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OBJECTIVE An autologous formalin-fixed tumor vaccine (AFTV) derived from resected glioblastoma (GBM) tissue can be used against unidentified tumor antigens. Thus, the authors conducted a multicenter double-blind phase IIb trial to investigate the efficacy of an AFTV. METHODS Eligible patients were adults with supratentorial GBMs, 16–75 years of age, with Karnofsky Performance Scale (KPS) scores ≥ 60%, and no long-term steroid administration. An AFTV comprising fixed paraffin-embedded tumor tissue with immune adjuvants or an identical placebo without fixed tumor tissue was injected intradermally over three courses before and after chemoradiotherapy. The primary and secondary end points were overall survival (OS), progression-free survival (PFS), and 3-year survival rate. RESULTS Sixty-three patients were enrolled. The average patient age was 61 years. The median KPS score was 80%, and the median resection rate was 95%. The full analysis set of 57 patients indicated no significant difference in OS (p = 0.64) for the AFTV group (median OS 25.6 months, 3-year OS rate 38%) compared with the placebo group (31.5 months and 41%, respectively) and no difference in PFS (median PFS 13.3 months in both groups, p = 0.98). For patients with imaging-based total tumor removal, the 3-year PFS rate was 81% in the AFTV group versus 46% in the placebo group (p = 0.067), whereas the 3-year OS rate was 80% versus 54% (p = 0.16), respectively. Similar results were obtained in the p53-negative subgroups. Severe adverse effects were not observed. CONCLUSIONS The AFTV may have potential effects in certain patient subgroups. A phase III study for patients with total tumor removal remains warranted to confirm these findings. Clinical trial registration no.: UMIN000010602 (UMIN Clinical Trials Registry)

Surgical site infections (SSIs) after neurosurgery are common in daily practice. Although numerous reports have described SSIs in neurosurgery, reports specific to gliomas are limited. This study aimed to investigate the relationship between SSIs and glioma treatment characteristics, such as reoperations, radiation therapy, and chemotherapy.We examined 1012 consecutive patients who underwent craniotomy for glioma between November 2013 and March 2022. SSIs were defined as infections requiring reoperation during the observation period, regardless of their location. We retrospectively analyzed SSIs and patient factors.During the observation period, SSIs occurred in 3.1% (31/1012). In the univariate analysis, three or more surgeries (P = 0.007) and radiation therapy (P = 0.03) were associated with SSIs, whereas intraoperative magnetic resonance imaging (MRI) was not significantly associated (P = 0.35). Three or more surgeries and radiation therapy were significantly correlated with each other (P .0001); therefore, they were analyzed separately in the multivariate analysis. Three or more surgeries were an independent factor triggering SSIs (P = 0.02); in contrast, radiation therapy was not an independent factor for SSIs (P = 0.07). Several SSIs localized in the skin occurred more than 1 year after surgery.Undergoing three or more surgeries for glioma is an independent risk factor for SSIs. Glioma SSIs can occur long after surgery. These results are considered characteristic of gliomas. We recommend careful long-term observation of patients at a high risk of SSIs.

Background and objective The isocitrate dehydrogenase (IDH) status of patients with World Health Organization (WHO) grade II or III astrocytoma is essential for understanding its biological features and determining therapeutic strategies. This study aimed to use radiological analysis to predict the IDH status of patients with lower-grade astrocytomas and to verify the pathological implications. Methods In this study, 47 patients with grade II (17 cases) or III astrocytomas (30 cases), based on 2016 WHO Classification, underwent methionine (MET) positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) on the same day between January 2013 and June 2020. The patients were retrospectively assessed. Immunohistochemistry showed 23 cases of IDH-mutant and 24 of IDH-wildtype. Based on fluid-attenuated recovery inversion (FLAIR)/T2 imaging, three doctors blinded to clinical data independently allocated 18 patients to the clear boundary group between the tumor and the normal brain and 29 to the unclear boundary group. The peak ratios of N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, and Cho/NAA and the tumor-to-normal region (T/N) ratio for maximum accumulation in MET-PET were calculated. For statistical analysis, Fisher's exact test was used to assess associations between two variables, and the Mann-Whitney U test to compare the values between the IDH-wildtype and IDH-mutant groups. The optimal cut-off values of MET T/N ratio and MRS parameters for discriminating IDH-wildtype from IDH-mutant were obtained using receiver operating characteristics curves. Results The unclear boundary group had significantly more IDH-wildtype cases than the clear boundary group (P0.001). The IDH-wildtype group had significantly lower Cho/Cr (1.84) and Cho/NAA (1.62) ratios (P=0.02 and P=0.047, respectively) and a higher MET T/N ratio (1.44, P=0.02) than the IDH-mutant group. The odds for the IDH-wildtype were 0.22 for patients who fulfilled none of the four criteria, including boundary status and three ratios, and 0.9 for all four criteria. Conclusions These results suggest that the combination of MRI, MRS, and MET-PET examination could be helpful for the prediction of IDH status in WHO grade II/III gliomas.

Purpose Thalamic diffuse glioma is classified as WHO grade 4 as Diffuse midline glioma, H3K27M mutation if H3K27M mutation was found regardless of its histological findings, but the significance of H3K27M mutation is not clear compared with pediatric cases. We aimed to find genetic prognostic factors in adult thalamic diffuse gliomas. METHODS Pathological diagnosis, genetic abnormalities, and clinical course of adult newly diagnosed thalamic gliomas diagnosed and treated at our institution from July 2007 to March 2020 were retrospectively analyzed. RESULTS The number of cases was 41 (24 males, 17 females), median age was 47 years (20-75 years). Tumor localization was 20 cases on the left, 14 cases on the right, and 7 cases on both sides. The pathological diagnosis was GBM 15 cases, DMG 15 cases, AA-IDH WT 7 cases, DA-IDH WT 4 cases, all of which were IDH wild type, and none of them had IDH mutation and 1p/19q co-deletion. H3K27M mutations were found in 15 cases and TERT promoter mutations were found in 12 cases, both of which were completely mutually exclusive. Tumor resection and biopsy was performed in 33 and 8 cases, respectively, and the median removal rate was 95% for those who underwent tumor resection. The median PFS and OS of all cases were 14.3 months and 38 months, respectively, and the median OS by pathological diagnosis was GBM 12.4 months, DMG 47.4 months, AA-IDH WT 37.3 months, DA-IDH WT not reached. The median OS in the H3K27M mutant group (47.4 months) was significantly better (p=0.02) than that in the TERT promoter mutation group (13.5 months). CONCLUSION There was no IDH mutation in adult thalamic gliomas, the H3K27M mutation and the TERT promoter mutation were mutually exclusive. The H3K27M mutation was not a prognostic factor, but the TERT promoter mutation was the strongest prognostic factor.

Background In the course of treatment of malignant gliomas, the appearance of contrast-enhanced lesions and surrounding T2/FLAIR high-signal after treatment is often experienced. There is no modality that can reliably diagnose whether the lesion is a recurrence or a response to treatment, including radiation necrosis. Furthermore, the choice of treatment modality is often difficult, such as reexcision, stereotactic irradiation, Avastin. Very few reports have examined the relationship between the irradiation field and histology. Methods Thirty-seven lesions in 30 patients who underwent repeat resection of malignant gliomas at our institution from October 2019 to December 2021 were analyzed retrospectively. Based on postoperative pathology, the patients were classified into two groups: recurrence group and radiation necrosis group.In each group, age, gender, histology at initial surgery, IDH status, radiation and chemotherapy, TNR of Methionine-PET, and the number of days after the end of treatment until the appearance of contrast lesions were considered. Results The recurrence group consisted of 20 patients with 26 lesions, mean age 48 years, male/female = 13/7, pathology was GBM 13, DA 1, AA 3, AO 2, AE 1, TNR 3.33 (1.41-6.32), and time to contrast appearance 547 (14-2427) days. PDT in combination with initial surgery was seen in 9 patients.The necrosis group consisted of 10 patients with 11 lesions, mean age 47 years, male/female = 4/6, pathology GBM 5, AA 2, AO 1, PXA 2. TNR 2.51 (1.20-3.75), 318 (24-678) days to contrast appearance, 2 patients had PDT. Conclusions Radiation necrosis tended to have lower TNR and shorter time to lesion appearance than recurrence, but no significant difference was observed. Improvement of diagnostic accuracy with modalities is desirable, and unnecessary irradiation is highly likely to contribute to ADL deterioration such as leukoencephalopathy and higher functional impairment.

BACKGROUND Surgical site infection(SSI) in neurosurgery can increase mortality and worsen functional outcome. There are few reports on risk factors for SSI in glioma surgery. In this study, we investigated the risk factors for SSI in glioma surgery at our institution. METHODS We included 1013 patients with gliomas who underwent craniotomy between November 2013 and March 2022 at our institution. SSI was defined as requiring surgical treatment. Various factors including age, gender, number of operations, prior radiology, prior chemotherapy, use of intraoperative MRI, operation time, tumor WHO grade were investigated. RESULTS Among 1013 craniotomies, 31 (3.06%) cases of SSI required surgical procedure. In univariate analysis, the most significant factors were multiple prior craniotomy (p = 0.0067) and prior radiation therapy ( p = 0.0286). Among these factors, multivariate analysis revealed the number of surgeries ( p = 0.0151) as a significant independent factor for infection.Discussion and CONCLUSION Patients with gliomas often requires multiple craniotomy due to tumor recurrence. Although there have been reported the reoperation is an independent risk factor for postoperative infection, the is the first time that a specific number of prior surgeries ( 2 or more) has been reported. Radiotherapy is said to cause skin damage at a threshold of 10 Gy or less. Since radiation therapy for gliomas is given a dose of 50 Gy or more and irradiated scalp causes radiation dermatitis, and patients who have undergone prior radiotherapy must be carefully monitored.

INTRODUCTION Glioblastoma has the worst prognosis of brain tumors. Evidence for improving prognosis by maximal tumor removal is being established, and in recent years, new treatments such as photodynamic therapy (PDT, 2014 in Japan), and TTF therapy (2018) have been approved, the treatment results are improving. In principle, our facility performs maximum tumor removal using intraoperative MRI (iMRI) follow by the standard chemoradiation. Intraoperative PDT and autologous tumor vaccine (AFTV) will be given to desired patients. We retrospectively analyzed the long-term clinical results of the patients with newly diagnosed glioblastoma who underwent surgical treatment at our facility, and the treatment results by era and treatment method. METHODS The clinical features, extent of removal (EOR), OS and PFS of the adult patients with newly diagnosed glioblastoma treated from 2001 to 2021 were analyzed retrospectively. Clinical results of those patients who received PDT and AFTV treatment was also investigated. RESULTS The number of cases was 493, median age 58 years (18-85 years), 293 males, 200 females. The median and average EOR of contrast-enhanced lesions were 98% and 96.6%, respectively. The median PFS and OS of all cases (including biopsy) were 9.4 months and 22.7 months, respectively. When the cases were analyzed separately for 2001-2006 (before TMZ), 2007-2010, 2011-2015, and 2016-2021, the median OS for each age group was 12.9 months, 22.9 months, 23 months, and 31.1 months. The treatment results improved with age ( p < 0.0001). In particular, the median OS of 23 cases treated with PDT and AFTV was 63.1 months. The efficacy of AFTV for newly diagnosed glioblastoma is currently being verified in a multicenter Investigator-led clinical trial. CONCLUSION The treatment results for glioblastoma have improved over the years. The combination of maximal tumor removal using iMRI, PDT and AFTV may aim for a 5-year survival rate of 50%.

OBJECTIVEIn this study on the effectiveness and safety of photodynamic therapy (PDT) using talaporfin sodium and a semiconductor laser, the long-term follow-up results of 11 patients with glioblastoma enrolled in the authors’ previous phase II clinical trial (March 2009–2012) and the clinical results of 19 consecutive patients with newly diagnosed glioblastoma prospectively enrolled in a postmarket surveillance (March 2014–December 2016) were analyzed and compared with those of 164 patients treated without PDT during the same period.METHODSThe main outcome measures were the median overall survival (OS) and progression-free survival (PFS) times. Moreover, the adverse events and radiological changes after PDT, as well as the patterns of recurrence, were analyzed and compared between the groups. Kaplan-Meier curves were created to assess the differences in OS and PFS between the groups. Univariate and multivariate analyses were performed to identify the prognostic factors, including PDT, among patients with newly diagnosed glioblastoma.RESULTSThe median PFS times of the PDT and control groups were 19.6 and 9.0 months, with 6-month PFS rates of 86.3% and 64.9%, respectively (p = 0.016). The median OS times were 27.4 and 22.1 months, with 1-year OS rates of 95.7% and 72.5%, respectively (p = 0.0327). Multivariate analyses found PDT, preoperative Karnofsky Performance Scale score, and IDH mutation to be significant independent prognostic factors for both OS and PFS. Eighteen of 30 patients in the PDT group experienced tumor recurrence, including local recurrence, distant recurrence, and dissemination in 10, 3, and 4 patients, respectively. Conversely, 141 of 164 patients in the control group experienced tumor recurrence, including 101 cases of local recurrence. The rate of local recurrence tended to be lower in the PDT group (p = 0.06).CONCLUSIONSThe results of the present study suggest that PDT with talaporfin sodium and a semiconductor laser provides excellent local control, with few adverse effects even in cases of multiple laser irradiations, as well as potential survival benefits for patients with newly diagnosed glioblastoma.

Tumor recurrence patterns after resection of intracranial low-grade gliomas (LGG) generally remain obscured. The objective of the present retrospective study was their multifaceted analysis, evaluation of associated factors, and assessment of impact on prognosis. Study group comprised 81 consecutive adult patients (46 men and 35 women; median age, 37 years) with recurrent diffuse astrocytomas (DA; 51 cases) and oligodendrogliomas (OD; 30 cases). The median length of follow-up after primary surgery was 6.7 years. Early (within 2 years after primary surgery) and non-early (> 2 years after primary surgery) recurrence was noted in 23 (28%) and 58 (72%) cases, respectively. Fast (≤ 6 months) and slow ( > 6 months) radiological progression of relapse was noted in 31 (38%) and 48 (59%) cases, respectively. Tumor recurrence was local and non-local in 71 (88%) and 10 (12%) cases, respectively. Recurrence patterns have differed in OD, IDH1-mutant DA, and IDH wild-type DA. Early onset, fast radiological progression, and non-local site of relapse had statistically significant negative impact on overall survival of patients and were often associated with malignant transformation of the tumor (38 cases). However, in subgroup with extent of resection ≥ 90% (56 cases) no differences in recurrence characteristics were found between 3 molecularly defined groups of LGG. Recurrence patterns after resection of LGG show significant variability, differ in distinct molecularly defined types of tumors, and demonstrate definitive impact on prognosis. Aggressive resection at the time of primary surgery may result in more favorable characteristics of recurrence at the time of its development.

Purpose A major adverse effect arising from nimustine hydrochloride (ACNU) therapy for brain tumors is myelosuppression. Because its timing and severity vary among individual patients, the ACNU dose level has been adjusted in an empiric manner at individual medical facilities. To our knowledge, ours is the first study to develop a machine-learning approach to estimate myelosuppression through analysis of patient factors before treatment and attempts to clarify the relationship between myelosuppression and hematopoietic stem cells from daily clinical data. Adverse effect prediction will allow ACNU dose adjustment for patients predicted to have decreases in blood cell counts and will enable focused follow-up of patients undergoing chemoradiotherapy. Patients and Methods Patients were newly pathologically diagnosed with WHO grade 2 or 3 tumors and were treated with ACNU-based chemoradiotherapy. For detailed analysis of the timing and intensity of adverse effects in patients, we developed a data-weighted support vector machine (SVM) based on adverse event criteria (nadir-weighted SVM [NwSVM]). To evaluate the estimation accuracy of blood cell count dynamics, the determination coefficient ( r2) between real and estimated data was calculated by three regression methods: polynomial, SVM, and NwSVM. Results Only the NwSVM-based regression enabled estimation of the dynamics of all blood cell types with high accuracy (mean r2 = 0.81). The mean timing of nadir arrival estimated using this regression was 35 days for platelets, 41 days for RBCs, 52 days for lymphocytes, 57 days for WBCs, and 62 days for neutrophils. Conclusion The NwSVM can be used to predict myelosuppression and clearly depicts nadir timing differences between platelets and other blood cells.

OBJECTIVEWHO Grade III gliomas are relatively rare and treated with multiple modalities such as surgery, chemotherapy, and radiotherapy. The impact of the extent of resection (EOR) on improving survival in patients with this tumor type is unclear. Moreover, because of the heterogeneous radiological appearance of Grade III gliomas, the MRI sequence that best correlates with tumor volume is unknown. In the present retrospective study, the authors evaluated the prognostic significance of EOR.METHODSClinical and radiological data from 122 patients with newly diagnosed WHO Grade III gliomas who had undergone intraoperative MRI–guided resection at a single institution between March 2000 and December 2011 were analyzed retrospectively. Patients were divided into 2 groups by histological subtype: 81 patients had anaplastic astrocytoma (AA) or anaplastic oligoastrocytoma (AOA), and 41 patients had anaplastic oligodendroglioma (AO). EOR was calculated using pre- and postoperative T2-weighted and contrast-enhanced T1-weighted MR images. Univariate and multivariate analyses were performed to evaluate the prognostic significance of EOR on overall survival (OS).RESULTSThe 5-, 8-, and 10-year OS rates for all patients were 74.28%, 70.59%, and 65.88%, respectively. The 5- and 8-year OS rates for patients with AA and AOA were 72.2% and 67.2%, respectively, and the 10-year OS rate was 62.0%. On the other hand, the 5- and 8-year OS rates for patients with AO were 79.0% and 79.0%; the 10-year OS rate is not yet available. The median pre- and postoperative T2-weighted high–signal intensity volumes were 56.1 cm3 (range 1.3–268 cm3) and 5.9 cm3 (range 0–180 cm3), respectively. The median EOR of T2-weighted high–signal intensity lesions (T2-EOR) and contrast-enhanced T1-weighted lesions were 88.8% (range 0.3%–100%) and 100% (range 34.0%–100%), respectively. A significant survival advantage was associated with resection of 53% or more of the preoperative T2-weighted high–signal intensity volume in patients with AA and AOA, but not in patients with AO. Univariate analysis showed that preoperative Karnofsky Performance Scale score (p = 0.0019), isocitrate dehydrogenase 1 (IDH1) mutation (p = 0.0008), and T2-EOR (p = 0.0208) were significant prognostic factors for survival in patients with AA and AOA. Multivariate analysis demonstrated that T2-EOR (HR 3.28; 95% CI 1.22–8.81; p = 0.0192) and IDH1 mutation (HR 3.90; 95% CI 1.53–10.75; p = 0.0044) were predictive of survival in patients with AA and AOA.CONCLUSIONST2-EOR was one of the most important prognostic factors for patients with AA and AOA. A significant survival advantage was associated with resection of 53% or more of the preoperative T2-weighted high–signal intensity volume in patients with AA and AOA.

INTRODUCTION Tumor recurrence patterns after resection of intracranial low-grade gliomas (LGG) generally remain obscured. The objective of the present retrospective study was their multifaceted analysis, evaluation of associated factors, and assessment of impact on prognosis. METHODS Study group comprised 81 consecutive adult patients (46 men and 35 women; median age, 37 years) with recurrent diffuse astrocytomas (DA; 51 cases) and oligodendrogliomas (OD; 30 cases). The median length of follow-up after primary surgery was 6.7 years. RESULTS Early (within 2 years after primary surgery) and non-early ( > 2 years after primary surgery) recurrence was noted in 23 (28%) and 58 (72%) cases, respectively. Fast (≤ 6 months) and slow ( > 6 months) radiological progression of relapse was noted in 31 (38%) and 48 (59%) cases, respectively. Tumor recurrence was local and non-local in 71 (88%) and 10 (12%) cases, respectively. Recurrence patterns have differed in OD, IDH1-mutant DA, and IDH wild-type DA. Early onset, fast radiological progression, and non-local site of relapse had statistically significant negative impact on overall survival of patients and were often associated with malignant transformation of the tumor (38 cases). However, in subgroup with extent of resection ≥ 90% (56 cases) no differences in recurrence characteristics were found between 3 molecularly defined groups of LGG. Follow-up MRI also showed same results. CONCLUSIONS Recurrence patterns after resection of LGG show significant variability, differ in distinct molecularly defined types of tumors, and demonstrate definitive impact on prognosis. Aggressive resection at the time of primary surgery may result in more favorable characteristics of recurrence at the time of its development.

Rapid immunohistochemistry (R-IHC) has been developing mainly as a support technique in the rapid diagnosis of central nervous system tumors; however, there have been problems regarding instability in specimen preparation and immunostaining. To overcome the weakness of this technology, the instability of immunostaining, we developed a modified R-IHC. This was achieved by switching to 4% paraformaldehyde as the fixative solution and utilizing a commercially available Polymer Refine Detection Kit, as a high-sensitivity kit, in place of the secondary antibodies. In this study, we tested the modified R-IHC by evaluating rapid immunostaining on new staining items in 94 brain tumor removal cases, which took place at Tokyo Women's Medical University from 2014 to 2015. The results showed that, based on GFAP and p53 markers, the modified method obtained a higher stability in specimens than the standard rapid immunostaining method. It also achieved stainability on the same level as that of a permanent specimen. The modified method tested 86.6% (46/53) and 82.8% (24/29) in pHH3 and ATRX, respectively, in the percentage of correct classification (PCC) against the permanent specimens, and 100% (7/7) in the PCC against malignant lymphomas and gliomas that used CD20/CD3 for discrimination. We concluded that the modified R-IHC method indicated a higher stainability and PCC against the permanent specimens in comparison to the standard method in GFAP, p53, CD20/CD3, pHH3, and ATRX.

Background Photodynamic therapy (PDT) uses a photosensitizer and light to destroy abnormal cells. Talaporfin sodium (NPe6) is a second-generation photosensitizer. Methods We evaluated the toxic effects of different combinations of laser and NPe6 doses on squamous cell carcinoma (KLN205) and sarcoma (Meth A) cell lines. The cells were incubated with 0, 5, 10, or 30 μg/mL NPe6 for 24 h. The cells were then irradiated with 0, 5, 15, or 30 mW/cm 2 of laser power, and 0, 1, 5, 10, or 20 J/cm 2 of laser energy. Cell viability was evaluated after 24 h. We also evaluated the cytotoxic effects of continuous wave or square-wave modulated laser irradiations (2, 5, or 10 Hz, 50% duty) on Meth A cells. Results The median lethal doses of NPe6 against the KLN205 and Meth A cells after treatment at a fluence rate of 15 mW/cm 2 and a light dose of 20 J/cm 2 were 18.6 and 5.0 μg/mL, respectively. Meth A cells were more sensitive to PDT than KLN205 cells. There was no significant difference between the effects of continuous wave and square-wave modulated lasers on Meth A cell viability. Conclusions NPe6 PDT induced cell death in a dose-dependent manner in KLN205 and Meth A cells. More work is required to evaluate the cytotoxic effects of square-wave modulated laser therapy at low light doses.

Background Extent of resection (EOR) remains controversial in therapy for glioblastoma (GBM). However, an increasing number of studies favor maximum EOR as being associated with longer patient survival. Residual tumor volume (RTV) has also recently emerged as a prognostic factor. Low-field intraoperative magnetic resonance imaging (iMRI) has contributed to improve the EOR of GBM. The purpose of this study was to analyze the relationships between EOR/RTV and overall survival (OS)/progression-free survival (PFS) in patients with newly diagnosed GBM using low-field iMRI. Methods Adult patients who underwent surgery for newly diagnosed supratentorial GBM between 2000 and 2012 were retrospectively reviewed. Three-dimensional volumetric tumor measurements were made. Multivariate analysis was used to evaluate the relationships between EOR/RTV and OS/PFS. Results Of 168 patients, 126 (75%) died and 154 (91%) showed tumor recurrence. Median OS and PFS for patients with iMRI were 19.3 months (95% confidence interval, 15.4–23.7 months) and 9.5 months (95% confidence interval, 7.8–10.8 months). Median preoperative tumor volume was 37.0 cm 3 (interquartile range [IQR], 19.9–59.8 cm 3 ). Median RTV was 0 cm 3 (IQR, 0–1.6 cm 3 ). Median EOR was 100% (IQR, 96.2%–100%). In multivariate analysis, after controlling for age and Karnofsky Performance Status, EOR and RTV remained significantly associated with survival (hazard ratio, 1.56; P = 0.018) and recurrence (hazard ratio, 1.53; P = 0.013). Maximum RTV for survival was 3 cm 3 . Conclusions This volumetric analysis for low-field iMRI showed that both EOR and RTV were significantly associated with survival and recurrence. We determined a threshold RTV of 3 cm 3 as the maximum RTV associated with survival.

Introduction: Differentiation between glioma grade 2 and 3 was performed based on histological findings. The current grade is an important prognostic factor due to its widespread use, economic efficiency, and data accumulation, but analog elements remain and the genetic marker is unknown. The concept of Lower-grade glioma including G2/3 is spreading. On the other hand, WHO grade is the criteria of clinical trials, and evidence is established for G2 with low risk and high risk, G3 alone or with G4. In Japan, JCOG 1303 and 1016 have been implemented for high-risk G2 and G3, respectively and will be finished next year. Therefore, we examined the feasibility and design of novel clinical trial for patients with grade 2/3 glioma. Method: With reference to clinical trials of high evidence level and public database registration, we researched trials, arms, and designs for each of 3 genotypes, oligodendroglioma (OD), astrocytoma IDH mutant and IDH wild (A-IDHm, A-IDHw). Results: The standard arm common to all genotypes is follow-up (EORTC22845) for G2 low-risk, and chemoradiotherapy (CRT) for G3. Standard arm for G2 high risk, depending on a genotype, is follow-up (EORTC22845), radiation alone (A-IDHm and IDHw, A-IDHw: RTOG9802 subanalysis), or PCV chemoradiotherapy (OD and A-IDHm: 9802). Furthermore, the standard arm and the test arm were replaced by the matrix-like method on each genotype. Results in the G2/3-targeted trial, there was no standard arm all in the three genotypes. In addition, there were a design of master protocols for many genotype and a design that has arms of randomization and observation. Conclusion: Applying the master protocol, the possibility of novel G2/3 target trial in which the arms existing in MATRIX form was suggested. With the improvement of the genetic analysis infrastructure, prospective observational research and a well-designed intervention research plan for each genotype are required.

OBJECTIVEPositron emission tomography (PET) is important in the noninvasive diagnostic imaging of gliomas. There are many PET studies on glioma diagnosis based on the 2007 WHO classification; however, there are no studies on glioma diagnosis using the new classification (the 2016 WHO classification). Here, the authors investigated the relationship between uptake of 11C-methionine (MET), 11C-choline (CHO), and 18F-fluorodeoxyglucose (FDG) on PET imaging and isocitrate dehydrogenase (IDH) status (wild-type [IDH-wt] or mutant [IDH-mut]) in astrocytic and oligodendroglial tumors according to the 2016 WHO classification.METHODSIn total, 105 patients with newly diagnosed cerebral gliomas (6 diffuse astrocytomas [DAs] with IDH-wt, 6 DAs with IDH-mut, 7 anaplastic astrocytomas [AAs] with IDH-wt, 24 AAs with IDH-mut, 26 glioblastomas [GBMs] with IDH-wt, 5 GBMs with IDH-mut, 19 oligodendrogliomas [ODs], and 12 anaplastic oligodendrogliomas [AOs]) were included. All OD and AO patients had both IDH-mut and 1p/19q codeletion. The maximum standardized uptake value (SUV) of the tumor/mean SUV of normal cortex (T/N) ratios for MET, CHO, and FDG were calculated, and the mean T/N ratios of DA, AA, and GBM with IDH-wt and IDH-mut were compared. The diagnostic accuracy for distinguishing gliomas with IDH-wt from those with IDH-mut was assessed using receiver operating characteristic (ROC) curve analysis of the mean T/N ratios for the 3 PET tracers.RESULTSThere were significant differences in the mean T/N ratios for all 3 PET tracers between the IDH-wt and IDH-mut groups of all histological classifications (p < 0.001). Among the 27 gliomas with mean T/N ratios higher than the cutoff values for all 3 PET tracers, 23 (85.2%) were classified into the IDH-wt group using ROC analysis. In DA, there were no significant differences in the T/N ratios for MET, CHO, and FDG between the IDH-wt and IDH-mut groups. In AA, the mean T/N ratios of all 3 PET tracers in the IDH-wt group were significantly higher than those in the IDH-mut group (p < 0.01). In GBM, the mean T/N ratio in the IDH-wt group was significantly higher than that in the IDH-mut group for both MET (p = 0.034) and CHO (p = 0.01). However, there was no significant difference in the ratio for FDG.CONCLUSIONSPET imaging using MET, CHO, and FDG was suggested to be informative for preoperatively differentiating gliomas according to the 2016 WHO classification, particularly for differentiating IDH-wt and IDH-mut tumors.

BACKGROUND The highly fatal glioblastoma has an extremely poor prognosis and development of a new treatment is desired. Local treatment is limited due to its high invasiveness, and immunotherapy utilizing self-immune mechanism is theoretically expected. An autologous formalin-fixed tumor vaccine (AFTV) is a vaccine that is prepared using formalin-fixed tumor tissue and recognizes tumor antigen peptides to induce cytotoxic T cells. We have previously conducted three clinical trials using AFTV for patients with newly diagnosed glioblastoma since 2004. The third trial was a double-blind multicenter phase IIb/III trial with 63 case registries, which did not make a significant difference in OS (study group 25 months, placebo group 31 months), the total removal group showed excellent clinical results (3-year survival rate; 65%, median survival; not reached). Since the study was designed to go to Phase III if the test group was not inferior to the placebo group, so it went on to go to Phase III. METHODS Target patients will be 80 patients with newly diagnosed glioblastoma undergoing pathologic diagnosis, who have undergone total removal of contrast-enhanced lesions and receive standard chemoradiation therapy. STUDY DESIGN Double-blind, 3-year enrollment period, 18-month observation period. Stratification factor: Photodynamic therapy (PDT), facility, age, KPS. Administration method: After standard chemoradiotherapy, in parallel with maintenance chemotherapy, a total of 9 times intradermal administration of vaccine. Primary endpoint: PFS of FAS patients, Secondary endpoints: 18 months PFS of the FAS patient, OS, PFS of the ITT analysis target case. Based on the results of the IIb trial, we limited the registered patients with total tumor removal, and in view of the fact that the prognosis of patients with combined PDT and AFTV were excellent, PDT was added to the stratification factor. We outline our efforts and problems aimed at clinical approval of AFTV for glioblastoma.

Aggressive resection of intracranial gliomas has a positive impact on patients' prognosis, but is associated with a risk of neurological complications. For preservation of brain functions and avoidance of major postoperative morbidity various methods of intraoperative neurophysiological monitoring have been introduced into clinical practice. At present, somatosensory evoked potentials (SSEP), motor evoked potentials (MEP), visual evoked potentials (VEP), brainstem auditory evoked potentials (BAEP), and electrocorticography (ECoG) are used routinely during neurosurgical procedures. To maximize the efficacy of these neurophysiological techniques, it is most preferable to apply total intravenous anesthesia with continuous infusion of propofol and opioids and avoidance of long-acting muscle relaxants. Surgery for brainstem gliomas requires specific mapping with direct electrical stimulation (DES), corticobulbar tract MEP monitoring, and free-running electromyography (EMG) of the various muscles innervated by the cranial nerves. Awake craniotomy and intraoperative mapping of language and sensorimotor functions with DES allow precise identification of the functionally important neuronal structures and have become standard techniques for removal of cerebral neoplasms affecting eloquent cortical areas and subcortical pathways. Overall, contemporary neurophysiology plays a very important role in guidance of brain tumor surgery, in which it helps to maximize the extent of resection and to minimize the risk of permanent neurological morbidity.

Aggressive resection of intracranial gliomas has a positive impact on patients' prognosis, but is associated with a risk of neurological complications. For preservation of brain functions and avoidance of major postoperative morbidity various methods of intraoperative neurophysiological monitoring have been introduced into clinical practice. At present, somatosensory evoked potentials (SSEP), motor evoked potentials (MEP), visual evoked potentials (VEP), brainstem auditory evoked potentials (BAEP), and electrocorticography (ECoG) are used routinely during neurosurgical procedures. To maximize the efficacy of these neurophysiological techniques, it is most preferable to apply total intravenous anesthesia with continuous infusion of propofol and opioids and avoidance of long-acting muscle relaxants. Surgery for brainstem gliomas requires specific mapping with direct electrical stimulation (DES), corticobulbar tract MEP monitoring, and free-running electromyography (EMG) of the various muscles innervated by the cranial nerves. Awake craniotomy and intraoperative mapping of language and sensorimotor functions with DES allow precise identification of the functionally important neuronal structures and have become standard techniques for removal of cerebral neoplasms affecting eloquent cortical areas and subcortical pathways. Overall, contemporary neurophysiology plays a very important role in guidance of brain tumor surgery, in which it helps to maximize the extent of resection and to minimize the risk of permanent neurological morbidity.

Low-grade glioma patients have relatively long life expectancy for gliomas, but once they recur in malign, their prognosis can be poor. We analyzed factors corresponding to malignant recurrence by uni- and multi-variate analysis applying their treatment backgrounds. SUBJECTS: 261 newly diagnosed WHO grade 2 adults gliomas in 2004 to 2014. Malignant recurrence was determined by pathological diagnosis if the patient had a surgery (69% of the recurrent patients), otherwise contrast T1WI or 11C- methionine PET images if the patient was unable to undergo any surgery or biopsy.

Object Temozolomide (TMZ) may enhance antitumor immunity in patients with glioblastoma multiforme (GBM). In this paper the authors report on a prospective Phase I/IIa clinical trial of fractionated radiotherapy (FRT) concomitant with TMZ therapy, followed by treatment with autologous formalin-fixed tumor vaccine (AFTV) and TMZ maintenance in patients with newly diagnosed GBM. Methods Twenty-four patients (age 16–75 years, Karnofsky Performance Scale score ≥ 60% before initiation of FRT) with newly diagnosed GBM received a total dose of 60 Gy of FRT with daily concurrent TMZ. After a 4-week interval, the patients received 3 AFTV injections and the first course of TMZ maintenance chemotherapy for 5 days, followed by multiple courses of TMZ for 5 days in each 28-day cycle. Results This treatment regimen was well tolerated by all patients. The percentage of patients with progression-free survival (PFS) ≥ 24 months was 33%. The median PFS, median overall survival (OS), and the actuarial 2- and 3-year survival rates of the 24 patients were 8.2 months, 22.2 months, 47%, and 38%, respectively. The median PFS in patients with a delayed-type hypersensitivity (DTH) response after the third AFTV injection (DTH-2) of 10 mm or larger surpassed the median length of follow-up for progression-free patients (29.5 months), which was significantly greater than the median PFS in patients with a smaller DTH-2 response. Conclusions The treatment regimen was well tolerated and resulted in favorable PFS and OS for newly diagnosed GBM patients. Clinical trial registration no.: UMIN000001426 (UMIN clinical trials registry, Japan).

Our policy for insular glioma has achieved more than 90% removal. The policy influence grade 2 to postpone farther treatment and grade 3 to extend prognosis. In this study, we analyzed our clinical data to be sure how this policy effect to insular glioma. First-onset tumor since 2006 to 2015 were collected and following parameters were analyzed retrospectively, such as the tumor, extension, surgical removal rate, complications, pathological and genomic diagnosis. Of all 70 cases, the average age was 41 years old (24–76). The pathological diagnosis and number of patients were DAmt 20, DAwt 1, AAmt 8, AAwt 5, AO 5, O 18. PFS of each pathological grade(2,3,4) were 55,5m, 42,6m and 4,7m, OS were nr, nr, 32,8 months. 57 cases of IDHmt showed 60,2m of PFS and n.r of OS. 10 cases of IDHwt showed 19,9m PFS and 35,8m OS. The average and median removal rate were 91.4% and 95%. The number of complication case were mild 9 and moderate 2 at 3 months after surgery. The invasion pattern from temporal stem showed that frontal base invasion cases was resulted as poor prognosis comparing with temporal or parietal extension. Number of patients with IDHwt, Oligodedroglial tumor and GBM were relatively low. Surgical complications are mainly caused in the first half of the proficiency process, 15% had paralysis due to LSA infarction. Most of grade 2 cases were treated without post-operative treatment and the prognosis was almost same as grade 3 cases which were treated by chemo and radiation therapy such as 55m, 43m of PFS and n.r of OS. AA wt and GBM showed almost same OS of 32m.We have reconsidered a new classification based on temporal stem extension from surgical point of view. Insular glioma is somewhat different from the other location glioma.

INTRODUCTION Awake craniotomy (AS) with intraoperative mapping can be compatible to obtain maximal resection and preserve neurological function for glioma surgery. However, there is less evidence to improve overall survival for glioma patients. We compared the long-term outcome of glioma resection during AS and general anesthesia (GA). METHODS Continuous 335 patients with newly diagnosed glioma of WHO grade2 (G2) or higher who underwent surgery with intraoperative MRI between 2000 and 2013 were reviewed. Three-dimensional volumetric tumor measurements before and after operation were made. Multivariate analysis was used to evaluate the effect of awake surgery on overall survival (OS). RESULTS The mean age of all cases was 46 years, male: female 199: 136, mean preoperative tumor volume (PTV) 44.5cc, mean extent of resection (EOR) 88.31%, and median survival (MST) 82.6 months. MST of G4 was significantly longer in the AS group (AS 38.9 months vs. GA group 22.0 months: p = 0.03), while multivariate analysis showed that age and KPS was a significant prognostic factor, but AS was not. There was no significant difference in the EOR of G3 (AS group 80.1% vs. general anesthesia 84.2%: p = 0.365), and MST was also not significantly different (AS group 134.8 months vs. GA group 117.9 months: p = 0.338). G2 also had no significant difference in the EOR (AS group 84.6% vs. GA group 86.7%; p = 0.92), and MST was also not significantly different (AS group 152.9 months vs. GA group 135.1 months: p = 0.235). Analysis of G2 or G3 showed no significant differences in PTV, KPS, and age at the surgery between two groups. CONCLUSION Even if a glioma is located close to or within the eloquent area, AS can lead to EOR and OS equivalent to the removal of the non-eloquent area under GA.

BACKGROUND There are several treatment options, including observation, after surgical removal of low-grade gliomas (LGG). If postoperative chemotherapy and/or radiotherapy are not provided, resection-alone approach will probably be alternative to a natural course of LGG under observation. The objective of this study was evaluation of prognostic factors associated with overall survival (OS) of patients with LGG treated with surgery alone. METHODS A consecutive series of 236 adult patients who underwent surgery for LGG without adjuvant therapy was analyzed retrospectively. In 193 cases (82%) histopathology of the tumor was re-classified based on evaluation of IDH1 mutational status and 1p/19q co-deletion according to criteria of WHO classification 2016. Cox proportional hazards model was used for statistical analysis. RESULTS Median extent of resection (EOR) was 95% (range, 1–100%) and in 210 cases (89%) EOR was >=90%. During postoperative follow-up tumor progression was noted in 106 patients, and 30 patients died of disease. Overall, 10-year OS rate was 82.0%. There was statistically significant difference (P =90% 10-year OS rate was 75%. Multivariate analysis revealed that only EOR >=90% (RR, 0.23; 95% CI, 0.09–0.66; P=90% such factors as type of disease manifestation, time interval between onset of symptoms and surgery, and molecular subtype of the tumor did not show significant associations with OS. CONCLUSION Survival outcome in patients with LGG who underwent surgical resection alone may be predicted by EOR and presence of 1p/19q co-deletion. In cases with EOR >=90% molecular subtype of the neoplasm does not impact OS.

BACKGROUND Positron emission tomography (PET) is important in noninvasive diagnostic imaging of gliomas. There are many PET studies on glioma diagnosis based on the 2007 World Health Organization (WHO) classification; however, there are no studies on glioma diagnosis using the new classification (the 2016 WHO classification).Here we investigated the relationship between PET imaging using 11C-methionine (MET), 11C-choline (CHO), and 18F-fluorodeoxyglucose (FDG) and wildtype isocitrate dehydrogenase (IDH) (IDH-wt)/mutant IDH (IDH-mut) in astrocytic and oligodendroglial tumors according to the 2016 WHO classification. MATERIAL AND METHODS In total, 105 patients with newly diagnosed cerebral gliomas (six diffuse astrocytomas [DAs] with IDH-wt, six DAs with IDH-mut, seven anaplastic astrocytomas [AAs] with IDH-wt, 24 AAs with IDH-mut, 26 glioblastomas [GBMs] with IDH-wt, five GBMs with IDH-mut, 19 oligodendrogliomas [ODs], and 12 anaplastic oligodendrogliomas [AOs]) were included. All OD and AO patients had both IDH-mut and 1p/19q codeletion. The maximum standardized uptake values (SUVs) of the tumor/normal cortex mean SUV ratios (T/N ratios) for MET, CHO, and FDG were calculated; the mean T/N ratios of DA, AA, and GBM with IDH-wt/IDH-mut were compared. The diagnostic accuracy for distinguishing gliomas with IDH-wt from those with IDH-mut was assessed using receiver operating characteristic (ROC) curve analysis of the mean T/N ratios for the three PET tracers. RESULTS There were significant differences in the mean T/N ratios for all three PET tracers between the IDH-wt and IDH-mut groups including all histological classifications (p CONCLUSIONS PET imaging using MET, CHO, and FDG was confirmed to be informative for preoperatively differentiating gliomas according to the 2016 WHO classification, particularly for differentiating IDH-wt and IDH-mut 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/m2) 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/cm2 and a radiation energy density of 27 J/cm2. 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).

The dedicated intraoperative examination monitor for awake surgery (IEMAS) was originally developed by us to facilitate the process of brain mapping during awake craniotomy and successfully used in 186 neurosurgical procedures. This information-sharing device provides the opportunity for all members of the surgical team to visualize a wide spectrum of the integrated intraoperative information related to the condition of the patient, nuances of the surgical procedure, and details of the cortical mapping, practically without interruption of the surgical manipulations. The wide set of both anatomical and functional parameters, such as view of the patient's mimic and face movements while answering the specific questions, type of the examination test, position of the surgical instruments, parameters of the bispectral index monitor, and general view of the surgical field through the operating microscope, is presented compactly in one screen with several displays. However, the initially designed IEMAS system was occasionally affected by interruption or detachment of the connecting cables, which sometimes interfered with its effective clinical use. Therefore, a new modification of the device was developed. The specific feature is installation of wireless information transmitting technology using audio-visual transmitters and receivers for transfer of images and verbal information. The modified IEMAS system is very convenient to use in the narrow space of the operating room.

BACKGROUND: Standard therapeutics for glioblastoma is tumor removal followed by radiotherapy and chemotherapy with temozolomide (TMZ). Additional six cycles of TMZ is usually given, but it is unclear whether six cycles is sufficient to reduce recurrence. In our series, 25% of patients with GBM treated with TMZ lived more than one year without recurrence, and most of them received 12 cycles or more of TMZ chemotherapy. We retrospectively assessed the efficacy of long term TMZ in these case series. METHODS: Patients with newly diagnosed GBM, treated with 12 cycles or more TMZ after concomitant radiotherapy without relapse, were consecutively sampled at our institution from 2006 to 2014. The patents were categorized into 4 groups according to number of TMZ chemotherapy A) 12 cycles, B) 24 cycles, C) more than 24 cycles until relapse, D) beyond 12 cycles (included B, C). Progression free survival (PFS) after initial surgery, and PFS after the date of the final chemotherapy were analyzed by Kaplan-Meier estimate. RESULTS: A total of 52 patients met the criteria. Groups A, B, C and D included 12, 14, 12 and 40 patients, respectively. Each group had similar backgrounds. Median survival time (MST) and PFS of all patients was 6.8 and 4.3 years, respectively. There were no significant differences in PFS after the initial surgery between group A and B (p = 0.5889) and between C and D (p = 0.9243). Also, PFS after the final date of chemotherapy between group A and D (p = 0.5778), C and D (p = 0.8498) showed no difference, suggesting no benefit of more than 12 cycles of chemotherapy. CONCLUSION: This study suggested that patients with newly diagnosed GBM who are able to continue 12 cycles of TMZ chemotherapy can expect 6.3 years of OS and 4.3 years of PFS. More than 12 cycles of chemotherapy showed no additional survival benefit.

Photodynamic therapy (PDT) is based on biochemical reaction between oxygen, photosensitizer (PS) and light. PS is safe by itself and selectively accumulates in tumor cells and become activated by exposure to specific wavelengths of light. PS then releases energy, which is transferred to oxygen to generate reactive oxygen species (ROS), such as singlet oxygen and free radicals. ROS induces cell death in tumor cells. PDT for malignant gliomas are conducted as follows: 1) PS administration on the day before surgery. 2) Maximum tumor resection. 3) Targets for PDT are decided based on anatomical structure of removal cavity. Sites of recurrence are predicted such as corpus callosum and surrounding T2 high lesion should be selected. 4) PD laser is irradiated to the targets. We have conducted a phase II clinical trial of PDT for malignant glioma in 2009-2012. 27 patients were registered and 13 patients with glioblastoma were analyzed and positive outcomes were obtained (1-year OS rate: 100% and MST: 24.8 months). PDT was approved for clinical use in Japan in September 2013. Then we have continued follow-up of the patients in the clinical study and obtained updated excellent clinical results (MST: 31.5 months, median PFS: 19.6 months). We have also experienced PDT for 16 patients with recurrent glioblastoma and 1-year OS rate and median OS after PDT were 77.1% and 13.8 months, respectively. PDT appears to be a promising, new local therapeutics for glioblastoma.

OBJECT There is no standard therapeutic strategy for low-grade glioma (LGG). The authors hypothesized that adjuvant therapy might not be necessary for LGG cases in which total radiological resection was achieved. Accordingly, they established a treatment strategy based on the extent of resection (EOR) and the MIB-1 index: patients with a high EOR and low MIB-1 index were observed without postoperative treatment, whereas those with a low EOR and/or high MIB-1 index received radiotherapy (RT) and/or chemotherapy. In the present retrospective study, the authors reviewed clinical data on patients with primarily diagnosed LGGs who had been treated according to the above-mentioned strategy, and they validated the treatment policy. Given their results, they will establish a new treatment strategy for LGGs stratified by EOR, histological subtype, and molecular status. METHODS One hundred fifty-three patients with diagnosed LGG who had undergone resection or biopsy at Tokyo Women's Medical University between January 2000 and August 2010 were analyzed. The patients consisted of 84 men and 69 women, all with ages ≥ 15 years. A total of 146 patients underwent surgical removal of the tumor, and 7 patients underwent biopsy. RESULTS Postoperative RT and nitrosourea-based chemotherapy were administered in 48 and 35 patients, respectively. Extent of resection was significantly associated with both overall survival (OS; p = 0.0096) and progression-free survival (PFS; p = 0.0007) in patients with diffuse astrocytoma but not in those with oligodendroglial subtypes. Chemotherapy significantly prolonged PFS, especially in patients with oligodendroglial subtypes (p = 0.0009). Patients with a mutant IDH1 gene had significantly longer OS (p = 0.034). Multivariate analysis did not identify MIB-1 index or RT as prognostic factors, but it did identify chemotherapy as a prognostic factor for PFS and EOR as a prognostic factor for OS and PFS. CONCLUSIONS The findings demonstrated that EOR was significantly correlated with patient survival; thus, one should aim for maximum tumor resection. In addition, patients with a higher EOR can be safely observed without adjuvant therapy. For patients with partial resection, postoperative chemotherapy should be administered for those with oligodendroglial subtypes, and repeat resection should be considered for those with astrocytic tumors. More aggressive treatment with RT and chemotherapy may be required for patients with a poor prognosis, such as those with diffuse astrocytoma, 1p/19q nondeleted tumors, or IDH1 wild-type oligodendroglial tumors with partial resection.

OBJECTIVE: Intraoperative histopathological investigation plays an important role during surgery for gliomas. To facilitate the rapid characterization of resected tissue, an original technique of intraoperative flow cytometry (iFC) was established. The objective in this study was evaluation of this technique's efficacy for rapidly determining tumor presence in the surgical biopsy sample and WHO histopathological grade of the neoplasm. METHODS: In total, 328 separate biopsy specimens obtained during the resection of 81 intracranial gliomas were analyzed with iFC. The evaluated malignancy index (MI) was defined as the ratio of the number of cells with greater than normal DNA content to the total number of cells. The duration of iFC in all cases was approximately 10 minutes. Each sample was additionally investigated histopathologically on frozen and permanent formalin-fixed paraffin-embedded tissue sections. The latter process was used as a "gold standard" control for evaluation of the diagnostic efficacy of iFC analysis. RESULTS: The MI differed significantly between neoplastic and perilesional brain tissue (25.3% ± 22.0% vs 4.6% ± 2.6%, p < 0.01). Receiver operating characteristic curve analysis revealed a corresponding area under the curve value of 0.941. The optimal cutoff level of the MI for identification of tumor in the biopsy specimen was 6.8%, which provided 0.88 sensitivity, 0.88 specificity, 0.97 positive predictive value, 0.60 negative predictive value, and 0.88 diagnostic accuracy. Additionally, the MI showed a significant association with WHO histopathological grades of glioma (p < 0.01), but its values in Grade II, III, and IV tumors overlapped prominently and were on average 13.3% ± 11.0%, 35.0% ± 21.8%, and 46.6% ± 23.1%, respectively. CONCLUSIONS: Results of this study demonstrate that iFC with the determination of the MI may be feasible for rapidly determining glioma presence in a surgical biopsy sample.

Temozolomide (TMZ) may enhance antitumor immunity in patients with glioblastoma multiforme (GBM). In this paper the authors report on a prospective Phase I/IIa clinical trial of fractionated radiotherapy (FRT) concomitant with TMZ therapy, followed by treatment with autologous formalin-fixed tumor vaccine (AFTV) and TMZ maintenance in patients with newly diagnosed GBM.Twenty-four patients (age 16-75 years, Karnofsky Performance Scale score ≥ 60% before initiation of FRT) with newly diagnosed GBM received a total dose of 60 Gy of FRT with daily concurrent TMZ. After a 4-week interval, the patients received 3 AFTV injections and the first course of TMZ maintenance chemotherapy for 5 days, followed by multiple courses of TMZ for 5 days in each 28-day cycle.This treatment regimen was well tolerated by all patients. The percentage of patients with progression-free survival (PFS) ≥ 24 months was 33%. The median PFS, median overall survival (OS), and the actuarial 2- and 3-year survival rates of the 24 patients were 8.2 months, 22.2 months, 47%, and 38%, respectively. The median PFS in patients with a delayed-type hypersensitivity (DTH) response after the third AFTV injection (DTH-2) of 10 mm or larger surpassed the median length of follow-up for progression-free patients (29.5 months), which was significantly greater than the median PFS in patients with a smaller DTH-2 response.The treatment regimen was well tolerated and resulted in favorable PFS and OS for newly diagnosed GBM patients. Clinical trial registration no.: UMIN000001426 (UMIN clinical trials registry, Japan).

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.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).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.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).

The importance of surgical resection for patients with supratentorial low-grade glioma (LGG) remains controversial. This retrospective study of patients (n = 153) treated between 2000 to 2010 at a single institution assessed whether increasing the extent of resection (EOR) was associated with improved progression-free survival (PFS) and overall survival (OS). Histological subtypes of World Health Organization grade II tumors were as follows: diffuse astrocytoma in 49 patients (32.0%), oligoastrocytoma in 45 patients (29.4%), and oligodendroglioma in 59 patients (38.6%). Median pre- and postoperative tumor volumes and median EOR were 29.0 cm(3) (range 0.7-162 cm(3)) and 1.7 cm(3) (range 0-135.7 cm(3)) and 95%, respectively. Five- and 10-year OS for all LGG patients were 95.1% and 85.4%, respectively. Eight-year OS for diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma were 70.7%, 91.2%, and 98.3%, respectively. Five-year PFS for diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma were 42.6%, 71.3%, and 62.7%, respectively. Patients were divided into two groups by EOR ≥90% and