Long-term effectiveness of Gliadel ® implant for malignant glioma and prognostic factors for survival: 3-year results of a post-marketing surveillance in Japan

Background Adjuvant treatment with Gliadel wafers may prolong overall survival (OS) for malignant glioma patients without increasing toxicity. In Japan, the long-term OS of these patients treated with Gliadel 7.7 mg implants has not been studied. We evaluated OS and prognostic factors that might affect OS in Japanese patients with malignant glioma who received the Gliadel 7.7 mg implant. Methods This observational, long-term, post-marketing surveillance was an extension of a previous surveillance. Data were collected through case report forms at 2 and 3 years after Gliadel implant. Up to 8 Gliadel wafers (61.6 mg of carmustine) were placed over the tumor resection site. Primary endpoints were OS and prognostic factors that may influence OS. Results Among the 506 patients analyzed, 62.6% had newly diagnosed disease, and 37.4% had recurrent disease; 79.1% had glioblastoma histological type and 79.6% had World Health Organization Grade IV disease. Patients received a median of 8 wafers. The median OS was 18.0 months; OS rates were 39.8% and 31.5% at 2 and 3 years, respectively. Age ≥65 years (hazard ratio [HR]: 1.456; P = 0.002), lower resection rate (HR: 1.206; P < 0.001), recurrence (HR: 2.418; P < 0.001), and concomitant radiotherapy (HR: 0.588; P < 0.001) were identified as significant prognostic factors. Conclusions This study confirmed the 2- and 3-year OS of Japanese malignant glioma patients with varied backgrounds after Gliadel implant. With a careful interpretation of indirect comparisons with previously reported data, the results suggest that prognosis could be improved with Gliadel implants.

NI-7 Diffusion-weighted imaging for monitoring acute response and recurrence after photodynamic therapy in malignant gliomas

Background Photodynamic therapy (PDT) subsequent to surgical tumor removal is a novel light-activated localized treatment for malignant glioma. Although PDT provides effective local control, even PDT cannot completely suppress local recurrence of malignant glioma. We previously reported that the acute response of malignant glioma to PDT could be detected as linear hyperintense signals on diffusion-weighted imaging (DWI) and a decline in apparent diffusion coefficient (ADC) values that were asymptomatic and transient. However, their long-term clinical significance has not yet been examined. This study aimed to clarify the link between the hyperintense signal on DWI as an acute response and recurrence after PDT in malignant glioma. Methods Thirty consecutive patients (16 men, 14 women; median age 60.5 years) underwent PDT for malignant glioma at our institution between 2017 and 2020. We analyzed signal changes on DWI after PDT and the link between these findings and the recurrence pattern. Results In all patients, linear hyperintense signals of 5–7 mm on DWI were detected at the surface of the resected cavity from day 1 after PDT. These changes matched the PDT-irradiated area and disappeared in about 30 days without any neurological deterioration. Of the 30 patients, 19 (63%) exhibited recurrence: local recurrence in 10 (33%), distant recurrence in 1 (3%), and dissemination in 8 (27%). All local recurrences arose from areas that did not show a hyperintense signal on DWI obtained on day 1 after PDT. Patients with distant recurrence or dissemination tended to have uninterrupted hyperintense signal on DWI obtained on day 1 after PDT. Conclusion The local recurrence in malignant glioma after PDT occurred in the areas without hyperintense signal on DWI as the acute response to PDT. This characteristic finding could aid in the monitoring of not only PDT-irradiated area but also local recurrence site after PDT.

IMT-1 A translational research for practical use of dendritic cell-based immunotherapy against malignant glioma

Background: Although a therapeutic effect of dendritic cell (DC)-based immunotherapy, a kind of regenerative medicine, has been recognized in various types of cancer including malignant glioma, it is still impractical because of several unsolved problems. This study is aimed to solve the problems in regenerative medicine through a clinical trial of immunotherapy using fusions of DCs and glioma cells (GCs) against malignant glioma, and to put it into practical use. Methods: Primary cultured GCs and glioma stem cells (GSCs) were generated from surgical specimens of patient. DCs were generated from PBMC of same patient, and were fused with GCs and GSCs. The entire process of cell production must be performed by pairs of two cell-culture operators in a dedicated cell processing facility. We developed a remote cell-observation system for reducing hands work of operators. As a project to establish a preservation method, cryopreservation of glioma tissues, GCs/GSCs, DCs and fusion cells followed by their viability examination. Results: The remote cell-observation system worked stable in morphological observation and cell-counting for adhesion cells. A growth curve was also automatically and accurately created. Although a morphological observation of floating cells such as GSCs and DCs was possible, there was some error in counting of those cells. A project to establish a preservation method is currently underway, including the development of storage containers and storage liquids. Conclusions: Although the remote cell-observation system required some modifications at the observation site, depth of focus, etc. for floating cells, there was no problem in accuracy for adhesion cells compared with operator’s observation. This system, which can be easily installed at low cost, seemed to be helpful for practical use of regenerative medical products including this therapy. We are working on a project to establish a stable transportation and preservation method for prevalence of this treatment.

STMO-7 Usefulness of NU-KNIT in retractorless surgery for malignant glioma

On the removal of the brain tumor, securing of appropriate working corridor and the maintenance of the visibility are one of the most relevant elements regardless of tumor local existence. This is unchangeable extract in these days when a support apparatus such as navigation system and the nerve monitoring was enriched, and, in the malignant glioma that a tumor border is relatively indistinct, the importance does not change either.At our hospital, I protect the access route by two folds of coating of absorbable hemostat(Surgical NU-KNIT) and neurosurgical patties (Delicot) on the removal of the malignant brain tumor in the brain deep part instead without using as possible fixed retractor for the purpose of securing of working corridor under minimum retraction and extract deep part tumor. In this way, normal real protection, wet maintenance, maintenance of the visibility by the control of the bleeding and pressure reduction of the neighborhood organization extracting are provided, and postoperative function recovery gets an early impression. About a method of the securing of working corridor at our hospital, I inspect the usefulness and limit by showing representative cases and want to have an opinion, criticism.

RT-1 Treatment results of salvage gamma knife stereotactic radiosurgery and bevacizumab (AVAgamma therapy) for recurrent malignant glioma

Purpose: We report the treatment results of AVAgamma therapy combining gamma knife (GK) and bevacizumab for recurrent malignant glioma. Subjects: From August 2013 to January 2021, 71 patients (Grade 2:8 patients, Grade3:16 patients, Grade 4:47 patients) with recurrent malignant glioma treated with AVAgamma therapy as salvage therapy at the time of relapse after initial treatment. The average age is 55.7 years, with 44 men and 27 women. The tumor volume is 150 ml or less, and KPS is 40% or more as the indication of AVAgamma therapy. When the irradiation volume of the gamma knife was 15 ml or less, the marginal dose was 20 to 26 Gy, and when the irradiation volume was 15 ml or more, the marginal dose was 12 to 15 Gy in two divided doses.The mean therapeutic borderline dose was 24 Gy. Bevacizumab was administered 10 mg / kg or 15 mg / kg 1 to 10 times after GK. Methods: Median progression-free survival (mPFS) from AVAgamma treatment, median survival (mOS), and mOS from initial treatment were examined and compared with mOS in the RPA classification of recurrent glioma. Results: In relapsing glioma RPA classification, NABTT CNC class 2 mOS is 17.2 months, class 3 mOS is 3.8 months, class 5 mOS is 5.6 months, class 6 mOS is 6.4 months, but mOS from AVAgamma therapy is 18 months in class 3, 11 months in class 5, 9 months in class 6. The survival time has been extended in class3, class5, class6. Discussion: By AVAgamma therapy, it was thought that recurrent lesions were locally controlled and life prognosis was prolonged. Conclusion: AVAgamma therapy is thought to prolong the survival of recurrent malignant glioma and play an important role as salvage treatment.

COT-13 Luminance analysis of 5-aminolevulinic acid using Image J for malignant brain tumor

Purpose: For malignant brain tumor surgery, photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA) is useful for maximal removal of the tumor. Although it has the advantage of identifying the presence or absence of residual tumors during surgery, there are variations in positive rates, and the classification is limited, based on visual inspection such as Stummer’s classification (strong, vague, none). We analyzed the luminance of positive findings using software Image J for brain tumor surgery using 5-ALA, and we report the results. Materials and Methods: From April 2018 to March 2021, 31 patients with suspected malignant glioma before surgery were included. Intraoperative 5-ALA positive findings were analyzed by software Image J (Wayne Rasband: NIH), the luminance was measured with a histogram, and compared the maximum luminance titer. Results: Among the positive cases, the average maximum luminance value for malignant glioma was 101 (50–168), which consisted of 11 cases of Glioblastoma, 1 case of Oligodendroglioma, and 1 case of anaplastic astrocytoma. The average maximum brightness of metastatic brain tumors is lower than that of malignant gliomas, even if they are visually strong, 83.5 (28–121). Conclusions: Even if it is visually strong in the conventional Stummer classification, it may be possible to classify in detail by analyzing luminance with Image J. In addition, more objective index is necessary to classify the vague findings.

Correction: Shao et al. AKT Axis, miR-21, and RECK Play Pivotal Roles in Dihydroartemisinin Killing Malignant Glioma Cells. Int. J. Mol. Sci. 2017, 18, 350

The authors wish to make the following corrections to this paper [...]

Temozolomide sensitivity of malignant glioma cell lines – a systematic review assessing consistencies between in vitro studies

Background Malignant glioma cell line models are integral to pre-clinical testing of novel potential therapies. Accurate prediction of likely efficacy in the clinic requires that these models are reliable and consistent. We assessed this by examining the reporting of experimental conditions and sensitivity to temozolomide in glioma cells lines. Methods We searched Medline and Embase (Jan 1994-Jan 2021) for studies evaluating the effect of temozolomide monotherapy on cell viability of at least one malignant glioma cell line. Key data items included type of cell lines, temozolomide exposure duration in hours (hr), and cell viability measure (IC50). Results We included 212 studies from 2789 non-duplicate records that reported 248 distinct cell lines. The commonest cell line was U87 (60.4%). Only 10.4% studies used a patient-derived cell line. The proportion of studies not reporting each experimental condition ranged from 8.0–27.4%, including base medium (8.0%), serum supplementation (9.9%) and number of replicates (27.4%). In studies reporting IC50, the median value for U87 at 24 h, 48 h and 72 h was 123.9 μM (IQR 75.3–277.7 μM), 223.1 μM (IQR 92.0–590.1 μM) and 230.0 μM (IQR 34.1–650.0 μM), respectively. The median IC50 at 72 h for patient-derived cell lines was 220 μM (IQR 81.1–800.0 μM). Conclusion Temozolomide sensitivity reported in comparable studies was not consistent between or within malignant glioma cell lines. Drug discovery science performed on these models cannot reliably inform clinical translation. A consensus model of reporting can maximise reproducibility and consistency among in vitro studies.

Preliminary Report: Rapid Intraoperative Detection of Residual Glioma Cell in Resection Cavity Walls Using a Compact Fluorescence Microscope

Objective: The surgical eradication of malignant glioma cells is theoretically impossible. Therefore, reducing the number of remaining tumor cells around the brain–tumor interface (BTI) is crucial for achieving satisfactory clinical results. The usefulness of fluorescence–guided resection for the treatment of malignant glioma was recently reported, but the detection of infiltrating tumor cells in the BTI using a surgical microscope is not realistic. Therefore, we have developed an intraoperative rapid fluorescence cytology system, and exploratorily evaluated its clinical feasibility for the management of malignant glioma. Materials and methods: A total of 25 selected patients with malignant glioma (newly diagnosed: 17; recurrent: 8) underwent surgical resection under photodiagnosis using photosensitizer Talaporfin sodium and a semiconductor laser. Intraoperatively, a crush smear preparation was made from a tiny amount of tumor tissue, and the fluorescence emitted upon 620/660 nm excitation was evaluated rapidly using a compact fluorescence microscope in the operating theater. Results: Fluorescence intensities of tumor tissues measured using a surgical microscope correlated with the tumor cell densities of tissues evaluated by measuring the red fluorescence emitted from the cytoplasm of tumor cells using a fluorescence microscope. A “weak fluorescence” indicated a reduction in the tumor cell density, whereas “no fluorescence” did not indicate the complete eradication of the tumor cells, but indicated that few tumor cells were emitting fluorescence. Conclusion: The rapid intraoperative detection of fluorescence from glioma cells using a compact fluorescence microscope was probably useful to evaluate the presence of tumor cells in the resection cavity walls, and could provide surgical implications for the more complete resection of malignant gliomas.