BIOM-06. MOLECULAR SIGNATURES UNDERLIE THE DISTINCT FAILURE PATTERNS OF MALIGNANT GLIOMAS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi10-vi11
Author(s):  
Seung Won Choi
Keyword(s):  
Local Recurrence ◽  
Synaptic Transmission ◽  
Malignant Glioma ◽  
Malignant Gliomas ◽  
Failure Pattern ◽  
Molecular Characteristics ◽  
P Value ◽  
Failure Patterns ◽  
Leptomeningeal Seeding ◽  
Combined Failure

Abstract BACKGROUND Malignant gliomas exhibit varied failure patterns upon recurrence; however, genomic backgrounds of these distinct phenotypes have not been evaluated. We aimed to explore the genomic traits associated with distinct failure patterns in malignant glioma patients. METHODS This study involved 272 malignant glioma patients. Failure pattern was defined for the spatial relationship between recurrent tumor and the original tumor as follows: local recurrence (LR), remote recurrence, leptomeningeal seeding (LMC), and combined failure pattern. Molecular characteristics underlying different failure patterns were investigated for the mutation profile, copy number variation (CNV), and transcriptomic signatures. RESULTS Local recurrence was the most prominent failure pattern (62.9%), followed by combined recurrence (22.8%). Multivariate Cox regression analysis confirmed failure pattern as one of the independent prognostic factors. Patients with combined failure patterns exhibited the worst prognoses, whereas patients with remote recurrence exhibited the most favorable outcomes (median overall survival = 11.4 and 25.2 months, respectively). In IDH1-wild type glioblastoma (GBM) patients, TERT and PIK3CA mutation were significantly associated with the development of combined failure pattern and leptomeningeal seeding, respectively (p-value=0.015 & p-value=0.004, respectively). Transcriptomic analysis exhibited that inter-neuronal synaptic transmission was enriched in GBMs with combined failure pattern and this finding was further validated in proteomic analysis; neuronal myelination and synaptic transmission-related pathways were upregulated in GBMs which exhibited combined failure pattern. CONCLUSIONS Collectively, we demonstrated that the inherent molecular characteristics of the tumors might contribute to the eventual relapse patterns; tracking their evolutionary pathways may unravel novel therapeutic vulnerabilities of these tumors.

scholarly journals GENE-12. ANALYSIS OF FAILURE PATTERNS IN MALIGNANT GLIOMA: EXPLORING THE GENETIC LANDSCAPE OF PATTERN OF FAILURE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi100-vi100
Author(s):  
Seung Won Choi ◽  
Do-Hyun Nam ◽  
Jason Sa ◽  
Harim Koo
Keyword(s):  
Local Recurrence ◽  
Malignant Glioma ◽  
Malignant Gliomas ◽  
Genomic Data ◽  
Distant Recurrence ◽  
P Value ◽  
Significant Prognostic Factor ◽  
Pattern Of Failure ◽  
Failure Patterns ◽  
Leptomeningeal Seeding

Abstract Failure patterns in malignant gliomas have been described in previous literatures, however, studies were limited to analyze clinical features to account for predisposition to distinct failure patterns. Present study aimed to describe the landscape of failure patterns in malignant glioma from large cohort by integrating multi-omics data and investigate the genetic backgrounds of distinct failure patterns. A total of 423 cases from 325 patients who enrolled at the registry of IRCR at SMC were reviewed for their pattern of failure. Failure patterns were categorized into local, distant recurrence and leptomeningeal seeding regarding recurrent tumors’ spatial relation to primary location. Genomic data was available for 327 (DNAseq) and 259 samples (RNAseq), respectively. Glioblastoma was the most prevalent histologic type in study cohort (81.2%)) and majority of cases experienced the recurrence (79.0%). None of clinical parameters (e.g. age, sex, extent of operation and history of prior therapy) failed to show any significant association with failure patterns. Although local recurrence was most prevalent (63.8%) among failure patterns in malignant gliomas, considerable portion of patients (37.8%) demonstrated other types of failure patterns even in their initial relapse. Multivariate analysis demonstrated that failure pattern was significant prognostic factor to overall survival (remote recurrence, HR=1.59, p-value=0.009; leptomeningeal seeding, HR=2.17, p-value< 0.001). Genomic analysis including mutational profile revealed distinct molecular landscape of malignant gliomas according to failure patterns, which suggested that innate biologic characteristics of tumors might contribute to develop distinct failure patterns upon recurrence. PTEN mutation was significantly enriched in tumors of distant recurrence (p-value=0.026). We described the landscape of failure patterns in malignant gliomas by integrating clinical and genomic data. Considerable amount of malignant glioma patients experienced distinct failure patterns other than local recurrence and their clinical outcome as well as genetic background demonstrated invasive characteristic of these tumors.

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

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi19-vi19
Author(s):  
Yuichi Fujita ◽  
Hiroaki Nagashima ◽  
Kazuhiro Tanaka ◽  
Mitsuru Hashiguchi ◽  
Tomoo Itoh ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Local Recurrence ◽  
Malignant Glioma ◽  
Diffusion Weighted Imaging ◽  
Malignant Gliomas ◽  
Distant Recurrence ◽  
Acute Response ◽  
Diffusion Weighted ◽  
Hyperintense Signal ◽  
Apparent Diffusion

Abstract 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.

scholarly journals Hyperintense Signal on Diffusion-Weighted Imaging for Monitoring The Acute Response and Local Recurrence After Photodynamic Therapy in Malignant Gliomas

2021 ◽  
Author(s):  
Yuich Fujita ◽  
Hiroaki Nagashima ◽  
Kazuhiro Tanaka ◽  
Mitsuru Hashiguchi ◽  
Tomoo Itoh ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Local Recurrence ◽  
Malignant Glioma ◽  
Diffusion Weighted Imaging ◽  
Malignant Gliomas ◽  
Acute Response ◽  
Diffusion Weighted ◽  
Hyperintense Signal ◽  
Apparent Diffusion ◽  
Adc Values

Abstract Purpose Photodynamic therapy (PDT) subsequent to surgical tumor removal is a novel localized treatment for malignant glioma that provides effective local control. The acute response of malignant glioma to PDT can be detected as linear transient hyperintense signal on diffusion-weighted imaging (DWI) and a decline in apparent diffusion coefficient (ADC) values without symptoms. However, their long-term clinical significance has not yet been examined. The aim of this study was to clarify the link between hyperintense signal on DWI as an acute response and recurrence after PDT in malignant glioma. Methods Thirty patients (16 men; median age, 60.5 years) underwent PDT for malignant glioma at our institution between 2017 and 2020. We analyzed the signal changes on DWI after PDT and the relationship between these findings and the recurrence pattern. Results All patients showed linear hyperintense signal on DWI at the surface of the resected cavity from day 1 after PDT. These changes disappeared in about 30 days without any neurological deterioration. During a mean post-PDT follow-up of 14.3 months, 19 patients (63%) exhibited recurrence: 10 local, 1 distant, and 8 disseminated. All of the local recurrences arose from areas that did not show hyperintense signal on DWI obtained on day 1 after PDT. Conclusion The local recurrence in malignant glioma after PDT occurs in an area without hyperintense signal on DWI as an acute response to PDT. This characteristic finding could aid in the monitoring of local recurrence after PDT.

scholarly journals Dendritic cell–based immunotherapy targeting Wilms’ tumor 1 in patients with recurrent malignant glioma

2015 ◽  
Vol 123 (4) ◽  
pp. 989-997 ◽  
Author(s):  
Keiichi Sakai ◽  
Shigetaka Shimodaira ◽  
Shinya Maejima ◽  
Nobuyuki Udagawa ◽  
Kenji Sano ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Malignant Glioma ◽  
Stable Disease ◽  
Wilms Tumor ◽  
Malignant Gliomas ◽  
Tumor Lysate ◽  
Dc Vaccine ◽  
Pulsed Dc ◽  
Wilms Tumor 1 ◽  
Vaccination Therapy

OBJECT Dendritic cell (DC)-based vaccination is considered a potentially effective therapy against advanced cancer. The authors conducted a Phase I study to investigate the safety and immunomonitoring of Wilms’ tumor 1 (WT1)-pulsed DC vaccination therapy for patients with relapsed malignant glioma. METHODS WT1-pulsed and/or autologous tumor lysate-pulsed DC vaccination therapy was performed in patients with relapsed malignant gliomas. Approximately 1 × 107 to 2 × 107 pulsed DCs loaded with WT1 peptide antigen and/or tumor lysate were intradermally injected into the axillary areas with OK-432, a streptococcal preparation, at 2-week intervals for at least 5–7 sessions (1 course) during an individual chemotherapy regimen. RESULTS Ten patients (3 men, 7 women; age range 24–64 years [median 39 years]) with the following tumors were enrolled: glioblastoma (6), anaplastic astrocytoma (2), anaplastic oligoastrocytoma (1), and anaplastic oligodendroglioma (1). Modified WT1 peptide–pulsed DC vaccine was administered to 7 patients, tumor lysate-pulsed DC vaccine to 2 patients, and both tumor lysate–pulsed and WT1-pulsed DC vaccine to 1 patient. The clinical response was stable disease in 5 patients with WT1-pulsed DC vaccination. In 2 of 5 patients with stable disease, neurological findings improved, and MR images showed tumor shrinkage. No serious adverse events occurred except Grade 1–2 erythema at the injection sites. WT1 tetramer analysis detected WT1-reactive cytotoxic T cells after vaccination in patients treated with WT1-pulsed therapy. Positivity for skin reaction at the injection sites was 80% (8 of 10 patients) after the first session, and positivity remained for these 8 patients after the final session. CONCLUSIONS This study of WT1-pulsed DC vaccination therapy demonstrated safety, immunogenicity, and feasibility in the management of relapsed malignant gliomas.

CBIO-01. INHIBITION OF EXTRACELLULAR CARBONIC ANHYDRASES INHIBITS GLIOBLASTOMA CELL INVASION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi27-vi27
Author(s):  
Martin Proescholdt ◽  
Zhenwei Qiu ◽  
Johannes Falter ◽  
Anette Lohmeier ◽  
Nils-Ole Schmidt
Keyword(s):  
Malignant Glioma ◽  
Cell Lines ◽  
Proteolytic Enzymes ◽  
Malignant Gliomas ◽  
Invasive Treatment ◽  
Matrigel Invasion ◽  
Hypoxic Conditions ◽  
Ca Ix ◽  
Caix Expression ◽  
Oxygenation Status

Abstract BACKGROUND Malignant gliomas metabolize glucose preferably by glycolysis which is in accordance with the Warburg effect. This induces a high demand of glucose combined with a significant lactic acid load. The hypoxia-inducible carbonic anhydrase (CA) IX has been shown to moderate the extrusion of hydrogen ions into the extracellular space. Since the acidification of the extracellular environment contributes to host tissue invasion due to activation of proteolytic enzymes, we hypothesized that CA IX plays an important role in malignant glioma Recently, specific small molecule inhibitors of this enzyme have been developed and may provide an innovative strategy for anti – invasive treatment. METHODS Two established and 4 primary GBM cell lines (2 with mesenchymal and 2 with proneural transcriptional profile) were exposed to the CAIX inhibitor U104 under normoxic and hypoxic conditions. Cell toxicity was measured by ATP and crystal violet assay. For invasion assessment, a matrigel invasion chamber system with 8 µm pore size polycarbonate filter was used. CAIX expression was analyzed by quantitative RTPCR and Western Blot. RESULTS Hypoxia significantly induced CAIX expression in all cell lines. Invasiveness increased significantly under hypoxic conditions in the mesenchymal cells (p &lt; 0.01). Regardless of oxygenation status, the mesenchymal group displayed significantly higher invasiveness compared to the proneural group (p = 0.006). Looking at all cell lines, invasion is significantly inhibited by U104, both under normoxic and hypoxic conditions (p &lt; 0.01). However, while the mesenchymal group showed the highest susceptibility to CAIX inhibition followed by the proneurally differentiated group, the established cell lines were entirely refractory to CAIX inhibition. CONCLUSION Our data demonstrate that CAIX inhibition can effectively inhibit invasion in malignant glioma cells independent from oxygenation status, however the effects are significantly influenced by cell type specific biological features.

scholarly journals 3D Conformal Radiotherapy and Cisplatin for Recurrent Malignant Glioma

2008 ◽  
Vol 35 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Lauren VanderSpek ◽  
Barbara Fisher ◽  
Glenn Bauman ◽  
David Macdonald
Keyword(s):  
Malignant Glioma ◽  
Malignant Gliomas ◽  
Conformal Radiotherapy ◽  
Maximum Tolerated Dose ◽  
External Beam Radiation ◽  
Recurrent Malignant Glioma ◽  
Beam Radiation ◽  
Fractionated Radiotherapy ◽  
3D Conformal Radiotherapy ◽  
Grade 3

Purpose:To determine the maximum tolerated dose of 3D conformal radiotherapy in combination with Cisplatin for patients with recurrent malignant gliomas.Methods:From 1999-2003, nine patients with recurrent malignant glioma received fractionated radiotherapy and Cisplatin (20 mg/m2/d IV on days 1-5) in a Phase I radiation dose escalation trial. Three sequential dose levels were evaluated: 25 Gy, 30 Gy, and 35 Gy, using 5 Gy fractions. All patients received prior external beam radiation (median dose 59.4 (20-60) Gy) and five patients received prior chemotherapy.Results:Six male and three female patients were enrolled with a median age of 52 years, and a median Karnofsky performance status score of 70. The median re-irradiated tumor volume was 18.9 (0.1-78.5) cm3 and the median follow-up was 8.8 (3.2-31.2) months. One patient (30 Gy/ 6 fractions) experienced medically reversible acute grade 3 toxicity. A second patient (35 Gy/ 7 fractions) experienced acute grade 2 toxicity and histology showed tumor and radiation effect. A third patient (25 Gy/ 5 fractions) experienced late grade 3 toxicity from radiation necrosis. The radiological responses consisted of complete response (1 patient), partial response (1 patient), and stable disease (2 patients). The median overall survival was 8.8 months (95% CI 8.0-9.9), and the median disease free interval was 2.0 months (95% CI 1.4-4.4). Seven patients received chemotherapy following re-irradiation and Cisplatin.Conclusion:The maximum tolerated dose of 3D conformal fractionated radiotherapy was 30 Gy in 6 fractions with low dose Cisplatin, which was well tolerated in terms of acute toxicity for our patient population. This regimen demonstrated only modest efficacy in the treatment of recurrent malignant glioma. Combinations of conformal re-irradiation and other systemic agents may merit investigation. Currently our recommended dose is 30 Gy in 6 fractions for selected patients.

scholarly journals P14.120 Phase II study of weekly carboplatin in pretreated adult malignant gliomas

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii97-iii97
Author(s):  
V Villani ◽  
A Pace ◽  
A Vidiri ◽  
A Tanzilli ◽  
F Sperati ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Phase Ii Study ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Single Agent ◽  
Malignant Gliomas ◽  
Recurrent Malignant Glioma ◽  
Eligibility Criteria

Abstract BACKGROUND Patients with relapse of recurrent glioma have a poor outcome and limited treatment options. The aim of this study is to investigate the clinical benefit and tolerability of weekly intravenous administration of carboplatin-based monotherapy in adult glioma patients who had progressed from previous chemotherapy lines based on temozolomide and nitrosoureas MATERIAL AND METHODS This was a single arm, Phase II study. Eligibility criteria included progressive or recurrent malignant glioma after radiotherapy and chemotherapy-based treatments and Karnofsky Performance Status (KPS) > 60. RESULTS Thirty-two patients (median age: 43.5 y) were enrolled to receive weekly carboplatin monotherapy in intravenous mode of administration. The median duration of response was 7.3 months with an overall disease control rate of 31.3%. Median progression-free survival (PFS) was 2.3 months while overall survival (OS) was 5.5 months. Patients achieving clinical benefit exhibited a longer PFS (4.6 vs 1.5 months; p>0.001) and OS (7.9 vs 3.2 months; p=0.041) compared to those not achieving clinical benefit. CONCLUSION Our findings show that single agent, weekly, intravenous carboplatin may have a role in the treatment patients with recurrent malignant glioma

scholarly journals Laser Ablation of Recurrent Malignant Gliomas

Neurosurgery ◽  
2016 ◽  
Vol 79 (suppl_1) ◽  
pp. S35-S39 ◽  
Author(s):  
Analiz Rodriguez ◽  
Stephen B. Tatter
Keyword(s):  
Laser Ablation ◽  
Minimally Invasive ◽  
Malignant Glioma ◽  
Malignant Gliomas ◽  
Invasive Technique ◽  
Recurrent Malignant Glioma ◽  
Repeat Surgery ◽  
Advantages And Disadvantages ◽  
Adjuvant Therapies ◽  
Clinical Challenge

Abstract Recurrent malignant glioma continues to be a clinical challenge, and repeat surgery is an option in only select patients. Stereotactic laser ablation, a new minimally invasive technique, can be used as an alternative to surgery. We review the current literature on laser ablation for recurrent malignant gliomas as well as discuss practical and theoretical advantages and disadvantages of this emerging technique in comparison with repeat surgery or radiation. We also discuss the potential for laser ablation to augment adjuvant therapies, namely, chemotherapy, radiation, and immunotherapy.

Clinical effect of intra-arterial tumor necrosis factor-α for malignant glioma

1992 ◽  
Vol 77 (1) ◽  
pp. 78-83 ◽  
Author(s):  
Jun Yoshida ◽  
Toshihiko Wakabayashi ◽  
Masaaki Mizuno ◽  
Kenichiro Sugita ◽  
Tazuka Yoshida ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Malignant Glioma ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Tumor Regression ◽  
Malignant Gliomas ◽  
Human Tumor ◽  
Content Type ◽  
Factor Α ◽  
Necrosis Factor

✓ Recombinant human tumor necrosis factor-α was administered intra-arterially to treat 20 cases of malignant gliomas, mostly progressive or recurrent. The optimum dosage was determined to be 1 × 105 U/sq m/day. Among the 10 evaluable patients treated at this dosage, two responded (one completely and one partially), resulting in a 20% response rate. Side effects were mild and easily controllable. Improvement of neurological symptoms was noted in 47% of the patients a few days after treatment, even when computerized tomography showed no tumor regression. This might have been due to the pleiotypic biological activity of tumor necrosis factor-α. Neuroradiographic observations revealed narrowing of the tumor-feeding artery, a decrease in tumor staining ability, and necrosis in the central part of a tumor. The authors suggest that intra-arterial administration of tumor necrosis factor-α may be an effective treatment for malignant glioma, including recurrent cases.

scholarly journals RT-02 POTENTIAL OF PROTON BEAM THERAPY FOR THE TREATMENT OF GLIOBLASTOMA

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii21-ii21
Author(s):  
Masahide Matsuda ◽  
Eiichi Ishikawa ◽  
Masashi Mizumoto ◽  
Hidehiro Kohzuki ◽  
Narushi Sugii ◽  
...  
Keyword(s):  
Local Recurrence ◽  
Adverse Events ◽  
Survival Time ◽  
Proton Beam ◽  
Radiation Necrosis ◽  
Proton Beam Therapy ◽  
High Dose ◽  
Failure Patterns ◽  
Survival Difference ◽  
Significant Difference

Abstract INTRODUCTION Recently, proton beam therapy has attracted increasing interest in the Japanese neuro-oncological field because of the insurance approval for pediatric brain tumor, chordoma, and chondrosarcoma. We have developed the high dose radiotherapeutic strategy using proton beam for malignant glioma in our institution since long before. Here we retrospectively analyzed the efficacy of this treatment strategy. METHODS Thirty-four patients with newly diagnosed GBM who underwent high dose proton beam therapy were investigated. All patients received hyperfractionated concomitant radiotherapy consisting of X-ray radiotherapy (50.4Gy in 28 fractions) and proton beam therapy (46.2Gy [RBE] in 28 fractions). Concurrent chemotherapy consisted of ACNU in the early 6 cases or TMZ in the late 28 cases. The survival outcome and adverse events were analyzed. RESULTS The median overall survival time and progression free survival time for all 34 patients were 35.7 months (95%CI, 28.1–43.4) and 11.2 months (95%CI, 6.8–15.7), respectively. No significant survival difference according to the chemotherapy regimen was shown. Failure patterns after proton beam therapy include 19 cases of local recurrence, 3 cases of distant recurrence, and 5 cases of dissemination. Although there was no significant difference in time to recurrence according to the failure pattern, there was a tendency of longer survival in the local recurrence group. As for adverse events, symptomatic radiation necrosis was observed in 9 cases. The median time to onset of necrosis after radiation was 18.2 months (95%CI, 10.2–26.2). There were 8 cases of long survivors over 5 years out of 34 cases (23.5%). Of these, 6 cases developed symptomatic radiation necrosis. CONCLUSIONS Our results indicate that high dose proton beam therapy of 96.6Gy (RBE) prolonged survival in selected GBM patients. With appropriate patient selection and potent treatment for radiation necrosis, high dose proton beam therapy has a great potential to improve survival in GBM patients.

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