Utility of molecular markers in predicting local control specific to lung cancer spine metastases treated with stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: We report outcomes following spine stereotactic body radiotherapy (SBRT) in metastatic non-small cell lung cancer (NSCLC) and the significance of programmed death-ligand 1 (PD-L1) status, epidermal growth factor receptor (EGFR) mutation and timing of immune check point inhibitors (ICI) on local failure (LF). MATERIALS AND METHODS: 165 patients and 389 spinal segments were retrospectively reviewed from 2009 to 2021. Baseline patient characteristics, treatment and outcomes were abstracted. Primary endpoint was LF and secondary, overall survival (OS) and vertebral compression fracture (VCF). Multivariable analysis (MVA) evaluated factors predictive of LF and VCF. RESULTS: The median follow-up and OS were: 13.0 months (range, 0.5-95.3 months) and 18.4 months (95% CI 11.4-24.6). 52.1% were male and 76.4% had adenocarcinoma. Of the 389 segments, 30.3% harboured an EGFR mutation and 17.0% were PD-L1 ≥ 50%. The 24 months LF rate in PD-L1 ≥ 50% vs PD-L1 < 50% was 10.7% vs. 38.0%, and in EGFR-positive vs. negative was 18.1% vs. 30.0%. On MVA, PD-L1 status of ≥ 50% (HR 0.32, 95% CI 0.15-0.69, p = 0.004) significantly predicted for lower LF compared to PD-L1 < 50%. Lower LF trend was seen with ICI administration peri and post SBRT (HR 0.41, 95% CI 0.16-1.05, p = 0.062). On MVA, polymetastatic disease (HR 3.28, 95% CI 1.84-5.85, p < 0.0001) and ECOG ≥ 2 (HR 1.87, 95% CI 1.16-3.02, p = 0.011) significantly predicted for worse OS and absence of baseline VCF predicted for lower VCF rate (HR 0.20, 95% CI 0.10-0.39, p < 0.0001). CONCLUSION: We report a significant association of PD-L1 ≥ 50% status on improved LC rates from spine SBRT in NSCLC patients.

A current review of spinal meningiomas: epidemiology, clinical presentation and management.

PURPOSE: To provide an up-to-date review of the epidemiology, histopathology, molecular biology, and etiology of spinal meningiomas, as well as discuss the clinical presentation, clinical evaluation, and most recent treatment recommendations for these lesions. METHODS: PubMed and Google Scholar search was performed for studies related to meningiomas of the spine. The terms "meningioma," "spinal meningioma," "spine meningioma," "meningioma of the spine," "benign spinal tumors," and "benign spine tumors," were used to identify relevant studies. All studies, including primary data papers, meta-analyses, systematic reviews, general reviews, case reports, and clinical trials were considered for review. RESULTS: Eighty-four studies were identified in the review. There were 22 studies discussing adverse postoperative outcomes, 21 studies discussing tumor genetics, 19 studies discussing epidemiology and current literature, 9 studies discussing radiation modalities and impact on subsequent tumor development, 5 studies on characteristic imaging findings, 5 studies discussing hormone use/receptor status on tumor development, 2 discussing operative techniques and 1 discussing tumor identification. CONCLUSION: Investigations into spinal meningiomas generally lag behind that of intracranial meningiomas. Recent advancements in the molecular profiling of spinal meningiomas has expanded our understanding of these tumors, increasing our appreciation for their heterogeneity. Continued investigation into the defining characteristics of different spinal meningiomas will aid in treatment planning and prognostication.

Radiomics of Spinal Metastases Originating From Primary Nonsmall Cell Lung Cancer or Breast Cancer and Ability to Predict Epidermal Growth Factor Receptor Mutation/Ki-67 Levels.

OBJECTIVES: The aims of the study are to explore spinal magnetic resonance imaging (MRI)-based radiomics to differentiate spinal metastases from primary nonsmall cell lung cancer (NSCLC) or breast cancer (BC) and to further predict the epidermal growth factor receptor (EGFR) mutation and Ki-67 expression level. METHODS: In total, 268 patients with spinal metastases from primary NSCLC (n = 148) and BC (n = 120) were enrolled between January 2016 and December 2021. All patients underwent spinal contrast-enhanced T1-weighted MRI before treatment. Two- and 3-dimensional radiomics features were extracted from the spinal MRI images of each patient. The least absolute shrinkage and selection operator regression were applied to identify the most important features related to the origin of the metastasis and the EGFR mutation and Ki-67 level. Radiomics signatures (RSs) were established using the selected features and evaluated using receiver operating characteristic curve analysis. RESULTS: We identified 6, 5, and 4 features from spinal MRI to develop Ori-RS, EGFR-RS, and Ki-67-RS for predicting the metastatic origin, EGFR mutation, and Ki-67 level, respectively. The 3 RSs performed well in the training (area under the receiver operating characteristic curves: Ori-RS vs EGFR-RS vs Ki-67-RS, 0.890 vs 0.793 vs 0.798) and validation (area under the receiver operating characteristic curves: Ori-RS vs EGFR-RS vs Ki-67-RS, 0.881 vs 0.744 vs 0.738) cohorts. CONCLUSIONS: Our study demonstrated the value of spinal MRI-based radiomics for identifying the metastatic origin and evaluating the EGFR mutation status and Ki-67 level in patients with NSCLC and BC, respectively, which may have the potential to guide subsequent individual treatment planning.

Malignant Brain and Spinal Tumors Originating from Bone or Cartilage.

Malignant bone tumors affecting the brain and spine are a rare and exceedingly difficult-to-treat group of diseases. Most commonly consisting of chordoma and chondrosarcoma, these tumors also include giant-cell tumors and osteosarcomas. This chapter will cover the background, epidemiology, genetics, molecular biology, histopathology, radiographic features, clinical manifestations, therapeutic approaches, and clinical management of each entity.

Metastatic Lesions of the Brain and Spine.

Brain and spinal metastases are common in cancer patients and are associated with significant morbidity and mortality. Continued advancement in the systemic care of cancer has increased the life expectancy of patients, and consequently, the incidence of brain and spine metastasis has increased. There has been an increase in the understanding of oncogenic mutations, and research has also demonstrated spatial and temporal mutations in patients that may drive overall treatment resistance and failure. Combinatory treatments with radiation, surgery, and newer systemic therapies have continued to increase the life expectancy of patients with brain and spine metastases. Given the overall complexity of brain and spine metastases, this chapter aims to give a comprehensive overview and cover important topics concerning brain and spine metastases. This will include the molecular, genetic, radiographic, surgical, and non-surgical treatments of brain and spinal metastases.

Malignant Spinal Tumors.

Malignant spinal tumors constitute around 22% of all primary spinal tumors. The most common location of metastases to the spinal region is the extradural compartment. The molecular and genetic characterization of these tumors was the basis for the updated WHO classification of CNS tumors in 2016, where many CNS tumors are now diagnosed according to their genetic profile rather than relying solely on the histopathological appearance. Magnetic resonance imaging (MRI) is the current gold standard for the initial evaluation and subsequent follow-up on intradural spinal cord tumors, and the imaging sequences must include T2-weighted images (WI), short time inversion recovery (STIR), and pre- and post-contrast T1-WI in the axial, sagittal, and coronal planes. The clinical presentation is highly variable and depends on the tumor size, growth rate, type, infiltrative, necrotic and hemorrhagic potential as well as the exact location within the spinal compartment. Surgical intervention remains the mainstay of management of symptomatic and radiographically enlarging spinal tumors, where the goal is to achieve maximal safe resection. Tumor recurrences are managed with repeat surgical resection (preferred whenever possible and safe), radiotherapy, chemotherapy, or any combination of these therapies.

Brain parenchymal angiomatoid fibrous histiocytoma and spinal myxoid mesenchymal tumor with FET: CREB fusion, a spectrum of the same tumor type.

Angiomatoid fibrous histiocytomas (AFH) is a rare soft tissue tumor of intermediate malignant potential, and its histology is diverse. It can occur in several organs including intracranial and soft tissues. Here, we report two cases of brain parenchymal classic AFH and spinal extramedullary myxoid mesenchymal tumor with clinicopathological and molecular investigations by next-generation sequencing and a comprehensive review. The current brain parenchymal AFH occurred in a 79-year-old woman, and the spinal myxoid mesenchymal tumor arose in the thoracic spine of a 28-year-old woman; both harbored FET:CREB fusion. The current brain parenchymal AFH has not recurred for 15-months follow-up period, but the spinal myxoid mesenchymal tumor recurred three times and metastasized to T8 spine level for 30-months follow-up period. We reviewed 40 reported cases of central nervous system (CNS) AFHs/myxoid mesenchymal tumors including our two cases to identify clinicopathological features and biological behaviors. They occur with a slight female predominance (M:F = 1:1.7) in children and young adults (median age: 17 years; range: 4-79 years old). Approximately 80% of CNS AFHs were younger than 30 year. Most of them were dura-based and were not just intracranial tumors as they occurred anywhere in the CNS including spinal dura. EWSR1 rearrangement was the most common driver (98%), including FET:CREB (33%), EWSR1:ATF1 (30%), and EWSR1:CREM (27%) fusions, but FUS:CREM fusion (2%) was also present. During the follow-up period (median: 27 months), 43% (17/40) of CNS AFHs recurred between two months and 11 years, and multiple recurrences were also observed. One case showed metastases to the lymph nodes and vertebrae, and among 11 cases that resulted in death, four cases provided available clinical data. Because these tumors are identical to soft tissue AFH or primary pulmonary myxoid sarcoma with an FET:CREB fusion in morphological and immunohistochemical spectra, the authors propose incorporating the two tumor terms into one.

Poorly differentiated chordoma with whole-genome doubling evolving from a SMARCB1-deficient conventional chordoma: A case report.

Evolution of poorly differentiated chordoma from conventional chordoma has not been previously reported. We encountered a case of a poorly differentiated chordoma with evidence of whole-genome doubling arising from a SMARCB1-deficient conventional chordoma. The tumor presented as a destructive sacral mass in a 43-year-old man and was comprised of a highly cellular poorly differentiated chordoma with small, morphologically distinct nodules of conventional chordoma accounting for <5% of the total tumor volume. Immunohistochemistry (IHC) revealed both components were strongly reactive for brachyury and lacked normal staining for INI1. Single nucleotide polymorphism (SNP) array analysis identified multiple genomic imbalances in the conventional component, including deletions of 1p, 3p, and 22q (involving SMARCB1) and loss of chromosomes 5 and 15, while the poorly differentiated component exhibited the same aberrations at a more profound level with additional loss of chromosome 4, low level focal deletion of 17p (involving TP53), and tetraploidy. Homozygous deletion of SMARCB1 was present in both components. Fluorescence in situ hybridization (FISH) analysis confirmed the relevant deletions in both components as well as genome doubling in the poorly differentiated tumor. This case suggests that SMARCB1 loss is an early event in rare conventional chordomas that could potentially evolve into poorly differentiated chordoma through additional genomic aberrations such as genome doubling. Further studies with additional patients will be needed to determine if genome doubling is a consistent pathway for evolution of poorly differentiated chordoma.

Long non-coding RNA LINC00525 interacts with miR-31-5p and miR-125a-5p to act as an oncogenic molecule in spinal chordoma.

LINC00525 is a new-researched long non-coding RNA (lncRNA) in a few cancers. This study aims at researching the function of LINC00525 in spinal chordoma and the underlying mechanism of action. LINC00525, microRNA-31-5p (miR-31-5p) and microRNA-125a-5p (miR-125a-5p) detection was performed by quantitative real-time polymerase chain reaction (qRT-PCR). We found the high expression of LINC00525 but the low levels of miR-31-5p and miR-125a-5p in spinal chordoma tissues. After LINC00525 was downregulated in spinal chordoma cells, there were inhibitory effects on cell proliferation, migration, invasion and EMT but a promoting effect on cell apoptosis. MiR-31-5p and miR-125a-5p were the downstream targets of LINC00525. The function of LINC00525 knockdown in spinal chordoma cells were achieved by upregulating miR-31-5p and miR-125a-5p. Tumorigenesis of spinal chordoma in vivo was also inhibited by knockdown of LINC00525 via the promotion of miR-31-5p and miR-125a-5p. All these results suggested that LINC00525 targeted miR-31-5p and miR-125a-5p to promote the tumorigenesis and progression of spinal chordoma. LINC00525 can be a novel molecular target in spinal chordoma.

The importance of genetic counseling and screening for people with pathogenic SMARCE1 variants: A family study.

Clear cell meningioma (CCM) is a rare variant of meningioma. In recent years, an association between cranial and spinal CCMs and germline loss of function mutations in the SMARCE1 gene (SWI/SNF chromatin remodeling complex subunit gene) has been discovered. We report a family with an incidental large spinal clear cell meningioma in a young adult following reflex screening for a germline loss of function pathogenic variant (PV) in the SMARCE1 gene. The index patient's mother and maternal grandfather were both also tested positive presymptomatically for SMARCE1. His mother developed intracranial and spinal meningiomas and his maternal grandfather developed a spinal CCM 4 years following a clear spinal MRI scan which required surgical excision. In this report we particularly emphasize the importance of genetic counseling and screening in siblings, parents and offspring of patients who are diagnosed with intracranial or spinal CCM in the context of SMARCE1 PVs. We recommend brain and spine Imaging screening of asymptomatic SMARCE1 PV carriers at least every 3 years, even if the baseline scan did not show any tumors.

Primary Primitive Neuroectodermal Tumor of the Spine With t(11;22): Report of 3 Cases and Review of Literature.

Intradural extramedullary peripheral primitive neuroectodermal tumor (pPNET) with t(11;22) is a rare clinical finding in the pediatric population with few published cases in the literature. The authors report 3 cases of intradural primary pPNET and discuss the clinical presentation, treatment, and survival of the patients. Clinicians should be vigilant in considering pPNET in the differential diagnosis of extradural masses. The authors also compare the clinical course and outcome of therapy with primary PNET of the central nervous system and Ewing sarcoma family of tumors. In addition, this report highlights the risk for leptomeningeal dissemination at recurrence and discusses the importance of central nervous system-targeted therapy for durable disease control.

Longest survival by the combination of radiation-therapy and resection in patient with metastatic spinal paragangliomas from primary-neck lesion with succinate dehydrogenase subunit B (SDHB) mutation.

Metastatic paraganglioma (MPG) of the spine is a rare condition, with no established management. Herein, we report the longest survival case of a primary neck tumor that caused spinal MPG with a succinate dehydrogenase subunit B (SDHB) mutation (c.470delT, p.L157X) which could have promoted its malignancy. This male patient initially presented with a left neck PG which was diagnosed by a biopsy when he was 54 years-old. Simultaneously performed additional examinations revealed the spinal metastatic tumors on the T5-7 vertebrae and L3 vertebra-sacrum. These primary neck and metastatic spinal tumors' growths were once suppressed under the radiation therapy. Nineteen years later, he developed acute progressive paraparesis due to a mass located at the T2-3 level, tightly compressing the spinal cord, and protruding into the left thoracic cavity. We resected the maximum possible area of tumor in the spinal canal, confirmed MPG by histological examination, and then, we administered radiation therapy of 40 Gy in 20 fractions. Eventually, the patient was able to walk unaided with no evidential tumor recurrence for 3 years after treatment. Generally, clinical feature of MPG with SDHB mutation from abdominal lesion is thought to be poor prognosis. However, our case suggests the possibility of long-term control of spinal MPG with the adequate combination of radiation therapy and resection if metastatic lesions from primary-neck lesion with an SDHB mutation are remained to spine.

Ligand-Dependent and Ligand-Independent Effects of Ephrin-B2-EphB4 Signaling in Melanoma Metastatic Spine Disease.

Tumor-endothelial cell interactions represent an essential mechanism in spinal metastasis. Ephrin-B2-EphB4 communication induces tumor cell repulsion from the endothelium in metastatic melanoma, reducing spinal bone metastasis formation. To shed further light on the Ephrin-B2-EphB4 signaling mechanism, we researched the effects of pharmacological EphB4 receptor stimulation and inhibition in a ligand-dependent/independent context. We chose a preventative and a post-diagnostic therapeutic window. EphB4 stimulation during tumor cell seeding led to an increase in spinal metastatic loci and number of disseminated melanoma cells, as well as earlier locomotion deficits in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, reduction of metastatic loci with a later manifestation of locomotion deficits occurred. Thus, EphB4 receptor stimulation affects metastatic dissemination depending on the presence/absence of endothelial Ephrin-B2. After the manifestation of solid metastasis, EphB4 kinase inhibition resulted in significantly earlier manifestation of locomotion deficits in the presence of the ligand. No post-diagnostic treatment effect was found in the absence of endothelial Ephrin-B2. For solid metastasis treatment, EphB4 kinase inhibition induced prometastatic effects in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, both therapies showed no effect on the growth of solid metastasis.

Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing.

BACKGROUND: von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood. CASE PRESENTATION: We report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A > G (p.Pro138Pro). At 47-years, MRI revealed pheochromocytoma in the left adrenal gland and hemangioblastomas in the spine and brain. Pheochromocytoma was treated by adrenalectomy. Radiotherapy, followed by craniotomy and resection were needed to reduce hemangioblastomas to residual lesions. Two of three of the proband's children inherited the mutation and both presented with retinal hemangioblastomas without pheochromocytoma at age 7: one twin needed four laser treatments. Primary skin fibroblasts carrying the heterozygous mutation or wild type VHL were established from the family. Mutant fibroblasts downregulated full-length VHL mRNA and protein, and upregulated the short VHL mRNA isoform (a result of exon 2 skipping in splicing) at the mRNA level but not at the protein level. CONCLUSIONS: Our study shows that the synonymous VHL mutation c.414A > G can within 7 years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma. This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease. This is also the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts. The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2. The reduced but not completely abolished pVHL protein in a loss-of-heterozygosity genetic backdrop may underlie the etiology of VHL disease.

ß adrenergic receptor modulated signaling in glioma models: promoting ß adrenergic receptor-ß arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma.

Neoplastically transformed astrocytes express functionally active cell surface ß adrenergic receptors (ßARs). Treatment of glioma models in vitro and in vivo with ß adrenergic agonists variably amplifies or attenuates cellular proliferation. In the majority of in vivo models, ß adrenergic agonists generally reduce cellular proliferation. However, treatment with ß adrenergic agonists consistently reduces tumor cell invasive potential, angiogenesis, and metastasis. ß adrenergic agonists induced decreases of invasive potential are chiefly mediated through reductions in the expression of matrix metalloproteinases types 2 and 9. Treatment with ß adrenergic agonists also clearly reduce tumoral neoangiogenesis, which may represent a putatively useful mechanism to adjuvantly amplify the effects of bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor. We may accordingly designate ßagonists to represent an enhancer of bevacizumab. The antiangiogenic effects of ß adrenergic agonists may thus effectively render an otherwise borderline effective therapy to generate significant enhancement in clinical outcomes. ß adrenergic agonists upregulate expression of the major histocompatibility class II DR alpha gene, effectively potentiating the immunogenicity of tumor cells to tumor surveillance mechanisms. Authors have also demonstrated crossmodal modulation of signaling events downstream from the ß adrenergic cell surface receptor and microtubular polymerization and depolymerization. Complex effects and desensitization mechanisms of the ß adrenergic signaling may putatively represent promising therapeutic targets. Constant stimulation of the ß adrenergic receptor induces its phosphorylation by ß adrenergic receptor kinase (ßARK), rendering it a suitable substrate for alternate binding by ß arrestins 1 or 2. The binding of a ß arrestin to ßARK phosphorylated ßAR promotes receptor mediated internalization and downregulation of cell surface receptor and contemporaneously generates a cell surface scaffold at the ßAR. The scaffold mediated activation of extracellular regulated kinase 1/2, compared with protein kinase A mediated activation, preferentially favors cytosolic retention of ERK1/2 and blunting of nuclear translocation and ensuant pro-transcriptional activity. Thus, ßAR desensitization and consequent scaffold assembly effectively retains the cytosolic homeostatic functions of ERK1/2 while inhibiting its pro-proliferative effects. We suggest these mechanisms specifically will prove quite promising in developing primary and adjuvant therapies mitigating glioma growth, angiogenesis, invasive potential, and angiogenesis. We suggest generating compounds and targeted mutations of the ß adrenergic receptor favoring ß arrestin binding and scaffold facilitated activation of ERK1/2 may hold potential promise and therapeutic benefit in adjuvantly treating most or all cancers. We hope our discussion will generate fruitful research endeavors seeking to exploit these mechanisms.

MicroRNA-493-5p inhibits proliferation and metastasis of osteosarcoma cells by targeting Kruppel-like factor 5.

Osteosarcoma, including spinal osteosarcoma, has properties of high degree of malignancy, high rate of recurrence, and high incidence of metastasis. microRNAs can exert oncogenic or tumor suppressive roles in cancer cells. This study explored the effects of microRNA-493-5p (miR-493-5p) on osteosarcoma cell viability, migration, invasion, and apoptosis, as well as the underlying possible mechanism. First, the expression of miR-493-5p in osteosarcoma tissues and cells was detected using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Then, the effects of miR-493-5p overexpression (or suppression) on osteosarcoma cell viability, migration, invasion, and apoptosis, as well as Kruppel-like factor 5 (KLF5) expression, were assessed using the Cell Counting Kit-8 assay, two-chamber transwell assay, Annexin V-FITC/PI apoptosis detection kit, qRT-PCR, and western blotting, respectively. Finally, the roles of KLF5 in miR-493-5p suppression-induced U20S cell viability, migration, and invasion enhancement, as well as the PI3K/AKT pathway activation, were evaluated. We found that miR-493-5p had lower expression in tumor tissues of spinal osteosarcoma and osteosarcoma cells. Overexpression of miR-493-5p inhibited osteosarcoma U20S cell viability, migration, and invasion, but induced cell apoptosis. On the contrary, suppression of miR-493-5p-promoted U20S cell viability, migration, and invasion. KLF5 was a direct target gene of miR-493-5p, which participated in the effects of miR-493-5p on U20S cell viability, migration, invasion, and apoptosis. Furthermore, suppression of the miR-493-5p activated PI3K/AKT pathway in U20S cells by upregulating KLF5. In conclusion, we revealed that miR-493-5p exerted tumor suppressive roles in spinal osteosarcoma and osteosarcoma cells. Overexpression of miR-493-5p inhibited proliferation and metastasis of osteosarcoma cells by downregulating KLF5 and inactivating the PI3K/AKT signaling pathway.

Y-box binding protein-1 promotes tumorigenesis and progression via the epidermal growth factor receptor/AKT pathway in spinal chordoma.

Chordomas are rare bone tumors with a poor prognosis and no approved targeted therapy. Y-box binding protein-1 (YBX1) promotes tumor growth, invasion and drug resistance. However, the role of YBX1 in chordoma is unclear. In this study, we examined the expression of YBX1 using immunohistochemistry and found that YBX1 was significantly upregulated in 32 chordoma tissues compared to distant normal tissues. In addition, YBX1 upregulation was associated with surrounding tissue invasion, recurrence and poor prognosis. Biological function studies demonstrated that YBX1 promoted cell proliferation and invasion, accelerated G1/S phase transition, and inhibited apoptosis. Further investigation revealed that YBX1 enhanced epidermal growth factor receptor (EGFR) transcription by directly binding to its promoter in chordoma cells. YBX1 regulated protein expression of p-EGFR, p-AKT and its downstream target genes that influenced cell apoptosis, cell cycle transition and cell invasion. YBX1 activated the EGFR/AKT pathway in chordoma and YBX1-induced elevated expression of key molecules in the EGFR/AKT pathway were downregulated by EGFR and AKT pathway inhibitors. These in vitro results were further confirmed by in vivo data. These data showed that YBX1 promoted tumorigenesis and progression in spinal chordoma via the EGFR/AKT pathway. YBX1 might serve as a prognostic and predictive biomarker, as well as a rational therapeutic target, for chordoma.

MYCN amplification drives an aggressive form of spinal ependymoma.

Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification.

Incidence of initial spinal metastasis in glioblastoma patients and the importance of spinal screening using MRI.

PURPOSE: Intracranial glioblastomas with simultaneous spinal lesions prior to chemoradiation therapy or craniotomy, defined as initial spinal metastasis, are not well understood. Herein, we investigated intracranial glioblastoma and demonstrated the importance of spinal screening using gadolinium enhanced spinal magnetic resonance imaging (Gd-MRI). METHODS: Consecutive adult patients with intracranial glioblastoma were treated between 2010 and 2014 and received spinal screening using Gd-MRI. Spinal screening was performed regardless of spine-related symptoms, and patients presenting with and without initial spinal metastasis (spinal and non-spinal groups, respectively) were compared based on patient demographics, tumor characteristics, radiological and molecular features, and overall survival (OS). RESULTS: During the study period, 116 glioblastoma cases were treated and 87 of these (76%) underwent spinal screening. Among these patients, 11 (13%) were included in the spinal group, and 76 (87%) were included in the non-spinal group. All patients of the spinal group were free of symptoms related to spinal lesions. Compared with the non-spinal group, intracranial lesions of the spinal group presented higher incidences of intracranial dissemination and were located at subventricular zones (P = 0.0012 and 0.020, respectively). MIB-1 labeling index, molecular alterations such as IDH1 mutation, TERT promoter mutation, and immunoreactivity of ATRX and MGMT did not differ between two groups. OS was significantly shorter in the spinal group than in the non-spinal group (P = 0.0054). CONCLUSIONS: This study revealed a relatively high incidence of spinal metastasis. A subset of glioblastoma patients benefited from spinal screening, through which early detection of asymptomatic spinal metastasis was achieved.

Comparison of dysregulated long noncoding RNAs in lung adenocarcinoma and spinal metastasis: A genome-wide analysis.

Long noncoding RNAs (lncRNAs) have been shown to play crucial roles in cancer metastasis, yet the lncRNAs landscape of lung adenocarcinoma has not been completely characterized. The aim of this study was to assess the expression profile and potential function of lncRNA in lung adenocarcinoma and in spinal metastasis (SM). A genome-wide microarray analysis was conducted on lung adenocarcinoma and SM tissue from ten Chinese patients. A total of 3,345 differentially expressed lncRNAs were detected. Of those, 761 lncRNAs were upregulated and 2,584 were downregulated (fold-change >2.0, p<0.05). These differentially expressed lncRNAs were not evenly distributed among the chromosomes of human genome. Volcano plots of these differentially expressed lncRNAs revealed large variability in lncRNAs expression among 12 patients, indicating that certain lncRNAs may play a positive role in SM of lung adenocarcinoma. Gene Ontology enrichment and pathway analysis identified several remarkably dysregulated biological pathways that affect cell adhesion and the interaction of cytokines and cytokine receptors. Co-expression network analysis showed that 9,458 lncRNAs had verified cis- and trans- target genes. All 2,317 cis targeted genes were confirmed to be differentially expressed and influenced by dysregulated lncRNAs in SM of lung adenocarcinoma. Top ten markedly dysregulated lncRNAs and mRNAs were verified from the co-expression network. In conclusion, this study was a genome-wide survey of dysregulated lncRNAs and corresponding mRNAs that comprise co-regulation networks for SM and lung adenocarcinoma tissues. These dysregulated lncRNAs and mRNA networks could be used as therapeutic gene targets to prevent SM of lung adenocarcinoma and to predictively evaluate treatment efficacy.