bluuebunny/crossref_metadata_2025_split huggingface dataset:
P09.07.A SYMPTOM AND DISTRESS IN PATIENTS WITH MALIGNANT BRAIN TUMOR TREATED WITH PROTON BEAM THERAPY. A FIVE-YEAR FOLLOW-UP STUDY
Authors: Kunni K , Langegård U , Fransson P , Proton Care Study Group T 
Published: September 2023

Abstract

BACKGROUND
Due to new treatment regimes, an increasing proportion of patients with malignant brain tumors will likely be long-term survivors. To ensure optimal care for this patient group, it is crucial to conduct further research, including long-term follow-up of treatment-related symptoms, and distress. Patients with malignant brain tumors experiencing distressing symptoms will result in poorer overall survival and decreased quality of life. Despite this, the correlation between symptoms and distress in adults with malignant brain tumors undergoing proton beam therapy remains poorly understood. This study aimed to explore if symptoms and distress change over five years in adults with malignant brain tumors treated with proton beam therapy. An additional aim was to explore if symptoms and distress correlate.

MATERIAL AND METHODS
The study had a quantitative longitudinal multicenter design.Adult (≥18 years) patients (n = 149) with malignant brain tumors treated with proton beam therapy were followed over five years. The degree of symptom and distress were evaluated using the patient-reported Radiotherapy-Related Symptom Assessment Scale. Data from baseline, 1, 12-, and 60 months were analyzed using non-parametric tests. The correlation between symptoms and distress were analyzed using Spearman’s correlation.

RESULTS
Levels of symptoms and distress were generally low. Fatigue had the highest levels at all timepoints. Cognitive impairment increased significantly at 12-months (P=0.002) and was the most distressing symptom at 60-months follow-up. The results showed a significant, moderate to strong, correlation at all time points between symptoms and distress of fatigue, insomnia, pain, cognitive impairment, worry, anxiety, nausea, sadness, and skin reactions.

CONCLUSION
Our study highlights the correlation between symptoms and distress in adults with malignant brain tumors treated with proton beam therapy. Further, this study emphasizes that nursing should focus on what patients experience as the most distressing symptoms. Research should identify effective interventions to alleviate symptoms and reduce patient distress. Given the significant correlation between symptoms and distress in our study, we suggest developing cancer rehabilitation. Reduced levels of distressing symptoms would lead to a better quality of life and increased survival for this vulnerable group of patients.
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

Abstract

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 &lt;16), mild depressive symptoms (CES-D 16-20) or moderate to severe depressive symptoms (CES-D &gt;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

Abstract

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

Abstract

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

Abstract

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

Abstract

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 (&gt;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 &gt;8 μM. Only in Abcg2 KO mice, the B/P ratio increased to levels of DKO mice at tariquidar plasma levels of &gt; 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

Abstract

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

Abstract

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

Abstract

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.