Upfront chemotherapy and subsequent resection for molecularly defined gliomas.

Functional preservation is critical in glioma surgery, and the extent of resection influences survival outcome. Neoadjuvant chemotherapy is a promising option because of its potential to facilitate tumor shrinkage and maximum tumor resection. The object of this study was to assess the utility of the neoadjuvant strategy in a prospective series of gliomas with favorable molecular status. Twenty-six consecutive cases of diffuse gliomas of WHO grade II or III with either 1p19q codeletion or MGMT methylation were treated with upfront chemotherapy following maximal safe removal. In cases of incomplete initial surgery, second-look resection was intended after tumor volume decrease by chemotherapy. Among 22 evaluable cases, chemotherapy led to a median change in the sum of the product of perpendicular diameters of -35 %, and 14 out of the 22 cases (64 %) showed objective response. Second-look resection after tumor volume decrease was performed in 12 out of 19 cases of incomplete initial surgery (GTR/STR 9, removal of residual methionine PET uptake 3). The median progression-free survival among the 22 patients with grade II tumors was 57 months, with some cases showing durable progression-free survival after second-look resection. MIB-1 indices of the second-look resected tumors were lower than those of the initial tumors, and the methylation status of the MGMT gene was unchanged. Neoadjuvant chemotherapy based on molecular guidance often produces significant volume decrease of incompletely resected gliomas. Radical second-look resection is an optional advantage of upfront chemotherapy for chemosensitive gliomas compared with initial radiotherapy.

[A case of pituitary metastasis in a patient with male breast cancer developing anterior lobe dysfunction successfully treated by using hormone replacement therapy].

Male breast cancer is a rare disease and accounts for <1% of all breast cancers. Anterior lobe dysfunction of the pituitary gland is known to occur in only 15% of patients with pituitary gland metastasis, and diabetes insipidus occurs in 70% of patients in this subset. We report a case of pituitary metastasis in a patient with male breast cancer that resulted in anterior lobe dysfunction. A 64-year-old man presented with consciousness loss and gait disturbance. His serum sodium level was 117mEq/L. Magnetic resonance imaging revealed a suprasellar tumor that showed inhomogeneous enhancement and was attached to the optic chiasm. Diabetes insipidus was not evident at admission, but was observed immediately after the administration of the steroid hormone complement. The patient underwent subtotal resection of the tumor via a transsphenoidal approach. Pathological examination revealed metastasis from estrogen receptor-positive breast cancer. The patient underwent conventional post-operative radiotherapy combined with hormone replacement therapy and has remained free of symptoms for 16 months. Herein, we discuss the neuroendocrinology of and treatment for pituitary gland metastasis.

A recommendation on the basis of long-term follow-up results of our microvascular decompression operation for hemifacial spasm.

BACKGROUND: Microvascular decompression (MVD) for hemifacial spasm (HFS) has been popular, but it may take enough time to master this special operative technique and procedure. This may induce uneven distribution of the number of MVD operations in each institute, possibly resulting in an overall unsatisfactory quality of MVD surgeons. Nakanishi's approach to MVD operations has the feature of using a, "supine, no retractor" technique, which would achieve various benefits for patients and medical professionals. We would like to recommend this approach for MVD surgeons on the basis of our follow-up outcomes. METHODS: A questionnaire, which was based on the method of evaluation for the long-term results of post-MVD operation as recommended by the Japanese Society of MVD, was sent by mail to the 154 HFS patients who had received Nakanishi's approach at our hospital. RESULTS: Except for 42 patients who had changed their residences, 89 patients (79.5 % of 112) fully answered. The mean postoperative follow-up term was 13.0 years. The 76.4 % of the patients was estimated as excellent. Postoperative deafness was not present. The average value of satisfaction degree for the results of the MVD operation was 87.9 %. CONCLUSIONS: This study revealed that Nakanishi's approach produced good results equivalent of other approaches for HFS patients. This approach is considered to have many advantages comparing to the other approaches. Therefore, we would like to recommend that Nakanishi's approach would contribute to overall advancement of the level of MVD surgeons.

Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305).

PURPOSE: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA). METHODS: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108. RESULTS: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone (n = 55) or ACNU + PCZ (n = 56) in the intention-to-treat population were 27.4 and 22.4 months (p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone (n = 40) or ACNU + PCZ (n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events. CONCLUSIONS: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM.

Neuroendoscope-assisted removal of an organized chronic subdural hematoma in a patient on bevacizumab therapy--case report.

A 78-year-old Japanese man with a history of colon cancer was referred to our department of neurosurgery for the management of asymptomatic left chronic subdural hematoma (CSDH). He was receiving bevacizumab therapy for colon cancer, and the size of the CSDH increased or decreased depending on bevacizumab administration. Simple drainage was performed because of the risk of a critical increase in the size of CSDH during bevacizumab therapy, but since the CSDH was organized and firm, the drainage was insufficient. Therefore, neuroendoscope-assisted craniotomy was performed, and the organized CSDH was almost completely removed. The present case indicates the possible involvement of bevacizumab in the occurrence of CSDH and the efficacy of the neuroendoscopic approach in the surgical treatment of organized CSDH.

Inhibition of 90-kD heat shock protein potentiates the cytotoxicity of chemotherapeutic agents in human glioma cells.

OBJECT: The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. A considerable number of glioblastoma cases are refractory to TMZ, however, and the development of novel chemotherapeutic regimens is needed. The authors of previous studies have revealed that hsp90 is expressed at higher levels in human neoplastic tissues, including gliomas, than in normal tissues. Heat shock protein 90 is involved in a cytoprotective mechanism against cellular stressors such as DNA damage, and the authors hypothesized that hsp90 inhibitors might act as antitumor agents against gliomas and potentiate the cytotoxicity of DNA-damaging agents. METHODS: The authors examined the cytotoxicity of an hsp90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), both alone and in combination with 1 of 3 DNA-damaging agents (cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea, and TMZ) in human glioma cell lines. The cytotoxicity of these agents to glioma cells was measured using a colony formation assay. The cell cycle phase distribution, protein expression, and number of apoptotic cells were measured using a fluorescence-activated cell sorting assay, immunoblot assays, and double staining with annexin V and propidium iodide. In an in vivo experiment, 17-AAG, cisplatin, or 17-AAG and cisplatin were administered intraperitoneally to mice with xenografted U87MG cells, and the resulting tumor volumes were measured. RESULTS: The authors found that 17-AAG reduced the clonogenicity of U87MG cells, and at a low concentration (< 100 nM) potentiated the cytotoxicity of the DNA-crosslinking agents cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea, but not that of the DNA-methylating agent TMZ. This 17-AAG-induced potentiation of DNA crosslinking agent-induced cytotoxicity was a consequence of prolonged G(2)-M arrest accompanied by the suppression of cdc2 and cdc25C and of increased apoptotic cell death accompanied by the degradation of the antiapoptosis proteins Akt and survivin. Similar effects were observed when cells were treated with radicicol, another hsp90 inhibitor. The 17-AAG-induced enhancement of DNA crosslinking agent-induced cytotoxicity was also observed in other cell lines. In addition, 17-AAG sensitized xenografted U87MG cells to cisplatin in nude mice. CONCLUSIONS: Heat shock protein 90-targeted therapy may be an effective strategy for potentiating chemotherapy using DNA-crosslinking agents for TMZ-refractory gliomas.

ABC Surgical Risk Scale for skull base meningioma: a new scoring system for predicting the extent of tumor removal and neurological outcome. Clinical article.

OBJECT: Surgery for skull base meningiomas (SBMs) can lead to complications because these lesions are difficult to approach and can involve cranial nerves and arteries. The authors propose a scoring system to evaluate the relative risks and benefits of surgical treatment of SBMs. METHODS: The authors used a 2-step process to construct their scale. First, they derived significant predictive variables from retrospective data on 132 SBM cases treated surgically (primary surgeries only) between May 2000 and December 2005. Next, they validated the predictive accuracy of their scoring system in 60 consecutive cases treated surgically between January 1995 and April 2000, including both primary and repeated surgeries. Finally, they investigated the effect of the surgery on the patients' preoperative symptoms for consecutive cases treated surgically between January 1995 and December 2005, including both primary surgeries and retreatments. RESULTS: Five items that predicted surgical risk were identified: 1) tumor attachment size; 2) arterial involvement; 3) brainstem contact; 4) central cavity location; and 5) cranial nerve group involvement. The authors named their scoring system the ABC Surgical Risk Scale, after the initial letters of these items. Each factor was assigned a score of 0-2 points, and an additional point was added for previous surgical treatment or for radiation, giving a possible total score of 12 points. On average, the scoring system allocated 2 points for gross-total resections, 6.1 points for near-total resections, and 9 points for subtotal resections, with significant differences between groups. For cases scoring >or= 8 points, the percentage of cases showing neurological deterioration postoperatively exceeded the percentage showing improvement. CONCLUSIONS: The authors conclude that this scoring system can be used to predict the extent of tumor removal and that the scores reflect the surgical risk.

Dumbbell-shaped intradiploic epidermoid cyst involving the dura mater and cerebellum.

A 55-year-old woman presented with an epidermoid cyst extending to the cerebellum manifesting as headaches and pain in the left eye. Magnetic resonance imaging showed an intradiploic part with ring enhancement and an intracerebellar part. Intraoperative inspection revealed erosion of the occipital bone and defective dura mater. The tumor was located both epidurally and subdurally and the cyst consisted of pearly white keratin. The tumor was totally removed and the patient was discharged with no neurological deficit. The intradiploic part of the tumor formed the body and the intracerebellar part was caused by inflammatory reaction, which resulted in the atypical enhancement of the intradiploic part.

Augmented therapeutic efficacy of an oncolytic herpes simplex virus type 1 mutant expressing ICP34.5 under the transcriptional control of musashi1 promoter in the treatment of malignant glioma.

Although second-generation replication-conditional herpes simplex virus type 1 (HSV-1) vectors defective for both ribonucleotide reductase (RR) and the virulence factor gamma(1)34.5 have been proven safe through a number of animal experiments and clinical trials, their therapeutic efficacy was also markedly reduced. To overcome this situation, we concentrated on the use of a tumor-specific promoter in this study, to express ICP34.5 selectively in malignant glioma cells. As a molecular marker for malignant glioma, we focused on the neural RNA-binding protein, Musashi1. On the basis of the results of defective vector dvM345, as reported previously, we created, via homologous recombination, a novel HSV-1 vector termed KeM34.5, which expresses ICP34.5 under the transcriptional control of the musashi1 gene promoter (P/musashi1). Cytotoxicity mediated by KeM34.5 was significantly enhanced in human glioma cell lines (U87MG, U87MG-E6, U251, and T98G), resulting in an approximately 2-log increase in viral yield, compared with its parental vector G207. This virus also showed much higher therapeutic efficacy in the in vivo glioma model, while maintaining the desirable neuroattenuated phenotype. These results suggest that oncolytic HSV-1 expressing ICP34.5 under the transcriptional control of the musashi1 gene promoter could be a promising therapeutic agent for the treatment of malignant glioma.

Enhanced therapeutic efficacy of oncolytic herpes vector G207 against human non-small cell lung cancer--expression of an RNA-binding protein, Musashi1, as a marker for the tailored gene therapy.

BACKGROUND: Oncolytic herpes vectors like G207 have shown considerable promise in the treatment of solid tumors, but their potency must be enhanced for the full achievement of therapeutic efficacy. Deletion of the innate gamma34.5 gene made these vectors extremely safe, but their efficacy was also severely attenuated. Use of tumor-specific promoters is one method to direct toxicity and enhance efficacy against tumors. Recently, Musashi1 has been shown expressed in some tumor tissues. METHODS: Eleven human cancer cell lines including five non-small cell lung cancers (NSCLCs) were investigated. Musashi1 mRNA expression was examined by RT-PCR analysis. Western blotting was also performed. Transcriptional activity of P/musashi1 in NSCLCs was assayed by GFP reporter plasmids. Then we constructed a defective amplicon vector containing musashi1 promoter/ICP34.5 with G207 as helper virus (dvM345). In vitro cytotoxicity against NSCLCs and growth characteristics of helper virus were examined. A Lu-99 subcutaneous tumor model was used in an animal study. The tumor volume treated with G207 alone or dvM345 was measured. RESULTS: Musashi1 mRNA was detected in four cell lines. Two in five NSCLCs were positive, and P/musashi1 was proved functional within them. Against these cell lines, dvM345 showed enhanced cytotoxicity, and helper viral growth was augmented. A subcutaneous tumor study confirmed the enhanced therapeutic efficacy of G207 by dvM345 without compromising safety. CONCLUSIONS: These results suggest that Musashi1 might be involved in the development of several carcinomas including NSCLC. In the context of oncolytic herpes vector strategy, the P/musashi1-ICP34.5 method could be used for the treatment of cancers expressing Musashi1.