA families, defined by the presence of pituitary adenomas in two or more members of a family without other associated clinical features (1 (link)– (link)3 (link), 17 (link)) (familial cohort), or sporadically diagnosed pituitary adenoma patients with disease onset at 30 years of age or younger (sporadic cohort). As an exception to these inclusion criteria, one AIPmut-positive sporadic patient older than 30 years was found thanks to AIP screening in the setting of a research study, and the screening of his relatives detected a second AIPmut-positive pituitary adenoma case; this family was included in the familial cohort. The first patient reported in each FIPA family and all the sporadic patients were considered probands. All the patients received treatment and were followed up in accordance with the guidelines and clinical criteria of their respective centers. Relevant clinical and family structure data were received from clinicians and/or patients, and genetic screening was performed in the families of all the AIPmut-positive probands, selecting individuals according to their risk of inheriting the mutation, based on their position in the family tree, and extending the screening to as many generations as possible. In both familial and sporadic cases, other causes of familial pituitary adenomas, such as MEN1 and MEN4, Carney complex, pheochromocytoma/paraganglioma and pituitary adenoma syndrome, and X-linked acrogigantism were ruled out by clinical, biochemical and, in some cases, genetic tests, as appropriate.
The study population included a great majority of new cases but also previously diagnosed patients being followed up by the participating centers and a few historical cases, corresponding to deceased members of FIPA families (further details in Supplemental Results). Four AIPmut-positive patients (two with diagnosis of acromegaly and two with gigantism) died in the postrecruitment period. Three of the deaths were due to cardiovascular causes (stroke, chronic heart failure, and acute coronary syndrome), whereas the exact cause of death is unknown in the fourth, a patient with long-standing untreated familial acromegaly.
All the patients and family members included agreed to take part by providing signed informed consent forms approved by the local ethics committee. Further details on the study population and the procedures for genetic/clinical screening and search for disease-modifying genes are described in the Supplemental Material.

Inclusion criteria: 1) MRI examination showed lesions diameter ≥ 4 cm in sellar region; 2) Tumor resection was performed in Department of Neurosurgery, Fuzhou General Hospital, Fujian Medical University; 3) Pituitary adenoma was diagnosed by pathological examination. Exclusion criteria: 1) Pituitary adenoma resection was performed before admission; 2) History of preoperative radiotherapy.

The detailed experimental procedures and statistical analyses are provided in Supplemental Methods. In brief, in AIP half-life experiments, HEK293 and EBV-immortalized cells (derived from a control subject [EBV-LC-AIP_WT] and a patient with a heterozygous AIPmut [EBV-LC-AIP_p.R304*]) were treated with cycloheximide (CHX, 100 μg/mL) and total protein was extracted at various time points for Western blot (WB). RNA stability was analyzed using RT-qPCR. Fifteen AIP variant plasmids (obtained by site-directed mutagenesis, Tables 1 and 2) were transfected into HEK293 cells for half-life experiments (CHX, 20 μg/mL, Table 2), in the presence or absence of the proteasome inhibitor MG-132 (20 μM). Genetic and clinical data were collected from 100 pituitary adenoma patients [60 from our cohort (4 (link)) and 40 cases reported in the literature] carrying the missense AIP variants as well as the nonsense mutation we have studied here. AIP interacting partners were identified in a pull-down assay from rat GH-secreting GH3 cells using glutathione-S-transferase-fused WT and mutant AIP synthetic proteins followed by quantitative mass spectrometry. Coimmunoprecipitation and siRNA knockdown (KD) of FBXO3 were used to study the role of FBXO3 in AIP degradation. Half-life experiments were analyzed using a one-phase decay equation, and the degradation speed (K) was compared between each mutant protein and the WT protein using the extra sum-of-squares F test. Correlation between half-life and clinical features was analyzed using data derived from studies listed in Table 3 using the Spearman R test. For other analyses, Kruskal-Wallis, one-way ANOVA, and linear regression tests were used as appropriate, and significance was taken as P < .05.

This meta-analysis was performed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two independent investigators (Nie and Fang) conducted literature (from inception to May 15, 2022), using the following databases: PubMed, Cochrane, and Ovid MEDLINE. Search strategy based on keywords is as follows: “pituitary adenoma,” “growth hormone pituitary adenoma,” “growth hormone-producing pituitary adenoma,” “somatotroph tumor,” “acromegaly,” “endoscopic surgery,” “endoscopic transsphenoidal surgery,” “anterior pituitary function,” “pituitary insufficiency,” “hypothyroidism,” “thyroid insufficiency,” “adrenal insufficiency,” “hypoadrenalism,” and “endoscopic.”
Two researchers (Nie and Fang) independently conducted literature screening, data extraction, and quality evaluation. If there is any disagreement, another researcher will help mediate it (Zhang). The inclusion criteria were English original research articles. Case reports, conference abstracts, meta-analyses, and reviews were excluded. This article should describe the pituitary hormone before and after endoscopic transsphenoidal pituitary tumor surgery in patients with somatotroph tumors. References to all selected articles are reviewed.

We collected the following data on patients who underwent ETSS for pituitary adenomas: patient basic information (age, sex, duration of visual symptoms); tumor characteristics (tumor maximum diameter identified by MRI, tumor texture, categorized as not hard (easily or difficultily removed by suction), or hard (not removable by suction and excised en bloc)) (18 (link)); radiological examination (optic chiasm compression identified via MRI); visual field testing (diffuse defect or not, preoperative MD); laboratory values on admission (Ki67, CD34, EGFR, Mmp9, P53, neutrophil (×10⁹/L), platelet (×10⁹/L), lymphocyte (×10⁹/L), neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index(SII)(×10⁹/L), and platelet-to-lymphocyte ratio (PLR)); and outcome (the improvement of VFD after ETSS).