Volume 5
Archive

1: Cancer. 2006 Dec 5; [Epub ahead of print]

 
Temozolomide in advanced malignant melanoma with small brain metastases: can we Withhold Cranial Irradiation?

Boogerd W, de Gast GC, Dalesio O.

Department of Neuro-oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.

BACKGROUND.: The efficacy of radiotherapy (RT) in patients who have brain metastases from melanoma is limited. In this study, the authors evaluated the efficacy of treatment with temozolomide in patients with metastatic melanoma, including small brain metastases, who did not require immediate RT and investigated the feasibility of deferring RT. METHODS.: Patients with brain metastasis were identified from 3 prospective studies of temozolomide (with or without immunotherapy) for metastatic melanoma. Patients with brain metastasis that measured >2 cm, extensive edema, and localization in the brain stem were excluded from the study. For the current analysis, patients with leptomeningeal metastasis and patients who received previous stereotactic RT were excluded. In patients who achieved a systemic response or stabilization to temozolomide, the response of brain metastasis and the necessity for palliative cranial RT were evaluated. RESULTS.: Among 179 patients who received temozolomide for advanced melanoma, 52 patients with brain metastasis were evaluable. Stabilization of systemic metastasis was noted in 7 of 52 patients (13%), and there were 6 responses (5 partial responses and 1 complete response; 11%); thus, in those 13 patients, 6 had stabilization of brain metastasis (11%) and 5 had a response (2 partial responses and 3 complete responses; 9%). Immunotherapy did not influence the neurologic response. The median time to neurologic progression was 7 months (range 2-15, months). RT for cerebral recurrence was required in 2 patients. The median survival of patients with brain metastases was 5.6 months (95% confidence interval, 4.4-6.8 months). Intracranial hemorrhagic complications were not observed. CONCLUSIONS.: The current results indicated that it is feasible to treat patients who have advanced melanoma and small brain metastasis with temozolomide as the single treatment. The small subset of patients with systemic response usually showed durable stabilization or a response of brain metastasis. With this approach, neurologic disease can be controlled, and cranial irradiation may be deferred and even withheld in most of patients. Cancer 2007. (c) 2006 American Cancer Society.

PMID: 17149755 [PubMed - as supplied by publisher]

 

2: Cancer Res. 2006 Dec 1;66(23):11331-11340.

 
The PTEN/Akt Pathway Dictates the Direct {alpha}V{beta}3-Dependent Growth-Inhibitory Action of an Active Fragment of Tumstatin in Glioma Cells In vitro and In vivo.

Kawaguchi T, Yamashita Y, Kanamori M, Endersby R, Bankiewicz KS, Baker SJ, Bergers G, Pieper RO.

Brain Tumor Research Center, Department of Neurological Surgery and The University of California-San Francisco Comprehensive Cancer Center, University of California San Francisco, San Francisco, California and Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee.

The collagen type IV cleavage fragment tumstatin and its active subfragments bind to integrin alpha(V)beta(3) and inhibit activation of focal adhesion kinase, phophoinositol-3 kinase, Akt, and mammalian target of rapamycin (mTOR) in what is thought to be an endothelial cell-specific manner. The resultant endothelial cell apoptosis accounts for the ability of tumstatin to function as an endogenous inhibitor of angiogenesis and an indirect suppressor of tumor growth. We hypothesized that the inability of tumstatin to directly suppress tumor cell growth might be the result of the constitutive activation of the Akt/mTOR pathway commonly seen in tumors. Consistent with this idea, several integrin alpha(V)beta(3)-expressing glioma cell lines with PTEN mutations and high levels of phospho-Akt (pAkt) were unaffected by exposure to an active fragment of tumstatin (T3), whereas alpha(V)beta(3)-expressing glioma cell lines with a functional PTEN/low levels of pAkt exhibited T3-induced growth suppression that could be bypassed by small interfering RNA-mediated suppression of PTEN, introduction of a constitutively expressed Akt, or introduction of the Akt and mTOR target eukaryotic translation initiation factor 4E. The direct tumor-suppressive actions of T3 were further shown in an alpha(V)beta(3)-deficient in vivo mouse model in which T3, while unable to alter the tumstatin-insensitive vasculature contributed by the alpha(V)beta(3)-deficient host, nonetheless suppressed the growth and proliferative index of i.c. implanted alpha(V)beta(3)-expressing PTEN-proficient glioma cells. These results show that tumstatin, previously considered to be only an endogenous inhibitor of angiogenesis, also directly inhibits the growth of tumors in a manner dependent on Akt/mTOR activation. (Cancer Res 2006; 66(23): 11331-40).

PMID: 17145879 [PubMed - as supplied by publisher]

 

3: Cancer Res. 2006 Dec 1;66(23):11172-8.

 
Genome-wide allelic imbalance analysis of pediatric gliomas by single nucleotide polymorphic allele array.

Wong KK, Tsang YT, Chang YM, Su J, Di Francesco AM, Meco D, Riccardi R, Perlaky L, Dauser RC, Adesina A, Bhattacharjee M, Chintagumpala M, Lau CC.

Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center.

Using single nucleotide polymorphic (SNP) allele arrays, we analyzed 28 pediatric gliomas consisting of 14 high-grade gliomas and 14 low-grade gliomas. Most of the low-grade gliomas had no detectable loss of heterozygosity (LOH) in any of the 11,562 SNP loci; exceptions were two gangliogliomas (3q and 9p), one astrocytoma (6q), and two subependymal giant cell astrocytomas (16p and 21q). On the other hand, all high-grade gliomas had various degrees of LOH affecting 52 to 2,168 SNP loci on various chromosomes. LOH occurred most frequently in regions located at 4q (54%), 6q (46%), 9p (38%), 10q (38%), 11p (38%), 12 (38%), 13q (69%), 14q (54%), 17 (38%), 18p (46%), and 19q (38%). We also detected amplifications of epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor alpha (PDGFRalpha) in a few of the 13 cases of glioblastoma multiforme analyzed. Interestingly, the amplified EGFR and PDGFRalpha were located within regions of LOH. SNP loci with LOH and copy number changes were validated by sequencing and quantitative PCR, respectively. Our results indicate that, in some pediatric glioblastoma multiforme, one allele each of EGFR and PDGFRalpha was lost but the remaining allele was amplified. This may represent a new molecular mechanism underlying tumor progression. (Cancer Res 2006; 66(23): 11172-8).

PMID: 17145861 [PubMed - in process]

 

4: Clin Cancer Res. 2006 Dec 1;12(23):7132-9.

 
Monitoring of singlet oxygen is useful for predicting the photodynamic effects in the treatment for experimental glioma.

Yamamoto J, Yamamoto S, Hirano T, Li S, Koide M, Kohno E, Okada M, Inenaga C, Tokuyama T, Yokota N, Terakawa S, Namba H.

Authors' Affiliations: Department of Neurosurgery and Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan.

PURPOSE: Singlet oxygen ((1)O(2)) generated in photodynamic therapy (PDT) plays a very important role in killing tumor cells. Using a new near-IR photomultiplier tube system, we monitored the real-time production of (1)O(2) during PDT and thus investigated the relationship between the (1)O(2) production and photodynamic effects. EXPERIMENTAL DESIGN: We did PDT in 9L gliosarcoma cells in vitro and in an experimental tumor model in vivo using 5-aminolevulinic acid and nanosecond-pulsed dye laser. During this time, we monitored (1)O(2) using this system. Moreover, based on the (1)O(2) monitoring, we set the different conditions of laser exposure and investigated whether they could affect the tumor cell death. RESULTS: We could observe the temporal changes of (1)O(2) production during PDT in detail. At a low fluence rate the (1)O(2) signal gradually decreased with a low peak, whereas at a high fluence rate it decreased immediately with a high peak. Consequently, the cumulative (1)O(2) at a low fluence rate was higher, which thus induced a strong photodynamic effect. The proportion of apoptosis to necrosis might therefore be dependent on the peak and duration of the (1)O(2) signal. A low fluence rate tended to induce apoptotic change, whereas a high fluence rate tended to induce necrotic change. CONCLUSIONS: The results of this study suggested that the monitoring of (1)O(2) enables us to predict the photodynamic effect, allowing us to select the optimal laser conditions for each patient.

PMID: 17145838 [PubMed - in process]

 

5: J Neurooncol. 2006 Dec 7; [Epub ahead of print]

 
Genetic variation in p53 and ATM haplotypes and risk of glioma and meningioma.

Malmer BS, Feychting M, Lonn S, Lindstrom S, Gronberg H, Ahlbom A, Schwartzbaum J, Auvinen A, Collatz-Christensen H, Johansen C, Kiuru A, Mudie N, Salminen T, Schoemaker MJ, Swerdlow AJ, Henriksson R.

Department of Radiation Sciences, Oncology, Umea University Hospital, 901 85, Umea, Sweden, Beatrice.malmer@onkologi.umu.se.

BACKGROUND: P53 and ATM are central checkpoint genes involved in the repair of DNA damage after ionising irradiation, which has been associated with risk of brain tumours. Therefore, we tested the hypothesis that polymorphisms and haplotypes in p53 and ATM could be associated with glioma and meningioma risk. MATERIAL AND METHODS: Six hundred and eighty glioma cases (298 glioblastoma (GBM)), 503 meningioma cases, and 1555 controls recruited in the Nordic-UK Interphone study, were analysed in association with three polymorphisms in p53 (rs2287499, rs1042533, rs1625895) and five polymorphisms in ATM ( rs228599, rs3092992, rs664143, rs170548, rs3092993). Haplotypes were constructed using the HAPLOSTAT program. RESULTS: The global statistical test of glioblastoma and p53 haplotypes was p = 0.02. The haplotype analysis on glioblastoma revealed the 1-2-2 haplotype (promotor-codon72-intron 6) had a frequency of 6.1% in cases compared with 9.8% in controls (p = 0.003).The 1-2-1 haplotype was significantly more frequent in GBM cases, 10.2%, than in controls, 7.3% (p = 0.02). The haplotype analysis in ATM revealed an increased frequency of the 1-1-1-2-1 haplotype in meningioma cases (33.8%) compared with controls (30.3%) (p = 0.03). The 2-1-2-1-1 haplotype had a lower frequency in meningioma cases (36.1%) than controls (40.7%) (p = 0.009). CONCLUSIONS: This study found both positive and negative associations of haplotypes in p53 for glioblastoma and ATM for meningioma. This study provides new data that could add to our understanding of brain tumour susceptibility.

PMID: 17151932 [PubMed - as supplied by publisher]

 

6: J Neurooncol. 2006 Dec 7; [Epub ahead of print]

 
Single nucleotide polymorphisms and expression of ERCC1 and ERCC2 vis-a-vis chemotherapy drug cytotoxicity in human glioma.

Chen H, Shao C, Shi H, Mu Y, Sai K, Chen Z.

State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.

ERCC1 and ERCC2 have been known to belong to the nucleotide excision repair (NER) pathway and are essential to the repair of cisplatin DNA adducts. In the present study, we have examined the potential correlation of ERCC1, ERCC2 mRNA expression and single nucleotide polymorphism (SNP) to chemotherapy drug cytotoxicity from 49 human gliomas. Fresh human glioma specimens were obtained during surgery. SNPs of ERCC1 and ERCC2 was determined by single strand conformation polymorphism (SSCP) and sequencing. ERCC1 and ERCC2 expression was quantified using real-time quantitative reverse transcription-PCR. Chemotherapy drug cytotoxicity was determined by the tetrazolium (MTT) assay for cisplatin (CDDP), 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), vincristine (VCR) and teniposide (VM26). The results show that there was no statistically significant association between the C8092A polymorphism of ERCC1 or codon 312 and codon 751 polymorphisms of ERCC2 and the chemotherapy drug cytotoxicity. However there was a strong correlation between ERCC1 and ERCC2 mRNA expression levels (Spearman r = 0.42; P < 0.003). Further more, tumor samples with low ERCC1 mRNA expression levels showed enhanced CDDP cytotoxicity (P = 0.0001) while ERCC2 expression was reversely correlated with BCNU cytotoxicity (P = 0.004). In sum, Our results indicated that ERCC1 mRNA expression is associated with CDDP cytotoxicity and ERCC2 mRNA levels is related with BCNU cytotoxicity, while there was no correlation between SNP of ERCC1, ERCC2 and in vitro cytotoxicity of four anticancer drugs, CDDP, BCNU, VCR and VM26.

PMID: 17151930 [PubMed - as supplied by publisher]

 

7: J Neurooncol. 2006 Dec 7; [Epub ahead of print]

 
Impact of novel PTEN mutations in Turkish patients with glioblastoma multiforme.

Tunca B, Bekar A, Cecener G, Egeli U, Vatan O, Tolunay S, Kocaeli H, Aksoy K.

Department of Medical Biology, School of Medicine, Uludag University, Bursa, Turkey, btunca@uludag.edu.tr.

Glioblastoma multiforme (GBM) represents the most common and aggressive type of primary neoplasms of the central nervous system. The PTEN (phosphatase, tensin homologue, deleted on chromosome TEN; MIM # 601728) tumor suppressor gene has an essential biological role in the formation of glioblastomas. It is known that there are variations in genetic alterations in tumors that develop in patients with different ethnic backgrounds and because there is no study evaluating PTEN mutation in Turkish patients with GBM, we aimed to realize the present study. We investigated 62 GBM tumors for mutations of the PTEN gene using single strand conformational polymorphism (SSCP) method followed by DNA sequencing. As a result of our investigation, PTEN mutations were detected in 15 of 62 tumors (24.19%). Nine different sequence variants were identified: one novel promoter site mutation (5'UTR -9C-->T), one novel intronic mutation (IVS2-2delA), four novel point mutations (61A-->G, 105T-->G, 248C-->G, and 364C-->G), two novel frameshift mutations (213delC) and 378delGATA) and one previously reported global exonic transition type mutation (129G-->A). Since the majority of PTEN mutations identified in the present study are novel, we believe that these alterations may be specific to Turkish population. Furthermore, though no significant correlation was found between PTEN mutations and histopathological properties of GBM tumors, our findings indicate that localizations of mutations in PTEN gene may have an effect on clinical aggressiveness of GBM tumors.

PMID: 17151929 [PubMed - as supplied by publisher]

 

8: J Neurooncol. 2006 Dec 5; [Epub ahead of print]

 
Anaplastic variant of medulloblastoma mimicking a vestibular schwannoma.

Santagata S, Kesari S, Black PM, Chan JA.

Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.

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PMID: 17146596 [PubMed - as supplied by publisher]

 

9: J Neuropathol Exp Neurol. 2006 Dec;65(12):1181-1188.

 
Activation of STAT3, MAPK, and AKT in Malignant Astrocytic Gliomas: Correlation With EGFR Status, Tumor Grade, and Survival.

Mizoguchi M, Betensky RA, Batchelor TT, Bernay DC, Louis DN, Nutt CL.

From the Molecular Pathology Unit and Molecular Neuro-Oncology Laboratory, Department of Pathology, Cancer Center and Neurosurgical Service (MM, DCB, DNL, CLN), Massachusetts General Hospital and Harvard Medical School, Boston, MA; the Department of Biostatistics (RAB), Harvard School of Public Health, Boston, MA; and the Stephen E. & Catherine Pappas Center for Neuro-Oncology, Department of Neurology (TTB), Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Diffuse astrocytic gliomas are the most common human glial tumors with glioblastoma being the most malignant form. Epidermal growth factor receptor (EGFR) gene amplification is one of the most common genetic changes in glioblastoma and can lead to the activation of various downstream signaling molecules, including STAT3, MAPK, and AKT. In this study, we investigated the activation status of these 3 signaling molecules as well as wild-type (EGFRwt) and mutant (EGFRvIII) EGFR in 82 malignant astrocytic gliomas (55 glioblastomas and 27 anaplastic astrocytomas) using immunohistochemistry. The presence of EGFRwt, but not EGFRvIII, immunopositivity correlated significantly with prevalent EGFR gene amplification in glioblastomas. STAT3 and AKT activation correlated significantly with EGFR status, although the correlation for p-STAT3 was attributed exclusively to EGFRvIII. The distribution of these 3 activated molecules varied significantly with tumor grade; although activation of STAT3 was essentially identical between anaplastic astrocytomas and glioblastomas, an increase in the activation of MAPK and AKT appeared to correlate with the progression of anaplastic astrocytoma to glioblastoma. Finally, activated STAT3 and AKT were marginally predictive of improved and worse prognosis, respectively. Taken together, these findings begin to elucidate the interrelationship between these signaling pathways in astrocytic gliomas in vivo.

PMID: 17146292 [PubMed - as supplied by publisher]

 

10: J Neuropathol Exp Neurol. 2006 Dec;65(12):1149-1156.

 
Expression of Oligodendroglial and Astrocytic Lineage Markers in Diffuse Gliomas: Use of YKL-40, ApoE, ASCL1, and NKX2-2.

Rousseau A, Nutt CL, Betensky RA, Iafrate AJ, Han M, Ligon KL, Rowitch DH, Louis DN.

From the Molecular Pathology Unit (AR, CLN, AJI, MH, DNL), Massachusetts General Hospital and Harvard Medical School, Boston, MA; Neurooncology Unit (AR), INSERM U711, Groupe Hospitalier Pitie-Salpetriere, Paris, France; Department of Biostatistics (RAB), Harvard School of Public Health, Boston, MA; and Department of Pediatric Oncology (KLL, DHR), Dana-Farber Cancer Institute, Boston, MA.

The phenotypic heterogeneity of astrocytic and oligodendroglial tumor cells complicates establishing accurate diagnostic criteria, and lineage-specific markers would facilitate diagnosis of glioma subtypes. Based on data from the literature and from expression microarrays, we selected molecules relevant to gliogenesis and glial lineage specificity and then used immunohistochemistry to assess expression of these molecules in 55 diffuse gliomas, including 8 biphasic oligoastrocytomas, 21 oligodendrogliomas (all with 1p/19qloss), 21 astrocytomas, and 5 glioblastomas. For the astrocytic lineage markers (GFAP, YKL-40, and ApoE), GFAP expression was significantly higher in the astrocytic component of oligoastrocytomas compared with the oligodendroglial part; similar patterns were detected for YKL-40 and ApoE, although the differences were not significant. GFAP, YKL-40, and ApoE reliably distinguished grade II-III oligodendrogliomas from grade II-IV astrocytomas (p < 0.0001, p = 0.002, and p < 0.0001, respectively). Among the oligodendroglial lineage markers (Olig2, Sox10, ASCL1, and NKX2-2), ASCL1 and NKX2-2 displayed significantly different immunostaining between oligodendrogliomas and astrocytomas (p = 0.017 and 0.004, respectively), but none clearly differentiated between the 2 glial populations of oligoastrocytomas. In addition to GFAP, therefore, YKL-40, ApoE, ASCL1, and NKX2-2 represent promising tumor cell markers to distinguish oligodendrogliomas from astrocytomas.

PMID: 17146289 [PubMed - as supplied by publisher]

 

11: J Neuropathol Exp Neurol. 2006 Dec;65(12):1111-1117.

 
Brain Tumors in S100beta-v-erbB Transgenic Rats.

Ohgaki H, Kita D, Favereaux A, Huang H, Homma T, Dessen P, Weiss WA, Kleihues P, Heppner FL.

From the International Agency for Research on Cancer (HO, DK, AF, HH, TH, PD), Lyon, France; the Department of Neurology (WAW), University of California, San Francisco, CA; and the Department of Pathology (PK) and the Institute of Neuropathology (FLH), University Hospital Zurich, Zurich, Switzerland.

We have established a line of transgenic rats expressing v-erbB, the viral form of epidermal growth factor receptor (EGFR), under transcriptional regulation of the S100beta promoter. Reverse transcriptase-polymerase chain reaction revealed highest transgene expression in the cerebellum followed by the cerebrum, ovary, and testis. Other organs, including the lung, heart, salivary gland, colon, liver, kidney, and spleen, did not show detectable transgene expression. Of 23 homozygous rats that died or were killed because they became moribund between 25 and 91 weeks of age, 15 (65%) showed the presence of brain tumors (mean age, 59 weeks). Of the 10 heterozygous rats killed between 61 and 91 weeks of age, 4 (40%) showed the presence of brain tumors (mean, 77 weeks). With 3 exceptions, all tumors were located within or near the cerebellum (83%). There were 2 major histologic types; one type displayed a solid growth pattern with predominantly perivascular infiltration of adjacent central nervous system tissue and the meninges. Tumors showed histologic features of malignancy with occasional lung metastases. There was a consistent, strong immunoreactivity for S100 protein but no significant expression of glial, neuronal, or meningothelial markers. These tumors were classified as malignant gliomas. A second tumor type was less invasive and characterized by isomorphic cells with round to ovoid nuclei and clear perinuclear halos expressing S100 but no neuronal or glial marker proteins. They were diagnosed as oligodendrogliomas. This is the first transgenic rat model that spontaneously develops brain tumors. Because v-erbB is structurally and functionally similar to the truncated form of EGFR amplified and overexpressed in human glioblastomas, S100beta-v-erbB transgenic rats may serve as a useful animal model for the identification of EGFR-related molecular targets and as a tool for the assessment of novel therapeutic approaches.

PMID: 17146284 [PubMed - as supplied by publisher]

 

12: Neurosurgery. 2006 Nov;59(5):1109-20; discussion 1120-1.

 
Calcium channel antagonists augment hydroxyurea- and ru486-induced inhibition of meningioma growth in vivo and in vitro.

Ragel BT, Gillespie DL, Kushnir V, Polevaya N, Kelly D, Jensen RL.

Department of Neurosurgery, University of Utah, 30 North 1900 East, Suite 3B409, Salt Lake City, UT 84132, USA.

OBJECTIVE: Although the chemotherapy drug hydroxyurea (HU) and the antiprogesterone mifepristone (RU486) have been used to treat meningiomas for which surgical and radiation therapies have failed, results have been disappointing. The addition of calcium channel antagonists (CCAs) to chemotherapeutic drugs enhances tumor growth inhibition in other tumor types, and the authors demonstrated that CCAs can block meningioma growth in vitro and in vivo. The purpose of this study was to test the effects of the addition of a CCA to HU or RU486 on meningioma growth. METHODS: Primary and malignant (IOMM-Lee) meningioma cell lines were treated with HU, RU486, or either of these plus diltiazem or verapamil. Assays for cell growth, apoptosis, and fluorescent-activated cell sorting were performed on in vitro cultures. Similar cell lines were implanted into nude mice and were treated with HU or RU486, in combination with a CCA. Tumors were analyzed by light microscopy, MIB-1, and factor VIII immunohistochemical staining studies. RESULTS: The addition of diltiazem or verapamil to HU or RU486 augmented meningioma growth inhibition by 20 to 60% in vitro. In vivo, tumors treated with combination drugs were smaller; and immunohistochemical analysis of the IOMM-Lee tumors showed a 10% decrease in the MIB-1 ratio (from 0.41 to 0.30) and an approximate 75% decrease in microvascular density. CONCLUSION: The addition of diltiazem or verapamil to HU or RU486 augments meningioma growth inhibition in vitro by inducing apoptosis and G1 cell-cycle arrest. The combination of HU and diltiazem inhibited the growth of meningiomas in vivo by decreasing proliferation and microvascular density. These results suggest a possible role for these drugs as an additional adjuvant therapy for recurrent or unresectable meningiomas.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 17143245 [PubMed - in process]

 

13: Neurosurgery. 2006 Nov;59(5):1019-28; discussion 1028-9.

 
Tuberculum sellae meningiomas: clinical outcome considering different surgical approaches.

Nakamura M, Roser F, Struck M, Vorkapic P, Samii M.

Department of Neurosurgery, Nordstadt Hospital, Klinikum Hannover, Hannover, Germany. mnakamura@web.de

OBJECTIVE: Tuberculum sellae meningiomas present a special challenge because of their proximity to arteries of the anterior circulation, anterior visual pathways, and the hypothalamus. The authors report on the clinical outcome after surgical treatment of tuberculum sellae meningiomas in our neurosurgical department. METHODS: A retrospective study was conducted analyzing the charts of the patients, including surgical records, discharge letters, histological records, follow-up records, and imaging studies. Patients with associated neurofibromatosis Type 2 were excluded from the study. RESULTS: One thousand eight hundred meningiomas were operated on between 1978 and 2002. Seventy-two of these patients had tuberculum sellae meningiomas; four had undergone previous surgical procedures in outside hospitals. Fifty-five patients were women; 17 were men. Their mean age was 54.3 years (range, 30-86 yr). All patients had visual disturbances at presentation. Tumors were operated through the bifrontal approach (n = 21, from 1978 through 1995), the pterional/frontotemporal approach (n = 21, from 1982 through 2002), and the frontolateral approach (n = 30, from 1984 through 2002). Total tumor removal was achieved in most patients (Simpson 1 + 2, 91.7%). The perioperative mortality rate was 2.8% (two out of 72 patients). Immediate postoperative improvement of visual disturbance was observed in 65% of patients. Visual improvement was dependent on the duration of preoperative visual symptoms, but not on preoperative visual acuity or tumor size. The visual improvement rate was significantly better in patients who underwent frontolateral tumor resection (77.8%) compared with those who underwent bifrontal craniotomy (46.2%). The overall recurrence rate was 2.8% (two out of 72 patients). The mean follow-up time for all patients was 4 to 238 months (mean, 45.3 mo [3.8 yr]). CONCLUSION: From 1978 through 2002, tuberculum sellae meningiomas were removed microsurgically using three different surgical approaches. Considering the operative morbidity and mortality, the frontolateral and pterional approach provided remarkable improvement compared with the bifrontal approach. These approaches allowed quick access to the tumor and were minimally invasive with less brain exposure, but still engendered high rates of total tumor removal. By comparison, the frontolateral approach provided the best results concerning visual outcome while representing the least invasive surgical approach.

PMID: 17143236 [PubMed - in process]

 

14: Neurosurgery. 2006 Nov;59(5):988-99; discussioin 999-1000.

 
Dendritic cell vaccination in patients with malignant gliomas: current status and future directions.

de Vleeschouwer S, Rapp M, Sorg RV, Steiger HJ, Stummer W, van Gool S, Sabel M.

Department of Neurosurgery, University Hospital Gasthuisberg, Leuven, Belgium. Steven.devleeschouwer@uz.kuleuven.ac.be

OBJECTIVE: Despite recent advances in neurosurgical resection techniques, radiation therapy, and chemotherapy, malignant gliomas continue to have a dismal prognosis because relapses are unavoidable. METHODS: Dendritic cell vaccination has recently emerged as a promising type of active immunotherapy that aims to induce rather than transfer specific antitumor immune responses in patients. Active immunotherapy is the only type of immunotherapy able to induce immunological memory. RESULTS: Although an increasing number of small clinical trials show safety, feasibility, and immunological and clinical responses, this technology requires further clarification of some critical basic and clinical issues before its presumed place in the treatment of malignant gliomas can be specified. This article addresses the basic and clinical pitfalls that, more than with conventional therapies, may interfere with the potential benefits of this approach. CONCLUSION: Considering the particular mechanisms involved in the immune modulation of tumor biology using dendritic cell-based vaccinations, the authors summarize the arguments in favor of a further, appropriate assessment of this technology.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 17143233 [PubMed - in process]

 

15: Neurosurgery. 2006 Nov;59(5):949-55; discussion 955-6.

 
Magnetic resonance imaging-guided, high-intensity focused ultrasound for brain tumor therapy.

Ram Z, Cohen ZR, Harnof S, Tal S, Faibel M, Nass D, Maier SE, Hadani M, Mardor Y.

Department of Neurosurgery, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel. zviram@inter.net.il

OBJECTIVE: Magnetic resonance imaging-guided high-intensity focused ultrasound (MRIgFUS) is a novel technique that may have the potential for precise image-guided thermocoagulation of intracranial lesions. The system delivers small volumetric sonications from an ultrasound phased array transmitter that focuses energy selectively to destroy the target with verification by magnetic resonance imaging-generated thermal maps. A Phase I clinical study was initiated to treat patients with recurrent glioma with MRIgFUS. METHODS: To date, three patients with histologically verified recurrent glioblastoma multiforme have been treated with MRIgFUS. All patients underwent craniectomy 7 to 10 days before therapy to create a bony window for the ultrasound treatment. Sonications were applied to induce thermocoagulation of the enhancing tumor mass. Long-term radiological follow-up and post-treatment tissue specimens were available for all patients. RESULTS: MRIgFUS treatment resulted in immediate changes in contrast-enhanced T1-, T2-, and diffusion-weighted magnetic resonance imaging scans in the treated regions with subsequent histological evidence of thermocoagulation. In one patient, heating of brain tissue in the sonication path resulted in a secondary focus outside the target causing neurological deficit. New software modifications were developed to address this problem. CONCLUSION: In this first clinical report, MRIgFUS was demonstrated to be a potentially effective means of destroying tumor tissue by thermocoagulation, although with an associated morbidity and the inherent invasive nature of the procedure requiring creation of a bone window. A modified technology to allow MRIgFUS treatment through a closed cranium is being developed.

PMID: 17143231 [PubMed - in process]

 

16: Oncogene. 2006 Dec 4; [Epub ahead of print]

 
The protein kinase C-eta isoform induces proliferation in glioblastoma cell lines through an ERK/Elk-1 pathway.

Uht RM, Amos S, Martin PM, Riggan AE, Hussaini IM.

[1] 1Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA, USA [2] 2Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA, USA.

Glioblastoma multiforme (GBM) is the highest grade of astrocytoma. GBM pathogenesis has been linked to receptor tyrosine kinases and kinases further down signal-transduction pathways - in particular, members of the protein kinase C (PKC) family. The expression and activity of various PKC isoforms are increased in malignant astrocytomas, but not in non-neoplastic astrocytes. This suggests that PKC activity contributes to tumor progression. The level of PKC-eta expressed correlates with the degree of phorbol-12-myristate-13-acetate (PMA)-induced proliferation of two glioblastoma cell lines, U-1242 MG and U-251 MG. Normally, U-1242 cells do not express PKC-eta, and PMA inhibits their proliferation. Conversely, PMA increases proliferation of U-1242 cells that are stably transfected with PKC-eta (U-1242-PKC-eta). PMA treatment also stimulates proliferation of U-251 cells, which express PKC-eta. Here, we determined that extracellular signal-regulated kinase (ERK) and Elk-1 are downstream targets of PKC-eta. Elk-1-mediated transcriptional activity correlates with the PKC-eta-mediated mitogenic response. Pretreatment of U-1242-PKC-eta cells with inhibitors of PKC or MAPK/ERK kinase (MEK) (bisindolyl maleimide (BIM) or U0126, respectively) blocked both PMA-induced Elk-1 transcriptional activity and PMA-stimulated proliferation. An overexpressed dominant-negative PKC-eta reduced the mitogenic response in U-251 cells, as did reduction of Elk-1 by small interfering RNA. Taken together, these results strongly suggest that PKC-eta-mediated glioblastoma proliferation involves MEK/mitogen-activated protein (MAP) kinase phosphorylation, activation of ERK and subsequently of Elk-1. Elk-1 target genes involved in GBM proliferative responses have yet to be identified.Oncogene advance online publication, 4 December 2006; doi:10.1038/sj.onc.1210090.

PMID: 17146445 [PubMed - as supplied by publisher]

 

17: Surg Neurol. 2006 Dec;66(6):627-630. Epub 2006 Oct 6.

 
Glioblastomatous recurrence of oligodendroglioma remote from the original site: a case report.

Kocaeli H, Yakut T, Bekar A, Taskapilioglu O, Tolunay S.

Department of Neurosurgery, Uludag University School of Medicine, 16059 Bursa, Turkey.

BACKGROUND: As in all diffuse gliomas, recurrence is an inherent feature of oligodendrogliomas, either as the same or higher grade neoplasm at the primary site. The rate of remote recurrence after surgery for the primary tumor cannot be estimated from the scarce literature, but delayed treatment of the primary tumor and genetic alterations may be associated with this phenomenon. CASE DESCRIPTION: A 40-year-old man presented with generalized seizures. A magnetic resonance imaging scan disclosed a right frontal mass lesion showing features of a low-grade glioma for which he refused any treatment. Seven months after diagnosis upon uncontrollable seizures, he underwent a stereotactic biopsy, which was followed by a right frontal craniotomy, both of which confirmed the lesion as a grade 2 oligodendroglioma. Six months after surgery, the patient presented with a left frontal lobe GBM without evidence of recurrence at the primary site. The genetic analysis of the primary and recurrent tumors showed trisomy 7, monosomy 10, but not 1p or 19q deletions, which have been proposed as markers for favorable prognosis. CONCLUSION: Recurrence of a frontal lobe oligodendroglioma remote from the primary site as a GBM is a rare occurrence. Single-cell invasion across the corpus callosum with subsequent or simultaneous malignant degeneration into a secondary GBM is the likely mechanism. As the genetic analysis suggests, conversion of oligodendroglioma to GBM may be associated with gain of chromosome 7, loss of chromosome 10, and other genetic markers that may represent late events in the oncogenesis of oligodendroglial tumors.

PMID: 17145331 [PubMed - as supplied by publisher]