Drug resistance mechanisms in dopamine agonist-resistant prolactin pituitary neuroendocrine tumors and exploration for new drugs.

BACKGROUND: The treatment of dopamine agonists (DA) resistant prolactinomas remains a formidable challenge, as the mechanism of resistance is still unclear, and there are currently no viable alternative drug therapies available. This study seeks to investigate the mechanism of DA resistance in prolactinomas and identify new potentially effective drugs. METHODS: To explore the mechanism of DA resistance in prolactinomas, this study conducted transcriptome sequencing analysis on 27 cases of DA-resistant prolactinomas and 10 cases of sensitive prolactinomas. In addition, single-cell sequencing analysis was performed on 3 cases of DA-resistant prolactinomas and 3 cases of sensitive prolactinomas. Furthermore, to screen for potential therapeutic drugs, the study successfully established an organoids model for DA-resistant prolactinomas and screened 180 small molecule compounds using 8 organoids. The efficacy of the identified drugs was verified through various assays, including CCK-8, colony formation, CTG, and flow cytometry, and their mechanisms of action were confirmed through WB and IHC. The effectiveness of the identified drugs was evaluated both in vitro and in vivo. RESULTS: The results of transcriptome sequencing and single-cell sequencing analyses showed that DA resistance in prolactinomas is associated with the upregulation of the Focal Adhesion (FA) signaling pathway. Additionally, immunohistochemical validation revealed that FAK and Paxillin were significantly upregulated in DA-resistant prolactinomas. Screening of 180 small molecule compounds using 8 organoids identified Genistein as a potentially effective drug for DA-resistant prolactinomas. Experimental validation demonstrated that Genistein inhibited the proliferation of pituitary tumor cell lines and organoids and promoted apoptosis in pituitary tumor cells. Moreover, both the cell sequencing results and WB validation results of the drug-treated cells indicated that Genistein exerts its anti-tumor effect by inhibiting the FA pathway. In vivo, experiments also showed that Genistein can inhibit subcutaneous tumor formation. CONCLUSION: DA resistance in prolactinomas is associated with upregulation of the Focal Adhesion (FA) signaling pathway, and Genistein can exert its anti-tumor effect by inhibiting the expression of the FA pathway.

The effect of endoscopic transsphenoidal somatotroph tumors resection on pituitary hormones: systematic review and meta-analysis.

PURPOSE: Currently, endoscopic transsphenoidal surgery is the main treatment for pituitary neuroendocrine tumors (PitNETs). Excision of the tumor may have positive or negative effects on pituitary endocrine function, and the pituitary function of somatotroph tumors is a point of particular concern after the operation. This study aimed to conduct a meta-analysis on the effect of endoscopic transsphenoidal somatotroph tumor resection on pituitary function. METHODS: A systematic literature search was conducted for articles that included the evaluation of pituitary target gland before and after endoscopic transsphenoidal pituitary tumor resection and were published between 1992 and 2022 in PubMed, Cochrane, and Ovid MEDLINE. RESULTS: Sixty-eight studies that included biochemical remission rates in 4524 somatotroph tumors were concluded. According to the 2000 consensus, the biochemical remission rate after transsphenoidal endoscopic surgery was 66.4% (95% CI, 0.622-0.703; P = 0.000), the biochemical remission rate was 56.2% according to the 2010 consensus (95% CI, 0.503-0.620; P = 0.041), and with the rate of biochemical remission ranging from 30.0 to 91.7% with investigator's definition. After endoscopic resection, adrenal axis dysfunction was slightly higher than that before surgery, but the difference was not statistically significant. Hypothyroidism was 0.712 times higher risk than that before surgery (OR = 0.712; 95% CI, 0.527-0.961; P = 0.027). Hypogonadism was 0.541 times higher risk than that before surgery (OR = 0.541; 95% CI, 0.393-0.746; P = 0.000). Hyperprolactinemia was 0.131 times higher risk than that before surgery (OR = 0.131; 95% CI, 0.022-0.783; P = 0.026). The incidence of pituitary insufficiency was 1.344 times the risk before surgery after endoscopic resection of somatotroph tumors, but the difference was not statistically significant. CONCLUSIONS: In patients with somatotroph tumors after undergoing endoscopic surgery, the risk of dysfunction and pituitary insufficiency tend to increase, while preoperative thyroid insufficiency, gonadal insufficiency, and hyperprolactinemia will be partially relieved.

Analysis of the Prognostic and Immunological Role of HSPB1 in Pituitary Adenoma: A Potential Target for Therapy.

Background and Objectives: The diagnosis and treatment of pituitary adenomas with cavernous sinus invasion pose significant challenges for clinicians. The objective of this study is to investigate the expression profile and prognostic value of HSPB1 (heat shock protein beta-1) in pituitary adenomas with invasive and non-invasive features. Additionally, we aim to explore the potential relationship between HSPB1 expression and immunological functions in pituitary adenoma. Materials and Methods: A total of 159 pituitary adenoma specimens (73 invasive tumours and 86 non-invasive tumours) underwent whole-transcriptome sequencing. Differentially expressed genes and pathways in invasive and non-invasive tumours were analysed. HSPB1 was subjected to adequate bioinformatics analysis using various databases such as TIMER, Xiantao and TISIDB. We investigated the correlation between HSPB1 expression and immune infiltration in cancers and predicted the target drug of HSPB1 using the TISIDB database. Results: HSPB1 expression was upregulated in invasive pituitary adenomas and affected immune cell infiltration. HSPB1 was significantly highly expressed in most tumours compared to normal tissues. High expression of HSPB1 was significantly associated with poorer overall survival. HSPB1 was involved in the regulation of the immune system in most cancers. The drugs DB11638, DB06094 and DB12695 could act as inhibitors of HSPB1. Conclusions: HSPB1 may serve as an important marker for invasive pituitary adenomas and promote tumour progression by modulating the immune system. Inhibitors of HSPB1 expression are currently available, making it a potential target for therapy in invasive pituitary adenoma.

The intestinal flora of patients with GHPA affects the growth and the expression of PD-L1 of tumor.

CONTEXT: Pituitary adenoma (PA) is a common intracranial tumor. The evidence indicates that the tumor immune microenvironment (TIME) is associated with PA and that the intestinal flora influences other tumors' growth through interacting with the TIME. However, how the intestinal microbial flora contributes to the development of PA through the immune response is unknown. OBJECTIVE AND METHODS: Here we used high-throughput Illumina MiSeq sequencing targeting the V3-V4 region of the 16S ribosomal RNA gene to investigate the intestinal flora of patients with growth hormone-secreting pituitary adenoma (GHPA), nonfunctional pituitary adenoma (NFPA), and healthy controls. We determined their effects on tumor growth and the TIME. Fecal microbiota transplantation (FMT) was performed after adoptive transfer via peripheral blood mononuclear cells to tumor-bearing nude mice, which allowed the study of the immune response. RESULT: We discovered differences in the structures and quantities of intestinal flora between patients with GHPA, patients with NFPA, and healthy controls. After FMT, the intestinal flora of GHPA patients promoted the growth of tumors in mouse models. The number of programmed cell death ligand 1 (PD-L1)-positive cells increased in tumor tissues as well as the extent of infiltration of CD8+ cells. Increased numbers of CD3+CD8+ cells and increased levels of sPD-L1 were detected in peripheral blood. CONCLUSION: These findings indicated that the intestinal flora of patients with GHPA promoted tumor growth and that the immune system may mediate this change.

Radiomic Features on Multiparametric MRI for Preoperative Evaluation of Pituitary Macroadenomas Consistency: Preliminary Findings.

BACKGROUND: Preoperative assessment of the consistency of pituitary macroadenomas (PMA) might be needed for surgical planning. PURPOSE: To investigate the diagnostic performance of radiomics models based on multiparametric magnetic resonance imaging (mpMRI) for preoperatively evaluating the tumor consistency of PMA. STUDY TYPE: Retrospective. POPULATION: One hundred and fifty-six PMA patients (soft consistency, N = 104 vs. hard consistency, N = 52), divided into training (N = 108) and test (N = 48) cohorts. The tumor consistency was determined on surgical findings. FIELD STRENGTH/SEQUENCE: T1-weighted imaging (T1WI), contrast-enhanced T1WI (T1CE), and T2-weighted imaging (T2WI) using spin-echo sequences with a 3.0-T scanner. ASSESSMENT: An automated three-dimensional (3D) segmentation was performed to generate the volume of interest (VOI) on T2WI, then T1WI/T1CE were coregistered to T2WI. A total of 388 radiomic features were extracted on each VOI of mpMRI. The top-discriminative features were identified using the minimum-redundancy maximum-relevance method and 0.632+ bootstrapping. The radiomics models based on each sequence and their combinations were established via the random forest (RF) and support vector machine (SVM), and independently evaluated for their ability in distinguishing PMA consistency. STATISTICAL TESTS: Mann-Whitney U-test and Chi-square test were used for comparison analysis. The area under the receiver operating characteristic curve (AUC), accuracy (ACC), sensitivity (SEN), specificity (SPE), and relative standard deviation (RSD) were calculated to evaluate each model's performance. ACC with P-value<0.05 was considered statistically significant. RESULTS: Eleven mpMRI-based features exhibited statistically significant differences between soft and hard PMA in the training cohort. The radiomics model built on combined T1WI/T1CE/T2WI demonstrated the best performance among all the radiomics models with an AUC of 0.90 (95% confidence interval [CI]: 0.87-0.92), ACC of 0.87 (CI: 0.84-0.89), SEN of 0.83 (CI: 0.81-0.85), and SPE of 0.87 (CI: 0.85-0.99) in the test cohort. DATA CONCLUSION: Radiomic features based on mpMRI have good performance in the presurgical evaluation of PMA consistency. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Feasibility of endoscopic endonasal resection of intrinsic third ventricular craniopharyngioma in adults.

Intrinsic third ventricular craniopharyngiomas (IVCs) are usually considered as a contraindication of endoscopic endonasal approach (EEA). The aim of this study is to evaluate the safety and feasibility of EEA for the resection of IVCs based on MRI topographical diagnosis and surgical findings. We reviewed the data of 22 patients who were diagnosed to be IVCs according to five MRI criteria and underwent surgery through EEA. Sixteen IVCs were resected using endoscopic endonasal infrachiasmatic corridor, five IVCs by using endoscopic endonasal suprachiasmatic trans-lamina terminalis corridor, and one IVC by using both the infrachiasmatic and suprachiasmatic corridors. During the operation, all the 22 cases were verified to be IVCs. Gross total resection was achieved in 21 (95.5%) patients. After surgery, visual improvement was observed in 14 (63.6%) patients, no change in 6 (27.3%) patients, and some deterioration in 2 (9.1%) patients. An improvement in intellectual ability was observed in nine (40.9%) patients, no change in twelve (54.5%) patients, and some deterioration in one (4.5%) patient. Fifteen of the 22 patients (68.2%) developed new endocrinological deficit. One postoperative cerebral spinal fluid leakage occurred. EEA can be used as a safe and efficacious approach for the radical resection of IVCs. The combination of the five MRI criteria may serve as an accurate preoperative diagnostic tool to define the topographical relationships between craniopharyngiomas and the third ventricle. The endoscopic transnasal view from below has the advantage of clarifying the relationship between tumors and the third ventricle floor.

Mid-term follow-up surgical results in 284 cases of clival chordomas: the risk factors for outcome and tumor recurrence.

OBJECTIVE: Skull base chordoma (SBC) is rare and one of the most challenging diseases to treat. We aimed to assess the optimal timing of adjuvant radiation therapy (RT) and to evaluate the factors that influence resection and long-term outcomes. METHODS: In total, 284 patients with 382 surgeries were enrolled in this retrospective study. Postsurgically, 64 patients underwent RT before recurrence (pre-recurrence RT), and 47 patients underwent RT after recurrence. During the first attempt to achieve gross-total resection (GTR), when the entire tumor was resected, 268 patients were treated with an endoscopic midline approach, and 16 patients were treated with microscopic lateral approaches. Factors associated with the success of GTR were identified using χ2 and logistic regression analyses. Risk factors associated with chordoma-specific survival (CSS) and progression-free survival (PFS) were evaluated with the Cox proportional hazards model. RESULTS: In total, 74.6% of tumors were marginally resected [GTR (40.1%), near-total resection (34.5%)]. History of surgery, large tumor volumes, and tumor locations in the lower clivus were associated with a lower GTR rate. The mean follow-up period was 43.9 months. At the last follow-up, 181 (63.7%) patients were alive. RT history, histologic subtype (dedifferentiated and sarcomatoid), non-GTR, no postsurgical RT, and the presence of metastasis were associated with poorer CSS. Patients with pre-recurrence RT had the longest PFS and CSS, while patients without postsurgical RT had the worst outcome. CONCLUSION: GTR is the goal of initial surgical treatment. Pre-recurrence RT would improve outcome regardless of GTR.

The Clinical Features and Molecular Mechanism of Pituitary Adenoma Associated With Vestibular Schwannoma.

OBJECTIVES: To explore the clinical features and mechanism of pituitary adenoma associated with vestibular schwannoma (PAVS). PATIENTS AND METHODS: The authors retrospectively reviewed pituitary adenoma patients in Beijing Tiantan Hospital from January 1, 2008 to December 31, 2016. A total of two pituitary adenoma samples, 1 vestibular schwannoma sample and one paired pituitary adenoma/blood sample were subjected next-generation sequencing and sanger sequence. RESULTS: A total of 5675 pituitary adenoma patients from January 1, 2008 to December 31, 2016, were retrospectively analyzed; of these, 4 (7%) patients met the criteria of PAVS. Clinical variable analyses revealed significant correlations between PAVS and older age when compared with sporadic pituitary adenoma (SPA) or sporadic vestibular schwannoma (SVS). The authors found that there were 2 germline mutations of XKR3 in 2/4 PAVS patients. Therefore, the authors speculated that XKR3 might be a genetic predisposition factor. The result also showed that there was no NF2 mutation and NF2-related symptom in the 4 PAVS samples. CONCLUSIONS: PAVS had a significant correlation with older age when compared with SPA and SVS. XKR3 may be a genetic predisposition factor for PAVS, it represents a therapeutic target for PAVS in the future.

Development and Application of Three Steps Training Mode for Endoscopic Transnasal Transsphenoidal Approach.

OBJECTIVE: The model of endoscopic transnasal transsphenoidal approach (METTA) were made and the application of the 3-steps training mode in the endoscopic transnasal transsphenoidal approach (ETTA) training was discussed. METHODS: The plastic skull model was used to make a simple METTA model; the multicolor and multi-material 3D printing technology was used to make a METTA simulation model and the perfusion cadaver head specimen was used as the gold standard training model. Then 3 neurosurgeons evaluated the 3 types of models. Level 1 training group only received perfusion cadaveric head specimen training; level 2 training group with 3D printing METTA model plus cadaver head specimen training, and level 3 training group with simple model, 3D printing model and cadaver head specimen training group. The authenticity of the model and the training effect were evaluated according to the operation time and the damage degree to the surrounding structures. RESULTS: The results showed that perfusion cadaveric head specimens scored the highest in each item. The simplified model was superior to the 3D printing METTA in simulating the shape and elasticity of pituitary tumor tissue. The score of surgical skill training was the same as that of 3D printing METTA. In terms of the training effect, the doctors who had received 3 steps training had the highest score, which was better than the other 2 groups. CONCLUSIONS: The application of 3 steps training mode with simple training model, 3D printing model and perfusion cadaver head specimen can improve the effect of ETTA operation training.

Experience of Endoscopic Endonasal Approach for 803 Pituitary Tumors With Cavernous Sinus Invasion.

OBJECTIVE: The aim of this study was to investigate the effectiveness, safety, complications, and prognosis of endoscopic endonasal surgery for pituitary adenomas with cavernous sinus invasion (CSI). METHODS: The clinical data of 803 pituitary adenomas with CSI surgeries performed in our single ward between January 1, 2006 and December 31, 2018 were retrospectively reviewed. The resection degree, bone invasion, endocrine examination, complications, and outcome were retrospectively summarized. RESULTS: Gross total resection was achieved in 394 patients (49.1%) subtotal resection in 171 patients (21.3%) and partial resection in 238 patients (29.6%). Clinically variable analyses showed that there was a significant correlation between CSI and female, older age, operation history, and non-gross total resection (NGTR). Among the pituitary adenomas with CSI, there was a significant correlation between bone invasive and NGTR, Knosp classification, recurrence. K-M curves showed that young age, larger tumors, bilateral invasion, Grade 4 of Knosp classification, NGTR, and bone invasion were associated with pituitary adenomas regrowth. Multivariate analysis revealed that bone invasion, NGTR, and Grade 4 of Knosp classification were independent risk factors for pituitary adenomas regrowth. There was a significant correlation between CSI and female, older age, operation history, and tumor resection degree. CONCLUSIONS: There was a significant correlation between CSI and female, older age, operation history, and tumor resection degree. The patients with CSI and bone invasion were likely to recurrent. Non-gross total resection, bone invasion, and Grade 4 of Knosp classification were independent risk factors for pituitary adenomas regrowth. Endoscopic endonasal surgery is an excellent choice for pituitary adenomas with CSI.

LncRNA PCAT6 regulates the progression of pituitary adenomas by regulating the miR-139-3p/BRD4 axis.

BACKGROUND: Dysregulated lncRNA PCAT6 was discovered in many cancers excluding pituitary adenomas (PA). Therefore, we explored the role of PCAT6 in PA in this research. METHODS: Abnormally expressed miRNAs were analyzed by bioinformatics and RT-qPCR. The target and regulator of miR-139-3p were determined by bioinformatics, dual-luciferase reporter assay, or RIP. The correlation among PCAT6, miR-139-3p, and BRD4 was further analyzed. The viability, apoptosis, cell cycle distribution of PA cells, as well as their ability to invade, migrate, and proliferate, were tested after transfection through CCK-8, flow cytometry, transwell, wound healing, and colony formation assays. After construction of transplanted-tumor model in nude mice, cell apoptosis in the tumor was detected by TUNEL. The expressions of PCAT6, BRD4, miR-139-3p, and apoptosis-related factors in PA tissues, cells, or tumor tissues were detected by RT-qPCR, Western blot, or IHC. RESULTS: PCAT6 and BRD4 were high-expressed but miR-139-3p was low-expressed in PA. Both the 3'-untranslated regions of PCAT6 and BRD4 mRNAs were demonstrated to contain a potential binding site for miR-139-3p. PCAT6 was positively correlated to BRD4, and miR-139-3p was negatively correlated to PCAT6 and BRD4. MiR-139-3p mimic, shPCAT6 and siBRD4 inhibited the viability, migration, invasion, and proliferation of PA cells while inducing apoptosis. MiR-139-3p mimic and shPCAT6 inhibited the cell cycle progression of PA cells, decreased the weight and volume of the xenotransplanted tumor, and reduced the levels of Bcl-2 and BRD4 while enhancing the levels of Bax, miR-139-3p, and Cleaved caspase-3. MiR-139-3p inhibitor caused the opposite effect of miR-139-3p mimic and further reversed the effect of shPCAT6 on on PA cells. CONCLUSION: PCAT6 regulated the progression of PA via modulating the miR-139-3p/BRD4 axis, which might provide a novel biomarker for the prevention, diagnosis, and treatment of PA.

Up-regulation of the expressions of MiR-149-5p and MiR-99a-3p in exosome inhibits the progress of pituitary adenomas.

This study explored the function of microRNAs (miRNAs) in invasive pituitary adenomas (IPA), and developed a microRNA-exosome strategy for the disease treatment. Differentially expressed miRNAs and tumor-associated markers in IPA, non-invasive pituitary adenoma (NIPA), and rat pituitary adenoma cells were identified by bioinformatics analysis and qRT-PCR. Then, the cells were treated by miR-149-5p and miR-99a-3p mimics or inhibitors, or incubated with modified exosome with overexpressed or silenced miRNAs. The cell behaviors were analyzed by molecular experiments. Xenograft assays were constructed by injection of pituitary adenoma cells and exosome into NU/NU nude mice. Tumor size, weight, and expressions of markers related to miRNAs and angiogenesis were determined. Target genes for miR-99a-3p and miR-149 were predicted and verified by bioinformatics analysis and molecular experiments. Twenty differentially expressed miRNAs were identified, among which miR-99a-3p and miR-149 were inhibited in both pituitary adenoma cells and tissues significantly. Expressions of E-cadherin and p53 were down-regulated, while those of MMP-2, MMP-9, N-cadherin, Vimentin, and VEGF were up-regulated in pituitary adenoma cells and tissues, especially in IPA. Further experiments revealed that overexpressed miR-149 and miR-99a-3p inhibited the growth and metastasis of pituitary adenoma cells and tube formation of endothelial cells. MiR-149 and miR-99a-3p overexpressed by exosome showed similar suppressive effects on cell viability, metastasis, tube formation ability, in vivo tumor growth, and expressions of angiogenesis-related markers. Further analysis showed that NOVA1, DTL, and RAB27B were targeted by miR-99a-3p. This study found that overexpressed miR-149-5p and miR-99a-3p induced by exosome could suppress the progression of IPA. 1. MiR-149-5p and miR-99a-3p affect the expression of EMT- and ECM-related markers and tumor-related genes in rat pituitary adenoma cells treated with exosomes. 2. Exosome inhibited the tumor growth. 3. Overexpressed miR-149-5p and miR-99a-3p induced by exosome.

Suprasellar arachnoid cysts: systematic analysis of 247 cases with long-term follow-up.

At present, limited data exists to discuss the characteristics of suprasellar arachnoid cysts (SACs). The aim of this study is to elucidate the relationship between characteristics of cysts and outcomes, quantitatively analyze improvement in hydrocephalus, and evaluate the risk factors for the prognosis of SACs treated by endoscope. From June 2002 to 2017 December, 247 cases of SACs treated by endoscope in Beijing Tiantan Hospital were included in this study. The severity of hydrocephalus was evaluated by Evans' index (EI). The results showed that the slit-valve and the transparent/thin membrane were noted in 86.2% and 76.5% of overall patients, respectively, and the distribution differences among age-groups were statistically significant (p < 0.01). After a mean follow-up duration of 73.1 months, 18 patients underwent a reoperation. Ventriculocystostomy (VC) (hazard ratio (HR), 3.37; 95% confidence interval (CI), 1.2-9.47; p = 0.024) and history of treatment (HR, 3.98; 95% CI, 1.31-12.31; p = 0.015) were adverse factors for reoperation rate. MRI at 1-year follow-up revealed mean decreases of 78.4% and 9.13% in cyst size and EI. No paraventricular edema was an adverse factor associated with the improvement in hydrocephalus (HR, 11.22; 95% CI, 5.43-23.18; p < 0.01). These results indicated that ventriculocystocisternostomy (VCC) and no history of treatment is favorable factors for prognosis of SACs treated by endoscope. If feasible, VCC is the optimal choice for SACs. Slit-valve phenomenon and transparent/thin membrane are correlated with age but did not influence the outcomes of endoscopic fenestration. The mechanism for the expansion of cysts may be different between child and adult patients. Paraventricular edema is a favorable factor for the improvement in hydrocephalus after endoscopic surgery.

Suprasellar arachnoid cysts in adults: clinical presentations, radiological features, and treatment outcomes.

A tendency for suprasellar arachnoid cysts (SACs) to occur in young children is known. Data of adult SACs were rare in previous reports. The aim of this study is to discuss their clinical presentations, radiological features, and treatment outcomes based on 23 adult patients who underwent endoscopic fenestration in our hospital between January 2003 and December 2018. Preoperative cyst volume ranged from 12.3 to 72.5 cm3 (mean 39.8 ± 19.8). Endocrine disorders occurred in 7 (30.4%) patients. Hydrocephalus was observed in 20 patients. In the patients with hydrocephalus, the mean preoperative Evans' index (EI) (%) and frontooccipital horn ratio (FOHR) (%) were 44.8 (ranged 32.2-63.4) and 49.6 (ranged 36.7-59.8), respectively. A bivariate correlation showed significant positive association between preoperative cyst volume and preoperative EI or FOHR (Pearson correlation, r = 0.607, p = 0.005; r = 0.583, p = 0.007). The slit-valve phenomenon was observed in 13 (56.5%) patients. Pale/tenacious cyst walls were observed in 12 (52.2%) patients. Postoperatively, all patients achieved the improvement in clinical symptoms and a decrease in cyst size. The mean decreases in cyst volume, EI, and FOHR were 64.7%, 7.89%, and 5.8%, respectively. A bivariate correlation indicated the irrelevance between the postoperative cyst volume and postoperative EI or FOHR (Pearson correlation: r = 0.37, p = 0.11; r = 0.43, p = 0.054). These results reveal that there are a few differences in several aspects between adult patients and child patients. The severity of hydrocephalus is correlated with cyst size in adult patients. Additionally, the excellent outcomes in adult SACs can be obtained by endoscopic fenestration.

Research advances on the immune research and prospect of immunotherapy in pituitary adenomas.

BACKGROUND: Pituitary adenomas are one type of intracranial tumor, which can be divided into microadenoma (≤ 1 cm), macroadenoma (> 1 cm), and giant adenoma (≥ 4 cm) according to their diametral sizes. They are benign, typically slow-progressing, whereas the biological behavior of some of them is invasive, which presents a major clinical challenge. Treatment of some pituitary adenomas is still difficult due to drug resistance or multiple relapses, usually after surgery, medication, and radiation. At present, no clear prediction and treatment biomarkers have been found in pituitary adenomas and some of them do not cause clinical symptoms, so patients are often found to be ill through physical examination, and some are even found through autopsy. With the development of research on pituitary adenomas, the immune response has become a hot spot and may serve as a novel disease marker and therapeutic target. The distribution and function of immune cells and their secreted molecules in pituitary adenomas are extremely complex. Researchers found that infiltration of immune cells may have a positive effect on the treatment and prognosis of pituitary adenomas. In this review, we summarized the advance of tumor immunity in pituitary adenomas, revealing the immunity molecules as potential biomarkers as well as therapeutic agents for pituitary adenomas. CONCLUSION: The immune studies related to pituitary adenomas may help us find relevant immune markers. At the same time, the exploration of immunotherapy also provides new options for the treatment of pituitary adenomas.

Pituitary metastasis from renal cell carcinoma: case report and review of the literature.

Pituitary metastasis(PM) from renal cell carcinoma(RCC) is rare, and is easy to be misdiagnosed. Here, we present a case of pituitary metastasis from clear-cell renal cell carcinoma(ccRCC) which was difficult to distinguish from other sellar region tumors. In addition, we systematically review the literature to find the characteristics of different tumors of the sellar region. It provides a new idea for the diagnosis of sellar region tumors in the clinic.

Untargeted Lipidomics Reveals Specific Lipid Abnormalities in Nonfunctioning Human Pituitary Adenomas.

The pituitary gland is a small but important organ located in the base of the brain. Although mostly noncancerous, pituitary adenomas (PAs) can cause serious health problems such as headaches, visual field defects, double vision, and hypopituitarism by invasion of regional structures. Nonfunctioning PAs (NFPAs) approximately account for one-third of PAs manifested by no circulating hormone hypersecretion. Lipid reprogramming has been recognized as a hallmark of tumor cells and proven to play a crucial role in tumorigenesis. However, the lipid molecular pathogenesis of NFPAs has remained obscure to date. To uncover lipid alterations that may contribute to the development of NFPAs and define their molecular characteristics, we investigated tissue lipids of patients with NFPAs including eight null cell adenomas (NCAs) and eight oncocytomas (OCMs) and of five normal pituitary glands as the control (Ctrl) using nontargeted lipidomics based on ultrahigh-performance liquid chromatography-Orbitrap Q-Exactive HF mass spectrometry. The lipidomic results were further validated in another set of subjects consisting of 8 NCAs, 10 OCMs, and 6 Ctrls to define crucial lipids discriminating NFPAs from the normal pituitary tumors. Lipidomic analyses revealed that OCM showed more pronounced changes in lipid compositions than NCA and Ctrl. As expected, mitochondria abundant cardiolipins were remarkably increased in OCM, which was accordant with the biochemical evidence of mitochondria hyperplasia in OCM. Significantly increased levels of phospholipids (PLs), especially arachidonic acid (AA)-enriched PLs, were unique characteristics of lipid profiling in OCM vs Ctrl. Our results indicate that AA-PLs may have diagnostic potential for OCM.

Mean platelet volume and platelet distribution width serve as prognostic biomarkers in skull base chordoma: a retrospective study.

BACKGROUND: Increasing studies have demonstrated that activated platelets play an essential role in tumour progression. However, the level and prognostic role of platelet indices in chordoma patients remain unclear. The aim of the current study was to characterize the prognostic performance of platelet count (PLT), mean platelet volume (MPV) and platelet distribution width (PDW) in skull base chordoma patients. METHODS: 187 primary skull base chordoma patients between January 2008 and September 2014 were enrolled in this retrospective study. The optimal cut-off values were determined by X-tile software, and the correlations between PLT, MPV, PDW and clinicopathological features were further analysed. Kaplan-Meier curve and Cox regression analysis were used for survival analysis. RESULTS: The values of preoperative PTL, MPV and PDW ranged from 104 to 501 × 109/L, 6.7 to 14.2 fl, and 7.8 to 26.2%, respectively. Elevated PLT was associated with larger tumour volume (p = 0.002). Kaplan-Meier survival analysis revealed that increased MPV and PDW were associated with shorter overall survival (p = 0.022 and 0.008, respectively). Importantly, multivariate Cox analysis demonstrated that elevated PDW was an independent unfavourable predictive factor for overall survival (hazard ratio (HR), 2.154, 95% confidence interval (CI), 1.258-3.688, p = 0.005). CONCLUSIONS: Our data show that elevated MPV and PDW are associated with poor outcomes in skull base chordoma and that PDW may be helpful to identify patients with high risk.

A good choice for the patients with prior failed ventriculoperitoneal shunt treatment of suprasellar arachnoid cysts: endoscopic fenestration.

To investigate the effectiveness of endoscopic fenestration in the patients with prior failed ventriculoperitoneal (VP) shunt treatment of suprasellar arachnoid cysts (SACs). Between 2012 and 2018, four pediatric patients of SACs with previous failed VP shunt treatment were surgically treated using endoscopic ventriculocystocisternostomy (VCC) in our hospital. The clinical symptoms, imaging data, and surgical outcomes were collected and analyzed retrospectively. A literature review is provided with regard to the reasons of shunt failure and surgical outcome of further endoscopic fenestration in the previously reported patients of SACs with prior failed VP shunt. For the 4 cases, the initial clinical symptoms relieved or even disappeared after shunt placement, but, respectively, recurred 2, 6, 11, and 6 months later. MR scans were conducted when the clinical symptoms reappeared and showed a cyst had greatly enlarged after shunt placement. Furthermore, VP shunt-related slit ventricle was also demonstrated in 3 cases. Clinical improvement and cysts shrinkage occurred in all 4 patients after VCC. Slit ventricle and hydrocephalus were also resolved. Three patients had their shunt apparatus removed after VCC, and another patient's guardian refused to remove the shunt apparatus. Subdural hematoma occurred in one case after shunt apparatus removal. Four patients have been stable during follow-up period (mean follow-up 26.5 months). All the three patients whose VP shunt were removed were shunt independence. There were 24 patients who underwent endoscopic fenestration as an alternative to the failed VP shunt treatment in the published reports. Added our 4 patients to the published group, the effective rate of endoscopic fenestration for SACs following previous failed VP shunt treatment was approximately 93% (26/28). Of the 24 patients, the shunt apparatuses were in situ or reimplantation in 9 patients due to shunt dependence. The correction to recognize the SAC is the first condition to select the optimal management philosophy. The analysis of the series suggests endoscopic operation is still an effective and safe option in the SAC patients with previous failed VP shunt, and the shunt apparatus can be removed for some patients. The short interval time between shunt operation and endoscopic fenestration is conductive to return patients to the shunt-free state.

Identification of key genes in invasive clinically non-functioning pituitary adenoma by integrating analysis of DNA methylation and mRNA expression profiles.

BACKGROUND: Tumor surrounding the internal carotid artery or invading to the cavernous sinus is an important characteristic of invasive pituitary adenoma, and a pivotal factor of tumor residue and regrowth. Without specific changes in serum hormone related to the adenohypophyseal cell of origin, clinically non-functioning pituitary adenoma is more likely to be diagnosed at invasive stages compared with functioning pituitary adenoma. The underlying mechanism of tumor invasion remains unknown. In this study, we aimed to identify key genes in tumor invasion by integrating analyses of DNA methylation and gene expression profiles. METHOD: Genome-wide DNA methylation and mRNA microarray analysis were performed for tumor samples from 68 patients at the Beijing Tiantan Hospital. Differentially expressed genes and methylated probes were identified based on an invasive vs non-invasive grouping. Differentially methylated probes in the promoter region of targeted genes were assessed. Pearson correlation analysis was used to identify genes with a strong association between DNA methylation status and expression levels. Pyrosequencing and RT-PCR were used to validate the methylation status and expression levels of candidate genes, respectively. RESULTS: A total of 8842 differentially methylated probes, located on 4582 genes, and 661 differentially expressed genes were identified. Both promoter methylation and expression alterations were observed for 115 genes with 58 genes showing a negative correlation between DNA methylation status and expression level. Nineteen genes that exhibited notably negative correlations between DNA methylation and gene expression levels, are involved in various gene ontologies and pathways, or played an important role in different diseases, were regarded as candidate genes. We found an increased methylation with a decreased expression of PHYHD1, LTBR, C22orf42, PRR5, ANKDD1A, RAB13, CAMKV, KIFC3, WNT4 and STAT6, and a decreased methylation with an increased expression of MYBPHL. The methylation status and expression levels of these genes were validated by pyrosequencing and RT-PCR. CONCLUSIONS: The DNA methylation and expression levels of PHYHD1, LTBR, MYBPHL, C22orf42, PRR5, ANKDD1A, RAB13, CAMKV, KIFC3, WNT4 and STAT6 are associated with tumor invasion, and these genes may become the potential genes for targeted therapy.