Unravelling the role of immune cells and FN1 in the recurrence and therapeutic process of skull base chordoma.

BACKGROUND: Skull base chordoma is a rare and aggressive tumour of the bone that has a high likelihood of recurrence. The fundamental differences in single cells between primary and recurrent lesions remain poorly understood, impeding development of effective treatment approaches. METHODS: To obtain an understanding of the differences in single cells between primary and recurrent chordomas, we performed single-cell RNA sequencing and T-cell/B-cell receptor (BCR) sequencing. This allowed us to delineate the differences between the two types of tumour cells, tumour-infiltrating lymphocytes, myeloid cells, fibroblasts and B cells. Copy number variants (CNVs) were detected and compared between the tumour types to assess heterogeneity. Selected samples were subjected to immunohistochemistry to validate protein expression. Fluorescence in situ hybridisation experiments, Transwell assays and xenograft mouse models helped verify the role of fibronectin 1 (FN1) in chordoma. RESULTS: Promoting natural killer (NK) cell and CD8_GZMK T-cell function or inhibiting the transformation of CD8_GZMK T cells to CD8_ZNF683 T cells and promoting the transformation of natural killer T (NKT) cells to NK cells are promising strategies for preventing chordoma recurrence. Additionally, inhibiting the M2-like activity of tumour-associated macrophages (TAMs) could be an effective approach. Antigen-presenting cancer-associated fibroblasts (apCAFs) and dendritic cells (DCs) with high enrichment of the antigen-presenting signature were enriched in primary chordomas. There were fewer plasma cells and BCR clonotypes in recurrent chordomas. Remarkably, FN1 was upregulated, had more CNVs, and was more highly secreted by tumours, macrophages, CD4 T cells, CD8 T cells and fibroblasts in recurrent chordoma than in primary chordoma. Finally, FN1 enhanced the invasion and proliferation of chordomas in vivo and in vitro. CONCLUSION: Our comprehensive picture of the microenvironment of primary and recurrent chordomas provides deep insights into the mechanisms of chordoma recurrence. FN1 is an important target for chordoma therapy.

Ectopic GH-secreting pituitary adenoma of the clivus: systematic literature review of a challenging tumour.

PURPOSE: Acromegaly is usually due to growth hormone (GH)-secreting pituitary adenomas, but it may be exceptionally caused by GH-secreting ectopic pituitary adenomas (EPA). EPA are defined as extra-sellar pituitary tumours, extra- or intra-cranially sited, entirely separated from the pituitary stalk and gland. The aim of the study is to address the challenges in the management of clival GHEPA. METHODS: We reported a case of a 53-year-old acromegalic patient with a primary clival GHEPA and reviewed systematically the relevant English literature between 1975 and 2019, in keeping with the PRISMA guidelines. RESULTS: Four cases of primary clival GHEPA have been described in literature apart from ours. All patients presented with acromegalic features, elevated circulating GH and/or insulin-like growth factor-1 levels. Hyperprolactinemia and empty sella were described in two cases, respectively. These tumours show the typical imaging characteristics of pituitary adenomas, but their neuroradiological diagnosis may be challenging due to their sizes and the difficulty in defining the absence of connections with the pituitary fossa. CONCLUSION: Although primary clival GHEPA are exceedingly rare, even if likely under-reported in literature, they should be considered in the differential diagnosis of clival tumours because of their specific management. Surgery represents the first-line treatment option, while medical and radiation therapies can be adopted as neo-adjuvant, adjuvant or primary treatments according to tumour and patient characteristics.

Brain tissue oxygenation during transnasal endoscopic skull base procedures.

PURPOSE: We aimed to study brain tissue oxygenation during the period of controlled reduction of arterial blood pressure - a maneuver often used in extended endoscopic skull base surgery for bloodless operative field. METHODS: Intracranial pressure, arterial blood pressure and the resultant cerebral perfusion pressure were measured during extended endoscopic skull base surgery in 5 patients with diagnosed tumors of the skull base and arterial hypertension. Simultaneously, in those patients, we measured partial pressure of oxygen in the brain parenchyma (PbtO2). RESULTS: Values of PbtO2 lower than 15 mm Hg (risk of brain ischemia) were observed in 3 patients for periods of 40 min, 110 min and 123 min, respectively. In 2 of these patients, no hypotension (mean arterial pressure <65 mm Hg) was necessary for bloodless operative field. Another 2 patients had PbtO2 above 30 mm Hg at the time when their mean arterial pressure was below 65 mm Hg. The time course of PbtO2 followed that of cerebral perfusion pressure with a time lag of 40-60 s in all patients. CONCLUSION: Moderate reduction of arterial pressure, often used to obtain bloodless operative field during extended endoscopic skull base surgery, may in patients with the medical history of arterial hypertension be associated with critically low values of partial oxygen pressure in brain tissue.

Symptomatic progestin-associated atypical grade II meningioma. A first case report.

BACKGROUND: Long-term use of high-dose progestin is known to promote the development of meningioma. Atypical meningioma in a patient under progestin has not previously been reported. CASE REPORT: A 53-year-old right-handed woman presented with focal onset seizures, without impaired consciousness. Medical history featured endometriosis, treated successively by cyproterone acetate 25mg/day for 2 months then 50mg/day for 101 months, and chlormadinone acetate 5mg/day for 68 months then 10mg/day for 83 months. Brain MRI revealed multiple extra-axial lesions suggestive of left central meningioma associated with anterior skull base meningiomatosis. Surgical resection of the left central meningioma was achieved and progestin was withdrawn. Neuropathology diagnosed grade II atypical meningioma. Close clinical and imaging monitoring was implemented without adjuvant oncological treatment. At 25 months, imaging follow-up showed no recurrence of the left central meningioma and a significant regression of all other lesions, except for the right frontal lesion. CONCLUSIONS: Neurosurgeons should be aware of the possible aggressiveness of meningioma in patients under progestin, and particularly those treated by different types of progestin over a long period of time without interruption. This may require systematic close monitoring, to adapt neurosurgical management.

Identification and Analyses of Extra-Cranial and Cranial Rhabdoid Tumor Molecular Subgroups Reveal Tumors with Cytotoxic T Cell Infiltration.

Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOX genes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1 mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients.

WHO grade, proliferation index, and progesterone receptor expression are different according to the location of meningioma.

BACKGROUND: Meningiomas may show a different WHO grade and variable biological and clinical behaviors. The aim of the present study is to assess whether WHO grade, proliferation index, progesterone receptor (PR) expression, histological subtype, neuroradiological features, and the recurrence rate differ depending on the tumor location. METHODS: Three hundred meningiomas operated on from 2006 to 2016 were reviewed. The WHO grade (2007 classification), Ki67-MIB1, progesterone receptor expression, and histological subtype were reexamined and correlated to the meningioma location, classified as medial skull base, lateral skull base, non-skull base, and spinal. RESULTS: Non-skull base and lateral skull base meningiomas showed significantly higher rates of atypical WHO II forms (34% and 25.5% respectively) than medial skull base (12.5%) and spinal ones (7%) (p = 0.0003) and also higher rates of tumors with Ki67-Li > 4% (42% and 38% vs 22% and 14%) (p = 0.0031). The rate of meningiomas with PR expression ≤ 50% was significantly lower in medial skull base (25%) than in non-skull base (48%) (p = 0.009). Meningothelial and transitional meningiomas were more frequent at the skull base (68.5% and 54.5%, respectively), the fibroblastic subtype at the non-skull base (48.5%), and the psammomatous at the spinal canal (50%) (p < 0.00001). Medial skull base and spinal meningiomas showed significantly lower size (p < 0.00001), lower rates of cases with lost arachnoid interface (p = 0.0022), and significantly lower recurrence rates (p = 0.0035) than lateral skull base and non-skull base meningiomas. CONCLUSION: Medial skull base meningiomas show lower size, lower rate of atypical forms, lower Ki67-Li values, and significantly higher PR expression than those at the lateral skull base and non-skull base. This corresponds to lesser aggressiveness and lower recurrence rates.

Long and Very-Long-Chain Ceramides Correlate with A More Aggressive Behavior in Skull Base Chordoma Patients.

BACKGROUND: Skull base chordomas are rare tumors arising from notochord. Sphingolipids analysis is a promising approach in molecular oncology, and it has never been applied in chordomas. Our aim is to investigate chordoma behavior and the role of ceramides. METHODS: Ceramides were extracted and evaluated by liquid chromatography and mass spectrometry in a cohort of patients with a skull base chordoma. Clinical data were also collected and correlated with ceramide levels. Linear regression and correlation analyses were conducted. RESULTS: Analyzing the association between ceramides level and MIB-1, total ceramides and dihydroceramides showed a strong association (r = 0.7257 and r = 0.6733, respectively) with MIB-1 staining (p = 0.0033 and p = 0.0083, respectively). Among the single ceramide species, Cer C24:1 (r = 0.8814, p ≤ 0.0001), DHCer C24:1 (r = 0.8429, p = 0.0002) and DHCer C18:0 (r = 0.9426, p ≤ 0.0001) showed a significant correlation with MIB-1. CONCLUSION: Our lipid analysis showed ceramides to be promising tumoral biomarkers in skull base chordomas. Long- and very-long-chain ceramides, such as Cer C24:1 and DHCer C24:1, may be related to a prolonged tumor survival and aggressiveness, and the understanding of their effective biological role will hopefully shed light on the mechanisms of chordoma radio-resistance, tendency to recur, and use of agents targeting ceramide metabolism.

Non-NF2 mutations have a key effect on inhibitory immune checkpoints and tumor pathogenesis in skull base meningiomas.

AIMS: Skull base meningiomas represent approximately 25% of all meningiomas, nearly 20% of which are atypical or anaplastic. To date, effective medical treatments for meningiomas are still lacking. Genetic aberrations (TRAF7, KLF4, AKT1, and SMO) and the effects of genetic aberrations on the expression of inhibitory immune checkpoint molecules (PD-L1, IDO, and TDO2) in skull base meningiomas are still unclear. METHODS: Genetic alterations in the four genes were identified in 92 skull base meningiomas by Sanger sequencing. The expression differences in immune checkpoints between mutant and wild-type (WT) tumors were determined by immunohistochemistry (IHC) and Western blot (WB). RESULTS: The four mutations were not concurrently detected in the patients with skull base meningiomas. Among the tumors from the KLF4-mutated group, almost half were petroclival meningiomas. KLF4- and TRAF7-mutated tumors were predominantly secretory meningiomas. SMO-mutated tumors exhibited higher calcification, and half of these tumors were observed in the brain midline. Receiver operating characteristic curve analysis indicated that tumor volume can predict KLF4 and TRAF7 mutation status with high sensitivity and specificity, respectively. The IHC and WB analyses indicated that PD-L1, IDO, and TDO2 levels in tumors with TRAF7 mutations were significantly higher than those in WT tumors. Meanwhile, there was a significant difference in TDO2 between tumors with AKT1 mutations and WT tumors. Specifically, TRAF7 mutations could play a key role in skull base meningiomas by regulating the expression of inhibitory immune checkpoints and thus suppressing immune responses. CONCLUSIONS: Checkpoint inhibitors may be potential strategies for targeted immunotherapies of these mutant meningiomas.

Prognostic significance of VEGF receptors expression on the tumor cells in skull base chordoma.

BACKGROUND: Chordoma is a rare refractory neoplasm that arises from the embryological remnants of the notochord, which is incurable using any multimodality therapy. Vascular endothelial growth factor (VEGF) is a potent activator of angiogenesis that is strongly associated with the tumor-immune microenvironment. These factors have not been elucidated for chordomas. METHODS: To evaluate the characteristics of vascular and tumor cells in chordoma, we first analyzed the expression of VEGF receptor (VEGFR) 1, VEGFR2, CD34, and Brachyury in a cell line and 54 tumor tissues. Patients with primary skull base chordomas were divided into the following two groups as per the tumor growth rate: patients with slow progression (SP: < 3 mm/year) and those with rapid progression (RP: ≥ 3 mm/year). Thus, the expressions of VEGF-A, VEGFR 1, and VEGFR2 on tumor cells; tumor infiltrative immune cells, including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs); and immune-checkpoint molecules (PD-1/PD-L1) were analyzed with the clinical courses, especially in a comparison between the two groups. RESULTS: In chordomas, both VEGFR1 and VEGFR2 were strongly expressed not only on vascular endothelial cells, but also on tumor cells. The recurrent cases showed significantly higher VEGFR1 expressions on tumor cells than the primary cases. The expression of VEGF-A was significantly higher in RP than that in SP group. The numbers of CD163+ TAMs and Foxp3+ Tregs were higher in RP than that in SP group. CONCLUSIONS: Expression of VEGFR1 and VEGFR2 on tumor cells and immunosuppressive tumor-microenvironment were related to tumor growth in patients with chordomas.

Predictive Value of Transforming Growth Factor-α and Ki-67 for the Prognosis of Skull Base Chordoma.

OBJECTIVE: We aimed to characterize the expression of transforming growth factor-α (TGF-α) and Ki-67 and to assess the relationship between TGF-α and Ki-67 expression and prognostic factors in skull base chordoma. METHODS: We retrospectively analyzed the data from 46 patients with skull base chordoma. The follow-up duration ranged from 1 to 168 months (mean, 74.1). The survival data were statistically analyzed using the Kaplan-Meier method and multivariate Cox regression analysis. The expression of TGF-α and Ki-67 were detected by immunohistochemical staining of paraffin-embedded patient tissue specimens. RESULTS: The total resection (TR) group had longer overall survival compared with the non-TR group (P = 0.042). The TR group also had longer progression-free survival (PFS) than did the non-TR group (P = 0.046). The group with a high Ki-67 labeling index (Ki-67LI) had shorter overall survival than did the group with a low Ki-67LI (P = 0.039). Also, the group with a high Ki-67LI had significantly shorter PFS than did the group with a low Ki-67LI (P = 0.016). Moreover, the group with high TGF-α expression had significantly shorter PFS compared with the group with low TGF-α expression (P = 0.005). CONCLUSIONS: Our results have shown that high levels of TGF-α and Ki-67 are associated with shorter PFS in patients with chordoma. We have confirmed the role of Ki-67 as a functional molecular marker of poor prognosis. We also identified TGF-α as a potential novel biomarker for predicting prognosis for patients with skull base chordoma.

Surgery of Small Anterior Skull Base Meningiomas by Endoscopic 5-Aminolevulinic Acid Fluorescence Guidance: First Clinical Experience.

BACKGROUND: Minimally invasive surgery of small skull base meningiomas is technically challenging. We report the role of endoscopic 5-aminolevulinic acid fluorescence guidance (e-5-ALA-FGS) for small and deep-seated anterior skull base meningiomas. METHODS: We report the cases of 2 patients. The first case was a small olfactory groove meningioma resected via a trans-eyebrow, subfrontal approach. The second case was a clinoid meningioma with invasion of the optic canal resected via a small frontolateral approach. Intraoperative documentation demonstrated the usefulness of 5-ALA endoscopy. In either case, residual fluorescing tumor tissue was detected. No complication was encountered. The clinical and radiological outcomes were good. No regrowth had occurred after 54 and 17 months of follow-up, respectively. RESULTS: Residual meningioma tissue on the far side of a keyhole approach (e.g., in the olfactory groove or at the optic canal) can be difficult to visualize. Visualization can be improved by use of an endoscope. To date, fluorescence guidance with a microscope was limited by insufficient fluorescence signals in deep corridors. With a specially equipped 5-ALA fluorescence endoscope, one can combine the advantages of both endoscopic vision and fluorescence guidance. The results of present report have demonstrated the usefulness of 5-ALA endoscopy for difficult to visualize areas. CONCLUSION: Endoscopic 5-ALA fluorescence guidance was shown to be feasible when resecting small and deep-seated skull base meningiomas via minimally invasive approaches. Based on this proof of principle, we encourage its evaluation for the middle or posterior fossa (e.g., internal auditory canal) and other difficult areas (e.g., behind neurovascular structures or the brainstem). The sensitivity and specificity of this method should be prospectively and systematically investigated.

Progesterone Receptor Is Responsible for Benign Biology of Skull Base Meningioma.

OBJECTIVE: Many studies have been performed to evaluate the roles of estrogen receptor and progesterone receptor (PGR) in meningiomas, but their influence on tumor behavior remains unclear. METHODS: We retrospectively analyzed patients with meningioma who underwent surgical resection at our institute. Patients with data for immunohistochemical staining of estrogen receptor, PGR, and Ki-67 were included. RESULTS: The study included 161 patients comprising 61 skull base and 100 non-skull base meningiomas. Histologically, the number of patients with World Health Organization (WHO) grade I, II, and III disease were 132 (82.0%), 22 (14.7%), and 7 (4.4%), respectively. Tumor recurrence was observed in 21 (13.0%). Negative PGR, high Ki-67 index, incomplete resection, and WHO grade II or III were significantly correlated with tumor recurrence and shorter recurrence-free survival. Skull base meningiomas were difficult to remove entirely; 31 patients (50.8%) with skull base and 77 patients (77.0%) with non-skull base meningiomas had overall complete removal (P = 0.0006). Ki-67 indices, proportion of WHO grade II or III, and recurrence rate or recurrence-free survival did not differ between the tumor locations. The only difference was the proportion of patients with positive PGR, which was significantly higher for skull base meningiomas (61.5 ± 33.4% vs. 42.2 ± 35.7%, P = 0.0009). CONCLUSIONS: Although skull base meningiomas are often incompletely resected, there were no differences in recurrence-free survival or recurrence rate between skull base and non-skull base meningiomas. As the Ki-67 index and WHO grade were not different between these locations, the high rate of positive PGR may be responsible for the benign biology of skull base meningiomas.

[Rare primary proximal epithelioid sarcoma in skull base: clinical analysis of four cases].

Objective: To report the clinical and pathological features of primary proximal epithelioid sarcoma (PES) in skull base. Methods: The clinical and pathological features of four cases of PES in skull base from Sanbo Brain Institute of Capital Medical University and Kunming Sanbo Brain Institute were analysed retrospectively. Results: Three cases was female, and one male, the age ranged from 46 to 52 years.All cases occurred in skull base, and sellar region was the main site of involvement.Under the microscope, the tumor cells characterized by epithelioid cell changes, with or without rhabdoid tumor cells.Mitotic figure was active.Immunohistochemical staining showed that AE1/AE3, EMA and CD34 were variously expression in tumor cells.INI-1 protein was lost in all cases.Three cases were detected by FISH, and INI1 (22q11.2) gene locus was absent in them.Three patients died less than 3 months after surgery, and case 4 was under treatment after five months of surgery. Conclusions: Primary PES in skull base mostly occurs in sellar region and its clinical prognosis is poor.It features with epithelioid/rhabdoid tumor cells with lack granuloma structure as distal ES.It has epithelial and mesenchymal differentiation characteristics.CD34 is always positive.INI1 gene deletion and protein loss expression are characteristic molecular alteration of PES.

Analysis of clinical factors and PDGFR-ß in predicting prognosis of patients with clival chordoma.

OBJECTIVEIn this study, the authors' aim was to research clinical features and prognostic factors in patients harboring clival chordomas and explore the relationship between platelet-derived growth factor receptor-ß (PDGFR-ß) expression and tumor invasion and prognosis of clival chordoma.METHODSA total of 242 patients were retrospectively analyzed. Clinical information, including extent of resection, Al-Mefty classification, postoperative complications, and postoperative radiotherapy, was reviewed. Kaplan-Meier analysis was used to estimate survival time. Immunohistochemical analysis, quantitative reverse transcription polymerase chain reaction, and Western blotting were used to measure the expression level of proteins or mRNA. Transwell assaying was performed to measure the invasive ability of the tumor cells.RESULTSAccording to the Al-Mefty classification, there were 37, 112, and 93 type I, II, and III tumors, respectively. Gross-total resection (GTR) was achieved in 86 cases (35.5%), subtotal resection (STR) in 63 cases (26.0%), and partial resection (PR) in 93 cases (38.4%). The 5-year progression-free survival (PFS) and overall survival (OS) rates in the GTR group were significantly higher than those in the non-total resection (NTR; i.e., STR and PR) group (p < 0.001). The 5-year PFS and OS rates for patients with type I tumors were significantly higher than those for patients harboring types II and III tumors (p < 0.001). In the NTR group, the median PFS and OS of patients with lower PDGFR-ß expression were significantly longer than those of patients with higher PDGFR-ß expression. Reduction of PDGFR-ß suppressed the invasion ability of cells in vitro. In addition, reduction of PDGFR-ß can obviously downregulate the expression levels of mammalian target of rapamycin (mTOR) or phospho-mTOR.CONCLUSIONSExtent of resection, Al-Mefty classification, primary tumor, postoperative radiotherapy, and PDGFR-ß expression level are valuable prognostic factors in patients with clival chordomas. PDGFR-ß could regulate invasion through the mTOR pathway in clival chordoma cells.

C-Cbl and Cbl-b expression in skull base chordomas is associated with tumor progression and poor prognosis.

Chordomas are rare, locally aggressive malignancies that are often difficult to eradicate. Surgery and radiotherapy are the first-line treatments, but the probability of local recurrence is high. According to our previous research, c-Cbl and Cbl-b have been linked to tumor progression and poor prognosis of glioma. However, their role in skull base chordomas is unclear. To clarify this issue, in the present study, we analyzed the expression of c-Cbl and Cbl-b in relation to the clinicopathological features and clinical outcome of skull base chordoma patients (n = 70). C-Cbl and Cbl-b expression was evaluated by immunohistochemistry, and a survival analysis was performed based on clinical data. We found that c-Cbl and Cbl-b were upregulated in 30 of 70 (42.9%) and 32 of 70 (45.7%) patients with skull base chordomas, respectively. A Kaplan-Meier analysis and log-rank test indicated that high c-Cbl and Cbl-b levels were significantly associated with overall survival (P = .003 and P = .008, respectively) and progression-free survival (P < .001 and P = .022, respectively). These data indicated that c-Cbl and Cbl-b expression in skull base chordomas can predict tumor invasion and poor prognosis and is therefore a potential therapeutic target for chordoma treatment.

Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma.

OBJECTIVE Chordoma is a slow-growing but clinically malignant tumor, and the prognosis remains poor in many cases. There is a strong impetus to develop more effective targeted molecular therapies. On this basis, the authors investigated the potential of Brachyury, a transcription factor involved in notochord development, as a candidate molecular target for the treatment of chordoma. METHODS Brachyury gene copy number and expression levels were evaluated by quantitative polymerase chain reaction in 27 chordoma samples, and the transcriptomes of Brachyury high-expression tumors (n = 4) and Brachyury low-expression tumors (n = 4) were analyzed. A chordoma cell line (U-CH2) was used to investigate the signaling pathways that regulate Brachyury expression. RESULTS All chordoma specimens expressed Brachyury, and expression levels varied widely. Patients with higher Brachyury expression had significantly shorter progression-free survival (5 months, n = 11) than those with lower expression (13 months, n = 16) (p = 0.03). Somatic copy number gain was confirmed in 12 of 27 (44%) cases, and copy number was positively correlated with Brachyury expression (R = 0.61, p < 0.001). Expression of PI3K/Akt pathway genes was upregulated in Brachyury high-expression tumors, and suppression of PI3K signaling led to reduced Brachyury expression and inhibition of cell growth in the U-CH2 chordoma cell line. CONCLUSIONS Activation of the PI3K/Akt pathway and Brachyury copy number gain are strongly associated with Brachyury overexpression, which appears to be a key event in chordoma growth regulation. These findings suggest that targeting Brachyury and PI3K/Akt signaling may be an effective new approach for treating chordoma.

Chordoma: Immunohistochemical Analysis of Brachury.

AIM: Chordomas are rare, slow growing but locally aggressive malignancies of the axial skeleton. Skull base chordomas, due to their intricate anatomical localization, pose significant challenges to managing physicians. In classical and chondroid chordomas, the disease course cannot be reliably determined using only morphological criteria. Brachyury (T Gene) was shown to play a central role in chordoma pathogenesis and several studies also showed that this gene also carries potential as a prognostic biomarker. This study aims to correlate Brachyury expression with the clinical course in surgically treated skull base chordomas. MATERIAL AND METHODS: Chordoma tumor samples from 14 patients with skull base chordomas, diagnosed using histopathological and immunohistochemistry criteria (epithelial membrane antigen (EMA), S100, pan cytokeratin (panCK)) were retrospectively analyzed for Brachyury expression using immunohistochemistry. Brachyury expression was graded using a 4 point semi-quantitative scoring system. Focal (grade II) and diffuse staining (grade III) were considered as overexpression. Patient recurrence-free survival and total survival were compared between Brachyury overexpressing and non-overexpressing groups using Kaplan-Meier survival analysis. RESULTS: Among the stained tumor samples, 85.7% were positive for brachyury expression. In both groups, there was one sample that was negative. We did not observe any significant difference among the groups for staining, grade and percentage of brachyury positive cells. CONCLUSION: Brachyury expression in tumor samples is not a sensitive indicator of prognosis in chordomas.

Transcriptome comparison identifies potential biomarkers of spine and skull base chordomas.

Chordomas are rare, slowly growing, locally aggressive bone neoplasms that arise from embryonic remnants of the notochord, showing dual epithelial-mesenchymal differentiation. The high plasticity probably is the main reason for the high variety in phenotypes of chordoma, from its high heterogeneity on a cellular level to its subtype variations depending on tissue location, with its potential to develop from an inactive quiescent form to an aggressive cancer with extreme adaptability and resistance to drugs and other treatments. Gene expression profiles of formalin-fixed, paraffin-embedded skull chordoma, spine chordoma, and normal tissue specimens were generated and compared. Using strict criteria, we identified 222 differentially expressed transcripts unique to skull base chordoma, 261 unique to spine chordoma, and 192 common to both chordoma subtypes. Further analysis of these three groups of transcripts allowed the selection of three subsets of highly differentially expressed genes as potential biomarkers, disease drivers, and therapeutic targets in both chordoma subtypes. Immunohistochemistry revealed LMX1A to be dominant in skull base chordoma, SALL3 to be unique to spine chordoma, and T to be common to both chordoma subtypes. In both chordoma subtypes, the genes with the highest expression were predominantly development-related genes, mostly transcription factors. Our findings indicate that these developmental genes play important oncogenic roles in chordoma, mainly causing high plasticity and resistance to therapy in both these cancer subtypes but also determining their differentiation status and proliferation activity, pointing to features expected of heterogeneous stem cell-like tissues with similarities to their notochord origins.

SNF5 as a prognostic factor in skull base chordoma.

The current study aimed to characterize SNF5 expression and investigate the relationship between SNF5 and clinicopathological features in skull base chordoma. 48 patients diagnosed with skull base chordoma were enrolled in this study. Tissue microarray and immunohistochemistry were performed to evaluate the expression of SNF5 in skull base chordoma. Kaplan-Meier survival analysis was used to assess survival. Multivariable Cox regression analysis was used to identify risk factors affecting patient survival. The H-scores for cytoplasmic SNF5 ranged from 124.47 to 254.52. Low expression of SNF5 was correlated with shorter overall survival (OS) (p = 0.021). Patients with age > 55 years old had shorter progression free survival (PFS) and OS times than patients whose age ≤ 55 years old (p = 0.005 and 0.003, respectively). The gross total resection group showed longer PFS than the non-gross total resection group (p = 0.024). Females showed shorter PFS times than males (p = 0.033). Multivariable Cox regression analysis showed that age, extent of resection and sex were independent prognostic factors for PFS (p = 0.010, 0.013 and 0.042, respectively). Age was an independent prognostic factor for OS (p = 0.010). Our study indicate that low expression of SNF5 is associated with poor prognosis in skull base chordoma.