Molecular landscape of IDH-mutant astrocytoma and oligodendroglioma grade 2 indicate tumor purity as an underlying genomic factor.

BACKGROUND: IDH-mutant astrocytoma and oligodendroglioma have an indolent natural history and are recognized as distinct entities of neoplasms. There is little knowledge on the molecular differences between IDH-mutant astrocytoma and oligodendroglioma grade 2. Therefore, we investigated the multiomics and clinical data regarding these two types of tumors. METHOD: In silico analyses were performed around mRNA, somatic mutations, copy number alternations (CNAs), DNA methylation, microRNA (miRNA), epigenetics, immune microenvironment characterization and clinical features of the two types of gliomas. A diagnostic model incorporating tumor purity was further established using machine learning algorithms, and the predictive value was evaluated by receiver operative characteristic curves. RESULTS: Both types of gliomas shared chromosomal instability, and astrocytomas exhibited increased total CNAs compared to oligodendrogliomas. Oligodendrogliomas displayed distinct chromosome 4 (chr 4) loss, and subtyping of chr 7 gain/chr 4 loss (+ 7/- 4) presented the worst survival (P = 0.004) and progression-free interval (PFI) (P < 0.001). In DNA damage signatures, oligodendroglioma had a higher subclonal genome fraction (P < 0.001) and tumor purity (P = 0.001), and astrocytoma had a higher aneuploidy score (P < 0.001). Furthermore, astrocytomas exhibited inflamed immune cell infiltration, activated T cells and a potential response to immune checkpoint inhibitors (ICIs), while oligodendrogliomas were more homogeneous with increased tumor purity and decreased aggression. The tumor purity-involved diagnostic model exhibited great accuracy in identifying astrocytoma and oligodendroglioma. CONCLUSION: This study addresses the similarities and differences between IDH-mutant astrocytoma and oligodendroglioma grade 2 and facilitates a deeper understanding of their molecular features, immune microenvironment, tumor purity and prognosis. The diagnostic tool developed using machine learning may offer support for clinical decisions.

Systematic identification, development, and validation of prognostic biomarkers involving the tumor-immune microenvironment for glioblastoma.

Gliomas are infiltrative neoplasms with a highly invasive nature. Due to its distinct genomic, genetic and epigenetic features, the immune prognostic signature (IPS) and immune microenvironment of glioblastoma (GBM) merit further research. We aimed to explore prognosis-related immune genes and develop an IPS model for predicting prognosis in GBM. RNA-sequencing data, as well as clinical information, from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) public cohorts were analyzed. To develop the IPS, least absolute shrinkage and selection operator (LASSO) Cox analysis was performed for immune-related genes that were differentially expressed between GBM and normal tissues. Then, interaction effects of the IPS on the immune microenvironment were systematically analyzed; the precise prognostic model was developed based on the IPS and clinical data and was then further validated. A total of 21 immune prognostic genes were identified based on GBM microenvironment status. An 8-gene IPS was established, and the GBM patients were effectively stratified into low- and high-risk groups in the TCGA cohort as a training set. Univariate and multivariate Cox analyses revealed that IPS was an independent prognostic factor, and the prognostic performance of individual IPS genes was systematically illustrated. In addition, a comprehensive and novel nomogram model was initially established to estimate overall survival in TCGA-GBM patients, and high-risk patients had higher levels of dendritic cell and neutrophil infiltration. Furthermore, the nomogram model was developed and validated in the CGGA validation set. The low-risk IPS was linked to a stronger response to anti-PD-L1 immunotherapy and clinical advantages in the IMvigor210 cohort. This novel IPS with promising biomarkers classifies GBM patients into subgroups with distinct clinical outcomes and immunophenotypes. Our findings and this resource may help to characterize the immune microenvironment, inform cancer immunotherapy and facilitate the development of precision immuno-oncology.

Predictors of Immediate Remission after Surgery in Cushing's Disease Patients: A Large Retrospective Study from a Single Center.

OBJECTIVE: Transsphenoidal surgery (TSS) is the first-line treatment of patients with Cushing's disease (CD). However, biochemical remission rates after TSS for CD vary from 59 to 95%, and the predictors of surgical outcomes remain unclear. The aim of this study was to identify the predictors of early outcomes in patients with CD treated with TSS. METHODS: The clinical features and outcomes of CD patients who underwent TSS between February 2000 and September 2019 at the Peking Union Medical College Hospital were collected from medical records and analyzed. Uni- and multivariate odds ratio (OR) analyses were performed to identify the predictors of early outcomes in patients with CD. RESULTS: A total of 1,045 patients were included. The median age at TSS was 34.0 years (IQR 26.0-45.0), with a female:male ratio of 4.2:1 (844/201). The median duration of symptoms was 46.0 months (IQR 24.0-72.0). After surgery, the overall postoperative immediate remission rate was 73.3%, and 26.7% of patients had persistent hypercortisolism. Univariate analysis demonstrated that the number of operations was correlated with a lower immediate remission rate (OR 0.393, 95% CI 0.266-0.580, p = 0.000), as was tumor size (OR 0.462, 95% CI 0.334-0.639, p = 0.000), the duration of disease (OR 0.996, 95% CI 0.993-0.999, p = 0.003), and preoperative ACTH concentration (0.998, 95% CI 0.996-0.999, p = 0.003). Cavernous sinus invasion has also been identified as an important factor associated with a lower immediate remission rate (OR 0.275, 95% CI 0.166-0.456, p = 0.000). No correlations were detected between the immediate outcomes and age, gender, BMI, the combination of a low- and high-dose dexamethasone suppression test, preoperative morning serum cortisol level, or 24-h urinary free cortisol level (all p > 0.05). The results of multivariate analysis were similar to those of univariate analysis. Preoperative ACTH ≤67.35 ng/L predicted remission with 60.9% sensitivity and 49.5% specificity (AUC 0.553; p = 0.008). A cutoff of ≤64.5 months for disease duration predicted immediate remission with 40.5% sensitivity and 71.0% specificity (AUC 0.552; p = 0.01). CONCLUSION: Early outcomes of TSS in CD patients can be predicted by factors including the number of operations, duration of disease, tumor invasion, tumor size, and preoperative ACTH concentration. These predictors can be used to improve the perioperative management of CD patients.

A Bayesian network meta-analysis regarding the comparative efficacy of therapeutics for ALK-positive, brain metastatic non-small cell lung cancer.

More clinical evidence is needed regarding the ranking priority of interventions for ALK-positive, brain metastatic (BM) non-small cell lung cancer (NSCLC). Eligible randomized controlled trials (RCTs) were identified. Progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) for the intended populations were analyzed with random effects, Bayesian network meta-analysis with the estimated hazard ratio (HR) and odds ratio (OR) with 95% credible interval (95% CrIs). We included 11 RCTs (2687 NSCLC and 991 BM patients) investigating 7 treatments and 5 medication classes. For PFS for BM patients, lorlatinib (hazard ratio (HR): 0.01, 95% CrI: 0.001-0.12), alectinib (HR: 0.05, 95% CrI: 0.01-0.21) and brigatinib (HR: 0.07, 95% CrI: 0.007-0.76) were top-ranking individual treatments; for ORR for BM patients, brigatinib, lorlatinib and alectinib were top-ranking treatments. For PFS for all NSCLC patients, the top-ranking individual treatments were lorlatinib (HR: 0.05, 95% CrI: 0.02-0.13), alectinib (HR: 0.09, 95% CrI: 0.05-0.18) and brigatinib (HR: 0.11, 95% CrI: 0.05-0.28). For OS for all NSCLC patients, we found that no individual treatments were superior to chemotherapy, whereas the following top-ranking interventions were alectinib (HR: 0.29, 95% CrI: 0.03-1.68), lorlatinib (HR: 0.41, 95% CrI: 0.04-4.13), and ceritinib (HR: 0.63, 95% CrI: 0.10-4.25). The results of individual treatments and medication classes were similar. Data were limited in regard to subgroup analyses and adverse events of BM patients. Lorlatinib has the most statistical superiority for BM patients, but ORR differences between third- and second-generation inhibitors are not obvious. All things considered, alectinib is recommended as first-line treatment, followed by lorlatinib, especially after developing drug resistance to alectinib.

Evolution of a refractory prolactin-secreting pituitary adenoma into a pituitary carcinoma: report of a challenging case and literature review.

BACKGROUND: Pituitary carcinomas (PCs), defined as distant metastases of pituitary neoplasms, are very rare malignancies. Because the clinical presentation of PCs is variable, early diagnosis and management remain challenging. PCs are always refractory to comprehensive treatments, and patients with PCs have extremely poor prognoses. CASE PRESENTATION: We describe one case of a prolactin-secreting pituitary adenoma (PA) refractory to conventional therapy that evolved into a PC with intraspinal metastasis. A 34-year-old female was diagnosed with an invasive prolactin-secreting PA in 2009 and was unresponsive to medical treatment with bromocriptine. The tumor was gross totally removed via transsphenoidal surgery (TSS). However, the patient experienced multiple tumor recurrences or regrowth despite comprehensive treatments, including medical therapy, two gamma knife radiosurgeries (GKSs), and four frontal craniotomies. In 2016, she was found to have an intradural extramedullary mass at the level of the fourth lumbar vertebra. The intraspinal lesion was completely resected and was confirmed as a metastatic PC based on histomorphology and immunohistochemical staining. The literature on the diagnosis, molecular pathogenesis, treatment, and prognosis of patients with prolactin-secreting PCs was reviewed. CONCLUSION: PCs are very rare neoplasms with variable clinical features and poor prognosis. Most PCs usually arise from aggressive PAs refractory to conventional therapy. There is no reliable marker to identify aggressive PAs with a risk for progression to PCs; thus, it is difficult to diagnose these PCs early until the presence of metastatic lesions. It is still very challenging to manage patients with PCs due to a lack of standardized protocols for diagnosis and treatment. Establishing molecular biomarkers and the pathobiology of PCs could help in the early identification of aggressive PAs most likely to evolve into PCs.

Outcomes of Transsphenoidal Surgery in Cushing Disease Patients with Negative Pituitary Magnetic Resonance Imaging Findings: A Single-Center Experience.

OBJECTIVE: Transsphenoidal surgery (TSS) is a first-line treatment for Cushing disease (CD). However, a subset of patients with CD have no visible adenoma on magnetic resonance imaging (MRI), and whether MRI results affect surgical outcomes is controversial. The aim of this study was to compare the surgical outcomes of CD patients with negative MRI findings to those of patients with positive MRI findings. METHODS: The clinical features and outcomes of CD patients who underwent TSS between January 2000 and July 2019 at Peking Union Medical College Hospital were collected from medical records. The clinical, endocrinologic, histopathologic, surgical outcomes, and a minimum 12-month follow-up of 125 consecutive CD patients with negative MRI findings were compared with those of 1,031 consecutive CD patients with MRI-visible adenomas. RESULTS: The total remission rate was 73.3% after TSS, and 11.8% of patients experienced recurrence. Of 1,031 patients with MRI-visible adenomas, postoperative remission was achieved in 762 patients (73.9%), and the recurrence of CD was observed in 94 (12.3%) patients. Of the 125 patients with negative MRI findings, postoperative remission was achieved in 85 (68%) patients, and recurrence was observed in 6 (7.1%) patients. The remission rate and recurrence rate were not significantly different between patients with negative MRI findings and those with positive MRI findings (all P>.05). The remission rate was not significantly different between patients who did or did not undergo bilateral inferior petrosal sinus sampling (BIPSS) in patients with negative MRI findings (P>.05). In the patients with negative MRI findings who underwent BIPSS, the remission rate of patients with positive BIPSS results was not different from that in patients with negative BIPSS results (P>.05). The lack of prior TSS, the detection of a tumor during operation, and pathologic confirmation of adenoma were associated with a higher surgical remission rate in patients with negative MRI findings (all P<.05). Similar results were observed in the patients with positive MRI findings (all P<.05). In addition, the major perioperative complications, including intraoperative cerebrospinal fluid leakage, hypopituitarism, and transient diabetes insipidus, were not related to the MRI results (all P>.05). CONCLUSION: The remission rate and recurrence rate were not different between patients with negative MRI findings and those with positive MRI findings. If CD is clearly diagnosed according to biochemical tests, radiologic examinations, and BIPSS, we recommend TSS as the first-line treatment for patients, even if the MRI results are negative.

Phenotype-Genotype Association Analysis of ACTH-Secreting Pituitary Adenoma and Its Molecular Link to Patient Osteoporosis.

Adrenocorticotrophin (ACTH)-secreting pituitary adenoma, also known as Cushing disease (CD), is rare and causes metabolic syndrome, cardiovascular disease and osteoporosis due to hypercortisolism. However, the molecular pathogenesis of CD is still unclear because of a lack of human cell lines and animal models. Here, we study 106 clinical characteristics and gene expression changes from 118 patients, the largest cohort of CD in a single-center. RNA deep sequencing is used to examine genotypic changes in nine paired female ACTH-secreting pituitary adenomas and adjacent nontumorous pituitary tissues (ANPT). We develop a novel analysis linking disease clinical characteristics and whole transcriptomic changes, using Pearson Correlation Coefficient to discover a molecular network mechanism. We report that osteoporosis is distinguished from the phenotype and genotype analysis. A cluster of genes involved in osteoporosis is identified using Pearson correlation coefficient analysis. Most of the genes are reported in the bone related literature, confirming the feasibility of phenotype-genotype association analysis, which could be used in the analysis of almost all diseases. Secreted phosphoprotein 1 (SPP1), collagen type I α 1 chain (COL1A1), 5'-nucleotidase ecto (NT5E), HtrA serine peptidase 1 (HTRA1) and angiopoietin 1 (ANGPT1) and their signalling pathways are shown to be involved in osteoporosis in CD patients. Our discoveries provide a molecular link for osteoporosis in CD patients, and may open new potential avenues for osteoporosis intervention and treatment.

[Use of inferior petrosal sinus sampling during the perioperative periodtreatment of Cushing's disease with negative magnetic resonance imaging].

OBJECTIVE: To analyze inferior petrosal sinus sampling (IPSS) in diagnosis and treatment of Cushing's disease with negative magnetic resonance imaging (MRI). METHODS: We retrospectively reviewed 79 cases of Cushing's disease with negative MRI in the Department of Neurosurgery of Peking Union Medical College Hospital from August 2012 to August 2014. Of the 79 patients, 58 underwent IPSS. There were 16 males and 42 females in this study, with age 12 to 65 years old. All 58 patients underwent endocrine assessment before transsphenoidal surgery, and pathology specimens were examined. RESULTS: The IPSS results of all the 58 patients suggested the excessive secretion of ACTH was from pituitary. Of the 58 patients, visible tumor was found in 56 cases during intraoperative exploration (96.6%). In 29 (50%) cases, the side of pituitary where tumor was located predicted by IPSS was the same with intraoperative exploration. Typical tumor was seen in 47 cases during exploration, and the endocrine remission rate was 83.0% after operation. Suspicious tumor was seen in 9 cases, and endocrine response rate was 44.4%. No tumor was found in two cases who had no remission after operation. Pituitary adenoma was confirmed in 41 patients (70.7%) by pathological exam. And anterior or posterior lobe of pituitary was reported in 12 cases, pituitary hyperplasia in 5 cases. CONCLUSIONS: IPSS is recommended in Cushing's disease patients with negative MRI, and it is helpful to judge whether the excessive secretion of ACTH is from pituitary, while its value in predicting the lateralization of tumor is low. If IPSS results are positive, transsphenoidal surgery should be performed.

[Diagnosis and surgical management in patients with Cushing disease with negative magnetic resonance imaging].

OBJECTIVE: To analyze the outcome in patients who underwent transsphenoidal surgery (TSS) with Cushing's disease (CD) with no visible adenoma on magnetic resonance imaging (MRI). METHODS: Between 2012 and 2014, 118 patients with CD underwent TSS at PUMCH. We retrospectively analyzed data in 43 patients without visible adenomas on MRI and compared them with 75 patients with MRI-visible microadenomas. RESULTS: Of 75 patients with MRI-visible microadenomas, postoperative remission was achieved in 64 patients (85.3%), and no recurrence or persistent of CD was observed during 2-year follow-up, and pituitary adenoma confirmed by pathology examination in 71 cases.Of 43 patients with negative MRI, postoperative remission was achieved in 32 patients (74.4%), and pituitary adenoma confirmed by pathology examination in 38 cases. No statistic difference was found between MRI-negative group and MRI-visible group after χ2 test (P value>0.05). BIPSS was performed in 32 cases, and 27 cases were positive. Pituitary adenoma was confirmed in 28 cases. CONCLUSION: There is no difference in remission rate of CD in MRI-visible and MRI-negative group. BIPSS should be performed in normal MRI cases. We recommend transsphenoidal surgery as the first-line treatment for CD. Selective adenomectomy was recommended when an adenoma was found during surgery, and partial or hemihypophysectomy when no adenoma was found.

[Correlation between Expression of Signal Transducer and Activator of Transcription 3 and Pituitary Adenoma Subtypes].

OBJECTIVE: To investigate the correlation between signal transducer and activator of transcription 3 (STAT3) expression and pituitary adenoma subtypes. METHOD: The STAT3 expression profiles in different pituitary adenomas from 74 patients were determined using quantificational real-time polymerase chain reaction,Western blot,and immunohistochemistry. RESULTS: Expression of STAT3 was observed in all pituitary adenoma subtypes. The STAT3 expression level was highest in growth hormone adenoma when compared with other tumors including prolactin,follicle-stimulating hormone/luteinizing hormone-secreting adenoma,and adrenocorticotrophic hormone-secreting adenoma. The follicle-stimulating hormone/luteinizing hormone adenomas exhibited the lowest STAT3 expression levels. CONCLUSION: STAT3 is differentially expressed in pituitary adenoma subtypes, suggesting the cell-specific features of STAT3 regulation,although further investigations are still warranted to clarify the underlying mechanisms.

[Diagnosis and Treatment of Pituitary Carcinoma].

The early diagnosis and treatment of pituitary carcinoma is difficult. The diagnosis is often delayed, and the confirmation of a diagnosis requires the presence of distant subarachnoid,brain or systemic metastasis from the primary pituitary tumor in the sella and also needs the evidences of pathology and imaging of the primary pituitary carcinoma and metastases. Treatment of pituitary carcinoma includes surgery, radiation therapy ,hormone therapy, chemotherapy, and molecularly targeted therapy; however, these methods are mainly palliative and can not prolong the survival. The prognosis remains poor. Efforts should be made to develop more effective diagnosis and treatment options.

The association of CXCR4 expression with prognosis and clinicopathological indicators in colorectal carcinoma patients: a meta-analysis.

AIMS: The clinical relevance of expression of chemokine receptor 4 (CXCR4) in colorectal carcinoma (CRC) remains controversial; our aim was to identify the precise relationship of CXCR4 to prognosis and clinicopathological features. METHODS AND RESULTS: A meta-analysis was performed. Original data included the hazard ratios (HRs) of recurrence-free survival (RFS), overall survival (OS) and odds ratio (OR) in CRC patients. We pooled HR/OR with 95% confidence intervals (CIs) to estimate the hazard. A total of 20 published studies (including 2253 patients) were eligible. RFS and OS were related significantly to CXCR4 expression, with HRs 1.62 (95% CI 1.24-2.11; P < 0.0001) and 1.68 (95% CI 1.31-2.14; P < 0.0001), respectively. In addition, a significant association was revealed between positive CXCR4 expression and age (less than median age: OR 0.78, 95% CI 0.62-0.98; P = 0.03), stage (I and II: OR 0.46, 95% CI 0.32-0.66; P < 0.0001), grade (well/moderately differentiated: OR 0.74, 95% CI 0.56-0.98; P = 0.04), location (colon: OR: 0.73, 95% CI 0.57-0.95; P = 0.02), lymph node invasion (present: OR2.14, 95% CI 1.36-3.37; P = 0.001),and distant metastasis (present: OR 2.40; 95% CI 1.36-4.23; P = 0.003). Heterogeneity was observed among the included studies with regard to stage (I(2) = 58 %), lymph node invasiveness (I(2) = 74%) and distant metastasis (I(2) = 56%). No publication bias was observed. CONCLUSIONS: Chemokine receptor 4 expression indicates poorer prognosis in older patients and advanced stage or poor differentiation in CRC, and also serves as an indicator of lymph node and distal organ metastasis. Surprisingly, high CXCR4 expression may indicate that the location of the tumour is the rectum. Thus, CXCR4 could help to predict outcome and guide clinical therapy.

Downregulation of Insulin-like growth factor binding protein 6 is associated with ACTH-secreting pituitary adenoma growth.

BACKGROUND: Adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome, called Cushing disease, is caused by a corticotroph tumor of the pituitary gland. Insulin-like growth factor binding protein 6 (IGFBP6), which regulates insulin-like growth factor (IGF) activity and inhibits several IGF2-dependent cancer growths, plays a pivotal role in the tumorigenesis of malignancy, but its roles in ACTH-secreting pituitary adenomas remain unclear. OBJECTIVE: To investigate IGFBP6 expression in ACTH-secreting pituitary adenomas, and its involvement in tumor growth. METHODS: Sporadic ACTH-secreting pituitary adenomas specimens (n = 41) and adjacent non-tumorous pituitary tissues (n = 9) were collected by transphenoidal surgery. IGFBP6 expression was assessed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and validated by Western blotting. Associations of IGFBP6 expression with maximum tumor diameter or Ki-67 labeling index were evaluated in ACTH-secreting pituitary adenomas. RESULTS: IGFBP6 mRNA and protein expression were both decreased in ACTH-secreting pituitary adenomas, compared to adjacent non-tumorous pituitary tissues (P < 0.01). IGFBP6 expression was correlated inversely with maximum tumor diameter (Rho = -0.53, P < 0.0001) and Ki-67 levels (Rho = -0.52, P < 0.05). Moreover, IGFBP6 downregulation activated PI3 K-AKT-mTOR pathway in ACTH-secreting pituitary adenomas. CONCLUSIONS: IGFBP6 attenuation in ACTH-secreting pituitary adenomas is associated with tumor growth, through activation of PI3K-AKT-mTOR pathway. The finding underlies IGFBP6 roles in Cushing disease and would potentially provide a novel target of medical therapies.

[Treatment of pituitary adenomas invading cavernous sinus with neuroendoscopy assisted by multiple techniques].

OBJECTIVE: To study the effectiveness of treating giant pituitary adenomas invading cavernous sinus with neuroendoscopy assisted by multiple techniques. METHODS: A total of 72 patients who underwent neuroendoscopic surgery and 55 patients who underwent microscopic surgery for giant pituitary adenomas were enrolled in this retrospective analysis. Both groups received expanded endoscopic endonasal transsphenoidal approach, intraoperative application of navigation, and Doppler.The clinical data of two groups were compared. RESULTS: The two groups were significantly different in total tumor removal rate, operation time, postoperative nasal patency, and postoperative recurrence rate (P=0.004, P=0.0003, P=0.000, and P=0.002, respectively), whereas the cerebrospinal fluid leakage, postoperative diabetes insipidus, and cranial nerve injury were not significantly different (P > 0.05). CONCLUSIONS: Expanded neuroendoscopic endonasal transsphenoidal approach assisted by multiple techniques is the preferred surgical method for giant invasive pituitary adenomas invading cavernous sinus.The lateral cavernous sinus approach and the further molecular biology research will bring more options for the treatment of invasive pituitary adenomas.

Craniofacial Fibrous Dysplasia in Fronto-Orbital Region: A Single-Center Retrospective Study of 38 Cases.

OBJECTIVE: This study presents the clinical characteristics, imaging manifestations, and surgical experience in 38 patients diagnosed with craniofacial fibrous dysplasia in fronto-orbital region (foFD). METHODS: We retrospectively analyzed the clinical data from 38 patients who had surgery for foFD. The surgical procedure typically involved extensive tumor removal, followed by immediate reconstruction of the frontal bone and orbit using synthetic materials. Additionally, 9 patients underwent simultaneous microscopic decompression of the optic canal. RESULTS: Common clinical manifestations included progressive fronto-orbital bone deformity (35), proptosis (28), orbital dystopia (21), and visual impairment (9). The disease primarily affecting the frontal bone (38), the sphenoid bone (28), and the ethmoid bone (24). The optic canal was involved in 9 patients with functional impairment. Computed tomography scans in all 38 cases revealed satisfactory repair material positioning and complete resolution of frontal deformities. Among the 9 patients who underwent optic canal decompression, 7 experienced partial recovery of visual acuity after surgery. CONCLUSIONS: In the surgical treatment of foFD, it is crucial to achieve maximal bone resection and repair skull defects, while decompressing the optic canal can provide significant benefits for patients with decreased visual function preoperatively. The use of preformed artificial materials offers advantages in aesthetic restoration after lesion excision.

Pyrimethamine sensitizes pituitary adenomas cells to temozolomide through cathepsin B-dependent and caspase-dependent apoptotic pathways.

Invasive pituitary adenomas (PAs) are generally refractory to conventional therapy and salvage treatment with temozolomide (TMZ). In addition to antiprotozoan effects, pyrimethamine (PYR) has recently shown its strong antitumor activity as an antineoplastic agent or in combination with TMZ in metastatic melanoma cells. In this study, the effects of TMZ, PYR or TMZ/PYR combination on rat/mouse PA cell lines αT3-1, GH3, MMQ and ATt-20 as well as GH3 xenograft tumor model were evaluated. TMZ/PYR combination synergistically inhibited proliferation, invasion and induced apoptosis of these PA cell lines in vitro. Strikingly, combination treatment with TMZ and PYR produced synergistic antitumor activity and enhanced the survival rate of GH3 xenograft tumor models without increasing systemic side effects. In addition, TMZ/PYR induced cell cycle arrest, increased DNA damage, upregulated the expression of cathepsin B, BAX, cleaved PARP and phosphorylated histone H2AX as well as elevated caspase3/7, 8 and 9 activities. The decreased expression of Bcl-2, MMP-2 and MMP-9 alone with cytochrome c release from mitochondria into the cytosol was also observed in the TMZ/PYR combination group. The increase in cell apoptosis due to combination with PYR was rescued by leucovorin. These data suggest that PYR may enhance the efficacy of TMZ via triggering both cathepsin B-dependent and caspase-dependent apoptotic pathways. Therefore, combination of PYR and TMZ may provide a novel regimen for invasive PAs refractory to standard therapy and TMZ.

[Significance of pseudocapsule in the excision of pituitary adenomas in transsphenoidal surgery].

OBJECTIVE: To explore the significance of pseudocapsule in the excision of pituitary adenomas in transsphenoidal surgery. METHODS: For 22 patients with pituitary adenomas over a period of 2 years at Peking Union Medical College Hospital, resection of pseudocapsule was applied for complete tumor removal. Pituitary function test and radiological imaging were performed at pre-operation, 3 months post-operation and at subsequent 6-12 months intervals postoperatively. RESULTS: All pituitary adenomas were totally removed under microscope. The symptoms of headache, disorder of sight and visual field disappeared postoperatively in nonfunctional pituitary adenomas. The GH levels of 2/5 growth hormone secreting adenoma patients were 4.2 and 7.7 µg/L while it was under 1 µg/L for another 3. The postoperative level of prolactin was 4.3 µg/L in prolactin secreting adenoma. The level of adrenocorticotropic hormone decreased under 5 ng/L except one was 15.7 ng/L. Leakage of cerebrospinal fluid occurred intraoperatively in 3 patients and postoperatively in 1. No leakage was found after repair. Diabetes insipidus occurred in one patient and was controlled with Minirin. Pseudocapsule was confirmed by pathological examination. Special staining revealed reticulum fibers in pseudocapsule. CONCLUSION: Resection of pseudocapsule may achieve a higher remission rate without deteriorating pituitary function.

Predicting delayed remission in Cushing's disease using radiomics models: a multi-center study.

Purpose: No multi-center radiomics models have been built to predict delayed remission (DR) after transsphenoidal surgery (TSS) in Cushing's disease (CD). The present study aims to build clinical and radiomics models based on data from three centers to predict DR after TSS in CD. Methods: A total of 122 CD patients from Peking Union Medical College Hospital, Xuanwu Hospital, and Fuzhou General Hospital were enrolled between January 2000 and January 2019. The T1-weighted gadolinium-enhanced MRI images and clinical data were used as inputs to build clinical and radiomics models. The regions of interest (ROI) of MRI images were automatically defined by a deep learning algorithm developed by our team. The area under the curve (AUC) of receiver operating characteristic (ROC) curves was used to evaluate the performance of the models. In total, 10 machine learning algorithms were used to construct models. Results: The overall DR rate is 44.3% (54/122). According to multivariate Logistic regression analysis, patients with higher BMI and lower postoperative cortisol levels are more likely to achieve a higher rate of delayed remission. Among the 10 models, XGBoost achieved the best performance among all models in both clinical and radiomics models with AUC values of 0.767 and 0.819 respectively. The results from SHAP value and LIME algorithms revealed that postoperative cortisol level (PoC) and BMI were the most important features associated with DR. Conclusion: Radiomics models can be built as an effective noninvasive method to predict DR and might be useful in assisting neurosurgeons in making therapeutic plans after TSS for CD patients. These results are preliminary and further validation in a larger patient sample is needed.

Advances in medical treatment of clinically nonfunctioning pituitary adenomas.

Clinically nonfunctioning pituitary adenomas are the most common types among pituitary adenomas. These tumors are usually diagnosed in their later stages due to the absence of clinical symptoms and detectable hormonal hypersecretion. Although these tumors are benign, they are hard to be completely removed during neurosurgery due to the massive invasion into the surrounding tissues at diagnosis. Furthermore, relapse is common. In recent years, medical treatment of pituitary adenomas has witnessed a rapid development. New medications have shown certain effectiveness in reducing the tumor size and improving the clinical symptoms.