Aberrant Expression of Extracellular Signal-Regulated Kinase and 15-Hydroxyprostaglandin Dehydrogenase Indicates Radiation Resistance and Poor Prognosis for Patients with Clival Chordomas.

OBJECTIVE: To explore molecular markers of radiosensitivity and prognostic factors in patients with clival chordomas. METHODS: Retrospective review was performed of 35 patients. Mean follow-up interval was 66.37 months (range, 29-106 months). Kaplan-Meier method was used for survival analysis. Immunohistochemical staining was used to detect expression levels of extracellular signal-regulated kinase (ERK) and 15-hydroxyprostaglandin dehydrogenase (HPGD). RESULTS: Total resection was achieved in 12 cases, subtotal resection was achieved in 12 cases, and partial resection was achieved in 11 cases. Radiation-sensitive group comprised 17 cases, and radiation-resistant (RR) group comprised 18 cases. Five-year progression-free survival (PFS) rates in total resection and nontotal resection groups were 46.3% and 10.1%, respectively (P = 0.005). Mean H-scores of ERK in radiation-resistant and radiation-sensitive groups were 110.38 and 82.98, respectively (P = 0.043). Mean H-scores of HPGD in radiation-resistant and radiation-sensitive groups were 178.62 and 203.47, respectively (P = 0.031). Mean PFS in low ERK expression group (58.61 months) was significantly longer than mean PFS in high ERK expression group (24.94 months) (P = 0.022). Mean PFS in high HPGD expression group (39.54 months) was significantly longer than mean PFS in low HPGD expression group (9.5 months) (P = 0.013). CONCLUSIONS: Radical resection with protection of important structures is the most effective treatment of clival chordomas. High HPGD expression and low ERK expression were associated with radiation sensitivity and better prognosis. HPGD and ERK can be used as biomarkers to predict prognosis and guide treatment.

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.

Connection between expression of inducible nitric oxide synthase (iNOS) in skull base chordoma and lower urinary tract symptoms.

OBJECTIVE: To provide first insights into the potential role of iNOS expressed by skull base chordoma, which causes brainstem compression in and around Barrington's nucleus, and its effect on the micturition center. METHODS: Urodynamic testing of 22 symptomatic patients was performed. All women and men with skull base chordoma treated in two hospitals in Germany between 1986 and 2007 were studied. Lower urinary tract symptoms (LUTS) were documented in patients with acute brainstem compression due to local chordoma growth positive for iNOS expression. Brain magnetic resonance (MRI) images of the lesions of the symptomatic patients were performed. RESULTS: Of 74 treated patients, 22 (7 women, 15 men) with a median age of 37 years were evaluated with voiding diaries and computer urodynamic investigation. Urodynamic testing of 22 symptomatic patients with positive iNOS expression of skull base chordoma revealed detrusor overactivity in 55 %, low-compliance bladder in 14 %, detrusor sphincter dyssynergia in 45 % and uninhibited sphincter relaxation in 27 %. There was a significant correlation between strong iNOS expression (score 3-6) in skull base chordoma and severe urinary symptoms (p = 0.003, Spearman ρ = 0.526). CONCLUSIONS: The expression of iNOS in skull base chordoma compressing the dorsolateral pons, in and around Barrington's nucleus, may influence the pontine micturition center (PMC) and be responsible for lower urinary tract symptoms. Nitric oxide may possibly act as a neurotransmitter. We assume that the high infiltration of chordoma with monocyte/macrophages enhances the release of nitric oxide, as monocyte/macrophages are the main source of iNOS.

Establishing tumor cell lines from aggressive telomerase-positive chordomas of the skull base. Technical note.

Permanent cell cultures are invaluable tools for understanding the biological characteristics of tumors. In the present study the authors report on the establishment of permanent human cell lines from three cases of aggressive chordomas of the clival region. All of the parental tumors showed telomerase activity. Cultured chordoma cells had a doubling time of 5 to 7 days and grew as a monolayer of cells that retained both the immunophenotype and the p53 status of the parental tumor. In vitro, chordoma cells overexpressed telomerase, supporting the hypothesis that this enzyme is required for the immortalization process.