Pituitary neuroendocrine tumor: A neuropsychological comparison with intra-axial tumor.

OBJECTIVE: Despite pituitary neuroendocrine tumor (PitNET) being extra-axial tumors without direct damage to brain tissue, patients with PitNET exhibit neuropsychological impairments. However, it remains unclear whether there are neuropsychological differences between PitNET and intra-axial tumors that directly destroy the brain parenchyma. This prospective study aims to clarify this distinction to inform decision-making for intracranial tumors of diverse origins. METHODS: A total of 146 patients with PitNET, 74 patients with glioma representing intra-axial tumors, and 52 age-, sex-, and education-matched healthy controls were recruited. All patients received standard treatment and postoperative rehabilitation. Clinical data were meticulously collected, and neuropsychological tests were administered to all participants both before and 3 months after surgery. RESULTS: Both PitNET and glioma patients experience the dual burden of cognitive and affective deficits. However, the feature of these deficits differs substantially. In PitNET patients, the deficits are relatively mild and focal, whereas in glioma patients, they are severe and extensive. Specifically, PitNET patients exhibit deficits in memory, anxiety, and negative affect. In contrast, glioma patients display deficits in executive function, attention, anxiety, positive/negative affect, and empathy. Notably, except for persistent memory deficits, the majority of neuropsychological scores declines in PitNET patients are restorable and can reach improvement within a short period after standard surgical therapy and perioperative management. Conversely, glioma patients not only fail to show improvements but also demonstrate worsening in terms of general cognition and memory postoperatively. INTERPRETATION: As an extra-axial tumor, PitNET may exhibit distinctive cognitive and affective functioning compared to intra-axial tumors, highlighting the need for specific treatment approaches for PitNET patients.

Clinical and Pathological Features of Pit1/SF1 Multilineage Pituitary Neuroendocrine Tumor.

BACKGROUND AND OBJECTIVES: Lineage-based classification has critical clinical implications in pituitary neuroendocrine tumor (PitNET). As the most prevalent subtype of multilineage PitNET, PitNET originating from both pituitary-specific positive transcription factor 1 (Pit1) and steroidogenic factor-1 (SF1) lineages (Pit1/SF1-adenoma) is expected to exhibit rich and varied clinical behaviors. A comprehensive understanding of the clinical and pathological characteristics of Pit1/SF1-adenoma will provide mechanistic insight and influence the prognosis and treatment of PitNET. METHODS: A retrospective study was conducted by reviewing 57 cases of Pit1/SF1-adenoma between 2018 and 2022. We also included 88 cases of PitNET arising from Pit1 cell lineage (Pit1-adenoma) and 70 cases of PitNET arising from SF1 cell lineage (SF1-adenoma) as controls. Comprehensive data, including demographic, symptom, endocrinal, radiological, surgical, pathological, and prognostic information, were systematically collected. All specimens were immunostained for pituitary transcription factors (PTFs) and pituitary hormones. RESULTS: The detection rate was 8.0% for Pit1/SF1-adenoma within PitNET surgical specimens. Pit1/SF1-adenoma displayed a male predominance, with the mean diagnosis age falling between Pit1-adenoma and SF1-adenoma. The endocrine activity of Pit1/SF1-adenoma was lower than Pit1-adenoma but higher than SF1-adenoma. Pit1/SF1-adenoma had a higher incidence of cavernous sinus invasion (56.1%) than both Pit1-adenoma (38.6%, P = .039) and SF1-adenoma (27.1%, P = .001). Furthermore, Pit1/SF1-adenoma showed more postoperative complications than Pit1-adenoma (29.8% vs 8.0%, P = .001). Nonfunctional Pit1/SF1-adenoma had a higher radiological tumor recurrence rate than nonfunctional SF1-adenoma (34.8% vs 10.9%, P = .021). Notably, the immunostaining pattern was diverse in Pit1/SF1-adenoma, with various combinations of staining intensity for PTFs and 15 combinations for 6 pituitary hormones. Intriguingly, various PTFs combinations had no different impact on the outcome of Pit1/SF1-adenoma. CONCLUSION: Pit1/SF1-adenoma represents a unique pathological subtype of PitNET, characterized by distinctive clinical behaviors. Identifying Pit1/SF1-adenoma can facilitate more precise management of PitNET by the practical use of Pit1/SF1 immunostaining.

Identification of HSPD1 as a novel invasive biomarker associated with mitophagy in pituitary adenomas.

BACKGROUND: The crucial role of mitophagy in tumor progression has been recognized. Therefore, our study aimed to investigate the potential correlation between pituitary adenoma invasiveness and the mitophagy processes. METHODS: In this study, we used transcriptomics of postoperative tissue from 32 patients and quantitative proteomics of 19 patients to screen for mitophagy-related invasion genes in pituitary adenomas. The invasive predictive value of target genes was analyzed by Lasso regression model, CytoHubba plugin and expression validation. Co-expression correlation analysis was used to identify paired proteins for target genes, and a predictive model for pituitary adenoma invasiveness was constructed by target genes and paired proteins and assessed using ROC analysis, calibration curves and DCA. GO function, pathway (GSEA or GSVA) and immune cell analysis (ssGSEA or CIBERSORT) were further utilized to explore the action mechanism of target gene. Finally, immunohistochemistry and cell function experiments were used to detect the differential expression and key roles of the target genes in pituitary adenomas. RESULTS: Finally, Heat shock protein family D member 1 (HSPD1) was identified as a target gene. The quality of a predictive model for pituitary adenoma invasiveness consisting of HSPD1 and its paired protein expression profiles was satisfactory. Moreover, the expression of HSPD1 was significantly lower in invasive pituitary adenomas than in non-invasive pituitary adenomas. Downregulation of HSPD1 may be significantly related to invasion process, mitochondria-related pathway and immune cell regulation in pituitary adenomas. CONCLUSION: The downregulation of HSPD1 may serve as a predictive indicator for identifying invasive pituitary adenomas.

Intraoperative cerebrospinal fluid leakage and residual tumors in endoscopic transsphenoidal surgery for pituitary adenoma: risk analysis and nomogram development.

BACKGROUND: Endoscopic transsphenoidal surgery is the primary method used to treat pituitary adenomas (PAs) at present; however, this technique is associated with certain risks, including cerebrospinal fluid leakage (CFL) and residual tumors (RTs). In this study, we aimed to identify specific risk factors for intraoperative CFL (ioCFL) and postoperative RT in patients with pituitary adenoma and construct a corresponding nomogram for risk assessment. METHODS: We collected a range of information from 782 patients who underwent endoscopic transsphenoidal PA resection in the Department of Neurosurgery at Beijing Tiantan Hospital between 2019 and 2021. Patients were then randomly assigned to training and validation groups (in a 8:2 ratio) with R software. Univariate and multivariable logistic regression models were then used to screen variables related to ioCFL and RT. These variables were then used to construct a predictive nomogram. Finally, the accuracy of the nomogram was validated by receiver operating characteristic curve (ROC) analysis, calibration plots, and decision curve analysis (DCA). RESULTS: Univariate and multivariable logistic regression models identified four risk factors for ioCFL (Hardy grade, tumor size, position, and consistency) and five risk factors for RT (operation time, tumor size, consistency, Knosp grade, and primary/recurrence type). The area under the ROC curve (AUC) for the ioCFL risk model was 0.666 and 0.697 for the training and validation groups, respectively. For RT, the AUCs for the two groups were 0.788 and 0.754, respectively. The calibration plots for the ioCFL and RT models showed high calibration quality and DCA analysis yielded excellent efficiency with regards to clinical decision making. CONCLUSION: Tumor size, growth characteristics, and invasion location were identified as the main factors affecting intraoperative CFL and RT. With our novel nomogram, surgeons can identify high-risk patients according to preoperative and intraoperative tumor performance and reduce the probability of complications.

Operative management of trigeminal schwannomas: based on a modified classification in a study of 93 cases.

BACKGROUND: Advances in microscopic and endoscopic surgical techniques have outpaced traditional classification and transcranial surgical strategies, especially with reference to the treatment of trigeminal schwannomas (TSs). A modified TS classification is proposed and appropriate surgical strategies are discussed. METHODS: The cases of 93 patients who underwent surgical treatment in Beijing Tiantan Hospital in the previous 6 years were analyzed retrospectively, and a literature review was conducted. RESULTS: Classification is based on surgical direction. Tumors were classified as follows: type A, backward orientation, located in the orbit or orbit and middle cranial fossa (8 cases, 8.6%); type B, upward orientation, located in the pterygopalatine fossa, infratemporal fossa or pterygopalatine fossa, infratemporal fossa, and middle cranial fossa (23 cases, 24.7%); type C, forward and backward orientations, located in the middle cranial fossa, posterior cranial fossa or both (58 cases, 62.4%); and type D, located in multiple regions (4 cases, 4.3%). 91.40% of patients underwent gross total resection (GTR) with 29 cases receiving endoscopic resection of whom 93.10% (27/29) experienced GTR. CONCLUSION: The 93 cases were satisfactorily divided into four types, according to tumor location and surgical orientation, enabling safe and effective removal by appropriate surgery.

Characteristics of Perioperative Cognitive and Affective Function in Patients with Somatotroph Adenoma.

OBJECTIVE: In the present study, we evaluate the characteristics of cognitive and affective function in patients with somatotroph adenomas (SAs) that secrete excess growth hormone and the effects of surgical intervention. METHODS: We conducted a prospective longitudinal study, recruiting 27 patients with SAs, 29 patients with nonfunctional pituitary adenomas (NFPAs) as the lesion control group, and 24 healthy participants as the healthy controls (HCs). These three groups were matched for sex, age, and years of education. We performed multidimensional cognitive function and neuropsychological assessments 1-2 days before endoscopic endonasal transsphenoidal surgery and at 3 months postoperatively. The Mini-mental state examination, Montreal cognitive assessment, Frontal assessment battery, Trail making test, and Digit span test were used to assess multidimensional cognitive function, including general intelligence, frontal lobe function, executive function, and memory. The Hamilton anxiety scale, Beck depression inventory, and Positive and Negative Affect Schedule scale were used for the neuropsychological assessment, including anxiety, depressed mood, and positive and negative emotions. RESULTS: Compared with the HCs, the patients with SAs showed poor performance in the memory (P = 0.009) and anxiety (P = 0.013) assessments. However, no statistically significant difference was observed between patients with SAs and NFPAs for either cognitive function or effective performance. Moreover, patients with SAs did not show significant changes in cognition and affective behavior after surgery. In contrast, patients with NFPAs displayed significant improvements in memory (P = 0.015), executive function (P < 0.001), and anxiety mood (P = 0.001) performance postoperatively. CONCLUSIONS: Patients with SAs showed specific cognitive deficits and abnormal moods, which might be attributed to the overproduction of growth hormone. However, surgical intervention had a limited effect on improving the impaired cognitive function and abnormal moods in patients with SAs at short-term follow-up.

Quantitative proteomics identified a novel invasion biomarker associated with EMT in pituitary adenomas.

Background: Complete resection of invasive pituitary adenoma is usually difficult, resulting in a high recurrence rate. Therefore, it is needed to find potential diagnostic markers and therapeutic targets for invasive pituitary adenoma. Methods: We collected samples from patients with invasive and non-invasive pituitary adenomas from Beijing Tiantan Hospital for protein extraction and quantitative analysis. We identified differential proteins (DEPs) by differential analysis of the two groups. The intersection of differential proteins related to invasion and epithelial-mesenchymal transition (EMT) in the GeneCards database was identified as EMT-DEPs. The protein network of EMT-DEPs was analyzed using the STRING database and Cytoscape software, and the hub EMT-DEPs were obtained by the MCC algorithm of the cytoHubba plugin. Correlation analysis was used to obtain the interpairing proteins among EMT-DEPs, and core EMT-DEPs were identified based on the number of paired proteins. The Venn program was used to identify the intersection of hub EMT-DEPs and core EMT-DEPs as key EMT-DEPs. Finally, a series of analyses plus experiments were used to verify the correlation of the target protein with invasion and EMT in pituitary adenoma. Results: Quantitative comparison of proteins between invasive and non-invasive pituitary adenomas indicated 833 differential proteins. The overlaps of EMT-related proteins and differential proteins consisted of 46 EMT-DEPs. There were 6 intersections between the hub EMT-DEPs and core EMT-DEPs. Using quantitative protein data and GSE169498 chip, we found that solute carrier family 2 member 1 (SLC2A1) was our target protein. SLC2A1 was significantly correlated with the invasiveness of pituitary adenoma, and the ROC curve was satisfactory. The functions and pathways of SLC2A1 and paired protein enrichment were closely linked to the EMT. Consistently, SLC2A1 expression was significantly and positively correlated with the expression of classical markers of EMT. The final experiment revealed that SLC2A1 was significantly upregulated in invasive pituitary adenoma. Conclusion: SLC2A1 is significantly upregulated in invasive pituitary adenoma with satisfactory predictive value. It may regulate EMT. It may be a potential diagnostic marker for invasive pituitary adenoma.

The characteristics of brain structural remodeling in patients with unilateral vestibular schwannoma.

PURPOSE: Brain structural remodeling alters related brain function. However, few studies have assessed morphological alterations of unilateral vestibular schwannoma (VS) patients. Therefore, this study examined the characteristics of brain structural remodeling in unilateral VS patients. METHODS: We recruited 39 patients with unilateral VS (19 left, 20 right) and 24 matched normal controls (NCs). We obtained brain structural imaging data using 3T T1-weighted anatomical and diffusion tensor imaging scans. Then, we evaluated both gray and white matter (WM) changes using FreeSurfer software and tract-based spatial statistics, respectively. Furthermore, we constructed a structural covariance network to assess brain structural network properties and the connectivity strength between brain regions. RESULTS: Compared with NCs, VS patients showed cortical thickening in non-auditory areas (e.g., the left precuneus), especially left VS patients, along with reduced cortical thickness in the right superior temporal gyrus (auditory areas). VS patients also showed increased fractional anisotropy in extensive non-auditory-related WM (e.g., the superior longitudinal fasciculus), especially right VS patients. Both left and right VS patients showed increased small-worldness (more efficient information transfer). Left VS patients had a single reduced-connectivity subnetwork in contralateral temporal regions (right-side auditory areas), but increased connectivity between some non-auditory regions (e.g., left precuneus and left temporal pole). CONCLUSION: VS patients exhibited greater morphological alterations in non-auditory than auditory areas, with structural reductions seen in related auditory areas and a compensatory increase in non-auditory areas. Left and right VS patients show differential patterns of brain structural remodeling. These findings provide a new perspective on the treatment and postoperative rehabilitation of VS.

Pituitary adenomas with multiple cell lineage combinations: clinicopathological features and short-term prognosis.

OBJECTIVE: There are few published data concerning pituitary adenomas (PAs) derived from multiple lineages. In this study the authors aimed to determine the clinicopathological characteristics and prognostic profiles of PAs with multiple cell lineage combinations (PAwMCs). METHODS: The authors reviewed data on 723 patients with PAs who had undergone surgery between 2018 and 2021 and identified 93 cases (12.9%) of PAwMC. They collected detailed data on these cases, including clinical information, pathological features, and prognosis. From among 589 cases of PAs with only one cell lineage (PAwOCs), they randomly selected 100 cases to investigate differences between the two tumors. To enable investigation of the characteristics of different subgroups, they further subclassified PAwMCs into 4 groups according to the following specified combinations of pituitary-associated transcription factors: group A, immunopositive for pituitary-specific positive transcription factor 1 (Pit1) and steroidogenic factor 1 (SF1); group B, immunopositive for Pit1 and T-box transcription factor (Tpit); group C, immunopositive for SF1 and Tpit; and group D, immunopositive for Pit1, SF1, and Tpit. RESULTS: Compared with PAwOC, PAwMC was more often associated with hormone hypersecretion (31.0% vs 50.0%, p = 0.037) and had worse short-term prognoses with lower complete response rates (58.7% vs 30.0%, p = 0.026) and more postoperative complications (19.4% vs 35.9%, p = 0.041). Each of the 4 PAwMC subgroups had its own clinical features. Overall, PAwMCs displayed more neurological manifestations than evidence of hypersecretion, which may be attributable to a disparity between pituitary-associated transcription factors and endocrine-related manifestations. Moreover, multiple cell lineages, tumor size (p = 0.011), and Knosp grade (p = 0.013) were all found to be critical predictors of the prognosis of PAwMC. CONCLUSIONS: The authors described a special subtype of PAs, which derived from multiple lineages. They found a unique effect of the combination of distinct cell lineages on PAs and present detailed clinicopathological and prognostic profiles of these special PAs. These data will contribute to a more comprehensive view of PAs and assist in the selection of treatment.

Qu-Du-San-Jie decoction induces growth inhibition and vascular normalization in NF2-associated vestibular schwannoma.

Background: Neurofibromatosis type 2 (NF2) is a rare genetic syndrome that predisposes individuals to develop bilateral vestibular schwannomas (VSs) causing a high risk of life-threatening neurological complications. Traditional treatment options for NF2-associated VS usually cause neurological damage, and to date, there are no FDA-approved pharmacotherapies for NF2. The aim of this study was to evaluate the antitumor efficacy of Qu-Du-San-Jie (QDSJ) decoction, a traditional Chinese medicine formula, on NF2-associated VS and to investigate the potential underlying mechanisms. Methods: Ultra high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) analysis was performed to identify the components of QDSJ and their targets. To determine the relationships between the putative targets of QDSJ and the differential genes of NF2-associated VS, the drug-disease crossover genes were screened using the UHPLC-MS data combined with our previous gene expression profiling data. The differentially expressed genes were imported into the STRING database to generate a PPI network. Differentially expressed gene targets and pathways were identified using GO and KEGG pathway enrichment analyses. The in vitro and in vivo drug efficacy of QDSJ decoction was tested using a patient-derived schwannoma cell line and a patient-derived xenograft mouse model, respectively. H&E staining, immunochemistry, and immunofluorescence staining were used to evaluate the cell proliferation and tumor vessels. Results: A total of 133 compounds were identified in QDSJ decoction using UHPLC-MS analysis. Network pharmacology showed that the regulation of necroptosis, apoptosis, cell cycle, angiogenesis, adherens junction, and neuroactive ligand-receptor interaction could be associated with the efficacy of QDSJ in treating NF2-associated VS. Treatment with QDSJ induced necrotic cell death and apoptosis of schwannoma cells in vitro and suppressed the tumor growth in vivo. Histopathological analysis revealed areas of cell necrosis and enlarged tumor blood vessels in the QDSJ-treated tumors. The numbers of cells positive for Cyclin D1 and Ki-67 were significantly reduced in QDSJ-treated tumors compared to control tumors. Immunofluorescence staining of CD31 and αSMA showed a decreased number and density of tumor vessels and normalized vessel structure in QDSJ-treated tumors. Conclusion: Our study demonstrates that QDSJ decoction shows significant antitumor activity against NF2-associated schwannoma and is a possible candidate for future clinical trials.