LIM and SH3 protein 1 (LASP1) differentiates malignant chordomas from less malignant chondrosarcomas.

PURPOSE: Chordomas are malignant tumors that develop along the neuraxis between skull-base and sacrum. Chondrosarcomas show similarities with chordomas, yet show less malignant behavior. LIM and SH3 protein 1 (LASP1) is a cytoskeletal protein known to promote the malignant behavior of tumors. LASP1 was previously identified as a possibly overexpressed protein in a chordoma proteomics experiment. In this study we compare LASP1 expression in chordoma and chondrosarcoma tissue. METHODS: Biopsies of primary tumors were collected from surgically treated chordoma (n = 6) and chondrosarcoma (n = 6) patients, flash-frozen upon collection and collectively analyzed for LASP1 RNA (real-time PCR) and protein expression (western blotting). Additionally, tissue micro array (TMA)-based immunohistochemistry was applied to an archive of 31 chordoma and 1 chondrosarcoma specimen. RESULTS: In chordoma samples, LASP1 mRNA was detected in 4/6 cases and a strong 36 kDa immunoreactive protein band was observed in 4/5 cases. In contrast, 0/6 chondrosarcoma samples showed detectable levels of LASP1 mRNA and only a weak 36 kDa band was observed in 4/5 cases. Immunohistochemical analysis showed LASP1 expression in all chordoma samples, whereas chondrosarcoma specimen did not show immunoreactivity. CONCLUSION: LASP1 is strongly expressed in the majority of chordoma cases and shows low expression in chondrosarcoma tissue. Since LASP1 is known to function as oncogene and regulate cell proliferation in other tumor types, this study implicates a role for LASP1 in chordoma biology. Further studies are warranted to improve understanding of LASP1's expression and functioning within chordoma, both in vitro and in vivo.

Genes Predicting Survival of Chordoma Patients.

BACKGROUND: A chordoma is a slow-growing, invasive neoplasm in the neuraxis that is thought to arise from notochordal cells. At 10-year follow-up, the average survival rate is 50%, though individual prognosis varies substantially. We aimed to provide a comprehensive overview of the genes and proteins expressed in these tumors and their prognostic value to facilitate prognostication for patients with chordoma. METHODS: A systematic search of clinical studies that investigated expressed factors related to chordoma survival was performed in PubMed. Data extracted included RNA and protein expression data and prognostic value (in terms of overall survival, progression-free survival, disease-free survival, and recurrence-free survival) from univariate and multivariate analyses. RESULTS: This review included 78 original studies that collectively evaluated 134 expressed factors. Of these molecular factors, 96 by univariate analysis and 32 by multivariate analysis had a predictive value for patient survival. Of the molecular factors studied in multivariate analyses, 26 factors had a negative effect while 6 had a positive effect on patient survival. CONCLUSIONS: Identification of molecular factors that are associated with survival contributes to better prognostication of patients with chordoma. Given the rarity of chordoma, often only univariate analyses can be performed. Robust multivariate analyses are scarcer but provide independently significant prognostic factors. The data presented in this review can aid in prognostication for the individual patient and facilitate the development of targeted therapies.

Kinome and phosphoproteome of high-grade meningiomas reveal AKAP12 as a central regulator of aggressiveness and its possible role in progression.

There is a need to better understand meningioma oncogenesis for biomarker discovery and development of targeted therapies. Histological or genetic criteria do not accurately predict aggressiveness. Post-translational studies in meningioma progression are lacking. In the present work, we introduce a combination of mass spectrometry-based phosphoproteomics and peptide array kinomics to profile atypical and anaplastic (high-grade) meningiomas. In the discovery set of fresh-frozen tissue specimens (14), the A-kinase anchor protein 12 (AKAP12) protein was found downregulated across the grades. AKAP12 knockdown in benign meningioma cells SF4433 increases proliferation, cell cycle, migration, invasion, and confers an anaplastic profile. Differentially regulated pathways were characteristic of high-grade meningiomas. Low AKAP12 expression in a larger cohort of patients (75) characterized tumor invasiveness, recurrence, and progression, indicating its potential as a prognostic biomarker. These results demonstrate AKAP12 as a central regulator of meningioma aggressiveness with a possible role in progression.

Oncogenic Viruses in Skull Base Chordomas.

BACKGROUND: Chordomas are rare tumors assumed to derive from notochordal remnants. We believe that a molecular switch is responsible for their malignant behavior. The involvement of oncogenic viruses has not been studied, however. Thus, in the present study, we investigated the presence of oncogenic viruses in chordomas. METHODS: DNA and RNA from snap-frozen chordoma (n = 18) and chondrosarcoma (n = 15) specimens were isolated. Real-time PCR or RT-PCR was performed to assess the presence of multiple oncogenic viruses, including herpesviridea (herpes simplex virus [HSV]-1, HSV-2, Epstein-Barr virus [EBV], cytomegalovirus, human herpesvirus [HHV]- 6, HHV-7, and Kaposi's sarcoma-associated herpesvirus), polyomaviridea (parvovirus B19 [PVB19], BK virus, JC virus, Simian virus 40, Merkel cell polyomavirus, human polyomavirus [HPyV]-6, and HPyV-7), papillomaviridae, and respiratory viruses. Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to validate the positive results. RESULTS: PVB19 DNA was detected in 4 of 18 chordomas (22%) and in 1 of 15 chondrosarcomas (7%). IHC recognizing the VP2 capsid protein of PVB19 showed a positive cytoplasmic staining in 44% of the cases (14 of 32). HHV7 DNA was present in 6 of the 18 chordomas (33%). Genomic DNA of EBV was found in 22% of the samples; however, no positive results were found on ISH. None of the chordoma cases showed any presence of DNA from the remaining viruses. CONCLUSIONS: Viral involvement in the etiology of chordomas is likely, with PVB19 the most distinguishing.

A novel drainage approach in patients with cholesterol granuloma: From petrous apex to mastoid air cell.

BACKGROUND: Cholesterol granulomas (CG) of the petrous apex (CGPA) are benign lesions that have high recurrence rates after surgical intervention. We describe the use of a robust silicon drain between the petrous apex and mastoid air cells to allow constant aeration of the lesion for preventing recurrence. CASE DESCRIPTION: A retrospective analysis was performed using the data of four patients treated at the Maastricht University Medical Centre between 2014 and 2016. Using the middle fossa approach, the petrous apex was reached, the cyst was opened, and the content aspirated. Subsequently, a robust silicon drain was placed between the cyst and mastoid air cell system. The outcome measures were clinical improvement of the symptoms and radiological parameters. The patients were female (n = 2) and male (n = 2) with an age range between 33 and 53 years at the time of the operation. Computed tomography and magnetic resonance imaging scans were used to confirm CG diagnosis. The most common presenting symptoms in our population were diplopia and headaches. The symptoms improved after surgery and there were no complications. Thus far, no recurrence has been observed and imaging shows aeration in the lesion area. CONCLUSION: The use of a robust drain seems to be an effective, safe, and feasible option to prevent recurrences in patients with CG.

Kinase Activity in Recurring Primary Skull Base Chordomas and Chondrosarcomas: Identification of Novel Pathways of Oncogenesis and Potential Drug Targets.

BACKGROUND: Chordomas and chondrosarcomas can occur in the skull base. Currently, 45% of chordomas and 56% of chondrosarcomas recur within 5 years of surgery. The role of adjuvant therapy is highly debated. No pharmacotherapies have been approved by the U.S. Food and Drug Administration for chordomas or chondrosarcomas. High propensity for recurrence and lack of definitive adjuvant therapy necessitate additional basic science research to identify molecular anomalies associated with recurrent disease. METHODS: We pooled tumor lysates from patients based on clinical criteria into 4 groups: primary chordomas, primary chordomas that recurred, primary chondrosarcomas, and primary chondrosarcomas that recurred. We used a peptide labeling method, isobaric tags for relative and absolute quantitation, to uniquely identify each tumor group. Phosphorylated peptides were identified and quantified via mass spectroscopy to determine and predict active kinases. RESULTS: Six groups of phosphorylated peptides were associated with primary tumors that later recurred. Specific kinases associated with primary chordomas that recurred were FES and FER. Specific kinases associated with primary chondrosarcomas that recurred were FES, FER, SRC family kinases, PKC, ROCK, and mitogen-activated protein kinase signaling (JNK, ERK1, p38). CONCLUSIONS: These data provide clinicians with a means to screen skull base chordomas and chondrosarcomas to help identify tumors with a propensity to recur. Many of these kinases can be efficaciously inhibited by Food and Drug Administration-approved drugs that have not yet been used in clinical trials for treatment of skull base chordomas or chondrosarcomas. Validation of kinases identified in this study may advance treatment options for patients with these tumors.

Chordoma: the entity.

Chordomas are malignant tumors of the axial skeleton, characterized by their locally invasive and slow but aggressive growth. These neoplasms are presumed to be derived from notochordal remnants with a molecular alteration preceding their malignant transformation. As these tumors are most frequently observed on the skull base and sacrum, patients suffering from a chordoma present with debilitating neurological disease, and have an overall 5-year survival rate of 65%. Surgical resection with adjuvant radiotherapy is the first-choice treatment modality in these patients, since chordomas are resistant to conventional chemotherapy. Even so, management of chordomas can be challenging, as chordoma patients often present with recurrent disease. Recent advances in the understanding of the molecular events that contribute to the development of chordomas are promising; the most novel finding being the identification of brachyury in the disease process. Here we present an overview of the current paradigms and summarize relevant research findings.

A neuroanatomical analysis of the effects of a memory impairing dose of scopolamine in the rat brain using cytochrome c oxidase as principle marker.

Acetylcholine plays a role in mnemonic and attentional processes, but also in locomotor and anxiety-related behavior. Receptor blockage by scopolamine can therefore induce cognitive as well as motor deficits and increase anxiety levels. Here we show that scopolamine, at a dose that has previously been found to affect learning and memory performance (0.1 mg/kg i.p.), has a widespread effect on cytochrome c oxidase histochemistry in various regions of the rat brain. We found a down-regulation of cytochrome c oxidase in the nucleus basalis, in movement-related structures such as the primary motor cortex and the globus pallidus, memory-related structures such as the CA1 subfield of the hippocampus and perirhinal cortex and in anxiety-related structures like the amygdala, which also plays a role in memory. However choline acetyltransferase levels were only affected in the CA1 subfield of the hippocampus and both, choline acetyltransferase and c-Fos expression levels were decreased in the amygdala. These findings corroborate strong cognitive behavioral effects of this drug, but also suggest possible anxiety- and locomotor-related changes in subjects. Moreover, they present histochemical evidence that the effects of scopolamine are not ultimately restricted to cognitive parameters.

A comparison of cell-cycle markers in skull base and sacral chordomas.

OBJECTIVE: Despite refinement of surgical techniques and adjuvant radiotherapy, the prognosis for patients with a chordoma remains poor. Identification of prognostic factors related to tumor biology might improve this assessment and result in molecular markers for targeted therapy. Limited studies have been performed to unravel the impact of cell-cycle markers in chordoma, and those performed have shown inconclusive results. In the current study, we aimed to discover the impact of cyclin-dependent kinase 4 (CDK4) expression and its relation to prognosis and other cell-cycle markers in chordoma. METHODS: Twenty-five human formalin-fixed, paraffin-embedded chordoma specimens were examined by immunohistochemistry for the expression of CDK4, protein 53 (p53), and murine double minute 2 (MDM2). The MIB-1 labeling index and mitotic index were used for the examination of proliferation. We collected detailed demographic and clinical data. RESULTS: Overexpression of CDK4, p53, and MDM2 was found in five (20%), seven (28%), and 14 (56%) of the cases, respectively. All three cell-cycle markers showed a significant correlation with MIB1 labeling index. Expression of CDK4 (P = 0.02) and p53 (P < 0.01) were both significantly correlated with poor overall survival. Also, histologically observed necrosis (P < 0.05) and a dedifferentiated tumor subtype (P < 0.01) were related to adverse patient outcome. CONCLUSION: Our results show that the expression of CDK4 and p53 are related to cell proliferation capacity and worse outcome in patients with chordoma.