bluuebunny/crossref_metadata_2025 huggingface dataset:
P11.14 The addition of hyperbaric oxygen to the treatment of T98G glioblastoma cell cultures with selected CK2 inhibitor TDB enhances its anti-tumour effect
Authors: Pucko E , Ostrowski R , Zielinska M , Matyja E
Published: September 2019

BACKGROUND

Glioblastoma (GBM) is the most aggressive glial neoplasm characterized by infiltrative cell growth in adults. The current standard of care for high-grade glioma patients includes surgery, radiotherapy and chemotherapy using temozolomide and other alkylating agents. Despite this, median survival of the patients with GBM is less than two years. One of the main factors related to the progression of neoplastic cells is hyperactivity of protein kinases, including CK2 kinase and a high level of tumor hypoxia, both of which also contribute to tumour resistance to treatment. Our previous study indicated that some CK2 inhibitors exhibit anti-proliferative effect on glioma cells. The aim of this study was to examine whether HBO may enhance the anti-tumour efficacy of 1-(β-D-2’-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole (TDB) - CK2 inhibitor, under combination HBO/TDB therapy.

MATERIAL AND METHODS

Studies were performed on human glioblastoma T98G cell line (ATCC). Cells were cultured in MEM medium supplemented with 1-(β-D-2’-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole in concentrations of 0.1 μM; 1 μM, 25 μM, 50 μM, 75μM, 100 μM. Cultures were sustained in various oxygen conditions: normoxia for 24 and 48 hours or1 hour of hyperbaric oxygen (HBO, 97,5% O2/2,5% CO2, pressure of 2 ATA) followed by 23 hours of normoxia (21% O2/5% CO2/78% N2). Control groups included the cultures sustained in normoxia conditions. The viability of glioma cell lines was established at 24 and 48 hours post TDB treatment by Cell Titer 96®A Queous One Solution Cell Proliferation Assay.

RESULTS

The study evidenced that TDB inhibited the viability of neoplastic cells at a concentration of 75 μM after 24 and 48 hours. Administration of hyperbaric oxygen alone also caused a reduction in viability of glioblastoma cells. The cytotoxic effect of the tested CK2 inhibitor was significantly enhanced when tested compound was combined with HBO. What’s more, under the influence of hyperbaric oxygen, TDB significantly reduced the viability of tumor cells already at a concentration of 25 μM after 24 hours.

CONCLUSIONS

Hyperbaric oxygen administration significantly reduces the viability of T98G line cells and increases their sensitivity to the tested CK2 kinase inhibitor. The beneficial cytotoxic effect of TDB/HBO can be obtained at lower concentrations of the tested compound and after shorter exposure time as compared to its administration without HBO. Acknowledgement: The research was supported by the Foundation for the Development of Diagnostic and Therapy, Warsaw
P11.20 Assessing TTFields-response and associated gene expression in various human cancer cell lines
Authors: Kinzel A , Lavy-Shahaf G , Giladi M , Schneiderman R , Gotlib K , Zeevi E , Porat Y , Munster M , Weinberg U , Kirson E , Palti Y
Published: September 2019

BACKGROUND

Various cancer cell lines were reported to be affected in an inhibitory manner of varying magnitude by tumor treating fields (TTFields). Here, we aimed to detect response markers for TTFields treatment by analyzing specific properties of cell lines according to their response pattern to these alternating electric fields of intermediate frequency and low intensity.

MATERIAL AND METHODS

We treated 45 cell lines of diverse types of human cancer with TTFields at their specific optimal frequency and equal nominal intensity of 1.7 V/cm for 72 h. In addition to investigating cytotoxicity and clonogenic potential, we used the Cancer Cell Line Encyclopedia (CCLE) database for further analysis: First, to functionally examine patterns of differentially expressed genes or mutations associated with response to TTFields; and second, to compare sensitivity to TTFields using pharmacological profiling (CCLE).

RESULTS

TTFields had a cytotoxic effect on tested cell lines of 50 % on average (range: 14–86% reduced cell counts), whereas the clonogenic effect varied between no effect and 88 % reduction in the number of colonies. With regard to differential gene expression and mutation analysis, our analysis detected upregulated pathways associated with migration, DNA damage repair response, oxidative stress, and hypoxia. Further, cells identified as having a better response to TTFields were also more sensitive to lapatinib, PHA-665752 and PLX-4720.

CONCLUSION

In this study, we determined the optimal frequency for maximum response to TTFields in numerous human cancer cell lines. Our results argue strongly for a vast effectiveness of TTFields treatment in cancer cells, and synergistic effects in combination with other therapeutic agents might be revealed in future studies using pharmacological profiling. Beyond that, further research is needed on the role of identified response-associated mutations.
P11.34 Bone Morphogenetic Protein 4 can sensitize glioblastoma cells to temozolomide
Authors: Verploegh I , Conidi A , Lamfers M , Dirven C , Leenstra S , Huylebroeck D
Published: September 2019

BACKGROUND

Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor. Its recurrence and resistance to current therapies, i.e. temozolomide (TMZ), is thought to result from a subpopulation of cells exhibiting stem cell properties, called glioblastoma stem-like cells (GSCs). Bone Morphogenetic Protein 4 (BMP4) induces GSCs differentiation, leading to a less resistant phenotype. In this study we show that co-treatment of BMP4 with TMZ has therapeutic benefit in a subset of GBM cell lines. Furthermore, we looked for patients’ molecular signatures that could predict sensitivity to this combination treatment.

MATERIAL AND METHODS

A panel of 17 primary GBM cultures (passages 5–10) were treated with increasing concentrations of TMZ, BMP4 and TMZ + BMP4 for 5 and 7 days and cell viability has been measured. The Combination Index (CI) of the two drugs was calculated to assess the response of each line to TMZ and BMP4 treatment. DNA was used to determine the MGMT promotor methylation status and for targeted exome sequencing. Expression levels of BMP signaling components and differentiation associated genes were determined by qPCR.

RESULTS

12 cultures of primary GBMs and 5 cultures of recurrent GBMs were included. Overall, 71% of the tested cell lines was resistant to TMZ, while 41% was resistant to BMP4. Strikingly, 53% of primary cultures show synergy between TMZ and BMP4 (CI < 1 at a Fraction Affected of 50% (Fa50)). There was no significant difference in synergy between five or seven days of treatment. However, combination treatment of BMP4 and TMZ was more effective than sequential treatment.

CONCLUSION

Co-treatment of BMP4 and TMZ could be of therapeutic benefit in GBM patients, irrespective of their sensitivity to TMZ. Further research regarding the mechanism behind this synergy is necessary as to identify predictive markers for treatment response.
P11.36 Ribosome hydroxylase Mina53 is required for Glioblastoma and is involved in regulation of translation rateand fidelity by regulating ribosomal biogenesis
Authors: Pandey D , Mohammad F , Weissmann S , Hallenborg P , Blagoev B , Helin K
Published: September 2019

Glioblastoma multiforme (GBM) is one of the most aggressive types of tumors with a poor response to standard treatment and a median 5-year survival of less than 5%. Therefore, there is an urgent need for new treatments. Recently, a large number of genome-wide studies have shown that the epigenetic modifiers are frequently deregulated in cancer. Using a mouse GBM model, we performed in vitro and in vivo shRNA screens to identify epigenetic regulators required for the tumorigenic process in GBM. Among these regulators is a ribosome hydroxylase Mina53 which hydroxylates His-39 of ribosomal protein, RPL27a. We have found that the knock-down (KD) of Mina53 reduces the in vitro proliferation and colony forming ability of mouse glioma initiating cells (mGIC) and this is dependent on the catalytic activity of Mina. Knock-down of Mina resulted into a small but significant reduction in the global protein synthesis rate. A tandem affinity purification experiment to identify proteins associated with Mina revealed that it is associated mainly with ribosomal proteins, including its substrate RPL27a. Global proteomic analyses revealed that final amounts and de novo protein synthesis of many ribosomal proteins were reduced upon Mina depletion. Isolation and identification of different polysome fraction bound mRNAs using high-throughput sequencing found that mRNAs encoding many ribosomal proteins have lower number of ribosomes loaded on them in the Mina depleted samples compared to the control. Taken together, this study has found that Mina53 is required for glioblastoma and it regulates translation through regulation of ribosomal biogenesis
P11.43 Deletions on Y chromosome are associated with shorter survival in glioblastoma
Authors: Lysiak M , Malmström A , Roodakker K R , Sandberg E , Dimberg A , Mudaisi M , Bratthäll C , Strandéus M , Milos P , Hallbeck M , Smits A , Söderkvist P
Published: September 2019

BACKGROUND

Apart from few exceptions, men are more likely to be diagnosed with cancer during their lifetime, including glioblastoma (GBM), but the gender-related differences in GBM are poorly understood. Loss of chromosome Y (LOY) in peripheral blood cells is associated with physiological ageing, but also with disorders like cardiovascular disease, Alzheimer’s disease and different cancer types. In this study, we determined deletions on Y chromosome in tumor tissue of male patients with GBM, and studied the impact of LOY on survival.

MATERIAL AND METHODS

Ten genes, serving as markers, were selected on both arms of chromosome Y for copy number analysis with droplet digital PCR (ddPCR), enabling detection of loss of a marker in a fraction of the tumor cells used for DNA extraction. A total of 114 tumor samples from male patients were used, derived from a cohort of IDH wild type GBM patients treated with standard radio-chemo therapy. For 61 of these 114 patients, corresponding blood samples were available and analyzed. Different cut-off values were tested for each marker and Kaplan-Meier log-rank analysis was used to estimate overall survival. The mRNA expression for nine of the ten tested genes was available in TCGA, and 225 IDH wild type male GBM were included in a separate survival analysis, where median value of expression was used as group separator.

RESULTS

Fractional loss, as well as gain of markers was detected. Decreased copy number of the following markers was associated with significantly shorter survival; amelogenin Y-linked (AMELY) (13.5 vs. 19.3 months, p=0.017), neuroligin 4 Y-linked (NLGN4Y) (11.8 vs. 18.9 months, p=0.03) and sex determining region Y (SRY) (10.3 vs. 18.7 months, p=0.002). Additional analysis of SRY in the blood samples verified that copy number alterations were predominantly present in tumors. Survival analysis using mRNA expression data from TCGA showed that reduced expression of SRY was associated with significantly shorter OS (13.8 vs. 19.8 months, p=0.008), but no significant correlation with OS for any of the other markers.

CONCLUSION

Our data suggests a clonal or at least sporadic occurrence of fractional loss of Y chromosome markers in GBM, as detected with ddPCR. Interestingly, such dosage changes may contribute to shorter survival in men and explain some of the sex disparity seen in GBM. More research is needed to elucidate the molecular mechanisms of LOY and the role of specific Y-linked genes in GBM but also other diseases.
P11.56 Oncolytic virus and tumor microenvironment modulators an alliance to fight glioblastoma
Authors: Puigdelloses M , Martinez-Velez N , García-Moure M , Gonzalez-Huarriz M , Iñigo I , Marta A M , Gallego Perez-Larraya J
Published: September 2019

BACKGROUND

Glioblastoma is the most common and malignant brain tumour in adults with a dismal overall survival. Several works demonstrated that its tumoral microenvironment is enriched of immunosuppressive cell populations resulting in a challenge for its treatment. In this study, we propose to use an oncolytic adenovirus (Delta-24-RGD) with an inhibitor of myeloid derived suppressor cells (MDSCs; pexidartinib). Therefore, we hypothesis that we will act on two arms of the immune response: the efector arm (with the virus) and the inhibitor arm (with the Pexidartinib) resulting in a greater antitumor immune response.

MATERIAL AND METHODS

We examined the benefit in survival of the combination Delta-24ACT with pexidarnitib (MDSC inhibitor) or a complement inhibitor in C57BL/6 mice bearing the CT-2A or the GLS61-5 murine glioblastoma models orthotopically. Three viral doses (1x108 pfu/mouse) were administered at 4, 8 and 11 days post cell implantation and the tumor microenvironment immunomodulators were administered following different schedules. Survival in different treatment groups were compared using the log-rank test.

RESULTS

We observed that the combination of Delta-24-ACT and pexidartinib, led to an increase in the median survival of the treated mice when compared with single treatments (PBS=24 days, pexidartinib=24 days, Delta-24-ACT= 35 days and Delta-24-ACT+Pexidartinib= 36 days). Moreover, the treatment led to 8 long-term survivors; Pexidartinib=1, Delta-24-ACT=3 and Delta-24-ACT+Pexidartinib=4. These data underscore that the combined treatment increase significantly the number of long-term survivors. These long-term survivors were subjected to a rechalleng experiment to assess the generation of immunological memory which is currently on going. We have observed that the combined treatment increase the tumor infiltratrion of CD4, CD8 and led to a less immunosuppressive microenvironment. Immunohistochemistry of macrophages and nanostring of FFPE brain samples in order to evaluate the differences of the cell populations present in the tumoral microenvironment and their functional studies is currently on going. These experiments are being also conducted in GL261-5.

CONCLUSION

Our data suggest that the combination of the Delta-24-ACT with the capacity of activate the immune system and a drug that downregulates the immunosupression results in a survival benefit in model of gliomas and warrants further investigation.
P13.05 Chemical Biopsy as an Alternative Sampling Method in Neurooncology
Authors: Bogusiewicz J , Goryńska P Z , Jaroch K , Goryński K , Paczkowski D , Furtak J , Harat M , Bojko B
Published: September 2019

BACKGROUND

Histopathology is a gold standard for diagnostics of brain tumors but it is time consuming, demands removal of the part of the tissue what makes it highly invasive. That is why it seems to be relevant to develop new diagnostic methods addressing the abovementioned drawbacks. Ideal tool should be easy to use, as low invasive as possible and of high clinical value.

The aim of the study was to assess the usefulness of chemical biopsy based on solid phase microextraction as a sampling method for lipidomic analysis of brain tumors.

MATERIAL AND METHODS

The experiment was carried out on 38 brain tumors. Sampling was performed ex vivo, directly after removal of brain tumors. SPME fibers (coated with biocompatible extraction phase, length and diameter of the coating 7mm and 200um, respectively) were inserted into the sample without prior preparation of the tissue. Desorption of lipids was performed in isopropanol-methanol mixture. Analysis of extracts was carried out using liquid chromatography coupled to high resolution mass spectrometry.

RESULTS

Wide range of tentative lipid species was obtained in the studies. Two histologically different types of brain tumors: gliomas and meningiomas were subjected to the chemical biopsy. The results showed very good separation between the tumor types in unsupervised chemometric tests. The lipid species responsible for this separation were previously reported in the literature as cancer biomarkers. With regards to malignancy grading of gliomas the separation was notable but not as clear as between the tumor types, what is probably related to high heterogeneity of this cancerous tissue and subjectivity of histopathological analysis which were a referring point in methods comparison. Very good agreement was noted for changes in lipidome obtained by chemical biopsy and histological subtypes of gliomas. However, the most promising results showed impact of IDH1 R132H mutation on lipidome of gliomas.

CONCLUSION

Chemical biopsy seems to be useful method in lipidomics studies and for differentiation of brain tumors according their histological origin and malignancy. It also enables to find a relation between IDH1 mutation and lipidomic profile.

ACKNOWLEDGMENTS

The work was supported by the grant 2015/18/M/ST4/00059 funded by National Science Centre, Poland. The authors want to acknowledge Supelco/MilliporeSigma for the SPME probes, Thermo Fisher Scientific for the access to Q-Exactive Focus mass spectrometer, Anchem for the technical support and Shim-Pol for the access to LCMS-8060 mass spectrometer and technical support.
P14.03 Adult medulloblastoma: Influence of risk stratification and molecular subtypes on chemotherapy efficacy
Authors: Absalyamova O , Kobiakov G , Agabekyan G , Ryzhova M , Kobiakov N , Lodygina K , Poddubsky A , Korshunov A
Published: September 2019

BACKGROUND

Incidence of medulloblastoma (MB) in adults is about 1%. Optimal treatment for adult medulloblastoma has not been defined. Published datasets were acquired over a long period of time, during which there were changes in surgical technique, radiotherapy, chemotherapy regimens; often disease stage was not considered in the analyses. Recently discovered molecular subgroups are not taken into account in studies concerning treatment of medulloblastoma in adults.

MATERIAL AND METHODS

Study includes 64 patients with medulloblastoma (median age 26.5 years (15–62)), who were first admitted to Burdenko Neurosurgery Institute for surgery from 2000 to 2017. 100 % patients included in the study received radiotherapy - craniospinal irradiation, 36 Gy (20 x 1.8 Gy) with boost to primary site (2 cm around tumor bed) up to 55 Gy total dose. 41 patients (64%) received chemotherapy (ChT). Chemotherapy was started 4–6 weeks after finishing craniospinal irradiation, the regimen included cisplatin 25 mg/m2 days 1–4+etoposide 100 mg/m2 days 1–4+cyclophosphamide 600 mg/m2 days 1–4; the cycles repeating every 28 days, 6 cycles in total. Treatment volume didn’t correspond with risk group and/or molecular genetic subgroup (these parameters were determined retrospectively). Median follow-up time is 4.45 years.

RESULTS

53% patients had classic histology MB, 27% - desmoplastic, 20% - large cell/anaplastic. High risk (HR), standard risk (SR) and unspecified risk (UR) groups included 23, 16 and 25 patients respectively. Molecular subgroup testing was performed in 39 cases: SHH-activated - 59%, WNT-activated - 18%, GROUP4 - 23%. Median time to tumor progression (MTTP) in patients who received radio-chemotherapy versus radiotherapy alone was 4.3 and 2.64 years, respectively (p=0.264). The differences in MTTP were the most pronounced in SR and UR patients who received radio-chemotherapy (5.5 and 6.0 months, respectively) versus radiotherapy alone (1.5 and 2.0 months, respectively). HR patients showed the least difference in MTTP for radiotherapy (2.0 years) versus radio-chemotherapy (2.5 years), p=0.093. The SHH-subgroup patients had MTTP of 3.1 years (3.1 and 3.0 years for ChT+ and ChT-, respectively). GROUP4 patients had MTTP of 4.3 years (4.3 and 1.5 years for ChT+ and ChT-, respectively). All WNT-subgroup patients received chemotherapy, MTTP was 9.0 years. Median overall survival cannot be defined in any of the subgroups.

CONCLUSION

Chemotherapy in adult medulloblastoma patients increases MTTP in SR and UR patients. Low efficacy of chemotherapy for high risk medulloblastoma urges search for more efficacious treatment protocols. WNT-activated adult medulloblastoma has the highest MTTP among other molecular subgroups.
P14.04 10 years of weekly web conference for brain tumor of Adolescent/Young Adult (AYA) on behalf of ANOCEF, GO-AJA and SFCE societies
Authors: Frappaz D , Bronnimann C , Faure Conter C , Vauleon E , Meyronnet D , Sunyach M , Leblond P , Tanguy R , Laurence V , Bonneville-Levard A
Published: September 2019

BACKGROUND

The skills of adult versus pediatric neuro-oncologists are not completely similar though additive. Because the tumors and their protocols are different and the tolerance and expected sequelae are specific. Multidisciplinary meetings including adult and pediatric neuro oncologists are warranted to share expertise.

MATERIAL AND METHODS

Since 2008, on behalf of ANOCEF, GO-AJA and SFCE societies, a weekly national web based conference was held in France. Any patient with the following criteria could be discussed: Adolescent and Young Adults aged between 15 and 25 years, and any adult with a pediatric type pathology, including medulloblastoma, germ cell tumors, embryonic tumors, ependymoma, pilocytic astrocytoma.

RESULTS

Number of cases discussed increased from 8 to 202/year, with a mean number of 3 cases (1 to 7) discussed at each meeting. In 2018, 36 meetings were held, with a mean of 8 participants (2 to 14) issued from various French centers. 168 cases were discussed in 2018. Mean age was 30 years old (7 to 67). 45% were discussed at diagnosis; The patients had mostly medulloblastomas (n=47), ependymomas (n=24), low (n=21) or high grade gliomas (n=11), pineal tumors (n=20), germ cell tumors (n=9) and embryonal tumors (n=6). The rate of inclusion in protocols was increased since the opening of this web conference, especially for the germ cell tumor GCT SIOP protocol that is opened without age restriction, and in RSMA standard risk or MEVITEM relapse adult medulloblastoma protocols.

CONCLUSION

Multidisciplinary Web conference for AYAs is feasible and fruitful. It shares knowledge and increases the inclusion rate in protocols. It should be developped further.
P14.08 Bevacizumab treatment for the lesion emerging after the radiotherapy for malignant glioma
Authors: Miwa K , Ito T , Yokoyama K , Shinoda J
Published: September 2019

BACKGROUND

Because blocking vascular endothelial growth factor from reaching leaky capillaries is a logical strategy for the treatment, we reasoned that bevacizumab might be an eﬀective treatment on recurrent malignant glioma and radiation necrosis (RN). In this study, the authors examined to diﬀerentiate RN from recurrent malignant glioma, and evaluated the results of bevacizumab treatment in each diagnosis.

MATERIAL AND METHODS

Four patients of malignant glioma (2 glioblastomas and 2 anaplastic astrocytomas), which demonstrated symptomatic lesion after radiotherapy, were involved in this study. All four patients were treated with bevacizumab on a 10 mg/kg biweekly (one cycle), for a total dose of 30 mg/kg (3 cycles) or furthermore. RN was diﬀerentiated from local recurrence in all four patients on the basis of 11C-methionine positron emission tomography and/or clinical course. Clinical evaluation and MRI studies were obtained after bevacizumab treatment in all cases repeatedly as possible.

RESULTS

Two patients were diagnosed as RN, and another two patients as tumor recurrence. Of the two patients with RN, neurological dysfunction was distinctly alleviated after bevacizumab treatment. Other two patients with tumor recurrence demonstrated no remarkable improvement in neurological dysfunction after bevacizumab treatment. Of all the two patients with RN, post-treatment MRI performed after the bevacizumab therapy showed a significant reduction of the massive lesion.

CONCLUSION

We concluded that bevacizumab could control the symptomatic massive lesion occurring after radiotherapy, and it might be more eﬀective with the patients of RN, than with those of recurrent tumor.
P14.09 INITIAL GLOBAL SYMPTOMS IN GLIOBLASTOMA ARE OFTEN MISINTERPRETED AND ASSOCIATED WITH SHORTER SURVIVAL
Authors: Bruhn H , Dahle C , Vrethem M , Henriksson R , Lindh J
Published: September 2019

BACKGROUND

A seizure as the only symptom before diagnosing glioblastoma improves survival rate. Apart from seizures, the main presenting symptom of glioma in adults is cognitive dysfunction. The effect of generalized symptoms or loss of function on lead times and survival of glioblastoma has not been studied. Generalized symptoms include cognitive dysfunction, headache, dizziness and fatigue. Loss of function comprise paresis, sensory deficit and speech aberrations. The objective of this study was to evaluate the influence of different presenting symptoms regarding health care level, lead times and survival.

MATERIAL AND METHOD

Medical case notes regarding 189 consecutive patients with histopathologically verified glioblastoma, were reviewed for information about the date and level of care of the first medical appointment, presenting symptom/s, and date of the diagnostic radiology. The extent of surgery was noted. Data on oncologic treatment was retrieved. Summary statistics were provided for patient demographics and treatment factors. The estimates of overall survival were calculated using the Kaplan-Meier method. Survival time was calculated from the date of radiological diagnosis.

RESULTS

The majority of patients (66%) presented with generalized symptoms, which significantly reduced survival compared to not having generalized symptoms (mean survival 10.5 months vs 19.9 months, p=0.001). The most common generalized symptom was cognitive dysfunction which further reduced survival (mean survival 9.0 months, p=0.0001). Among the different cognitive aberrations, personality change and memory impairment were associated with a significantly poorer survival, (mean survival 7.9 months, p=0.015 and 8.0 months p=0.010, respectively). Disorientation also significantly reduced survival (mean survival 8.2 months p=0.001). Presenting with loss of function (58%) did not influence survival (mean survival 12.3 months). 32% of patients with an epileptic seizure as initial symptom had significantly prolonged survival compared to those not having an epileptic seizure (mean 18.9 months vs 11.0 months p=0.002). When comparing focal and secondary generalized epileptic seizures, focal epileptic seizures were more favorable. The first medical appointment was evenly distributed between primary health care and the emergency units. 8.4% of patients had multiple contacts in primary health care without being admitted to radiology or specialized care. All but one of them presented with generalized symptoms.

CONCLUSION

Glioblastoma patients presenting with generalized symptoms such as cognitive dysfunction are difficult to identify and have significantly poorer survival than other glioblastoma patients. Patients presenting with an epileptic seizure have shorter leadtime and longer survival.
P14.13 Incidence of pseudoprogression in high-grade IDH-mutant gliomas
Authors: SEYVE A , Cartalat S , Meyronet D , D’hombres A , Barritault M , Jouanneau E , Berhouma M , Guyotat J , Honnorat J , Ducray F
Published: September 2019

BACKGROUND

Pseudoprogression (PsP) is a well-known concern in IDH-wildtype glioblastomas. The aim of the present study was to describe its incidence in high-grade IDH-mutant gliomas.

MATERIAL AND METHODS

We retrospectively analyzed the characteristics of a consecutive series of high-grade IDH-mutant gliomas treated with radiotherapy (RT) with or without chemotherapy between March 2009 and September 2017. PsP was defined as a new enhanced lesion that occurred after RT and subsequently disappeared or remained stable during follow-up for a least 6 months.

RESULTS

The study population consisted of 38 anaplastic IDH-mutant and 1p/19q codeleted oligodendrogliomas, 34 IDH-mutant anaplastic astrocytomas and 18 IDH-mutant glioblastomas. Treatment consisted of radiotherapy alone (n=8, 9%), radiotherapy and PCV chemotherapy (n=63, 70%) and temozolomide radiochemotherapy (n=19, 21%). After a median follow-up of 3.5 years (range 1–8 years), 24 patients (28%) presented a PsP that occurred after a median delay of 10 months after radiotherapy (2 to 32 months). PsP was more frequent in patients treated with RT+PCV than in those treated with RT+TMZ (34% vs 10%, p=0.05). During the first two years after RT completion, 19 patients (21%) presented a PsP and 15 patients (17%) a true progression. At last follow-up, 1 patient (4%) in the PsP group had died compared to 10 patients (16%) in the group of patients without PsP.

CONCLUSION

PsP is a frequent issue in IDH-mutant high-grade gliomas. Its timing of onset is delayed compared to the timing of PsP onset reported in IDH-wildtype glioblastomas. The association between the use of PCV chemotherapy and PsP requires validation in an independent series.
P14.22 Long-term survival of treatment of HGG using PDT
Authors: Rynda A , Olyushin V , Rostovtsev D , Zabrodskaya Y
Published: September 2019

BACKGROUND

As a supplement to the adjuvant treatment of malignant gliomas of the cerebral hemispheres, the substance of the 2nd generation chlorins e6 was investigated. This study reflects the survival and size of the relapse-free period of patients in the Polenov Russian Research Institute of Neurosurgery, using the base of patients who received adjuvant PDT therapy in addition to surgical resection of the tumor.

MATERIAL AND METHODS

The analysis of 160 patients with glial brain tumors of supratentorial localization, of various degrees of malignancy, operated on in the Department Neurooncology, Polenov Russian Research Institute of Neurosurgery from 2004 to 2015. 79 patients (study group) removal of a tumor with intraoperative photodynamic therapy with a drug of the chlorin e6 group of the 2nd generation. 81 patients (control group), tumor removal without photodynamic therapy.

RESULTS

The median survival for patients with Grade III gliomas using PDT was 40.4 ± 7.4 months; in the control group (without PDT) - 23.4 ± 3.9 months (p = 0.0003). The median survival for patients with Grade IV gliomas using PDT was 21.3 ± 5.1 months; in the control group (without PDT) - 13.7 ± 3.7 months (p = 0.0002). The median duration of the disease-free period for patients in the Grade III subgroup was: in the study group, 22.5 ± 3.79 months; in the control group, 16.1 ± 3.22 months (p = 0.0002). The median duration of the disease-free period for patients in the Grade IV subgroup was 11.4 ± 2.49 months in the study group; in the control group - 8.2 ± 2.13 months (p = 0.0001).

CONCLUSION

Photodynamic therapy is a promising and safe technique that allows intraoperative action on the residual volume of tumor cells located in the perifocal zone. The use of PDT in the complex treatment of glial brain tumors allows to increase the median of survival and the recurrence-free period.
P14.23 Risk of venous thromboembolism (VTE) in grade II-IV gliomas as a function of molecular subtype
Authors: Diaz M , Jo J , Schiff D
Published: September 2019

BACKGROUND

VTE affects up to 30% of patients with glioblastoma (GBM, WHO grade IV), but little is known about its incidence in lower-grade gliomas (LGG, WHO grade II-III). It has been suggested that isocitrate dehydrogenase (IDH) mutation status dramatically decreases the incidence of VTE in glioma patients, through a combination of F3 promoter hypermethylation leading to lower expression of the procoagulant protein tissue factor, and an increased production of D-2-hydroxyglutarate, which has anticoagulant properties (Unruh et al, 2016). Our objective was to determine the incidence of VTE in LGG and stratify VTE risk by molecular subtype in gliomas grade II-IV.

MATERIAL AND METHODS

We performed a retrospective analysis of 590 glioma patients with molecular testing seen at our institution (UVa) from January 2005 to August 2017. We divided LGG patients into 3 groups: IDH-wildtype (IDHwt); IDH-mutant (IDHmt), 1p/19q-codeleted; and IDHmt, 1p/19q-intact. GBM patients were divided according to MGMT methylation status. Estimates of cumulative incidence of VTE were calculated with death as competing risk, and significance testing was determined using the Fine and Gray model.

RESULTS

Of 256 LGG patients (147 grade II and 109 grade III), 81 were IDHwt, 113 IDHmt and 1p/19q-codeleted, and 62 IDHmt and 1p/19q-intact. There were 334 GBM patients, with MGMT methylation status available in 263 (98 (37%) methylated and 165 (63%) unmethylated). With a median follow-up of 545 days, the overall incidence of VTE was 8.2% for grade II, 9.2% for grade III and 30.5% for grade IV. The 6-, 12- and 24-month VTE incidence was 4.1%, 4.8% and 5.4% respectively for grade II, 4.6%, 7.3% and 9.2% for grade III and 23.1%, 26.6% and 29% for grade IV. In LGG patients, VTE incidence was slightly higher in IDHwt tumors (11.1%) vs IDHmt, 1p/19q-codeleted (8.8%) and IDHmt, 1p/19q-intact tumors (4.8%). However, this difference was not statistically significant (IDHwt vs IDHmt, 1p/19q-codeleted, sub-distribution hazard ratio (SHR)=1.67, 95% CI=0.59–4.72; IDHwt vs IDHmt, 1p/19q-intact, SHR=1.87, 95% CI=0.54–6.53). In GBM patients, there was no difference in the VTE incidence according to MGMT methylation status (SHR=0.99, 95% CI=0.64–1.54).

CONCLUSION

In our cohort, the risk of VTE in GBM patients was consistent with historical data; patients with LGG also had a higher VTE risk compared to the general population. In contrast to other retrospective studies in which the incidence of VTE for grade II-IV IDHmt gliomas was 0% (Unruh et al, 2016; Nazari et al, 2018), our data suggest that VTEs do occur in IDHmt LGG patients, although at a lower rate than in IDHwt. MGMT methylation does not seem to influence the incidence of VTE. VTE risk stratification in GBM patients based on IDH mutation is forthcoming.
P14.24 Bevacizumab treatment in atypical disseminated choroid plexus papilloma in adult patients
Authors: Colò F , Larrouquere L , Rivoirard R , Loiseau H , Lortholary A , Mervoyer A , Catry-Thomas I , Frappaz D
Published: September 2019

BACKGROUND

Choroid plexus tumours represent less than 1% of brain tumours. Low-grade papilloma may be treated with gross total surgical resection, while in disseminated progressive atypical choroid plexus papilloma (APP), there is no standard treatment: various chemotherapy regimens have been reported. Since this tumour is characterized by a rich vascular component, antiangiogenic therapy is an attractive treatment. The use of Bevacizumab has already been reported in three patients. Authors expand this experience with 5 further patients diagnosed with progressive APP treated with bevacizumab.

MATERIAL AND METHODS

Patients were recruited through the weekly Adolescent Young Adult French web conference. They have been treated with bevacizumab 10 mg/kg by intravenous injection each 2 to 3 weeks. Their clinical status and radiological response are reported: Karnofsky Index (KI), Pain Scale (PS) and RANO criteria were used.

RESULTS

All our patients had a progressive disease prior to bevacizumab. Pt 1: 41 years old; APP with cranio-spinal dissemination; Previous treatments: local and cranio-spinal irradiation in 2012 and in 2014; surgery: complete and partial resection in 2010, 2014, and VP shunt in 2018; Bevacizumab: total of 33 cures in 18 months. Result: radiological and clinical stabilization. Pt 2: 58 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: VP shunt and gross total resection, in 2006; VP shunt, in 2011. Bevacizumab: total of 4 cures, in 2 months. Result: radiological and clinical stabilization. Pt 3: 34 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: gross total resection, in 1992, and shunt in 2008. Bevacizumab: total of 21 cures, in 21 months. Result: radiological and clinical stabilization. Pt 4: 63 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: surgical resection and VP shunt in 2013; chemotherapy: temozolomide. Bevacizumab: 29 months (still treated). Result: radiological and clinical stabilization. Pt 5: 62 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: gross total resection in 1999 and VP shunt in 2009; chemotherapy: Carboplatin Vespesid. Bevacizumab: 23 cures, in 14 months. Result: radiological stabilization and clinical amelioration.

CONCLUSION

Despite their previous worsening disease, all patients obtained a stabilization or amelioration of their IK and PS under bevacizumab. Bevacizumab should be evaluated in a multicentric trial as standard therapy for disseminated metastasized progressive choroid plexus tumours.
P14.26 Autoimmune disease-associated primary CNS lymphoma: Meta-analysis and review of literature
Authors: Kaulen L D , Baehring J M
Published: September 2019

BACKGROUND

Recent studies suggest a relatively high prevalence of autoimmune diseases (AD) among primary CNS lymphoma (PCNSL) patients, however the literature is limited to case reports. To gain a better understanding of AD-associated PCNSL we reviewed all previous cases described in the literature.

MATERIAL AND METHODS

We mined the MEDLINE database using the search terms ‘central nervous system lymphoma’ or ‘CNS lymphoma’ along with AD-related terms, such as ‘immunosuppression’, ‘autoimmune’, the name of various AD, or commonly prescribed immunosuppressants. We selected 35 records for qualitative synthesis of data. We identified 43 AD-associated PCNSL in the literature and added five unpublished cases from our institution. Clinical, imaging and outcome data were collected.

RESULTS

Most prevalent ADs were systemic lupus erythematosus (22.9%), multiple sclerosis (18.8%) and myasthenia gravis (14.6%). Male-to-female ratio was 1:2 and median age at diagnosis was 57 years (range: 2.5–88). Most common immunosuppressants included prednisone (58.7%), mycophenolate (43.5%), and azathioprine (41.3%). Median interval from diagnosis of AD until diagnosis of PCNSL was 96 months (range: 11–360). Lesions typically localized to the hemispheres (64.1%) and displayed peripheral contrast enhancement (75.8%). Histology revealed diffuse large-B-cell lymphomas (76.7%) and Epstein-Barr virus (EBV) positivity (78.4%). Treatment included reduction of immunosuppression (100%) and chemotherapy (85.4%) in most cases. Median overall survival was 31 months.

CONCLUSION

AD-associated PCNSL are characterized by peripheral contrast enhancement on imaging and EBV positivity. AD that require severe immunosuppression appear over-represented. Median interval of immunosuppression and overall survival seem longer than in other immunodeficiency-associated PCNSL.
P14.36 Treatment patterns by O6-methylguanine DNA methyltransferase promoter (MGMT) status in newly-diagnosed glioblastoma multiforme (GBM): a multi-country chart review study
Authors: Fu A Z , Thompson G J , Hall J P , Bailey A , Kemp J , Lee C
Published: September 2019

INTRODUCTION

This study explored the relationship between MGMT testing and treatment patterns of patients with newly-diagnosed GBM from France, Germany, Italy, Spain, the UK (EU5), and Canada.

MATERIALS AND METHODS

Medical oncologists and neuro-oncologists across EU5 and Canada completed a point in time, cross-sectional survey for the next eight GBM patients seen between May and July 2016 (GBM Disease-specific ProgrammeTM). Statistically significant differences (p<0.05) between groups are presented.

RESULTS

A total of 241 physicians reported on 1,747 GBM patients. 1L patients had mean age 59.7 years (SD=12.3) and 36% were female. Of 1,113 (64%) patients who had an MGMT test performed with results recorded (tested), 58% (n=651) were methylated and 42% (n=462) were unmethylated. The remaining 634 patients (36%) were MGMT untested or awaiting MGMT results at time of survey (untested). Overall, 63% of patients received surgery prior to their 1L drug therapy, 78% received radiotherapy (RT; mean 4.3 sessions) in conjunction with 1L drug therapy, 90% received corticosteroids during RT, and 89% received temozolomide (TMZ). Patients who received corticosteroids during RT received similar drug treatments to those that did not, but were less likely to receive surgery prior to 1L treatment (65% vs 83%). MGMT-tested patients were more likely to receive surgery (66% vs 57%) and RT (81% vs 71%) than untested patients. Tested patients were also more likely to receive TMZ (92% vs 83%), and less likely to receive procarbazine+/lomustine+/vincristine (PCV; 3% vs 7%) or other chemotherapies (5% vs 11%). For 1L patients that experienced side effects, the most common effects included fatigue (74%), nausea (60%), and appetite loss (59%). Untested patients were more likely to stop their 1L drug treatment due to progression/recurrence of GBM (44% vs 36%). Patients who received surgery prior to 1L treatment were more likely to receive TMZ than those who did not (93% vs 82%). Among MGMT tested patients at 1L, methylated patients were more likely to receive RT (84% vs 78%) and TMZ (95% vs 89%) than unmethylated patients, and less likely to receive PCV (2% vs 5%) or other chemotherapy (4% vs 7%). Methylated patients with reported treatment-related side effects were less likely to experience dehydration (0% vs 10%), loss of strength/unusual weakness (5% vs 25%), memory problems (16% vs 35%), and nausea (51% vs 75%).

CONCLUSIONS

More than one-third of GBM patients in EU5 and Canada are not tested for MGMT-methylation. Untested patients are less likely to receive standard treatments than tested patients. Generally, TMZ is used in most patients regardless of MGMT testing and status. MGMT-methylated patients are more likely to receive standard treatments and experience fewer side effects than MGMT-unmethylated patients.
P14.44 Survival benefit of lobectomy over gross-total resection without lobectomy in cases of glioblastoma in the noneloquent area: a retrospective study
Authors: Roh T , Kang S , Hong C , Chang J
Published: September 2019

BACKGROUND

Following resection of glioblastoma (GBM), microscopic remnants of the GBM tumor remaining in nearby tissue cause tumor recurrence more often than for other tumors, even after gross-total resection (GTR). Although surgical oncologists traditionally resect some of the surrounding normal tissue, whether further removal of nearby tissue may improve survival in GBM patients is unknown. In this single-center retrospective study, the authors assessed whether lobectomy confers a survival benefit over GTR without lobectomy when treating GBMs in the noneloquent area.

MATERIAL AND METHODS

The authors selected 40 patients who had undergone GTR of a histopathologically diagnosed isocitrate dehydrogenase (IDH)-wild type GBM in the right frontal or temporal lobe and divided the patients into 2 groups according to whether GTR of the tumor involved lobectomy, defined as a supratotal resection (SupTR group, n = 20) or did not (GTR group, n = 20). Progression-free survival (PFS), overall survival (OS), and Karnofsky Performance Status (KPS) scores were compared between groups (p ≤ 0.05 for statistically significant differences).

RESULTS

The median postoperative PFS times for each group were as follows: GTR group, 11.5 months (95% CI 8.8–14.2) and SupTR group, 30.7 months (95% CI 4.3–57.1; p = 0.007). The median postoperative OS times for each group were as follows: GTR group, 18.7 months (95% CI 14.3–23.1) and SupTR group, 44.1 months (95% CI 25.1–63.1; p = 0.040). The mean postoperative KPS scores (GTR, 76.5; SupTR, 77.5; p = 0.904) were not significantly different. In multivariate analysis, survival for the SupTR group was significantly longer than that for the GTR group in terms of both PFS (HR 0.230; 95% CI 0.090–0.583; p = 0.002) and OS (HR 0.247; 95% CI 0.086–0.704; p = 0.009).

CONCLUSION

In cases of completely resectable, noneloquent area GBMs, SupTR provides superior PFS and OS without negatively impacting patient performance.
P14.49 Primary central nervous system lymphoma presenting as dementia: do not forget IL10 in CSF analysis
Authors: Blain A , Brinet A , Berthel M , Camoyret A , Gaultier C , Droy-Dupré L , Oesterlé H , Hurstel R , Debliquis A , Costopoulos M , Le Garff-Tavernier M , Sellal F , Ahle G
Published: September 2019

BACKGROUND

Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma that aﬀects the central nervous system without systemic involvement. Clinical presentation depends on its localization: Focal deficits usually lead to prompt neuroradiologic evaluation, whereas cognitive or behavioral changes can lead to diagnostic delay. Rapidly progressive dementia (RPD), defined as a 1- to 2-year course from symptom onset to cognitive and functional debilitation, is a clinical presentation of PCNSL and thus a potentially curable cause of dementia, leading to death if it remains untreated. Nevertheless, its diagnosis is frequently delayed as other origins (CJD, autoimmune, paraneoplastic, infectious, and neurodegenerative disorders) are more frequently considered. We aimed to describe diagnostic features and treatment modalities in a series of patients presenting with RPD diagnosed as PCNSL.

METHODS

Patients with RPD and final diagnosis of PCNSL were retrospectively identified from 2012 to 2019 from the database of our academic teaching hospital. Clinical presentation, neuroimaging, and cerebro-spinal fluid (CSF) analysis were assessed from their medical records. Interleukin (IL) 10 and 6 concentrations were measured by flow cytometry using the cytometric bead array (CBA) technique (BD Biosciences) with a detection limit set at 2.5 pg/ml.

RESULTS

50 patients with diagnosis of PCNSL were identified, 7 (3 women, 4 men) presented with RPD.Median age was 69 years (range 59–84). Time from symptom onset to diagnostic confirmation of PCNSL ranged from 1–12 months (median 3). All patients presented with cognitive impairment (disorientation, memory disorders), accompanied by psycho-behavioral disorders in 6 of them. MRI disclosed enhancing lesions in all patients. Lumbar puncture was performed in 5 patients. All of them presented pleiocytosis, and lymphomatous meningitis was detected in 4/5 of them by cytology or flow cytometry (FCM). Elevated interleukin 10 (IL-10) was found in all patients with available CSF sample, 4 of them had an IL-10/IL-6 ratio >1.

DISCUSSION AND CONCLUSION

Patients presenting with rapidly progressive dementia should be evaluated for treatable forms of dementia. PCSNL has to be considered as soon as possible as diagnostic delay impacts its outcome. Imaging studies, usually contrast-enhanced MRI, is recommended, although nonspecific findings are not uncommon, especially in case of non-enhancing lesions. CSF sampling can help to prove diagnosis of PCNSL by cytology (generally associated with FCM), but it requires an experienced cytologist and immediate sample analysis.IL10 and IL10/6 ratio can be used as a more easily available marker to support suspicion of PNSCL, leading to further specific workup.

ACKNOWLEDGMENTS

NENO & LOC Network