Tumour resection in the Rolandic region is a challenge. Aim of this study is to review a series of patients malignant glioma surgery in the Rolandic region which was performed by combinations of neuronavigation, sonography, 5-aminolevulinic acid fluorescence guided (5-ALA) surgery and intraoperative electrophysiological monitoring (IOM).29 patients suffering malignant gliomas in the motor cortex (17) and sensory cortex (12) were analyzed with respect to functional outcome and grade of resections.Improvement of motor function was seen in 41.5% one week after surgery, 41.5% were stable, only 17% deteriorated. After three months patients had an improvement of motor function in 56%, of Karnofsky Score (KPS) 27% and sensory function was improved in 8%. Deterioration of motor function was seen in 16%, in sensory function 4% and in KPS 28% after three months. 25% showed no residual tumour in early post surgical contrast enhanced MRI. 10% had less than 2% residual tumour and 15% had 2–5% residual tumour.Preoperative functional neuroimaging, neuronavigation for planning the surgical approach and resection margins, intraoperative sonography and 5-ALA guided surgery in combination with the application of IOM shows that functional outcome and total to subtotal resection of malignant glioma in the Rolandic region is feasible.

Heat shock protein 90 promotes tumor progression and survival and has emerged as a vital therapeutic target. Previously we reported that the combinatorial treatment of 17AAG/sihsp90α significantly downregulated Hsp90α mRNA and protein levels in Glioblastoma Multiforme (GBM). Here we investigated the ability of cell penetrating peptide (Tat48–60 CPP)-mediated siRNA-induced hsp90α knockdown as a single agent and in combination with 17-allylamino-17-demethoxygeldanamycin (17-AAG) to induce tumor growth inhibition in GBM and whether it possessed therapeutic implications. GBM and non-tumorigenic cells exposed to siRNA and/or 17-AAG were subsequently assessed by qRT-PCR, immunofluorescence, FACS analysis, quantitative Akt, LDH leakage and cell viability assays. PAGE was performed for serum stability assessment. A combination of siRNA/17-AAG treatment significantly induced Hsp90α gene and protein knockdown by 95% and 98%, respectively, concomitant to 84% Akt kinase activity attenuation, induced cell cycle arrest and tumor-specific cytotoxicity by 88%. Efficient complex formation between CPP and siRNA exhibited improved serum stability of the siRNA with minimal intrinsic toxicity in vitro. The preliminary in vivo results showed that combination therapy induced hsp90α knockdown and attenuated Akt kinase activity in intracranial glioblastoma mouse models. The results imply that RNAi-mediated hsp90α knockdown increases 17-AAG treatment efficacy in GBM. In addition, the cytotoxic response observed was the consequence of downregulation of hsp90α gene expression, reduced Akt kinase activity and S-G2/M cell cycle arrest. These results are novel and highlight the ability of Tat to efficiently deliver siRNA in GBM and suggest that the dual inhibition of Hsp90 has therapeutic potentials.

Dual-specificity phosphatase 14 (DUSP14, also known as MKP6) is a MAP kinase phosphatase that dephosphorylates JNK, ERK, and p38 in vitro. We recently reported that DUSP14 negatively regulates T-cell activation and immune responses by interfering activation of TAB1–TAK1 complex. However, the molecular mechanism that regulates the phosphatase activity of DUSP14 remains unclear. Here, we report the post-translational modification of DUSP14 by ubiquitination. Mass spectrometry and mutational analyses identified that DUSP14 was Lys63-linked ubiquitinated at lysine 103 residue. Furthermore, DUSP14 inducibly interacted with the E3 ligase TRAF2 during T-cell receptor (TCR) signaling; TRAF2 shRNA knockdown reduced the DUSP14 ubiquitination. We also show that ubiquitination of DUSP14 was required for its phosphatase activity during TCR signaling. Together, these findings reveal a novel mechanism by which TRAF2 mediates Lys63-linked ubiquitination of DUSP14, leading to DUSP14 activation in T cells.

Squamous cell carcinoma (SCC) of the oral tongue is characterized by a high propensity for cervical nodal metastasis, which affects the probability of regional control and survival. Until now, elective treatment of the clinically negative neck in early lesions (T1–2) of the oral tongue cancer remains controversial. This study attempted to identify predictive factor(s) for cervical nodal metastasis and treatment outcomes in patients with early stage SCC of the oral tongue treated primarily by surgery. Fifty patients with previously untreated Stage I/II primary tongue carcinomas with available archival specimens treated at the Royal Marsden Hospital between 1981 and 1998 were reviewed. Clinico-pathological features including age, gender, alcohol and tobacco consumption, tumour location, histological grade, tumour-stromal border, growth pattern, tumour thickness, and clinical stage were evaluated and the correlations with cervical metastases and outcome analysis were determined. The overall occult nodal metastatic rate was 40% (20/50). Tumour thickness exceeding 5 mm was statistically significantly correlated with cervical metastases (P=0.003; relative risk=2.429). No statistical correlation was observed between other clinico-pathological parameters and nodal metastasis. With a median follow-up of 98 months, 5-year actuarial overall, disease-specific (DSS), and relapse-free survival were 65.71, 67.77, and 68.18%, respectively. Univariate analysis for DSS showed poorer outcomes for patients with age >60 years (P=0.0423) and tumour thickness >5 mm (P=0.0067). The effect of tumour thickness was maintained (P=0.005) on multivariate analysis. The present study indicates that the thickness of primary tumour has a strong predictive value for occult cervical metastasis and poor outcomes in patients with Stage I/II oral tongue SCC. Thus, elective neck treatment (surgery or irradiation) is indicated for tumours exceeding 5 mm thickness.

The 17th Meeting of the European Association for Cancer Research (EACR), held in the spectacular Palacio de Exposiciones y Congresos in association with ASEICA, the Spanish Association for Cancer Research, attracted almost 700 delegates. This excellent modern facility was a perfect counterpoint to the beautiful old Alhambra, Granada's most famous landmark. The Conference Chairman, J.C. Lacal and Scientific Co-Chairs E. Olah and R. Rosell, together with the Scientific Organising Committee and the able FECS Secretariat, produced a packed and varied programme. Plenary Sessions were combined with parallel Basic Science and Translational Symposia, world-renowned Keynote speakers, plus 60 oral proffered papers and 315 posters. The venue being Spain, it goes without saying that the hospitality was also exceptional, with many social events continuing long after midnight. Indeed, the only complaint heard was: “we are on Spanish time at night, and British time in the mornings!” We hope that the following report gives a flavour of the event, and encourages you to attend the 18th Meeting of the EACR, 3–6 July 2004, Innsbruck, Austria.

Ten human head and neck squamous carcinoma (HNSCC) cell lines were established in order to study the role of c-erbB signaling pathways in HNSCC progression. Five cell lines were derived from primary tumors at four different sites, and five were from lymph node metastases in the neck. Two pairs of lines were derived from the primary tumor and metastatic lymph node in the same patient. Basic characteristics including morphology, doubling time, phenotypes, cytogenetic profiles and tumorigenicity in nude mice were described. We examined the expression of c-erbB receptors and ligands in early passage new HNSCC lines and compared with five long-term established lines, normal keratinocytes and fibroblasts. Amplification of c-erbB-1 (EGFR) gene was observed in only one cell line whereas no amplification of other c-erbB genes was found. Overexpression of EGFR, c-erbB-2, c-erbB-3 and c-erbB-4 mRNAs was observed in 10, 14, 10 and 8 out of 15 head and neck cell lines respectively. Overexpression of c-erbB-3 and c-erbB-4 was more frequently observed in newly derived HNSCC lines than in long-established cell lines. The majority of tumor cells also expressed multiple c-erbB ligands. One selected cell line, SIHN-006, was shown to exhibit tyrosine phosphorylation via all four receptors. These new cell lines could provide a useful experimental model to study the co-operative signaling of type I tyrosine kinase receptors in HNSCC progression.

Numerous reports have shown an association between overexpression of the epidermal growth factor receptor (EGFR), and poor prognosis in head and neck squamous cell carcinomas (HNSCC), however, the underlying mechanisms are still unclear. In the present study, we set out to determine whether EGFR expression was associated with in vitro invasive capacity in a panel of four established and ten newly derived HNSCC lines. Ten of the cell lines expressed high levels of EGFR as determined by a ligand-binding assay and dot blot analysis, whereas the remaining four showed weak overexpression or normal levels of EGFR. The ability of cells to invade through Matrigel was found to be higher in the EGFR overexpressing cell lines (p < 0.0001), Expression levels of matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, MTI-MMP) and tissue inhibitors of MMP (TIMP-1, TIMP-2) were evaluated by semiquantitative RT-PCR, substrate zymography and western blot. We found a strong positive correlation between EGFR levels and the expression of MMP-9 mRNA (r(2) = 0.95; p < 0.0001), MMP-9 enzyme activity (r(2) = 0.8099; p < 0.0001) and an inverse correlation with TIMP-1 (r(2) 0.48; p = 0.0059), In six selected HNSCC lines, in vitro invasion was assayed in the presence of an anti-EGFR monoclonal antibody, ICR62, A significant reduction of invasion in four selected EGFR-overexpressing cell lines was found with 30 nM ICR62 (from 50% to 70%; P < 0.001) but there was no effect in two cell lines with normal EGFR levels. Our results show that the in vitro invasive phenotype of HNSCC lines correlates with high EGFR and MMP-9 expression, and it is therefore suggested that the EGFR signaling pathway might play an important role in the invasive behavior of HNSCC via specific upregulation of MMP-9 and downregulation of TIMP-1, Int. J. Cancer 86:307-317, 2000, (C) 2000 Wiley-Liss, Inc.

We recently reported that multiple c‐erbB ligands differentially modulate in vitro proliferation, invasion and expression of matrix metalloproteinases in human head and neck squamous carcinoma cells (HNSCC). In order to evaluate further the importance of c‐erbB ligands in tumor progression, the expression and regulation of this growth factor family in HNSCC cells was studied. We demonstrate that mRNAs for the 6 major c‐erbB ligands, namely, epidermal growth factor (EGF), transforming growth factor‐alpha (TGF‐α), betacellulin (BTC), heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), amphiregulin (AR) and heregulin (HRG), are expressed in a large panel of HNSCC cell lines. In addition to TGF‐α, other ligands (notably BTC and HRG‐β1) are involved in the autocrine growth regulation of these cells. Each c‐erbB ligand when applied exogenously, induced mRNA expression of both itself and the remaining family members and a differential response in the kinetics of induction was found. HB‐EGF and HRG mRNAs were induced rapidly (within 1 hr) and to a greater extent (3.2–6.2‐ and 4.8–7.3‐fold increase) than TGF‐α, BTC and AR mRNAs (1.6–2.7, 1.8–3.6‐ and 1.6–4.2‐fold, respectively). This pattern was observed for all inducing ligands tested. Analysis of mRNA stability, and concurrent treatment with BTC (as an inducing ligand) and cycloheximide (to inhibit protein synthesis) suggested both transcriptional and post‐transcriptional regulatory mechanisms. These results support and extend previous observations of c‐erbB receptor signaling as a critical element in the pathogenesis and progression of HNSCC, and emphasize the role of autocrine ligand production. Int. J. Cancer 88:759–765, 2000. © 2000 Wiley‐Liss, Inc.