Epidemiology and survival of non-malignant and malignant meningiomas in middle-aged females, 2004-2018.

Background: The incidence of meningioma is disparate to sex: meningiomas are more common in women than in men, especially in middle-aged women. Understanding the epidemiology and survival of middle-aged women with meningiomas would help estimate their public health impacts and optimize risk stratification. Methods: Data on middle-aged (35-54 years) female patients with meningiomas between 2004 and 2018 were obtained from the SEER database. Age-adjusted incidence rates per 100 000 population-years were calculated. Kaplan-Meier and multivariate Cox proportional hazard models were utilized in the overall survival (OS) analysis. Results: Data from 18302 female patients with meningioma were analyzed. The distribution of patients increased with age. Most patients were White and non-Hispanic, according to race and ethnicity, respectively. Over the past 15 years, non-malignant meningiomas have shown an increasing trend; however, malignant meningiomas have shown an opposite trend. Older age, Black population, and large non-malignant meningiomas tend to have worse prognoses. Surgical resection improves OS, and the extent of resection is a critical prognostic factor. Conclusions: This study observed an increase in non-malignant meningiomas and a decrease in the incidence of malignant meningiomas in middle-aged females. The prognosis deteriorated with age, in Black people, and with large tumor size. Additionally, the extent of tumor excision was found to be a significant prognostic factor.

Epidemiology and risk stratification of low-grade gliomas in the United States, 2004-2019: A competing-risk regression model for survival analysis.

Background: Understanding the epidemiology and prognostic factors of low-grade gliomas (LGGs) can help estimate the public health impact and optimize risk stratification and treatment strategies. Methods: 3 337 patients diagnosed with LGGs were collected from the Surveillance, Epidemiology, and End Results (SEER) dataset, 2004-2019. The incidence trends of LGGs were analyzed by patient demographics (sex, age, race, and ethnicity). In addition, a competing risk regression model was used to explore the prognostic factors of LGGs by patient demographics, tumor characteristics (histological subtypes, invasiveness, and size), treatment modality, and molecular markers (IDH mutation and 1p/19q codeletion). Results: LGGs occurred more frequently in male, non-Hispanic, and White populations. The incidence rate of mixed gliomas was stable from 2004 to 2013 and decreased dramatically to nearly zero until 2019. The risk of death increased 1.99 times for every 20-year increase in patient age, and 60 years is a predictive cut-off age for risk stratification of LGGs. Male patients showed poorer LGG-specific survival. Among the different subtypes, astrocytoma has the worst prognosis, followed by mixed glioma and oligodendroglioma. Tumors with larger size (≥5 cm) and invasive behavior tended to have poorer survival. Patients who underwent gross total resection had better survival rates than those who underwent subtotal resection. Among the different treatment modalities, surgery alone had the best survival, followed by surgery + radiotherapy + chemotherapy, but chemotherapy alone had a higher death risk than no treatment. Furthermore, age, invasiveness, and molecular markers were the most robust prognostic factors. Conclusion: This study reviewed the incidence trends and identified several prognostic factors that help clinicians identify high-risk patients and determine the need for postoperative treatment according to guidelines.

Pharmacological Landscape of FDA-Approved Anticancer Drugs Reveals Sensitivities to Ixabepilone, Romidepsin, Omacetaxine, and Carfilzomib in Aggressive Meningiomas.

PURPOSE: To date, there are no systemic treatment options for patients with recurrent or refractory meningioma. EXPERIMENTAL DESIGN: To identify effective drugs, we performed a large-scale drug screening using FDA-approved drugs on several meningioma cell lines. The impact of the top four compounds was assessed on cell viability, proliferation, colony formation, migration, and apoptosis. In addition, the antineoplastic effects of the selected drugs were validated in a heterotopic xenograft mouse model. RESULTS: Analyses of the viability of meningioma cells treated with 119 antineoplastic FDA-approved drugs resulted in categorization into sensitive and resistant drug-response groups based on the mean IC50 values and peak serum concentrations (Cmax) in patients. Eighty drugs, including 15 alkylating agents, 14 antimetabolites, and 13 tyrosine kinase inhibitors, were classified as resistant (IC50 > Cmax). The sensitive drug-response group (n = 29, IC50 < Cmax) included RNA/protein synthesis inhibitors, proteasome inhibitors, topoisomerase, tyrosine-kinase, and partial histone deacetylase and microtubule inhibitors. The IC50 value of the four most effective compounds (carfilzomib, omacetaxine, ixabepilone, and romidepsin) ranged from 0.12 to 9.5 nmol/L. Most of them caused cell-cycle arrest in the G2-M-phase and induced apoptosis. Furthermore, all drugs except romidepsin significantly inhibited tumor growth in vivo. The strongest antineoplastic effect was observed for ixabepilone, which reduced tumor volume by 86%. CONCLUSIONS: In summary, a large-scale drug screening provides a comprehensive insight into the anti-meningioma activities of FDA-approved drugs, and identified carfilzomib, omacetaxine, ixabepilone, and romidepsin as novel potent antineoplastic agents for the treatment of aggressive meningiomas. The most pronounced effects were observed with ixabepilone mandating for further clinical investigation.

TGF-ß2 levels in the aqueous humor are elevated in the second eye of high myopia within two weeks after sequential cataract surgery.

Transforming growth factor-ß (TGF-ß) is the critical regulator of physiological and pathological conditions in lens. The TGF-ß signaling pathway is closely associated with high myopia patients. Thirty eyes from fifteen patients with high myopia who received sequential cataract surgery were enrolled in this prospective study. Ten cataract patients with non-myopia were chosen as a control group. Aqueous humor (AH) samples were used to detect the levels of TGF-ß1, TGF-ß2, and TGF-ß3 in both groups. Compared with the non-myopic cataracts patient group, the highly myopic cataracts group had a significantly higher TGF-ß2 (P = 0.019). Besides, the level of TGF-ß2 of the second eye was significantly higher than that in the first eye in high myopia cataract patients group (P = 0.037). And TGF-ß1 showed significant differences with age and axial length of high myopia cataract patients. Therefore, TGF-ß2 may contribute to the development of high myopia and cataract surgery increased the expression of TGF-ß2.

Berberine inhibits glioma cell migration and invasion by suppressing TGF-ß1/COL11A1 pathway.

Glioma is a clinically heterogeneous disease with a poor prognosis. Berberine (BBR), as a multi-target anti-tumor alkaloid, has the ability to penetrate the blood-brain barrier and shows cytotoxicity to glioma cells. In previous studies, we demonstrated that berberine inhibits glioma cell proliferation by inhibiting mutant p53 protein and promoting mitochondrial damage. In addition, berberine has been shown to reduce collagen accumulation in pulmonary fibrosis, diabetic nephropathy and arthritis. However, its effect on collagen in cancer needs to be further elucidated. In this study, we proved that the collagen XI alpha 1 chain (COL11A1) is highly expressed in glioma cell lines and associated with migration and invasion of glioma cells. Knocking down COL11A1 caused decreased expression of MMPs. Berberine could inhibit the migration and invasion of glioma cells by suppressing the TGF-ß1/COL11A1 pathway and changes actin cytoskeleton arrangement. Nude mouse subcutaneous xenografts model also showed that berberine inhibited the expression of COL11A1 in vivo. Collectively, berberine that targets COL11A1 to inhibit glioma migration and invasion, may serve as a promising candidate for the development of anti-glioma drugs in the future.

Incidence and survival of benign, borderline, and malignant meningioma patients in the United States from 2004 to 2018.

Meningioma is the most common primary central nervous system tumor, and its incidence is increasing. A systematic epidemiological and clinical analysis is required to better estimate its public health impact and understand its prognostic factors. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2018 for all types of meningiomas without an age restriction. Age-adjusted incidence rates (IRs) and 95% confidence intervals were estimated according to sex, age, race, ethnicity, and tumor location. Kaplan-Meier analysis and multivariate Cox proportional hazard models were used to analyze the overall survival (OS). The competing risk regression model of Fine-Gray was used to analyze cause-specific survival. Data from a total of 109 660 meningioma patients were analyzed. A majority of patients were older than 60 years, and only 0.41% of patients were 0-19 years. The meningioma IRs were higher in females, Black, and non-Hispanic patients than in males, White, and Hispanic patients, respectively, and IRs increased with age. The ratio of IRs for females to males was 2.1 and also increased with age, peaking at 3.6 in the 45-49-year-old group. Older and male patients with all types of meningiomas, Black patients with benign and borderline meningiomas, and patients with larger borderline and malignant meningiomas showed poorer prognosis. For all meningioma types, surgical resection improved survival. The reported incidence rates and survival trends covered all demographics and subtypes of meningiomas. Older age, male sex, Black race, and tumor size may be important prognostic factors for meningioma cases, and tumor resection can substantially improve survival among meningioma patients.

Receptor-Tyrosine Kinase Inhibitor Ponatinib Inhibits Meningioma Growth In Vitro and In Vivo.

To date, there is no standard-of-care systemic therapy for the treatment of aggressive meningiomas. Receptor tyrosine kinases (RTK) are frequently expressed in aggressive meningiomas and are associated with poor survival. Ponatinib is a FDA- and EMA-approved RTK inhibitor and its efficacy in meningioma has not been studied so far. Therefore, we investigated ponatinib as a potential drug candidate against meningioma. Cell viability and cell proliferation of ponatinib-treated meningioma cells were assessed using crystal violet assay, manual counting and BrdU assay. Treated meningioma cell lines were subjected to flow cytometry to evaluate the effects on cell cycle and apoptosis. Meningioma-bearing mice were treated with ponatinib to examine antitumor effects in vivo. qPCR was performed to assess the mRNA levels of tyrosine kinase receptors after ponatinib treatment. Full-length cDNA sequencing was carried out to assess differential gene expression. IC50 values of ponatinib were between 171.2 and 341.9 nM in three meningioma cell lines. Ponatinib induced G0/G1 cell cycle arrest and subsequently led to an accumulation of cells in the subG1-phase. A significant induction of apoptosis was observed in vitro. In vivo, ponatinib inhibited meningioma growth by 72.6%. Mechanistically, this was associated with downregulation of PDGFRA/B and FLT3 mRNA levels, and mitochondrial dysfunction. Taken together, ponatinib is a promising candidate for targeted therapy in the treatment of aggressive meningioma.

Insulin-like Growth Factor 2 mRNA-Binding Protein 2-a Potential Link Between Type 2 Diabetes Mellitus and Cancer.

CONTEXT: Type 2 diabetes mellitus (T2DM) and cancer share a variety of risk factors and pathophysiological features. It is becoming increasingly accepted that the 2 diseases are related, and that T2DM increases the risk of certain malignancies. OBJECTIVE: This review summarizes recent advancements in the elucidation of functions of insulin-like growth factor 2 (IGF-2) messenger RNA (mRNA)-binding protein 2 (IGF2BP2) in T2DM and cancer. METHODS: A PubMed review of the literature was conducted, and search terms included IGF2BP2, IMP2, or p62 in combination with cancer or T2DM. Additional sources were identified through manual searches of reference lists. The increased risk of multiple malignancies and cancer-associated mortality in patients with T2DM is believed to be driven by insulin resistance, hyperinsulinemia, hyperglycemia, chronic inflammation, and dysregulation of adipokines and sex hormones. Furthermore, IGF-2 is oncogenic, and its loss-of-function splice variant is protective against T2DM, which highlights the pivotal role of this growth factor in the pathogenesis of these 2 diseases. IGF-2 mRNA-binding proteins, particularly IGF2BP2, are also involved in T2DM and cancer, and single-nucleotide variations (formerly single-nucleotide polymorphisms) of IGF2BP2 are associated with both diseases. Deletion of the IGF2BP2 gene in mice improves their glucose tolerance and insulin sensitivity, and mice with transgenic p62, a splice variant of IGF2BP2, are prone to diet-induced fatty liver disease and hepatocellular carcinoma, suggesting the biological significance of IGF2BP2 in T2DM and cancer. CONCLUSION: Accumulating evidence has revealed that IGF2BP2 mediates the pathogenesis of T2DM and cancer by regulating glucose metabolism, insulin sensitivity, and tumorigenesis. This review provides insight into the potential involvement of this RNA binding protein in the link between T2DM and cancer.

KIF11 inhibitors filanesib and ispinesib inhibit meningioma growth in vitro and in vivo.

Treatment of aggressive meningiomas remains challenging due to a high rate of recurrence in higher-grade meningiomas, frequent subtotal resections, and the lack of effective systemic treatments. Substantial overexpression associated with a poor prognosis has been demonstrated for kinesin family member 11 (KIF11) in high-grade meningiomas. Due to anti-tumor activity for KIF11 inhibitors (KIF11i) filanesib and ispinesib in other cancer types, we sought to investigate their mode of action and efficacy for the treatment of aggressive meningiomas. Dose curve analysis of both KIF11i revealed IC50 values of less than 1 nM in anaplastic and benign meningioma cell lines. Both compounds induced G2/M arrest and subsequent subG1 increase in all cell lines. Profound induction of apoptosis was detected in the anaplastic cell lines determined by annexin V staining. KIF11i significantly inhibited meningioma growth in xenotransplanted mice by up to 83%. Furthermore, both drugs induced minor hematological side effects, which were less pronounced for filanesib. We identified substantial in vitro and in vivo anti-tumor effects of the KIF11 inhibitors filanesib and ispinesib, with filanesib demonstrating better tolerability, suggesting future use of filanesib for the treatment of aggressive meningioma.

Comparative transcriptome analysis of embryo invasion in the mink uterus.

INTRODUCTION: In mink, as many as 65% of embryos die during gestation. The causes and the mechanisms of embryonic mortality remain unclear. The purpose of our study was to examine global gene expression changes during embryo invasion in mink, and thereby to identify potential signaling pathways involved in implantation failure and early pregnancy loss. METHODS: Illumina's next-generation sequencing technology (RNA-Seq) was used to analyze the differentially expressed genes (DEGs) in implantation (IMs) and inter-implantation sites (inter-IMs) of uterine tissue. RESULTS: We identified a total of 606 DEGs, including 420 up- and 186 down-regulated genes in IMs compared to inter-IMs. Gene annotation analysis indicated multiple biological pathways to be significantly enriched for DEGs, including immune response, ECM complex, cytokine activity, chemokine activity and protein binding. The KEGG pathway including cytokine-cytokine receptor interaction, Jak-STAT, TNF and the chemokine signaling pathway were the most enriched. A gene network was constructed, and hub nodes such as CSF3, ICAM1, FOS, IL1B, IL8, CD14 and MYC were found through network analysis. DISCUSSION: This report provides a valuable resource for understanding the mechanisms of embryo implantation in mink.

Intramedullary bronchogenic cyst in the foramen magnum region accompanied with syringomyelia: A case report and literature review.

RATIONALE: Bronchogenic cysts refer to congenital anomalies derived from the primitive foregut. Spinal bronchogenic cysts are uncommon entities, and those occurring in the intramedullary sites are extremely rare. Bronchogenic cysts involving the foramen magnum region have only been described in 2 cases; however, intramedullary bronchogenic cysts with syringomyelia have not yet been reported. PATIENT CONCERNS: A 46-year-old woman presented with a 6-month history of pain in the posterior neck region and a 1-month history of numbness in the upper extremities. Neurological examination revealed a loss of sensation in bilateral upper extremities and sensory dissociation. Magnetic resonance imaging (MRI) showed an intramedullary cystic lesion in the foramen magnum region and syringomyelia. DIAGNOSIS: Histopathological findings were consistent with a bronchogenic cyst. INTERVENTIONS AND OUTCOMES: A surgical resection of the cystic lesion was performed via a posterior midline approach. Under neurophysiological monitoring, the cyst was punctured, yielding gelatinous liquid. The dorsal part of the cystic wall was removed. One month postoperatively, the symptoms were resolved completely. Three months after operation, MRI showed no recurrence of the cyst and the syringomyelia disappeared. LESSONS: Intramedullary bronchogenic cysts with syringomyelia are extremely rare. Preoperative identification is challenging and definitive diagnosis depends on histopathological evidence. Timely surgical resection should be highlighted.

Primary hypothyroidism in a child leads to pituitary hyperplasia: A case report and literature review.

RATIONALE: A sellar mass in children is most often seen in craniopharyngeal tumors, intracranial germ cell tumors, or pituitary adenomas. However, pituitary hyperplasia secondary to primary hypothyroidism (PHPH) is not commonly seen in children. PATIENT CONCERNS: A 10-year-old girl was admitted due to growth retardation and obesity for 4 years. On physical examination, the patient had a height of 118 cm, body weight of 46 kg, body mass index (BMI) of 33.0 kg/m. DIAGNOSES: After magnetic resonance imaging (MRI) and laboratory tests, her initial diagnosis was Hashimoto's thyroiditis, primary hypothyroidism, and reactive pituitary hyperplasia. INTERVENTIONS: She was treated with oral L-thyroxine tablets. OUTCOMES: After 6 months, physical examination showed a height of 125 cm, weight of 36 kg, BMI of 23.0 kg/m. She developed well, with 12 cm of yearly growth thereafter. LESSONS: The diagnosis of PHPH in a child is very important and sometimes difficult. Based on the summary and analysis of previous cases, we can learn that the main manifestations of PHPH include growth arrest and obesity, perhaps accompanied by symptoms caused by a decreased thyroid hormone concentration and elevated prolactin (PRL) concentration. Intracranial MRI shows diffuse enlargement of the anterior lobe of the pituitary gland, with a dome-shaped blunt edge change. Thyroid hormone levels may decrease, whereas the thyroid stimulating hormone (TSH) level increases, commonly accompanied by an elevated PRL, reduced growth hormone (GH) levels, and positive findings of TPOAb and TGAb. Improvement of symptoms and the normalization of hormone levels as well as restoration of pituitary size can be achieved after treated with thyroid hormone replacement therapy. And a hasty decision on surgical resection should be avoided when the diagnosis is uncertain.

Sellar chondrosarcoma presenting with amenorrhea: A case report.

RATIONALE: Intracranial chondrosarcomas are rare entities and most of which arise off the midline. Chondrosarcomas that occur in the sellar region are extremely rare, and to the best of our knowledge, there is no reporting about sellar chondrosarcoma with amenorrhea as the onset symptom. PATIENT CONCERNS: A 45-year-old woman presented with a 7-month history of amenorrhea and a 3-month history of progressive visual loss in the left eye. DIAGNOSIS: The patient was diagnosed with recurrent sellar chondrosarcoma arising from intrasellar with extensive tumor invasion into bilateral sphenoid sinuses. INTERVENTIONS: Twice endonasal transsphenoidal tumorectomies were performed followed with a stereotactic radiotherapy and hormone replacement therapy. OUTCOMES: The patient's condition was stable and her visual symptoms improved, the hormones returned to normal, and no recurrence was noted on MRI after six months. LESSONS: Sellar chondrosarcomas with the onset of endocrine dysfunctions are extremely rare, which may be misdiagnosed as pituitary adenoma and the definitive diagnosis depends on histopathological and immunohistochemical evidence. The first choice of treatment is surgery with the goal of complete resection, and postoperative adjuvant radiotherapy should be highlighted.

The Roles of Insulin-Like Growth Factor 2 mRNA-Binding Protein 2 in Cancer and Cancer Stem Cells.

RNA-binding proteins (RBPs) mediate the localization, stability, and translation of the target transcripts and fine-tune the physiological functions of the proteins encoded. The insulin-like growth factor (IGF) 2 mRNA-binding protein (IGF2BP, IMP) family comprises three RBPs, IGF2BP1, IGF2BP2, and IGF2BP3, capable of associating with IGF2 and other transcripts and mediating their processing. IGF2BP2 represents the least understood member of this family of RBPs; however, it has been reported to participate in a wide range of physiological processes, such as embryonic development, neuronal differentiation, and metabolism. Its dysregulation is associated with insulin resistance, diabetes, and carcinogenesis and may potentially be a powerful biomarker and candidate target for relevant diseases. This review summarizes the structural features, regulation, and functions of IGF2BP2 and their association with cancer and cancer stem cells.

Oncosis-like cell death is induced by berberine through ERK1/2-mediated impairment of mitochondrial aerobic respiration in gliomas.

Gliomas, the most common primary malignant brain tumor, exhibit high metabolic activity. The targeting of metabolism alterations, particularly in mitochondria, is emerging as an efficient approach for curing cancers. Here, we showed that berberine, a natural compound that is used as an antibacterial agent, could reduce cellular viability and induce oncosis-like death, characterized by cell swelling, cytoplasmic vacuoles and plasma membrane blebbing, in gliomas, and that these effects were correlated with intracellular adenosine triphosphate (ATP) depletion. We also found that berberine induced autophagy as a protective effect and decreased the oxygen consumption rate (OCR), which could inhibit mitochondrial aerobic respiration by repressing phosphorylated extracellular regulated protein kinases (p-ERK1/2). Furthermore, the down-regulation of mitochondrial p-ERK1/2 by berberine inhibited aerobic respiration and led to glycolysis, an inefficient energy production pathway. In addition, berberine reduced tumor growth and inhibited Ki-67 and p-ERK1/2 expression in vivo. The results demonstrate that berberine, which represses aerobic oxidation in mitochondria and decreases their energy production efficiency, decreases metabolic activity by reducing ERK1/2 activity.

Alternative splicing of human telomerase reverse transcriptase in gliomas and its modulation mediated by CX-5461.

BACKGROUND: Glioma is a heterogeneous, invasive primary brain tumor with a wide range of patient survival and a lack of reliable prognostic biomarkers. Human telomerase reverse transcriptase (hTERT) has been reported in the presence of multiple transcripts in various tumor systems. The biological function and precise regulatory mechanisms of hTERT transcripts remain uncertain. METHODS: Alternative splicing of hTERT and telomerase activity were examined in 96 glioma specimens, including 38 glioblastomas (GBMs), 23 oligodendrogliomas (ODMs), and 35 oligoastrocytomas (OAMs). The correlation between telomerase activity or hTERT transcripts and patient clinical characteristics was investigated. We examined the regulation of alternative splicing of hTERT and telomerase activity by G-quadruplex stabilizer CX-5461 in GBM cells. The biological effects of CX-5461 on GBM cell lines, including inhibition of cell proliferation, effects on cell cycle/apoptosis, and telomere DNA damage were further explored. RESULTS: The ß splicing was verified in human gliomas and hTERT+ß was significantly correlated with higher telomerase activity, higher KPS, larger tumor size, and higher tumor grades. Meanwhile, glioma patients lacking hTERT+ß expression or telomerase activity showed a significant survival benefit. Notably, CX-5461 altered hTERT splicing patterns, leading to an increase of hTERT-ß transcript and a decrease of hTERT+ß transcript expression, which inhibits telomerase activity. In addition, CX-5461 had cytotoxic effects on GBM cells and caused telomere DNA damage response, induced G2/M arrest and apoptosis. CONCLUSIONS: The hTERT+ß is verified to be correlated with clinical parameters in gliomas, and could serve as a prognostic marker or possibly therapeutic target for gliomas. CX-5461 can regulate the splicing pattern of hTERT, inhibit telomerase activity, and kill GBM cells.