The Cancer Genome Atlas (TCGA) aims to catalogue and discover major cancer-causing genetic alterations in large cohorts of human tumors through integrated multi-dimensional analyses. The first cancer studied by the TCGA pilot project was glioblastoma. Here, we review four topics ; 1) Frequent genetic alterations in three critical signaling pathways, 2) IDH1 gene, 3) Classification of GBM based on molecular profiling, and 4) Glioma CpG island methylator phenotype (G-CIMP) brought by the TCGA pilot study. These results confirmed the heterogeneity of GBM and may provide useful information for future molecular targeting therapies.
Despite the use of maximal standard treatments, the prognosis of patients with glioblastoma remains poor ; hence novel therapies are desperately needed. Molecular targeted therapies have shown some promise in other malignancies, while they have not demonstrated remarkable tumor response or improved patient survival in glioblastoma to date, due, in part, to the redundancy and crosstalk of multiple overactive molecular pathways and the lack of validated predictive biomarkers. At present, a comprehensive cancer genotyping platform that can reveal potentially targetable genes is being implemented into clinical practice at some cancer institutions in the United States. This may allow us to rationally tailor therapies to specific tumor genotypes that we predict may be susceptible. In this paper, an overview of current glioblastoma treatment strategies in the United States is presented.
Awake surgery is an important methodology, which can increase the indications of tumor removal in the eloquent area, to identify the structures crucial for brain functions, especially in language both at the cortical and subcortical areas, to optimize the extent of resection. To achieve maximum resection, a functional brain mapping technique can increase the percentage of patients in which total and subtotal resection is achieved and decreases the percentage of post-operative neurological deficit. In this paper, we selected several current issues in awake surgery such as : 1) What is the indication for the motor cortex, 2) Do we still need the Wada test, 3) How to select tasks for functional mapping and monitoring, 4) The negative mapping technique, 5) Management of a pseudo-positive result, and 6) Making the final decision to remove functional area.
Boron neutron capture therapy (BNCT) has been advocated as a novel particle radiation therapy for malignant tumors that targets tumor cells biologically. Since 2002, we have applied this unique radiotherapy for 133 malignant gliomas and malignant meningiomas at our institution. In addition, we recently applied anti-angiogenic agents aggressively for intractable symptomatic radiation necrosis in the brain. Here is our latest comprehensive data regarding these unique treatments, including those I presented at the 32nd annual meeting of the Japanese Neurosurgical Congress, along with some new findings.
The replication-competent herpes simplex viruses type 1 (HSV-1) are promising therapeutic agents for malignant glioma. They can replicate in situ, spread and exhibit oncolytic activity via a direct cytocidal effect. A number of oncolytic HSV-1 viruses have been developed in recent years that have mutations in genes associated with neurovirulence and/or viral DNA synthesis to restrict viral replication to transformed cells. In designing recombinant viruses for clinical use, it is essential that ample safeguards be employed. G207 has deletions in both copies of the γ34.5 gene and an inactivating insertion of the Escherichia coli lacZ gene into the infected cell protein 6 (ICP6) gene. ICP6 is the large subunit of ribonucleotide reductase, a key enzyme for nucleotide metabolism and viral DNA synthesis in nondividing cells but not in dividing cells. γ34.5 is the major determinant of HSV neurovirulence. A second function of γ34.5 is to block host-cell-induced shutoff of protein synthesis in response to viral infection. This double mutation confers important features to the virus, including minimal chance of wild type reversion, preferential replication in tumor cells, attenuated neurovirulence, and ganciclovir/acyclovir hypersensitivity. The phase I clinical study with G207 in recurrent malignant glioma patients has shown that oncolytic HSV-1 can be safely administered into the human brain. G47Δ is the third-generation, genetically engineered HSV-1 with triple mutations that realized augmented viral replication in tumor cells, strong induction of antitumor immunity and enhanced safety in normal tissues. A clinical trial of G47Δ in patients with recurrent glioblastoma was started in 2009. One of the advantages of HSV-1 is its capacity to incorporate large and/or multiple transgenes into the viral genome. In preclinical studies, “arming” G47Δ with transgenes encoding immunomodulatory molecules, such as interleukin 12, has been shown to greatly augment the efficacy of oncolytic HSV-1 therapy. Oncolytic virus therapy using G47Δ can be used in combination with chemotherapy or other conventional therapies, which may in turn lead to enhanced therapeutic effects. It may serve as a useful treatment for malignant glioma that can also function as an efficient in situ tumor vaccination. We anticipate that G47Δ will soon be established as an important therapeutic modality for malignant glioma.
The authors describe the current status of immunotherapy targeting Wilms' tumor 1 (WT1) peptide for malignant gliomas, as well as other hematological and solid malignancies. WT1 is expressed in various kinds of malignancies, having an oncogenic function. WT1 antibodies at higher titers and WT1-specific cytotoxic T lymphocytes (CTLs) at higher frequencies were detected in cancer patients than in healthy donors, indicating that WT1 protein has an immunogenic function. Those findings provided us with a rationale for cancer immunotherapy targeting WT1. Clinical trials of WT1 peptide vaccination were started, and definite immunological and clinical responses were observed. Especially in recurrent glioblastomas, a disease control rate of 57.1% was achieved, with a median progression-free survival period of 20.0 weeks and a progression-free survival rate at 6 months of 33.3%. The trial showed that WT1 vaccination for malignant gliomas, which are generally believed to be an intractable disease, was safe and had a clinical response. Further clinical studies with randomization to confirm the efficacy and immunological proof of concept in patients with malignant gliomas are warranted. An enhancement of efficacy of WT1 vaccination can be expected by combined use of WT1-specific helper peptide or anti-cancer chemotherapeutic agents. WT1 vaccination as one of the multiple modalities at initial treatment or in the setting of minimal residual disease may prolong survival time of patients with malignancies.
Eighty-two consecutive patients with chronic subdural hematoma (CSDH) were treated by burr hole craniostomy and closed system drainage with (irrigation drainage [ID] ) or without irrigation (simple drainage [SD] ) of the hematoma cavity. Patients were divided into an ID group (n=46) and an SD group (n=36). We compared the postoperative recurrence rates between the ID and SD groups, taking notice of the perioperative antithrombotic therapy (ATT). Recurrence occurred in 14 patients (25.9%) in the ID group and in 5 (12.8%) in the SD group, but the difference was not statistically significant. In the ID group, the recurrence rate of patients whose anticoagulants were restarted within 2 weeks after operation was significantly higher than that of patients who were not or had never been anti-coagulated (p=0.049). In the SD group, the recurrence rate did not increase regardless of postoperative early resumption of anticoagulants. Compared to the ID procedure, the influence of postoperative antithrombotic therapy seemed to be lower on the patients treated by the SD procedure. For the patients receiving ATT, the SD procedure might be useful to avoid not only the increasing risk of thromboembolic complication due to discontinuation of antithrombotic agents (ATA) but also the increasing risk of hematoma recurrence due to early resumption of ATA.
A baby was delivered by Cesarean section at 37 weeks gestation because of her rapidly growing giant protruding orbital tumor. Macroscopically the tumor was a hemangioma and bled easily. Magnetic resonance imaging at birth revealed a giant orbital tumor (3×3.4×5.1 cm) consistent with hemangioma originating from the right cavernous sinus. Tumor removal and ocular socket plasty were necessary but impractical given her low weight (2,400 g) and size. While waiting for surgery propranolol was administered to minimize the tumor growth. At four months old, the calculated tumor weight was 2.1 times heavier while her body weight was 2.7 times heavier than at birth. At six months she weighed 7,430 g and underwent surgical treatment. After tumor embolization we performed a right frontotemporal craniotomy. Following extra-dural tumor ligation at the orbital corn, a total orbital exenteration was done. The orbital socket was reconstructed using a free vascularized latissimus dorsi muscle anastomosed to the superficial temporal artery and vein. In our case study propranolol minimized infantile hemangioma growth and a waiting time of six months was adequate for reconstruction requiring vascular anastomosis.