bluuebunny/crossref_metadata_2025 huggingface dataset:
P09.09.A RESECTION CAVITY LOCATIONS ASSOCIATED WITH CHANGES IN DEPRESSIVE SYMPTOMS AFTER SURGERY IN PATIENTS WITH DIFFUSE GLIOMA
Authors: Belgers* V , van Genderen* M N G , Cakmak M , Douw L , Barkhof F , Klein M , Niers J M , Eijgelaar R S , De Witt Hamer P C
Published: September 2023

BACKGROUND

The aim of glioma resections is to maximize tumor removal while preserving functional integrity. Functional outcome usually focuses on neurological and neurocognitive functions. However, emotions may also be affected by surgery. Therefore, we determined the occurrence of depressive symptoms after surgery and investigated factors associated with changes in depressive symptoms after surgery, specifically focusing on the location of the resection cavity.

MATERIAL AND METHODS

This study included a single center retrospective cohort of patients with a diffuse glioma who underwent a surgical resection between 2009 and 2021. Patients completed the Center for Epidemiologic Studies Depression Scale (CES-D) before and after surgery, with cut-offs for no depressive symptoms (CES-D <16), mild depressive symptoms (CES-D 16-20) or moderate to severe depressive symptoms (CES-D >20). We calculated a change score with a minimum clinically important difference defined as 6 points. Surgical cavities were semi-automatically segmented based on postoperative MRIs. Patient characteristics, i.e. age, sex, education, epilepsy, and tumor characteristics, including tumor grade, and segmented cavity locations, were related to change in depression scores in a multivariable regression analysis and sparse canonical correlation analysis.

RESULTS

We included 83 patients with a mean age of 42 years (SD 11.8), consisting of 61% males, 49% with high education, 86% with epilepsy and 61% with a WHO grade 2 glioma, 27% grade 3 and 12% grade 4 glioma. Median change in depressive scores was 1, with a range from -25 to 30. Before surgery, 26% had at least mild depressive symptoms, after surgery, 33% had at least mild depressive symptoms. A clinically important increase (≥6) in depressive symptoms was seen in 25% of patients, whereas 15% had a clinically important decrease in depressive symptoms. Patient characteristics and tumor grade were not associated with change in depressive symptoms. Eight clusters of cavity locations were associated with change in depressive symptoms (CV corr = 0.224, p = 0.0419), including in the left and right frontal, temporal, and anterior cingulate regions.

CONCLUSION

Resection cavity locations are associated with changes in depressive symptoms in patients with diffuse glioma. This may be important for patient counseling and of potential use for neurosurgical decision making.

* These authors contributed equally
P09.11.A INDICATIONS AND OUTCOMES OF NERVE RECONSTRUCTIONS AFTER RESECTION OF EXTREMITY TUMORS: A SYSTEMATIC REVIEW
Authors: Schuitema B , Jansma C Y M , Martin E , Coert J H
Published: September 2023

AIMS

Peripheral nerve injuries resulting from tumor resection are unusual, but occasionally unavoidable. It can result in serious morbidity in motor deficits, sensory deficits, and even chronic pain. Nerve reconstruction after tumor resection is possible but rarely performed and outcomes are unclear. This study creates an overview of the indications and outcomes for nerve reconstructions after tumor resections.

METHODS

A systematic review was performed in March 2022 in PubMed and Embase according to the PRISMA guidelines. Search terms related to “tumor” and “nerve reconstruction” were used. Studies evaluating nerve reconstructions (nerve graft, transfer or coaptation) after tumor resection in extremities were included. A qualitative synthesis was performed on all studies. Patients with accurate description of their functional abilities were assigned to minimum grade on the MRC-scale.

RESULTS

Fifty-nine articles were included for quality synthesis after full text screening. A total of 84 patients were described of which 40 after resection of malignant tumors. Most patients improved in motor and sensory function after nerve reconstruction. In patients with benign tumors, 79% demonstrated functional recovery on the Medical Research Council (MRC) scale of ≥3, while 77% of patients with malignant tumors showed the same level of recovery. Most patients, 85%, recovered to a protective sensation of S2 or higher.

CONCLUSION

Nerve reconstruction after tumor resection can help recover both sensory and motor function. It should be considered in tumor surgery with chance of resection or damage to a nerve.
P10.02.B THE PSYCHOTROPIC AGENT THIORIDAZINE IMPEDES MELANOMA BRAIN METASTASIS CELL ACTIVITY THROUGH INHIBITION OF AUTOPHAGY
Authors: Moen Taule E , Wikerholmen T , Sarnow K , Rigg E , Feginn Berle B , Sundstrøm T , Wang J , Thorsen F
Published: September 2023

BACKGROUND

Neural tissue and melanocytes share the same germ layer in early embryonic development. It is then perhaps not by coincidence that melanoma is one of the most common cancer types to metastasize to the brain. With aggressive treatment the median survival of melanoma brain metastases (MBM) is now estimated to be approximately 13 months. Targeted therapies and immunotherapy have armed us with new systemic weapons and shown great responses, but unfortunately most of these patient relapse. Drug repurposing, using old drugs for new purposes, has had several successes for other diseases. The anti-psychotic drug thioridazine (THD), a dopamine receptor 2 antagonist, with properties to cross an intact blood brain barrier, has earlier shown promising effects on melanoma cells that escaped prior treatment and on cancer stem cells. However, the therapeutic effects on MBM have not been previously investigated.

MATERIAL AND METHODS

We used three BRAF V600E (H1, H2 and H10) and one L577F mutated patient derived MBM cell lines (H3) developed in our lab in our experiments. A monolayer viability assay (WST-1) was utilized to determine IC50 doses. Migrational and proliferational effects of THD was studied by IncuCyte live cell imaging. Colony forming properties and the ability of cells to grow in an anchorage independent environment after THD treatment was investigated using a 2D clonogenic assay and a 3D soft agar model. A potential therapeutic window was assessed through normal human astrocytes (NHA) and fetal rat brain organoids (FRBO). Apoptosis and necrosis were studied by Annexin V/propidium iodide (PI) double staining followed by flow cytometric analysis after 72 hours of treatment. Western blots after THD treatment was done to elucidate underlying molecular mechanisms.

RESULTS

Cell viability studies showed that THD exerted a dose-dependent inhibition of tumor cell viability (IC50 doses between 9-12 µM), while NHA tolerated similar drug concentrations. Tumor cell migration and proliferation were almost completely inhibited with concentrations below the IC50 doses. An inhibition of clonogenic formation and 3D growth was also observed. Bright field microscopy showed changes in MBM morphology in monolayers, but FRBOs were intact after drug treatment. Apoptosis in MBM cells was induced after treatment with THD through PARP/cleaved caspase 3/Bcl-2. Expression levels of LC3B-II and p62 were significant increase in treated cells, indicating inhibition of autophagic flux at a late stage.

CONCLUSION

Our data shows that THD has a strong selective cytotoxicity in MBM cells through inhibition of autophagic flux, with a minimal effect on NHA and FBRO.
P10.03.A ANTIPSYCHOTICS TO TREAT BRAIN TUMORS: DRUG REPURPOSING TO BYPASS THE BLOOD BRAIN BARRIER
Authors: Wikerholmen T , Taule E M , Rigg E , Sættem M , Sarnow K , Hoang T , Saed H S , Sundstrøm T , Thorsen F A
Published: September 2023

BACKGROUND

Approximately half of late-stage melanoma patients develop brain metastases (BM), once metastasized to the brain, survival is generally measured in months. Current treatments, although increasingly effective, are not sufficient for this patient group, necessitating development of new therapeutic options. Drugs targeting BM specifically are a scarcity. To broaden therapeutic options, drug repurposing, i.e. novel uses of drugs already approved for other medical conditions, may prove to be a valuable asset. By design, antipsychotics effectively cross an intact blood-brain barrier. Interestingly, although carrying an increased burden of comorbidity, the schizophrenic population has a similar incidence of cancer when compared to the normal population. Hypotheses regarding the antitumor effect of antipsychotics have therefore been postulated along with several other theories that seek to explain these seemingly contradictory incidence rates. We currently present preliminary data showing that clozapine, a second-generation antipsychotic, effectively inhibits growth of human melanoma brain metastasis (MBM) cell lines in vitro. Objective: To explore the potential of antipsychotics in treating MBM.

METHODS

Cell cultures including H1, H2, H3 MBM cell lines, as well as normal human astrocytes (NHA) were selected for our experiments. Monolayer, 3D, and IncuCyte viability experiments were performed to determine IC50 doses. FBRO, fetal rat brain organoids were used to study clozapine’s effect on the normal brain environment. Cell migration was measured by scratch wound assays. Apoptosis was studied by flow cytometry. Colony formation assays were performed using 2D clonogenic assays. A protein array was used to find signaling proteins potentially affected by clozapine, which where verified by western blots.

RESULTS

A viability screening using 6 different neuroleptics showed that clozapine was most effective in inhibiting MBM cell viability, with a favorable therapeutic window to astrocytes. Doses significantly above MBM IC50 doses did not affect viability of brain organoids. MBM cells exhibited a dose-dependent inhibition of cell proliferation, migration, and clonogenic formation. Flow cytometry demonstrated that apoptosis was a major mechanism of cytotoxicity. The protein array showed that CCL3, IL8 and VEGF were downstream targets of clozapine. These results were confirmed by western blots. A partnership with the Dept. of Chemistry (UiB) has resulted in the development and testing of several novel clozapine derivates to reduce therapeutic doses and hopefully minimize potential side effects.

CONCLUSION

Clozapine shows proof of concept in treating BM with antipsychotics and should be explored further as an adjuvant treatment for melanoma patients at risk of developing brain metastasis.
P10.21.A THE ABCB1/ABCG2 INHIBITOR ELACRIDAR IS A MORE POTENT PHARMACOENHANCER COMPARED TO TARIQUIDAR FOR TREATMENT OF INTRACRANIAL TUMORS WITH SMALL MOLECULE DRUGS
Authors: Lentzas A , de Gooijer M C , Zuidema S , Çitirikkaya C H , Venekamp N , Beijnen J H , van Tellingen O
Published: September 2023

BACKGROUND

The blood-brain barrier (BBB) is a major hurdle to successful pharmacotherapy of brain tumors. ABCB1 and ABCG2 are efflux transporters that are expressed in brain tumor vessels and reduce the uptake of many small molecule drugs. Elacridar and tariquidar are both dual ABCB1 and ABCG2 inhibitors. We aim to improve pharmacotherapy of brain cancer by concomitant use of potentially effective drugs with elacridar. Since tariquidar has mostly been used to assess the effects of ABC-transporters on brain uptake in human studies with PET tracers, we decided to compare both agents in our rodent models.

MATERIAL AND METHODS

We used Abcg2;Abcb1a/b double knockout (DKO), Abcb1a/b KO, Abcg2 KO and wild-type mice receiving a cocktail of 7 model drugs at a fixed low dose in combination with elacridar or tariquidar at a range of doses. Drugs were given by 3-h infusion. DKO mice are the reference for complete inhibition, while single KO mice allow interrogation of the remaining transporter in case of dual substrate drugs. Brain and plasma levels were measured by LC-MS/MS.

RESULTS

Complete inhibition of Abcb1 by elacridar was achieved when the plasma level is about 1.0 μM. However, a much higher plasma level (>4 μM) of tariquidar was needed. Inhibition of Abcg2 was more difficult. For erlotinib and palbociclib about 1.0 μM of elacridar was sufficient, but other more profound Abcg2 substrate drugs never reached the B/P ratios achieved in reference to DKO mice, even at 4 μM. Strikingly, tariquidar could not enhance the brain uptake of ABCG2-subtrate drugs in Abcb1a/b KO mice. The B/P ratio of elacridar in DKO mice was 6. Elacridar improved its own brain distribution in WT mice, achieving steady-state B/P ratios at plasma level above 1.4 μM. The B/P ratio of tariquidar in DKO mice was about 2, while in WT and Abcb1a/b KO mice was 0.3 and did not increase even at plasma concentration >8 μM. Only in Abcg2 KO mice, the B/P ratio increased to levels of DKO mice at tariquidar plasma levels of > 6 μM.

CONCLUSION

Elacridar is a much more potent inhibitor of Abcb1a/b and Abcg2 at the BBB. Elacridar can act as a pharmaco-enhancer of ABCB1 substrate drugs and weaker ABCG2 substrates. Tariquidar will enhance the brain penetration of ABCB1 substrates, but full inhibition is only achieved at levels above those reported in human subjects. The efflux of tariquidar by Abcg2 at the BBB severely compromises the usefulness of tariquidar as a pharmaco-enhancer for brain delivery.
P10.28.B INTERMODEL VARIATION OF BBB PERMEABILITY AFFECTS CNS DRUG DELIVERY IN PDX MODELS OF GBM
Authors: Ntafoulis I , Koolen S L W , den Hollander C W J , Goedknegt E , Haeck J , Kers T V , Dijkhuizen S , van Dis V , van den Bosch T P P , Gao Z , Mezzanotte L , van Tellingen O , Dirven C M F , Leenstra S , Lamfers M L M
Published: September 2023

BACKGROUND

Little progress has been made in the development of effective new therapies for glioblastoma (GBM) the past decades. One of the major obstacles in identifying novel candidate drugs against GBM remains the blood-brain barrier (BBB) and the efflux transporters. Therefore, it is crucial to select drugs able to cross BBB and reach the tumor tissue in therapeutically effective concentrations. In current study, we evaluated the anti-glioma effect of the protein synthesis inhibitor omacetaxine mepesuccinate (OMA) in vitro and its CNS penetrating properties in vivo.

MATERIAL AND METHODS

The FDA-approved Oncology Drug Set II library was tested on 55 patient-derived GBM cell cultures. We designed a drug shortlisting pipeline combining efficacy data with pharmacodynamic and pharmacokinetic characteristics of each compound. We developed and characterized 3 orthotopic mouse PDX models in terms of brain vascular integrity, BBB permeability and expression of ABC transporters. The PK profile of omacetaxine was assessed in these orthotopic mouse PDX models.

RESULTS

In vitro, OMA revealed anti-tumor activity at IC50 values well-below reported Cmax plasma value (Cmax=43nM) in approximately 80% of GBM cultures. Unexpectedly, OMA does not downregulate the expression of its acknowledged target, ribosomal protein 3 (RPL3). In glioma cells while activation of caspase 3/7 activity is linked to its anti-tumor effect. OMA is a substrate for ABCB1 (P-glycoprotein) but not for ABCG2 (BCRP). In vivo, dose escalation showed safety of the drug and OMA was found to reach the brain tumor tissue in concentrations similar or higher to the reported IC50 values in vitro, depending on the PDX model used. No adverse reactions were noted.

CONCLUSION

OMA is a CNS penetrant drug that reaches the brain tumor tissue in all tested concentrations. The inter-model variation in accumulation of OMA is associated to the extent of BBB disruption of each PDX model. Additional in vivo experiments are ongoing to investigate the therapeutic effect of OMA and longer exposure using in vivo models.
P10.31.A OSIMERTINIB AND OTX008 IMPAIR SURVIVAL OF GLIOBLASTOMA CELLS BY INHIBITING RAS
Authors: Barthelmay M , Goett H , Kolodziej M , Stein M , Uhl E
Published: September 2023

BACKGROUND

Tyrosine kinase receptors play a critical role in the progression of almost all malignancies. In 83% of glioblastoma the endothelial growth factor receptor (EGFR) is affected by genetic alterations leading to cell proliferation and therapy resistance. This leads to a constitutive activation of EGFR, following the activation of the PI3K/AKT and RAS/MAPK signalling pathways. The EGFR-inhibitor Osimertinib showed anti-tumor effect in lung cancer patients with cerebral metastasis. OTX008 is a selective inhibitor of Galectin-1, a small protein, which is involved in stabilising the active form of H-Ras and thereby enables the downstream PI3K/AKT and RAS/MAPK pathways. This study was performed to investigate whether OTX008, Osimertinib and a combination of both have an antiproliferative effect and inhibit the Ras downstream signalling pathways in glioblastoma cells.

MATERIAL AND METHODS

U87 and A172 glioblastoma cells were grown to 80% confluence and treated with Osimertinib in concentrations ranging from 3 μM to 7 μM. After 72 hours cell viability was quantified via XTT-assay. Dose-response curves were calculated by probit analysis. For investigation of the inhibitory effect of OTX008 and Osimertinib on the constitutive activation of Ras U87 cells were treated with 15 μM OTX008, 3 μM Osimertinib, a combination of 15 μM OTX008 and 3 μM Osimertinib and a combination of DMSO and hydrochloricacid. After 72 hours the cells were collected and lysed using Active Ras Detection Kit from Cell Signaling Technology for western blot analysis.

RESULTS

Osimertinib reduced cell survival in all tested glioblastoma cell lines with a mean ED50 of 6.81 (95%CI: 6.75-6.86) μM. Using western blot analysis to evaluate the effect on the effector protein Ras at the beginning of the PI3K/AKT and RAS/MAPK pathways the effect of OTX008 and Osimertinib on the proliferation of glioblastoma cell line U87 was shown with the inhibition of Ras.

CONCLUSION

The constitutive activation of the PI3K/Akt and RAS/MAPK pathways is associated with uncontrolled cell growth and therapeutic resistance. The EGFR-inhibitor Osimertinib and the selective Galectin-1 inhibitor OTX008 showed antiproliferative effect in immortalized glioblastoma cell line U87 and were also able to inhibit activation of Ras. Future experiments should focus on the downstream signalling of the pathways, especially in EGFR mutated glioblastoma stem cells.
P11.02.B DO GENOMIC ALTERATIONS INFLUENCE THE DEVELOPMENT OF BRAIN METASTASES IN ADVANCED AND METASTATIC NON-SMALL CELL LUNG CANCER?
Authors: Gillespie C S , Mustafa M A , Richardson G E , Alam A M , Lee K S , Hughes D M , Escriu C , Zakaria R
Published: September 2023

BACKGROUND

Lung cancer is the most common cause of cancer deaths worldwide. Development of brain metastases (BM) in patients with advanced (Stage III) and metastatic (Stage IV) non-small cell lung cancer (NSCLC) is linked with poor prognosis. Identifying mutations associated with BM development could influence screening and determine targeted treatment paradigms. We aimed to establish BM prevalence and incidence in patients with advanced and metastatic NSCLC, stratified by genomic alterations.

MATERIAL AND METHODS

A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines (PROSPERO ID CRD42022315915). Three databases were searched, and articles published between January 2000-May 2022 included (Search date 30th April 2022). Prevalence at diagnosis, and incidence of new BM per year were obtained, including patients with EGFR, ALK, KRAS, ROS1, RET, MET, and other genomic alterations. Pooled incidence rates were calculated using random effects models.

RESULTS

Of 960 articles identified, 65 were included in the study (24,784 patients). Pooled BM prevalence at diagnosis was 28.6% (45 studies, 95% Confidence Interval [CI] 26.1-31.0), and highest in patients with ALK (34.9%) and RET translocations (32.2%). With a median follow-up of 24 months, the per-year incidence of new BM was 12.5% in the wild-type group (14 studies, 95% CI 10.9-15.9). Incidence in the subgroups with different genomic alterations was 15.6% in the EGFR group (16 studies, 95% CI 11.4-21.2), 17.0% in the ALK group (6 studies, 95% CI 11.3-25.8), 9.8% in the KRAS group (4 studies, 95% CI 5.5-17.5), 12.5% in the ROS1 group (3 studies, 95% CI 5.7-27.6), and 11.8% in the RET group (2 studies, 95% CI 8.0-17.5). At the end of the follow-up period, a median of 55.0% of patients had BM (IQR 44.2-67.8).

CONCLUSION

This is the first study to show prevalence, and incidence of BM development in advanced and metastatic NSCLC, stratified by genomic alterations. Our data indicates a higher prevalence and incidence of BM in patients with targetable genomic alterations. This supports brain imaging at staging and follow-up, underlining the need for NSCLC therapies with brain penetrance and efficacy.
P11.18.B AIMING TOWARDS DIFFERENTIATING GLIOBLASTOMA PROGRESSION FROM PSEUDO PROGRESSION -PATIENTS COHORT ESTABLISHMENT AND PRELIMINARY RESULTS
Authors: Haisraely O , Taliansky A , Kaisman elbaz T , Abofani H , Siddeeq M
Published: September 2023

BACKGROUND

Longitudinal follow-up of glioblastoma patients includes advanced imaging modalities to identify tumor progression, which is of limited certainty and occasionally necessitates additional tissue sampling that has potential morbidity. Lately, the possibility of tumor-associated protein markers detection in patients' blood samples - liquid biopsies - has shown useful for this purpose in other cancers and has also gained significant interest in glioblastoma.

METHODS

This study presents data collected from 36histopathology-confirmed IDH-WT glioblastoma patientstreated in Sheba Medical Center between the years 2009 to 2021. Following their diagnosis, these patients were treated with radiation according to the Stupp protocol and subjected to repeated resection due to suspected tumor progressionbased on imaging studies. The data retrieved from patients' medical files include demographics, clinical outcomes, imaging characteristics, tumor molecular, andhistopathological markers. Notably, patients' selection and data retrieval were accomplished using a novel institutional AI algorithm software followed by complementary manual data retrieval of selected patients' medical files.

RESULTS

Patients demographics analysis showed that patientmedian age-at-diagnosis was 55.4 years (range, 21-82), and the male-to-female ratio was 3.5:1. The median overall survival (OS) was 25.1 months (range, 5.2-80.3) and the median follow-up duration was 23.1 months (range, 4.8-80.2).27 out of 36 patients had pathologically confirmed tumor progression while the remaining patients had post-radiation changes along with viable tumor or merely radiation necrosis identification. Pre-surgical resection blood samples were available for 27 out of 37 patients and will be used for a comprehensive glioblastoma-related proteins search using mass spectroscopy. In cases of patients' blood samples available both from the initial diagnosis surgical resection procedure and tumor progression surgical resection, a comparative analysis of those samples will be performed. The preliminary proteomics analysis and clinical outcomes measurements and volumetric tumor data will be presented.

CONCLUSION

s: Here, we present a glioblastoma patient cohort that was meticulously selected with the aim to examine our hypothesis that measuring glioblastoma-related proteins in patients' blood can be achieved and serve as a tool to distinguish between disease phases and monitor disease progression. Our comprehensive preliminary clinical, as well as proteomics data analysis, will be presented and discussed.
P11.30.A LONG-TERM SURVIVING GLIOBLASTOMA. CLINICAL, MOLECULAR AND SURVIVAL ANALYSES
Authors: Comas Antón S , Moreno S , Antelo M , Carrato C , Balaña C , Castañer S , Hernández A , Hostalot C , Domenech M , Villà S
Published: September 2023

BACKGROUND

Glioblastoma (GB) has a poor prognosis with median overall survival of 12-14 months. According to literature, patients surviving more than two years has progressively increased since 2005 and represent approximately 18% of this population, being considered long-term survivors (LTS). The aim of this study is to retrospectively analyze GB LTS treated in our Neurooncology Unit.

MATERIAL AND METHODS

From December 2009 to March 2021, 49 GB LTS patients were identified in our oncology data base, representing 21,7% of GB patients electronically registered during the same period. Patients were diagnosed and treated for GB according to the current WHO CNS classification at the time of diagnosis. Clinical and molecular characteristics as well as treatment and survival data were analyzed. Classic prognostic factors were analyzed including contact with the subventricular zone (SVZ) which has been identified as prognostic factor in some previous studies.

RESULTS

Median age at diagnosis was 57 years (range: 30-75 years). Median overall survival (OS) and median time to first progression were 43.6 months and 20.7 months respectively, with 9 patients alive and 6 patients without recurrence at the time of analyses. Rate of patients surviving more than 3, 4, 5 and 7 years were 55,1%, 20,4%, 12,24% and 6,12% respectively. Patients received a median of 2 rescue treatments after first relapse (range: 0-6 lines), including systemic therapies, surgery and re-irradiation. Rates for gross total resection, subtotal resection and biopsy were 32,6%, 47% and 20,4% respectively. pMGMT methylated patients and lesions without SVZ contact rates were 73,5% and 42,8% respectively. IDH analyses was available for 61.22% of our GB LTS patients (90% were IDH wild type and 10% mutant IDH, which according to WHO CNS 2021 classification would actually be defined as Astrocytoma grade 4). No statistical differences for OS or time to first progression were found according to sex, age (<55 years versus ≥55 years), pMGMT methylation status; Karnofsky performance status (≤70% versus >70%) and contact or not with the SVZ.

CONCLUSION

Classical prognostic factors did not show statistical differences for OS and time to first recurrence in our GB LTS sample, which could be explained by the small number of patients in the sample and the absence of statistically comparable differentiated groups for some of the variables. Larger and prospective analyses of GB LTS are needed. Molecular analyses with next generation sequencing (NGS) technics and radiomics analyses could apport new information predicting GB LTS.
P11.38.A CYSTIC VESTIBULAR SCHWANNOMA - A SUBGROUP ANALYSIS FROM A COMPARATIVE STUDY BETWEEN RADIOSURGERY AND MICROSURGERY
Authors: Wang S , Naros G , van Eck A , Horstmann G , Tatagiba M
Published: September 2023

BACKGROUND

Some vestibular schwannoma (VS), show cystic morphology. It is known that these cystic vestibular schwannomas (cVS) bear different surgical risk profile compared to non-cystic VS (ncVS) in surgical treatment. This study aims to analyze the management of cVS compared to ncVS in a dual center study of surgically (SURG) and radiosurgically (SRS) treated VS patients.

MATERIAL AND METHODS

This is a retrospective multi-center cohort study. Data was retrospectively collected from two large centers involved in the treatment of vestibular schwannomas for patients between 2005 und 2011 to enable long-term follow-up (FU). Tumor size was classified by Koos Classification. Previously treated VS and VS associated with Neurofibromatosis were excluded. Clinical state was reported by House and Brackmann (H&B) and Gardner-Robertson (G&R) scale (with H&B and G&R 1-2 considered as good outcome), and Recurrence-free-survival (RFS) was assessed radiographically by contrast-enhanced MR imaging. Data on VS-associated symptoms like trigeminal affection, tinnitus, and vertigo/imbalance were also collected.

RESULTS

The study population included N=901 patients, who were treated in both centers. N=559 (62%) patients were treated by SRS, and N=342 (38%) patients by SURGERY. N=55 (6%) of all patients showed cystic MR-morphology. These were more often treated by SURG (N=31/55, 58%) compared to ncVS (N=311/845, 37%) (p=0.002). Patients with cVS were indifferent in mean age compared to ncVS. The rate of women was higher in cVS (64%), compared to ncVS (55%) (p=0.001). The overall incidence of recurrence was 16% in cVS (8% in ncVS). Tumor control was worse in cVS treated by SRS (N=6/24, 25%) compared to SURGERY (N=3/32, 9%). When surgically treated, gross total resection (GTR) was achieved in 87% in cVS, whereas this rate was higher in non-cystic VS at 96% (p=0.001). The number of patients N=5/32 (16%) with postoperative relevant facial palsy (HB>2) was significantly higher in cVS (ncVS: N=28/310; 9%).

CONCLUSION

Tumor control in cVS is significantly worse in SRS compared to SURG and SRS-treated ncVS. However, when cVS is treated surgically, the rate of GTR is lower and the number of patients with relevant postoperative facial palsy higher compared to ncVS. Cystic morphology in VS poses a challenge in management (both SRS and SURG) compared to non-cystic tumors. Treatmend decision and patients' consultation should contemplate and address negative prognostic factor of cystic morphology in VS.
P11.39.B PREDICTING RESPONSE TO CHEMOTHERAPY IN RECURRENT HIGH GRADE GLIOMAS USINGEX VIVO 3D CELL CULTURE FUNCTIONAL PRECISION ONCOLOGY PLATFORM
Authors: Mrugala M M , Zimmerman R , Greene D , Fortin-Ensign S , Blomquist M , Swanson K , Bendok B
Published: September 2023

BACKGROUND

Treatment of recurrent high-grade glioma remains a clinical challenge. There are very few agents active in this disease and short of enrollment in a clinical trial, the choice of therapy for a patient at the time of recurrence remains challenging. Several groups, including our own have developed ex vivo drug sensitivity assays to evaluate susceptibility of the tumor tissue to specific chemotherapeutics. To our knowledge, there is only one commercially available platform from the US based company Kiyatec. This tool, in addition to the molecular analysis of the tumor might provide another layer of confidence in choosing treatments for patients with recurrent high-grade gliomas.

MATERIAL AND METHODS

We present the data from our initial experience with the 3D PredictTM platform (Kiyatec, Greenville, SC, USA). We used the platform for 6 patients with recurrent high-grade gliomas undergoing tumor resection at the time of recurrence. We followed the company protocol for obtaining, preserving and shipping the tissue.

RESULTS

Out of the 6 specimens shipped for analysis, 4 assays were completed with full results available for analysis and clinical use. In two cases, the ex vivo tissue expansion was unsuccessful and drug testing was not completed. For the remaining 4 cases, spheroids created from the expansion of the harvested tissue were exposed to 12 drugs (temozolomide, lomustine, procarbazine, abemaciclib, carboplatin, dabrafenib, etoposide, everolimus, irinotecan, osimertinib, rucaparib and trametinib). We have observed different levels of sensitivity to several agents graded as: NO RESPONSE, MODERATE RESPONSE and RESPONSE. In 3 cases the results were used for clinical decision making and 2 patients were started on temozlomidede and carboplatin respectively and remain on treatment. In one case where sensitivity to etoposide was detected, we were not able to proceed with therapy due to insurance denial for the chosen drug.

CONCLUSION

In our experience, this platform is easy to use in a standard clinical setting, the success rate for creating viable spheroids for testing is high and the information derived from the drug sensitivity testing can be useful in clinical practice. Large, prospective clinical trial is need to validate this approach for routine clinical use.
P11.40.A GLIOBLASTOMA WITH OSSEOUS METASTASES: A SINGLE INSTITUTION CASE SERIES
Authors: Webb L M , Webb M J , Campian J L , Caron S J , Sener U
Published: September 2023

BACKGROUND

Although glioblastoma (GBM) is the most common malignant primary brain tumor in adults, extracranial metastasis is rare, occurring in <2% of cases. This rarity has been attributed to the blood brain barrier, immunologic factors, lack of traditional lymphatics in the brain, and the poor prognosis of GBM, limiting its opportunity to metastasize. When GBM does metastasize, bone is the most common destination. GBM may spread hematogenously to bone, especially to vertebral bodies via the surrounding venous plexus. In this single-institution study, we review the clinical characteristics of GBM patients with osseous metastases and evaluate potential risk factors and prognostic significance.

MATERIAL AND METHODS

Using an institutional database, we identified and retrospectively analyzed 6 GBM patients with osseous metastases and studied their demographics, tumor genetics, clinical courses, and outcomes.

RESULTS

Five of 6 (83%) GBM patients with osseous metastases were male, with a median age of 46 years at GBM diagnosis (range: 20-84). All patients had IDH wild type and MGMT unmethylated GBM with mutations in TP53. Two patients (33%) were initially diagnosed with gliosarcoma. All patients were treated with surgical resection followed by radiation with concurrent and adjuvant temozolomide. Five patients (83%) received bevacizumab for vasogenic edema (n=4) or intracranial tumor progression (n=1) prior to bone metastasis diagnosis. Bone metastases were diagnosed a median of 12.2 months (range: 5.3-35.2) after GBM diagnosis and 4.8 months after starting bevacizumab (range: 3.5-13.2). Two patients (33%) received immune checkpoint inhibitor therapy and two patients (33%) received tumor-treating fields prior to bone metastasis discovery. Bone metastases were symptomatic in 2 patients, presenting with back pain (n=1) and leg weakness and urinary incontinence (n=1). Three patients (50%) had concurrent metastases to other organs. Osseous metastases were biopsy-confirmed in 3 (50%) cases, while the other 3 patients had no known alternative malignancy to explain their bone metastases. After osseous metastasis discovery, the median survival was 27 days (range: 13-225).

CONCLUSION

Most of our GBM patients with osseous metastases were male and most, but not all, were young at GBM diagnosis. Tumor genetics common to all patients included IDH wild type, MGMT unmethylated status, and TP53 mutation, which may be important for osseous metastasis. Most patients received bevacizumab, which may be associated with earlier metastasis. While rare, metastatic GBM should be within the differential for GBM patients with bone pain or progressive neurologic symptoms, as osseous metastases portend a dismal prognosis in an already aggressive malignancy.
P11.41.B PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM: CASE STUDY REPORTS
Authors: Guo C , Yang Q , Li J , Wu S , Cao X , Deng M , Du X , Bacha J , Kanekal S , Kwan C , Johnson G , Schwartz R , Langlands J , Brown D , Chen Z
Published: September 2023

BACKGROUND

VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro.

MATERIAL AND METHODS

A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM following surgical resection. Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT.

RESULTS

A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083. The median number of cycles completed by all patients was 9 (range 2-13). Consistent with our prior experience, myelosuppression was the most common adverse event. In a sub-group of patients, levels of VAL-083 in CSF were found to be at least as high as those in plasma. At study completion, the median progression free survival (PFS) for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. Here we report on two patient cases. The first, a 32-yo woman, WHO Gr. 4 GBM (MGMT unmethylated), who received conventional radiotherapy with concurrent chemotherapy with VAL-083 followed by adjuvant VAL-083, for a total of 13 cycles of VAL-083. This patient is tumor free suvival more than 4 years till last follow-up (Mar 2023 ). The second, a 49-yo man, WHO Gr. 4 GBM (MGMT unmethylated), who received radiotherapy with concurrent chemotherapy with VAL-083 followed by adjuvant VAL-083, for a total of 12 cycles of VAL-083. Two years after initial treatment with VAL-083 was discontinued, a new lesion was found, and the patient had a second resection, which revealed WHO Gr. 3 astrocytoma. The patient was re-treated with VAL-083,and was stable till last follow-up(Mar 2023).

CONCLUSION

The results from the study and these patient cases, support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736.
P11.56.A MODIFIED FRAILTY INDEX (MFI) AS A SURVIVAL AND FUNCTIONAL OUTCOME PREDICTOR IN OLDER PATIENTS UNDERGOING SURGERY FOR BRAIN METASTASES
Authors: Ersoy T F , Brainman D , Coras R , Simon M
Published: September 2023

BACKGROUND

Surgical decision making in older patients with brain metastases (BM) is challenging. Frailty and comorbidities are often thought to limit therapeutic options as well as functional and survival outcomes.

MATERIAL AND METHODS

139 consecutive patients undergoing surgery 2017-2021 for BM were analyzed retrospectively. Cut-off for age was ≥60 yrs. in accordance with the graded prognostic assessment (GPA) index. Frailty was investigated using the mFI index, a compound measure assessing comorbidities and the patients’ functional health status.

RESULTS

Median age was 69.0 (IQR: 63.0-74.5) yrs. 55.4% had multiple metastases. We recorded 9.4% major (CTCAE III-V) surgical and 10.1% medical complications. 7.9% of patients had major new focal neurological deficits ≥30 days. Median overall survival (mOS) was 7.8 (IQR: 5.0-10.6) months. Frailer patients lived shorter (mOS for “least-frail”/mFl 0: 13.6 [IQR: 8.6-18.6], “moderately frail”/mFl 1-2: 9.0 [IQR: 4.9-13.0] and “frailest”/mFl ≥3: 2.7 [IQR: 0.9-4.5] months; p<0.001). Multivariate analysis with all parameters correlating significantly with mOS in the univariate analysis (mFI, higher preop. KPS, younger age [<69 yrs.], female sex) revealed a higher preop. KPS to be the only independent significant survival predictor (70 vs. 80-100; HR 2.1, p<0.001). Frailer patients had poorer functional outcomes (patients w/ postop. KPS ≤70 vs. 80-100; mFI 0: 9/36 [25.0%], mFI 1-2: 20/65 [30.8%], mFI ≥3: 25/38 [65.8%]; p<0.001). Multivariate analysis with all parameters correlating significantly with better functional outcome in the univariate analysis (mFI, higher preop. KPS, younger age, female sex and single metastasis) showed that a higher preop. KPS was the strongest prognostic parameter (RR 17.2, p<0.001). The mFI was not an independent outcome predictor. In a ROC analysis the preoperative KPS proved a much better predictor of functional outcome than the mFI (AUC 92 vs. 71%; sensitivity/specificity optimum 80 vs. 2, resp.). mFI was not a predictor of complications (p=NS).

CONCLUSION

The mFI proved a strong survival and functional outcome predictor in older patients. However, this effect was no longer seen in multivariate analyses when the KPS was included as a covariate. This may suggest that surgical outcomes depend on the patients’ presurgical functional health status rather than comorbidities. The presence of comorbidities (if well treated) should therefore not deter from BM surgery in older patients.
P11.58.A CARDIOVASCULAR EVENTS AND VENOUS THROMBOEMBOLISM AFTER PRIMARY MALIGNANT AND NON-MALIGNANT BRAIN TUMOUR DIAGNOSIS: A POPULATION MATCHED COHORT STUDY IN WALES (UNITED KINGDOM)
Authors: Poon M T C , Brennan P M , Jin K , Sudlow C L M , Figueroa J D
Published: September 2023

BACKGROUND

Elevated standardised mortality ratio of cardiovascular diseases (CVD) in patients with brain tumours may result from differences in the distribution of risk factors. We compared the risk of CVD among patients with a primary malignant or non-malignant brain tumour to a matched general population cohort, accounting for other co-morbidities.

MATERIAL AND METHODS

Using data from the Secured Anonymised Information Linkage (SAIL) Databank in Wales (United Kingdom), we identified all adults aged ≥18 years in the primary care database with first diagnosis of malignant and non-malignant brain tumour identified in the cancer registry in 2000-2014, and a matched cohort (case-to-control ratio 1:5) by age, sex and primary care provider from the general population without any tumour diagnosis. Outcomes included fatal and non-fatal major vascular events (stroke, ischaemic heart disease, aortic and peripheral vascular diseases) and venous thromboembolism (VTE). We used multivariable cox models adjusted for clinical risk factors to compare risks, stratified by tumour behaviour and follow-up period.

RESULTS

There were 2,869 and 3,931 people diagnosed with malignant and non-malignant brain tumours, respectively, between 2000 and 2014 in Wales. They were matched to 33,785 controls. Within the first year of tumour diagnosis, malignant tumour was associated with a higher risk of VTE (hazard ratio [HR] 21.58, 95% confidence interval 16.12-28.88) and stroke (HR 3.32, 2.44-4.53). Risks of VTE (HR 2.20, 1.52-3.18) and stroke (HR 1.45, 1.00-2.10) remained to be higher than controls for those surviving one year. Patients with non-malignant tumours had higher risks of VTE (HR 3.72, 2.73-5.06), stroke (HR 4.06, 3.35-4.93) and aortic and peripheral arterial disease (HR 2.09, 1.26-3.48) within the first year of diagnosis compared with their controls.

CONCLUSION

The elevated CVD and VTE risks suggested risk reduction may be a strategy to improve life quality and survival in people with a brain tumour.
P11.59.B HIGH GRADE GLIOMAS IN PATIENTS WITH HISTORY OF EXTRACRANIAL CANCERS, A RETROSPECTIVE MULTICENTRIC STUDY
Authors: Kalita O , Kazda T , Reguli S , Jancalek R , Fadrus P , Slachta M , Pospisil P , Krska L , Vrbkova J , Cvek J , Dolezel M , Smrcka M , Lipina R , Hrabalek L
Published: September 2023

BACKGROUND

Metastases are most frequent brain cancer, involving 50-60% of all intracranial neoplasm. Dominated origins are lung, breast, colorectal cancers. A progress in diagnostic and treatment strategies significantly improved the life expectancy of patients with extracranial cancers. Patients with neurological symptoms should be recommended to the brain MRI. Rarely silent primary brain cancers are revealed. Metastases are considered as a first option, but brain lesions with contrast enhancement could be misdiagnosed. We more and more often meet with high grade glioma (HGG) in patients experienced with other primary cancer. Aim of our study is evaluated an incidence of concurrent cancers, relations between former cancer staging and malignant primary brain tumor evaluation, and also appreciation of treatment efficiency.

MATERIAL AND METHODS

Data of all glioma patients treated at the three Czech neuro-oncology centers are collected regularly and prospectively during routine maintenance of a database. This work focuses on adult patients with concurrent history both of extracranial cancers and HGGs who underwent resection and oncotherapy between January 2008 and December 2020. Information on the patients’ clinical condition (Karnofsky score (KS)) was collected along with imaging and histological data on each patient’s tumor and details of their cytogenic alterations. Also regarding former extracranial cancers they have been followed up by oncologic center. We excluded the patients with prostate cancer.

RESULTS

The analysis included 48 patients aged between 44 and 79 years. The median age was 65.3 years. The group contained more women (35/48) than men (13/48). Thirty one patients had a history of breast carcinoma, nine of renal carcinomas and eight of colorectal carcinomas. Following the diagnosis of carcinoma, forty four patients received oncotherapy and four had no adjuvant therapy. Surgery of brain tumors has always revealed HGGs, IDH wild-type. Following the diagnosis HGG thirty patients underwent chemoradiotherapy, thirteen had palliative radiotherapy and five had no oncotherapy. The average time from the diagnosis of extracranial cancer to that of GBM was 4 years. The OS was 11.4 months (range 3-29 months). All the patients succumbed to GBM progression.

CONCLUSION

Limited number of these patients has been selected. Prognosis was depended on staging of extracranial cancer and performance status. If these patients would be able to pass standard oncologic treatment of primary HGG, they did not find survival distinctions to compare with no extracranial cancer history patients. For right treatment strategy it is mandatory to eliminate misdiagnose of brain metastases and primary malignant brain tumors. This research was funded and supported by Ministry of Health of the Czech Republic (grant NU21-03-00195, NU20-03-00148)
P11.62.A GENDER-RELATED DIFFERENCES IN PATIENTS CHARACTERISTICS, AND TREATMENT OUTCOME IN A COMPARATIVE STUDY OF MICROSURGERY AND RADIOSURGERY OF VESTIBULAR SCHWANNOMA
Authors: Wang S , Machetanz K , van Eck A , Horstmann G , Tatagiba M , Naros G
Published: September 2023

BACKGROUND

Gender-related differences in patients with sporadic, unilateral vestibular schwannoma (VS) are poorly investigated so far. In studies focusing on natural history, tumor growth was described to be indifferent in either sex. However, it remains unclear whether patient’s sex affects the treatment response to stereotactic radiosurgery (SRS) or microsurgical resection (SURGERY). This study elucidates sex-related differences in VS care.

MATERIAL AND METHODS

This is a retrospective multi-center cohort study. Data was retrospectively collected from two large centers involved in the treatment of vestibular schwannomas for patients between 2005 und 2011 to enable long-term follow-up (FU). Tumor size was classified by Koos Classification. Previously treated VS and patients with Neurofibromatosis were excluded. Clinical state was reported by House and Brackmann (H&B) and Gardner-Robertson (G&R) scale (with H&B<3 and G&R 1-2 considered as good outcome), and Recurrence-free-survival (RFS) was assessed radiographically by contrast-enhanced MR imaging. Data on VS-associated symptoms like trigeminal affection, tinnitus, and vertigo/imbalance were also collected.

RESULTS

The study population included N=901 patients, who were treated in both centers. N=502 (56%) VS patients were female and N=399 (44%) were male. At time of treatment, women (56 years SD±13.50) were significantly older in age then men (53 years SD±13.80) (p=0.001). Tumor size, cystic morphology, intracanalicular extension, provided care (SRS, SURGERY), treatment related complications, and extent of surgical resection were insignificant in both gender-groups. The incidence of relevant preoperative vertigo was higher in women (67%) then in men (55%) (p=0.002). Pre- and postoperative facial function, hearing loss, and trigeminal symptoms were similar in both groups. Overall incidence of recurrence was insignificant (p=0.106). However, the in subgroups, tumor control with SRS was significantly worse in women compared to men (p=0.035).

CONCLUSION

Provided Care, functional outcome and peri-interventional morbidity were the same in either sex. Relevant vertigo was significantly more often present in women. The incidence of recurrence is higher in women with VS, when treated with SRS compared to men, although tumor characteristics were similar. Additional research is needed to elucidate gender-related difference in tumor biology affecting the response to VS treatment.