Taiichi Saito

Phase II clinical study on intraoperative photodynamic therapy with talaporfin sodium and semiconductor laser in patients with malignant brain tumors

OBJECT The objective of the present study was to perform a prospective evaluation of the potential efficacy and safety of intraoperative photodynamic therapy (PDT) using talaporfin sodium and irradiation using a 664-nm semiconductor laser in patients with primary malignant parenchymal brain tumors. METHODS In 27 patients with suspected newly diagnosed or recurrent primary malignant parenchymal brain tumors, a single intravenous injection of talaporfin sodium (40 mg/m(2)) was administered 1 day before resection of the neoplasm. The next day after completion of the tumor removal, the residual lesion and/or resection cavity were irradiated using a 664-nm semiconductor laser with a radiation power density of 150 mW/cm(2) and a radiation energy density of 27 J/cm(2). The procedure was performed 22-27 hours after drug administration. The study cohort included 22 patients with a histopathologically confirmed diagnosis of primary malignant parenchymal brain tumor. Thirteen of these neoplasms (59.1%) were newly diagnosed glioblastomas multiforme (GBM). RESULTS Among all 22 patients included in the study cohort, the 12-month overall survival (OS), 6-month progression-free survival (PFS), and 6-month local PFS rates after surgery and PDT were 95.5%, 91%, and 91%, respectively. Among patients with newly diagnosed GBMs, all these parameters were 100%. Side effects on the skin, which could be attributable to the administration of talaporfin sodium, were noted in 7.4% of patients and included rash (2 cases), blister (1 case), and erythema (1 case). Skin photosensitivity test results were relatively mild and fully disappeared within 15 days after administration of photosensitizer in all patients. CONCLUSIONS Intraoperative PDT using talaporfin sodium and a semiconductor laser may be considered as a potentially effective and sufficiently safe option for adjuvant management of primary malignant parenchymal brain tumors. The inclusion of intraoperative PDT in a combined treatment strategy may have a positive impact on OS and local tumor control, particularly in patients with newly diagnosed GBMs. Clinical trial registration no.: JMA-IIA00026 (https://dbcentre3.jmacct.med.or.jp/jmactr/App/JMACTRS06/JMACTRS06.aspx?seqno=862).

Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells

Glioblastoma is characterised by invasive growth and a high degree of radioresistance. Survivin, a regulator of chromosome segregation, is highly expressed and known to induce radioresistance in human gliomas. In this study, we examined the effect of survivin suppression on radiosensitivity in malignant glioma cells, while focusing on centrosome aberration and chromosome instability (CIN). We suppressed survivin by small interfering RNA transfection, and examined the radiosensitivity using a clonogenic assay and a trypan blue exclusion assay in U251MG (p53 mutant) and D54MG (p53 wild type) cells. To assess the CIN status, we determined the number of centrosomes using an immunofluorescence analysis, and the centromeric copy number by fluorescence in situ hybridisation. As a result, the radiosensitisation differed regarding the p53 status as U251MG cells quickly developed extreme centrosome amplification (=CIN) and enhanced the radiosensitivity, while centrosome amplification and radiosensitivity increased more gradually in D54MG cells. TUNEL assay showed that survivin inhibition did not lead to apoptosis after irradiation. This cell death was accompanied by an increased degree of aneuploidy, suggesting mitotic cell death. Therefore, survivin inhibition may be an attractive therapeutic target to overcome the radioresistance while, in addition, proper attention to CIN (centrosome number) is considered important for improving radiosensitivity in human glioma.

Role of perfusion-weighted imaging at 3 T in the histopathological differentiation between astrocytic and oligodendroglial tumors

OBJECTIVE The differentiation of oligodendroglial tumors from astrocytic tumors is important clinically, because oligodendroglial tumors are more chemosensitive than astrocytic tumors. This study was designed to clarify the usefulness of 3T MR perfusion imaging (PWI) in the histopathological differentiation between astrocytic and oligodendroglial tumors. This is because there is a growing interest in the diagnostic performance of 3T MR imaging, which has the advantages of a higher signal-to-noise ratio (SNR) and greater spatial and temporal resolution. MATERIALS AND METHODS This study retrospectively included 24 consecutive patients with supratentorial, WHO grade II and III astrocytic and oligodendroglial tumors (7 astrocytic, 10 oligoastrocytic, and 7 oligodendroglial tumors) that were newly diagnosed and resected between November 2006 and December 2009 at Hiroshima University Hospital. These patients underwent dynamic susceptibility contrast-enhanced (DSC) PWI relative cerebral blood volume (rCBV) measurements before treatment. Astrocytic tumors were designated as the astrocytic group, and oligoastrocytic and oligodendroglial tumors as the oligodendroglial group. The regions of interest with the maximum rCBV values within the tumors were normalized relative to the contra-lateral white matter (rCBVmax). RESULTS The average rCBVmax of astrocytic tumors (2.01±0.68) was significantly lower than that of the oligoastrocytic (4.60±1.05) and oligodendroglial tumors (6.17±0.867) (P<0.0001). A cut-off value of 3.0 allowed to differentiate the oligodendroglial group from the astrocytic group at 100% sensitivity and 87.5% specificity. CONCLUSION The rCBVmax values obtained from 3T MR PWI may be useful as an adjunct to the postoperative histopathological diagnosis of glioma patients.

Glioblastoma treated with postoperative radio-chemotherapy : Prognostic value of apparent diffusion coefficient at MR imaging

PURPOSE To retrospectively evaluate whether the mean, minimum, and maximum apparent diffusion coefficient (ADC) of glioblastomas obtained from pretreatment MR images is of prognostic value in patients with glioblastoma. MATERIALS AND METHODS The institutional review board approved our study and waived the requirement for informed patient consent. Between February 1998 and January 2006, 33 patients (24 males, 9 females; age range 10-76 years) with supratentorial glioblastoma underwent pretreatment magnetic resonance (MR) imaging. The values of the mean, minimum, and maximum ADC (ADC(mean), ADC(MIN), and ADC(MAX), respectively) of each tumor were preoperatively determined from several regions of interest defined in the tumors. After surgical intervention, all patients underwent irradiation and chemotherapy performed according to our hospital protocol. The patient age, symptom duration, Karnofsky performance scale score, extent of surgery, and ADC were assessed using factor analysis of overall survival. Prognostic factors were evaluated using Kaplan-Meier survival curves, the log-rank test, and multiple regression analysis with the Cox proportional hazards model. RESULTS Likelihood ratio tests confirmed that ADC(MIN) was the strongest among the three prognostic factors. Total surgical removal was the most important predictive factor for overall survival (P<0.01). ADC(MIN) was also statistically correlated with overall survival (P<0.05) and could be used to classify patients into different prognostic groups. Interestingly, ADC(MIN) was also the strongest prognostic factor (P<0.01) in the group of patients in whom total tumor removal was not possible. CONCLUSION The ADC(MIN) value obtained from pretreatment MR images is a useful clinical prognostic biomarker in patients with glioblastoma.

Intraoperative cortico-cortical evoked potentials for the evaluation of language function during brain tumor resection: initial experience with 13 cases

OBJECTIVES The objective in the present study was to evaluate the usefulness of cortico-cortical evoked potentials (CCEP) monitoring for the intraoperative assessment of speech function during resection of brain tumors. METHODS Intraoperative monitoring of CCEP was applied in 13 patients (mean age 34 ± 14 years) during the removal of neoplasms located within or close to language-related structures in the dominant cerebral hemisphere. For this purpose strip electrodes were positioned above the frontal language area (FLA) and temporal language area (TLA), which were identified with direct cortical stimulation and/or preliminary mapping with the use of implanted chronic subdural grid electrodes. The CCEP response was defined as the highest observed negative peak in either direction of stimulation. In 12 cases the tumor was resected during awake craniotomy. RESULTS An intraoperative CCEP response was not obtained in one case because of technical problems. In the other patients it was identified from the FLA during stimulation of the TLA (7 cases) and from the TLA during stimulation of the FLA (5 cases), with a mean peak latency of 83 ± 15 msec. During tumor resection the CCEP response was unchanged in 5 cases, decreased in 4, and disappeared in 3. Postoperatively, all 7 patients with a decreased or absent CCEP response after lesion removal experienced deterioration in speech function. In contrast, in 5 cases with an unchanged intraoperative CCEP response, speaking abilities after surgery were preserved at the preoperative level, except in one patient who experienced not dysphasia, but dysarthria due to pyramidal tract injury. This difference was statistically significant (p < 0.01). The time required to recover speech function was also significantly associated with the type of intraoperative change in CCEP recordings (p < 0.01) and was, on average, 1.8 ± 1.0, 5.5 ± 1.0, and 11.0 ± 3.6 months, respectively, if the response was unchanged, was decreased, or had disappeared. CONCLUSIONS Monitoring CCEP is feasible during the resection of brain tumors affecting language-related cerebral structures. In the intraoperative evaluation of speech function, it can be a helpful adjunct or can be used in its direct assessment with cortical and subcortical mapping during awake craniotomy. It can also be used to predict the prognosis of language disorders after surgery and decide on the optimal resection of a neoplasm.

Role of PROPELLER diffusion weighted imaging and apparent diffusion coefficient in the diagnosis of sellar and parasellar lesions

OBJECTIVE To evaluate the role of the apparent diffusion coefficient (ADC) using periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) diffusion weighted imaging (DWI) in the differentiation between sellar and parasellar mass lesions. MATERIALS AND METHODS The study protocol was approved by our institutional review board. We retrospectively studied 60 patients with sellar and parasellar lesions who had undergone PROPELLER DWI on a 3-T MR imager. Conventional MRI findings were expressed as the ratio of signal intensity (SI) in the lesions to the normal white matter and the degree of contrast enhancement. ADC values were calculated as the minimum (ADC-MIN), mean (ADC-MEAN), and maximum (ADC-MAX). All patients underwent surgery and all specimens were examined histologically. Logistic discriminant analysis was performed by using the SI ratios on T1- and T2-weighted images (T1-WI, T2-WI), the degree of enhancement, and absolute ADC values as independent variables. RESULTS ADC-MIN of hemorrhagic pituitary adenomas was lower than of the other lesions with similar appearance on conventional MRI (non-hemorrhagic pituitary adenomas, craniopharyngiomas, Rathkes cleft cysts; accuracy 100%); the useful cut-off value was 0.700 x 10(-3)mm(2)/s. ADC-MAX of meningiomas was lower than of non-hemorrhagic pituitary adenomas (accuracy 90.3%; p<0.01). ADC-MIN of craniopharyngiomas was lower than of Rathkes cleft cysts (accuracy 100%; p<0.05). CONCLUSION As PROPELLER DWI is less sensitive to susceptibility artifacts than single-shot echoplanar DWI, it is more useful in the examination of sellar and parasellar lesions. Calculation of the ADC values helps to differentiate between various sellar and parasellar lesions.

Geminin: A good prognostic factor in high‐grade astrocytic brain tumors

Geminin is a nuclear protein that belongs to the DNA replication inhibitor group. It inhibits DNA replication by preventing Cdt1 from loading minichromosome maintenance protein onto chromatin, as is required for DNA replication. For this study, the authors investigated geminin expression in high‐grade astrocytic tumors, including anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), with a view to predicting clinical outcomes on this basis in patients with these malignant brain tumors.

Cytoplasmic, but not nuclear, p16 expression may signal poor prognosis in high-grade astrocytomas.

SummaryBackgroundThe negative consequences of the cytoplasmic localization of p16 in patients with high-grade astrocytomas, on their prognosis, was investigated.Methodsp16 Expression was examined in 20 anaplastic astrocytoma and 42 glioblastoma patients by immunohistochemical analysis, and the relationship between both cytoplasmic and nuclear p16 expression and prognosis analyzed.ResultsThe cytoplasmic expression of p16 statistically correlated with poor prognosis. On the other hand, no correlation was observed between p16 nuclear expression and patient survival.ConclusionThe cytoplasmic immunoreactivity of p16 appears to be an unfavorable prognostic indicator in high-grade astrocytoma patients. The localization of p16 expression should be determined when evaluating the prognosis of these patients.

Intraoperative Functional Mapping and Monitoring during Glioma Surgery

Glioma surgery represents a significant advance with respect to improving resection rates using new surgical techniques, including intraoperative functional mapping, monitoring, and imaging. Functional mapping under awake craniotomy can be used to detect individual eloquent tissues of speech and/or motor functions in order to prevent unexpected deficits and promote extensive resection. In addition, monitoring the patient’s neurological findings during resection is also very useful for maximizing the removal rate and minimizing deficits by alarming that the touched area is close to eloquent regions and fibers. Assessing several types of evoked potentials, including motor evoked potentials (MEPs), sensory evoked potentials (SEPs) and visual evoked potentials (VEPs), is also helpful for performing surgical monitoring in patients under general anesthesia (GA). We herein review the utility of intraoperative mapping and monitoring the assessment of neurological findings, with a particular focus on speech and the motor function, in patients undergoing glioma surgery.

Functional Plasticity of Language Confirmed with Intraoperative Electrical Stimulations and Updated Neuronavigation: Case Report of Low-Grade Glioma of the Left Inferior Frontal Gyrus

Removal of glioma from the dominant side of the inferior frontal gyrus (IFG) is associated with a risk of permanent language dysfunction. While intraoperative cortical and subcortical electrical stimulations can be used for functional language mapping in an effort to reduce the risk of postoperative neurological impairment, the extent of resection is limited by the functional boundaries. Recent reports proposed that a two-stage surgical approach for low-grade glioma in eloquent areas could avoid permanent deficits via the functional plasticity that occurs between the two operations. The report describes a patient with World Health Organization (WHO) grade II oligoastrocytoma in the left IFG, in functional plasticity of language occurred in the interval between two consecutive surgeries. Intraoperative electrical stimulations suggested that a language area and related subcortical fiber crossed the pre-central sulcus during tumor progression owing to functional plasticity. In the present case, we integrated neurophysiological data into the intraoperative neuronavigation system. We also confirmed the peri-lesional shift of language area and related subcortical fiber on image findings. Consequently, the tumor was sub-totally removed with two separate resections. Permanent language disturbance did not occur, and this favorable outcome was attributed to functional plasticity. The present experience sustains the multistage approach for low-grade gliomas in the language area. A combination of intraoperative electrical stimulations and updated neuronavigation may facilitate the characterization of brain functional plasticity.