bluuebunny/crossref_metadata_2025 huggingface dataset:
OS09.7.A Experiences and unmet needs of grade 2-4 glioma patients and (health care) professionals regarding (return to) work: the BrainWork study
Authors: Zegers A , Coenen P , Heeren A , Takke N , Ardon H , Compter A , Dona D , Kouwenhoven M , Schagen S , de Vos F , Duijts S
Published: September 2022

Background

In the Netherlands, 1,200 persons are annually diagnosed with a glioma, of whom many are of working age. Studies regarding cancer and work often exclude primary brain tumour patients, due to specific problems these patients may experience. Hence, the aim was to explore the experiences and unmet needs regarding return to work, work retention, or work discontinuation of both grade 2-4 glioma patients, and involved (health care) professionals.

Material and Methods

Individual semi-structured interviews were held with grade 2-4 glioma patients as well as health care and occupational professionals involved in (the care for) glioma patients. Grade 2-4 glioma patients were eligible to participate if they were of working age and had an employment contract at time of diagnosis. Recruitment of patients was performed via three hospitals and via social media. The professionals were recruited via the network of researchers linked to BrainWork. Interviews were transcribed verbatim, and thematically analysed using ATLAS.ti9.

Results

Nineteen glioma patients participated in this study (68% male, mean age 45 (SD 11), 58% grade 2, 16% grade 3, 26% grade 4). The main themes identified were: 1) impact of glioma-specific consequences on work ability, 2) communicating about an invisible, progressive illness at work: discrepancies in perceptions, 3) working with a brain tumour: looking at possibilities, and 4) navigating offers of (work-related) support. Sixteen professionals were interviewed (e.g., clinical neuro-oncologist, insurance physician) with an average experience of fifteen years. Four key themes were identified: (1) distilling the right approach: generic or specific vocational rehabilitation?; (2) work adjustments are common, but information deficiency causes delay; (3) opinions about work ability are diverse and influenced by glioma-specific characteristics; and (4) need for attention and tailored recommendations regarding glioma and work.

Conclusions

Working is possible for glioma patients although they encounter glioma-specific problems, and commonly need work adjustments. These adjustments should be communicated early, to prevent employer-employee conflicts. A specific reintegration plan, including a neuropsychological assessment and a glioma-tailored rehabilitation program, is considered the most adequate approach. Open communication between the patient and the (work) environment in general is necessary to abate discrepancies in perception. Communication between health care professionals and occupational professionals should be improved to diminish differences in opinions about the work ability of glioma patients. Finally, more attention and more tailored recommendations regarding glioma and work are necessary.
P01.01.A Lesion-Function Analysis from Multimodal Imaging and Normative Brain Atlases for Prediction of Cognitive Deficits in Glioma Patients
Authors: Kocher M , Jockwitz C , Lohmann P , Stoffels G , Filss C , Motthagy F M , Ruge M I , Weiss Lucas C , Goldbrunner R , Shah N J , Fink G R , Galldiks N , Langen K , Caspers S
Published: September 2022

Background

Cognitive deficits are common in glioma patients following multimodality therapy, but the relative impact of different types and locations of treatment-related brain damage and recurrent tumors on cognition is not well understood.

Material and Methods

In 121 WHO Grade III/IV glioma patients, structural MRI, O-(2-[18F]fluoroethyl)-L-tyrosine FET-PET, and neuropsychological testing were performed at a median interval of 14 months (range, 1-214 months) after therapy initiation. Resection cavities, T1-enhancing lesions, T2/FLAIR hyperintensities, and FET-PET positive tumor sites were semiautomatically segmented and elastically registered to a normative, resting state (RS) fMRI-based functional cortical network atlas and to the JHU atlas of white matter (WM) tracts, and their influence on cognitive test scores relative to a cohort of matched healthy subjects was assessed.

Results

T2/FLAIR hyperintensities presumably caused by radiation therapy covered more extensive brain areas than the other lesion types and significantly impaired cognitive performance in many domains when affecting left-hemispheric RS-nodes and WM-tracts as opposed to brain tissue damage caused by resection or recurrent tumors. Verbal episodic memory proved to be especially vulnerable to T2/FLAIR abnormalities affecting the nodes and tracts of the left temporal lobe.

Conclusion

In order to improve radiotherapy planning, publicly available brain atlases, in conjunction with elastic registration techniques, should be used, similar to neuronavigation in neurosurgery.
P01.06.B Interim results from CAR-Study B: An ongoing randomized trial on the effect of SRS or WBRT on cognitive performance in patients with 11-20 brain metastases
Authors: Schimmel W C M , Verhaak E , Hanssens P E J , Kavelaars X M , Mulder J , Kaptein M C , Sitskoorn M M , Gehring K
Published: September 2022

Background

Both stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) have proven to be effective treatments for multiple brain metastases (BM) with similar overall survival. Cognition and Radiation (CAR) Study B is a randomized trial on the effect of Gamma Knife radiosurgery (GKRS) or WBRT on cognitive performance in patients with 11-20 BM. The primary and secondary aim of this interim analysis were to check whether Bayesian stopping rules for cognitive failure were met, and to compare cognitive changes after treatment respectively, for the first 45 patients enrolled.

Material and Methods

Patients with 11-20 newly diagnosed BM on a triple-dose contrast-enhanced MRI-scan, expected survival >3 months and Karnofsky Performance Status (KPS) ≥70, were stratified by age, histology, total BM volume, systemic treatment, KPS, and baseline Hopkins Verbal Learning total recall (HVLT-R TR) score, and randomized 1:1 (minimization) to GKRS or WBRT. Neuropsychological tests were administered before (T0) treatment (n=21 vs n=20), and at 3 (T3; n=16 vs n=14) and 6 (T6; n=9 vs n=9) months thereafter. A decline of ≥5 points in HVLT-R TR score was considered a cognitive failure. The trial would be halted if the posterior probability for a higher cognitive failure rate in one group versus the other was >0·975 at T3 or T6 according to the employed beta (2.09,2.91) prior (prior mean of 42%), based on the average failure rates at 4 months reported by Chang et al. (2009). Between-group differences in changes of test performances over 6 months were analyzed using mixed ANOVAs. Proportions of cognitive changes (T0-T6) at the individual level based on reliable change indices correcting for practice effects, were determined.

Results

HVLT-R TR failure rates in the GKRS versus WBRT group were 31% versus 29% at T3, and 0% versus 33% at T6. The observed failure rates after WBRT at T3 and T6 were lower than the average failure rates of Chang et al. (2009). Posterior probabilities were 0·451 at T3 and 0·918 at T6. Over 6 months, changes in performance on tests of immediate (p=·003) and delayed recall (p=·024), and information processing speed (p=·003) were significantly different between groups (large effect sizes), with significant declines after WBRT, but not after GKRS. Over 6 months, at the individual patient level, there were no declines in performances across all tests in the GKRS group (n=8) while performances declined in 4 out of 8 patients in the WBRT group.

Conclusion

The stopping rules were not met since the posterior probabilities did not cross the threshold. Other preliminary findings in this small sample suggest that cognitive decline, both at group and individual level, is more pronounced after WBRT compared to GKRS. Accrual is continued (NCT02953717; ZonMw 842003006).
P01.10.B The relation between executive functioning and MEG multilayer network centrality in glioma patients
Authors: van Lingen M R , Breedt L C , Hillebrand A , Klein M , Kouwenhoven M C M , Reijneveld J C , De Witt Hamer P C , Zimmermann M L M , Santos F A N , Douw L
Published: September 2022

Background

Many patients with glioma suffer from deficits in executive functioning (EF), regardless of tumor location and size. While some patients experience improving EF after tumor resection, others deteriorate over time. This variability in cognitive trajectories is still poorly understood, but neuroscientific approaches that view the brain as a network may bear correlative and predictive value in this respect. Particularly integrative network connectivity of the fronto-parietal network are crucial for EF, but studies so far have only investigated isolated neural frequency bands of interest. Here, we synergize fronto-parietal network connectivity across frequency bands and test its explanatory power for EF at diagnosis and 1 year after tumor resection.

Material and Methods

Patients with diffuse glioma (n=37) underwent neuropsychological assessments, including three tests for EF, and resting-state magnetoencephalography (MEG) at both time points. Patients’ EF performance was standardized to z-scores using validated norm scores, adjusting for age, sex and education. MEG was source-reconstructed using patients’ MRI in combination with a beamformer approach and time series were filtered into six classical frequency bands. Band-specific functional connectivity between 78 cortical regions was estimated, after which an interconnected multilayer, multi-frequency network was created per patient. Multilayer centrality was then calculated as a measure of integrative network connectivity per region, and averaged over all fronto-parietal network regions to yield a single value reflecting integrative, multi-frequency network connectivity per patient at each time point.

Results

At diagnosis, eight patients had z-scores <-1.5, indicating clinically relevant cognitive deficits. Preoperatively, poorer performance on the Concept Shifting Task was associated with lower multilayer centrality (p=.017), while improving performance on this task from diagnosis to 1 year after resection was associated with an increase in multilayer centrality (p=.022). Multilayer centrality at diagnosis did not significantly predict EF at follow-up.

Conclusion

Our results establish a significant relationship between poorer and decreasing EF with lower and decreasing multilayer, multi-frequency integrative connectivity of the fronto-parietal network in glioma patients. Studies with larger and more homogeneous samples may further explore the relevance of this multilayer approach in understanding and particularly predicting postoperative decline in EF in these patients, as our sample was characterized by large heterogeneity in cognitively relevant patient and tumor characteristics.
P02.08.A The relations of focal and total DNA methylation in gliomas
Authors: Majchrzak-Celińska A , Naskret-Barciszewska M , Giel-Pietraszuk M , Nowak W , Śron P , Barciszewska A
Published: September 2022

Background

The role of epigenetic events in gliomagenesis is undoubtful. However, the role of specific pathological events is not so clear. It was shown that loss in total DNA methylation correlates with higher tumor malignancy and oxidative DNA damage. But promoter methylation of many genes was reported to be significant for gliomas’ malignancy and predictive for the treatment outcome. In carcinogenesis in general global DNA hypomethylation and focal hypermethylation coexist. The aim of our project was to evaluate the correlation between total DNA methylation and promoter methylation of selected genes.

Material and Methods

We analysed glioma tissues from 60 patients. For total DNA methylation analysis we used the radiolabelling method with TLC separation of nucleotides and content estimation with phosphoimager. For promoter methylation analysis we have chosen: MGMT (O-6-Methylguanine-DNA Methyltransferase), MPG (DNA-3-methyladenine glycosylase), GJA1 (Gap junction alpha-1 protein / connexin 43). The promoter methylation level was evaluated with the methylation-sensitive high-resolution melting (MS-HRM) method.

Results

Total DNA methylation was reversely correlated with brain tumor grade, confirming that 5-methylcytosine loss is important step in gliomagenesis. From 3 genes only MPG promoter methylation showed clear low reverse correlation with tumor grade. Promoter methylation in GJA1 show low correlation with both, MGMT and MPG, but there was no link between MGMT and MPG. IDHwt presence was significantly correlated with higher tumor grade. Promoter methylations in MPG and GJA1 were better correlated with IDH status than in MGMT.

Conclusion

There is a clear correlation between total DNA methylation and tumor malignancy. Gene promoter methylation is not highly correlated with total DNA methylation and shows low significance in selected cases. Promoter methylation showed clear correlation with tumor grade only in MPG case. That suggests diverse mechanisms steering DNA methylation in general and local changes. It also shows that total DNA methylation is best predictor of tumor grade.
P03.02.B Vestibular side effects following robotic guided stereotactic radiosurgery of vestibular schwannoma
Authors: Rueß D , Pöhlmann L , Jünger S , Kocher M , Ruge M
Published: September 2022

Background

New-onset vestibular disorders (VD), such as dizziness and imbalance, are common side effects after stereotactic radiosurgery (SRS) for vestibular schwannomas (VS). Although these symptoms can severely affect the daily life of VS patients, there are limited data available providing prognostic information on the risk of developing VD after SRS.

Material and Methods

We included patients who received Cyberknife® SRS for newly diagnosed unilateral VS between 2012 and 2015. The incidence of vestibular disorders before and after treatment was recorded and correlated with tumor, patient, and treatment characteristics.

Results

We identified 71 patients with a median age of 58 years (range: 21-82) and a median follow-up of 66 months (range: 3-105). Tumor volume before treatment was 1.5 cm3 ± 1.4 (range: 0.1-8.6). A mean marginal dose of 12.9 Gy ± 0.3 (range: 12-14) was administered, and all studied patients remained free of tumor recurrence. Forty-one (58%) of the patients had VD prior to SRS. Of the remaining 30 patients who did not have VD before treatment, 16 (53%) developed new VD (vertigo, n=4; balance disorders, n=8; mixture of VD, n=4). The median time to onset of symptoms was 6 months (range: 2-36). In most patients (n=11, 69%), the new symptoms completely resolved within a median time of 21 months (range: 1-63). In multivariate analysis, neither tumor volume (p=0.7), age (p=0.06), nor radiation dose (p=0.16) were significantly associated with the occurrence of VD.

Conclusion

In this cohort, about half of the patients develop new onset of transient VD after SRS. The incidence of VD after SRS was found to be independent from usual tumor-, patient- and treatment-related factors. Therefore, a detailed analysis of the dose exposure to the structures of the vestibular apparatus is recommended.
P03.06.B Proton irradiation (PT) for benign meningiomas, Grade I clinical experience of the first 100 patients from REGI-MA-002015
Authors: Lütgendorf-Caucig C , Hug E , Pelak M , Flechl B , Mock U , Fossati P , Mumot M , Carlino A , Georg P , Georg P
Published: September 2022

Background

Meningiomas are the most common CNS tumors and the majority is regarded as benign. However, a subset of patients presents with complex tumors involving several anatomic compartments of the skull base - eluding any concepts of gross total resection. Proton therapy (PT) is applied as definitive treatment for primary or recurrent disease or postoperatively following subtotal resection. We report on the first 100 adult patients treated with PT at MedAustron.

Material and Methods

All patients were enrolled in a prospective registry trial (ClinicalTrials.gov Identifier: NCT03049072). Target volume definition was based on CT, MR and DOTA-PET/CT. PT treatment plans were generated by applying a Simultaneous Integrated Boost (SIB) concept with the Single Field-optimisation method and utilizing 2-4 beams per plan with a beam spacing of >30°. Prescribed doses to PTV1 were 50.49Gy_RBE at 1.87Gy_RBE/fr and 54.0Gy_RBE at 2.0Gy_RBE/fr to PTV2 in overall 27 fractions. Follow up status was assessed by MRI at 6, 12 months and annually thereafter, side effects were assessed using CTCAE v4.0. and quality of life (QoL) using EORTC-CTC30 and BN20 questionnaires. The scores entered by the patients were added and normalized to 0-100 scale according to previously described protocols.

Results

Between 08/2017 and 04/2021, 100 patients were treated, 22% (n=22) male and 78% (n=78) female patients. Median age at therapy was 54a (25a-82a). In 57% (n=57) PT was the definitive treatment (no resection or surgery >12 mo prior to PT). 43% (n=43) underwent postoperative PT with at least one surgery (range 1-3), and median time from last resection to start of PT of 6mo (3mo-11mo). 89% (n=89) meningiomas were located in the skull base with involvement of multiple anatomic compartments. The median GTV size was 24cc (1cc-226cc) and the median CTV 41cc (2cc-352cc), respectively. At median follow-up of 31.1 months (range 6.6-51.6), 2 local in-field failures were observed (both patients treated postoperatively) resulting in disease-specific survival of 100% and local control of 98% at 3 years, respectively. No > Grade 2 acute toxicity was observed. During follow-up two Grade 3 toxicities occurred: One patient developed symptomatic radiation induced brain lesion (RIBL) which resolved within 12 month; one patient was hospitalized for new onset of epilepsy without corresponding radiographic findings. 9% (n=9) developed G1/G2 RIBL, which resolved spontaneously. The general QoL including the global health status and all functioning domains remained stable and did not decrease significantly following PT.

Conclusion

First clinical data demonstrate that PT based on a SIB concept is a safe and efficient treatment of anatomically complex, low grade meningiomas. Acute and late toxicity incidences in our series were low with excellent, prospectively assessed preservation of QoL.
P04.03.B Rapid DNA methylation-based classification of pediatric brain tumors from ultrasonic aspirate specimens
Authors: Simon M , Kuschel L P , von Hoff K , Hernáiz Driever P , Hain E G , Koch A , Capper D , Schulz M , Thomale U , Euskirchen P
Published: September 2022

Background

Cavitating ultrasonic aspirator (CUSA) devices are commonly used in neurosurgical procedures to carefully debulk tumor from adjacent healthy brain tissue. Here, we explore the feasibility of using ultrasonic minced tumor tissue to classify otherwise discarded sample material by DNA methylation according to the respective World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) using low pass nanopore whole genome sequencing.

Material and Methods

21 ultrasonic aspirated specimens from patients undergoing surgery in the department of pediatric neurosurgery at the Charité-Universitätsmedizin Berlin with either newly diagnosed cerebral lesions or pre-treated lesions were processed by nanopore sequencing to generate copy number profiles and ad-hoc random forest classification. Results were compared to microarray-based routine profiling. Tumor purity was assessed.

Results

In 19/21 (90.5 %) samples the minimum amount of 1,000 CpG sites were sequenced. In 20/21 (95.2 %) cases copy number variation profiles could be generated and matched microarray derived copy number profiles, allowing for identification of diagnostically or therapeutically relevant pathognomonic alterations. 12/17 (70.6 %) samples were concordantly classified to the corresponding microarray-based diagnosis by routine neuropathological workup. Applying recently defined thresholds for nanopore-based classification resulted in sensitivity of 64.7 % and specificity of 100 %.

Conclusion

CUSA referred sample material of pediatric brain tumors allows for methylation-based classification according to the respective WHO classification of CNS tumors with acceptable sensitivity and high specificity. Hereby, a promising opportunity for accurate classification of pediatric brain tumors by a time- and cost-efficient advanced molecular technique is offered using otherwise discarded tumor tissue.
P05.01.B Distribution of the staining agent sodium-fluorescein in cerebral neoplasia - a comparison between intraoperative confocal laser endomicroscopy and in vitro fluorescence microscopy
Authors: Brielmaier M C , Reifenrath J , Pensel N , Ganster F , Bierlein J , Wagner A , Gempt J , Schlegel J
Published: September 2022

Background

While conventional frozen sections and other ex vivo microscopy always come along with artefacts, in vivo confocal laser endomicroscopy (CLE) offers less invasive, less manipulated imaging of living tissues. Understanding the distribution of the staining agent sodium-fluorescein (NaFl) plays a key role in establishing in vivo CLE as a new opportunity for real-time transmitted, in vivo imaging.

By comparing the distribution of NaFl in in vivo and ex vivo CLE to conventional fluorescence microscopy of NaFl incubated tumor cell cultures we gain a better understanding of the staining mechanism.

Material and Methods

Sodium-fluorescein is the water-soluble sodium salt of fluorescein and is used as a fluorescent tracer in neurosurgery. The staining agent was applied intravenously at the beginning of the surgical procedure. In vivo CLE of the lesion was performed 30 to 50 minutes later and compared to ex vivo CLE imaging and conventional fluorescence microscopy. In addition, different tumor cell lines derived from malignant gliomas and carcinomas, respectively, were incubated with NaFl in vitro and the uptake of the fluorescent dye was monitored over time.

Results

From initial results, the intraoperative images showed specific fluorescein distribution depending on the architecture of the tumor entity. In most cases, glial tumors demonstrated higher accumulation of the staining agent in the extracellular tumor matrix, whereas the cells of carcinoma metastases appeared to take up NaFl intracellularly. These results were corroborated by NaFl uptake in cell culture experiments.

Compared to ex vivo CLE, in vivo imaging offered a faster assessment of the tissue, brighter images and higher staining levels. Due to movement artefacts and the narrow intraoperative imaging time frame, in vivo CLE images were sometimes impaired by lower image quality.

Conclusion

The specific distribution of the fluorescent agent NaFl allowed for a discrimination between the different neoplastic entities. Images from in vivo and ex vivo confocal laser endomicroscopy showed NaFl uptake in concordance with the results of NaFl incubated cell cultures.

Intraoperative, in vivo confocal laser endomicroscopy shows promising first results in the understanding of brain tumor histomorphology in situ. Being faster and less manipulated by artefacts than ex vivo investigations, it opens up wider opportunities for research and intraoperative diagnostics.
P06.06.B standardization of therapy and manufacturing using tumor-associated antigen-stimulated autologous dendritic cells co-cultured with cytokine-induced killer cells in cancer immunotherapy
Authors: Yen C M , Fu Y Y , Yang M Y
Published: September 2022

Background

The application of DC-CIK in the field of cancer immunotherapy has been shown to be an effective treatment. However, the cost of DC-CIK treatment is prohibitive for many patients, and the lack of standard manufacturing processes and treatment strategies are the main limitations.

Material and Methods

Our experiments used tumor lysate instead of tumor cell line as tumor-associated antigen source with DCs co-culture. We provide the most efficient method for obtaining autologous DC-CIK cells from peripheral blood. Flow cytometry was used to evaluate DCs activation, CBA assay was used to quantify cytokines secreted by CIK cells, and the antitumor activity of DC-CIK was evaluated in vitro by K562 cell line.

Results

We demonstrate that the manufacturing process of employing frozen Peripheral Blood Mononuclear Cells (PBMCs) can balance patient’s comfort and economic benefits. DC-CIK can effectively upgrade the immunological specificity of CIK cells to tumors in the presence of tumor-associated antigen. In vitro experiments showed that when the number of DC: CIK cells was co-cultured in 1:20 ratio on the 14th day, the amount of cytokine secreted by CIK cells was the largest, and the anti-tumor immune effect was the most potent. When the number of CIK: K562 cells was in 25:1 ratio, the cytotoxic activity of CIK on K562 cells was the highest.

Conclusion

We developed an efficient activated fashion of DC:CIK, established the optimal ratio of DC-CIK immunologic activity and the best cytotoxic model of CIK to K562 cells.
P07.01.A Topical Fluorescent Probe for Visualization of Glioblastoma
Authors: Kim D
Published: September 2022

Background

Glioblastoma (GBM) is the most aggressive form of cancer that originates within the central nervous system (CNS). GBM represents 15% of all primary brain tumors, but the cause is unclear, and there is no clear way to prevent it. At the moment, various sophisticated and specific surgical procedures are being used, but there are relatively few simple methods.

Material and Methods

In this work, we used a turn-on type fluorescent probe that can sense cysteine (Cys) amino acid in the GBM site, and developed topical treatment methods for image-guided surgery (IGS).

Results

The probe can distinguish the GBM cells and disease sites in clinical samples from individual patients. Besides, the probe has no short or long-term toxicity and immune response.

Conclusion

The present findings hold promise for the application of the probe to a relatively simple and straightforward following of GBM at clinical sites.
P07.02.B Neuro-oncological augmented reality planning (NOA-p)
Authors: Van Gestel F , Frantz T , Neuville Q , Klein S , Bruneau M , Jansen B , Scheerlinck T , Vandemeulebroucke J , Duerinck J
Published: September 2022

Background

When preparing for the resection of an intracranial lesion, neuronavigation with a tracked pointer is most often used to determine lesion borders and the optimal approach. This can sometimes prove challenging, especially for deep-seated lesions. Augmented Reality (AR), directly displaying the lesion on the patient’s skin, can simplify and improve this step.

Material and Methods

We developed a system for inside-out infrared tracking that does not require an external tracking camera or external computer and allows for heads-up displaying an AR scene on the Microsoft HoloLens II. Twenty patients planned for the resection of an intracerebral lesion were included in our study. After patient registration, the lesion outlines were marked on the patient’s skin by different participants, consecutively using the Brainlab neuronavigation system and the HoloLens. Each registration on both systems provided a registration transform that was compared for accuracy and consistency. The performance of the participants was measured in terms of duration and accuracy and compared to expert registration and delineation.

Results

Both registration and delineation were significantly faster with AR (p=0.02 and p<0.001, respectively, and p<0.001 for the total duration), taking 79.23±17.48 and 39.58±39.10 seconds while neuronavigation required 96.61±24.54 and 90.80±44.09 seconds. AR had a registration offset of 3.3mm and 3.4°, and was more consistent compared to neuronavigation. AR facilitated more accurate and detailed lesion delineation, while neuronavigation often overestimated lesion size.

Conclusion

Augmented reality provides a faster and more accurate alternative for resection planning. Lesion delineation is more intuitive while remaining high in accuracy. Future research should focus on further intraoperative implementations.
P07.04.B Heme biosynthesis factors and 5-ALA induced fluorescence: analysis of mRNA and protein expression in fluorescing and non-fluorescing gliomas
Authors: Mischkulnig M , Roetzer-Pejrimovsky T , Lötsch-Gojo D , Kastner N , Bruckner K , Prihoda R , Lang A , Martinez-Moreno M , Furtner J , Berghoff A , Woehrer A , Berger W , Widhalm G , Kiesel B
Published: September 2022

Background

The intraoperative visualization of adult-type diffuse gliomas with 5-aminolevulinic acid (5-ALA) induced fluorescence is widely used in the neurosurgical field. While visible 5-ALA induced fluorescence is found in the majority of high-grade gliomas, most low-grade gliomas lack visible fluorescence during surgery. Recently, the heme biosynthesis pathway was identified as crucial influencing factor for presence of visible fluorescence since it metabolizes 5-ALA to fluorescing Protoporphyrin IX (PpIX). However, the exact alterations within the heme biosynthesis pathway resulting in visible 5-ALA induced fluorescence in gliomas are still unclear. The aim of the present study was thus to compare the mRNA and protein expression of promising intramitochondrial heme biosynthesis enzymes/transporters in glioma tissue samples of different fluorescence behavior.

Material and Methods

A total of 19 strongly fluorescing and 21 non-fluorescing tissue samples from neurosurgical adult-type diffuse gliomas (WHO grades II-IV) were included in the current analysis. In these samples, we investigated the mRNA expression by quantitative real time PCR and protein expression using immunohistochemistry of the intramitochondrial heme biosynthesis enzymes Coproporphyrinogen Oxidase (CPOX), Protoporphyrinogen Oxidase (PPOX), Ferrochelatase (FECH) and the transporter ATP-binding Cassette Subfamily B Member 2 (ABCG2).

Results

Regarding mRNA expression analysis, we found a significantly decreased ABCG2 expression in fluorescing specimens compared to non-fluorescing samples (p=0.001), whereas no difference in CPOX, PPOX and FECH was present. With respect to protein expression, significantly higher levels of CPOX (p=0.005), PPOX (p<0.01) and FECH (p=0.003) were detected in fluorescing samples. Similar to mRNA expression analysis, the protein expression of ABCG2 (p=0.001) was significantly lower in fluorescing samples.

Conclusion

Distinct alterations of the analyzed heme biosynthesis factors were found primarily on protein level. Our data indicate that heme biosynthesis pathway activity in general is enhanced in fluorescing gliomas with upregulation of PpIX generating enzymes and decreased ABCG2 mediated PpIX efflux outweighing the also increased further metabolization of PpIX to heme. Intramitochondrial heme biosynthesis factors thus constitute promising pharmacological targets to optimize intraoperative 5-ALA fluorescence visualization of usually non-fluorescing tumors such as low-grade gliomas.
P08.03.A Conversation tool for brain tumor patients - tailor-made support and guidance for the patient and their proxies
Authors: Dujardin K , de Peuter R , Dirven L , Gijtenbeek A , Manten-Horst E , Baas-Thijssen M
Published: September 2022

Background

An evaluation by the Dutch Neuro-Oncology Society (LWNO) showed that screening for psychosocial problems and the need for psychosocial care in glioma patients and their proxies is currently not optimal. Although tools to screen for psychosocial issues such as the Distress Thermometer exist, in daily practice they appear to be insufficient to discuss all disease-specific problems patients with brain tumors may encounter. We describe the development of a conversation tool to support the consultation between the patient with a brain tumor, their proxies and the health care professionals (HCPs).

Material and Methods

The development of the conversation tool for brain tumors was based on the tool used by the AYA Care Network in the Netherlands. Topics of importance for the entire care process were identified in a brainstorming session with 15 people (comprising HCPs, patients and proxies). Subsequently, the content of the conversation tool was determined by members of the LWNO and members of the LWNO-working group of nurses specialized in neuro-oncology (LWNO-v). Each topic in the conversation tool is supported by a visual, which was developed by a graphic design company in close collaboration with patients, proxies and HCPs.

Results

The conversation tool contains a total of 35 different topics covering six domains: physical health, daily life activities, psychological health, social relationships, loss of health and life, practical issues, all illustrated by a visual. The conversation tool can be given to the patient in booklet form before an appointment with the HCP, so they can prepare the conversation upfront. In addition, cards per domain will be available in the consultation room to be used during the appointment.

Conclusion:

By using the conversation tool, optimal individual guidance and support of patients with brain tumors is facilitated, as this patient population has unique issues that are often not covered by exiting tools. Using the conversation tool also promotes a nationally uniform way of working. Currently, an interactive tool for HCPs is being developed in which an overview of available interventions and best practices for the topics in the conversation tool are described, to ensure the needs of patients can be adequately addressed. The process of development of this tool can serve as an example for other cancer types.
P08.13.A CaPaBLE - Assessing the Patient Generated Index Methodology in High Grade Glioma Patients and Caregivers
Authors: Pakzad-Shahabi L , Tallant J , Le Calvez K , Wells M , Williams M
Published: September 2022

Background

CaPaBLE tests the feasibility and acceptability of assessing quality of life (QoL) using the patient-, or caregiver-generated index (PGI/CaGI) methodology in patients with HGG and their caregivers.

Material and Methods

CaPaBLE, (https://www.isrctn.com/ISRCTN45555598), followed patients and/ or their caregivers up to 6 months. Standard measures for patients were EORTC QLQ-C30/BN20, for caregivers the CarGOQOL questionnaire. The QoL topics raised through PGI/CaGI have been coded to the most relevant domain from their respective standard measure for an initial assessment of concordance.

Results

36 patients, 24 caregivers recruited to study; completing an average of 3 study assessment timepoints. PGI and CaGI generated 240 and 160 topics respectively. Patient concerns most frequently coded to EORTC domain of Role Functioning; Caregiver concerns mostly coded to CarGOQOL domain of Burden. Other topics frequently raised by patients such as the driving and sex life, and future planning by caregivers are not specifically raised in standard questionnaires.

Conclusion

Nearly all topics raised by patients and caregivers were mapped to the domains of their respective standard QoL measure. However, almost half of all topics raised by patients and caregivers mapped to a minority of the domains included in standard measures; whilst a notable number of topics are not specifically included in standard measures at all. This raises questions regarding the efficiency and relevance of such questionnaires to patient and caregivers’ daily lives.
P10.12.A CDK12/CDK13 inhibition disrupts a transcriptional program critical for glioblastoma survival
Authors: Lier S , Rein I , Lund S , Lång A , Lång E , Meyer N , Dutta A , Anand S , Nesse G , Johansen R , Klungland A , Rinholm J , Bøe S , Anand A , Pollard S , Lerdrup M , Pandey D
Published: September 2022

Background

Glioblastoma multiforme (GBM) is the most prevalent and aggressive malignant tumor of the central nervous system. With a median survival of only one year, GBM patients have a particularly poor prognosis, highlighting a clear need for novel therapeutic strategies to target this disease. Transcriptional cyclin-dependent kinases (CDK), which phosphorylate key residues of RNA polymerase II (RNAPII) C-terminal domain (CTD), play a major role in sustaining aberrant transcriptional programs that are key to development and maintenance of cancer cells.

Material and Methods

We used pharmacological inhibition and genetic ablation to study effects of CDK12/CDK13 depletion on the proliferatory and migratory capacity of GBM cells and mouse xenografts. SLAM-seq, CUT&RUN and cell cycle assays were used to study the mechanistic effects of CDK12/CDK13 depletion in GBM cells.

Results

CDK12/CDK13 depletion markedly reduced the proliferatory and migratory capacity of GBM cells, as well as in vivo growth. CDK12/CDK13 inhibition potentiated existing chemotherapeutic treatments. Mechanistically, inhibition of CDK12/CDK13 leads to a genome-wide abrogation of RNAPII CTD phosphorylation, which in turn disrupts transcription and cell cycle progression in GBM cells.

Conclusion

These results provide proof-of-concept for the potential of CDK12 and CDK13 as therapeutic targets for GBM.
P10.13.B Repurposing neuroleptics to treat brain metastases: Clozapine as a novel therapy for melanoma brain metastases
Authors: Wikerholmen T , Taule E , Thorsen F A , Sundstrøm T
Published: September 2022

Background

Around half of advanced melanoma patients develop brain metastases (BM) and survival is still 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. However, utilizing drug repurposing, i.e. novel uses of drugs already approved for other medical conditions, may broaden available therapy options. Medications used to treat psychosis can penetrate an intact blood-brain barrier and it has been shown that patients with schizophrenia have lower incidences of certain cancer types than the rest of the population. Still, little is known on antitumor effects of neuroleptics on BM. We have preliminary data showing that the antipsychotic drug clozapine effectively inhibits growth of human melanoma brain metastasis (MBM) cell lines in vitro.

Material and Methods

We used the H1, H2, H3 and H10 MBM cell lines, as well as normal human astrocytes (NHA). Monolayer viability and IncuCyte studies were performed to determine IC50 doses. Cell migration was measured by a scratch wound assay. Apoptosis was studied by flow cytometry. Colony formation assays were performed using 2D clonogenic assays and 3D soft agar models. A protein array was used to find signaling proteins potentially affected by clozapine. The effect of clozapine on the normal brain was assessed, using a novel brain organoid model developed from fetal rat brains.

Results

A viability screening using 6 different neuroleptics showed that clozapine was most effective in inhibiting MBM cell viability, while NHA tolerated the same doses. MBM cells exhibited a dose-dependent inhibition of cell proliferation, migration, clonogenic formation and 3D growth. 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 are currently being confirmed by western blots. Doses significantly above MBM IC50 doses did not affect viability of brain organoids. Currently, a partnership with the Dept. of Chemistry (UiB) has been initiated to develop and test novel clozapine derivates, to find a more effective derivative with a larger therapeutic window and lesser side effects.

Conclusion

Clozapine shows promise as a novel agent for use in cancer therapy due its favorable tolerability, small molecular size and established clinical safety.
P11.04.A Observational, prospective multicenter study on the role of body mass index (BMI) in the development of thrombotic complications in cancer patients with PICC: preliminary results
Authors: Simonetti G , Gammone M , Bersani A , Garofalo R , Anghileri E , Botturi A , Gaviani P , Redaelli V , Silvani A
Published: September 2022

Background

Peripherally inserted central catheters (PICC) became widespread and changed substantially the approach to the patients venous system. They guarantee, both in hospital and at home, a stable and safe vascular access to administer irritants or vesicants therapies. However, the benefit provided may occasionally be affected by relevant thrombotic complications especially in patients with hypercoagulability such as oncological patients. Among the identification of independent risk factors, the role of a BMI>25 kg/m2 is now emerging in literature with conflicting results.

Material and Methods

Oncological patients with PICC were included in this multicenter prospective study. We evaluated clinical data, BMI, KPS, steroid therapies and anticoagulants at the time of PICC positioning and at regular intervals.

Results

A total of 51 patients were analyzed. The median KPS was 90 (range 80-100), and the median ECOG was 1 (range 0-3). The most common tumors were represented by: lymphomas both Hodgkin and non-Hodgkin (38%), lymphatic and myeloid leukemia (35%), neurooncological tumors including glioblastoma, primary central nervous system lymphoma, anaplastic astrocytoma and meningioma (15%), other solid cancer (breast, gastroesophageal, rectal cancer) (12%).55% patients were at first diagnoses, 12% were at the first recurrence, and the remaining were at the second or third recurrence. No malpositioning were registered. 18% of patients were on anticoagulant/antiplatelet therapy, 67% were treated with steroids. Concerning BMI, 39% was normal weight, 43% overweight and 10% obese, only 2% was considered underweight. Overall, 8% of patients developed PICC related thrombosis within a median time of 68 days (49-87) after PICC implantation mainly occurred in upper right extremity insertion sites. We therefore assessed the incidence of PICC related thromboembolic events in the groups, with 4% of event registered in the cohort of patients overweight/obese, and 14% of events in the cohort of patients with normal weight/underweight.

Conclusion

Preliminary analysis does not allow to draw firm conclusions. It will therefore be necessary to reach the sample size for achieve generalizable results and confirm the risk of developing thromboembolic events in overweight/obese patients. Meanwhile, an accurate anamnesis and a physical evaluation with particular attention to the presence of malnutrition, both over nutrition and undernutrition, could help to identify potential oncological patients at risk of developing PICC related thrombosis.
P11.21.B Distinct age-related molecular and clinical features inIDH-Wildtype Glioblastoma
Authors: Richter S , Stasik S , Schackert G , Thiede C , Krex D , Juratli T A
Published: September 2022

Background

The incidence of IDH-wildtype Glioblastomas (IDH-wt GBM) are highest amongst the elderly. However, IDH-wt GBM can occur in younger patients, subsequently associated with a relatively better prognosis. We aimed for comprehensive molecular characterization of IDH-wt GBM in a cohort with large range of Age at onset (AAO) to investigate age-related molecular patterns with potential impact on clinical tumor features and patients′ outcome.

Material and Methods

We performed Whole Exome Sequencing (WES) on 55 patients with IDH-wt GBM. Sanger Sequencing was utilized for the TERT-promotor region as well as selected candidate genes to validate the results of the WES. Moreover, Progression-free- and Overall survival (PFS, OS) data, clinical- and tumor features were collected.

Results

The patients’ median AAO was 58 yrs. (range: 22.9-70.8 yrs.). We divided our study cohort into three subgroups based on AAO quartiles for further analysis: Group A: 22.9-40.4 yrs. (Q1), Group B: 44.5-71.0 yrs. (Q2-3) and Group C: 72.7-79.8 yrs. (Q4). The median OS for all patients was 15.9 months with a PFS of 9.5 months. The median tumor volume at initial presentation was 43.8 cm3 and correlated with AAO: 63.6 cm3 (Group A) vs. 41.2 cm3 (Group C).We identified a median of 32 mutations per tumor. Exome and Sanger sequencing detected frequent alterations on TERT-promoter (76.4%) and EGFR (90.9% gain, 50.1% amplification, 29.1% mutation). Chromosome 7 gain (92.7%) and Chromosome 10 deletion (85.5%) occurred significantly less in younger patients (Group A vs. Groups B/C; p=0.037, p=0.013). However, other individual alterations did not correlate with AAO. Via clustering of various alterations (e.g. TP53, PDGFRA, ATRX), we found an association between a proneural GBM signature and younger AAO (p=0.036). AAO itself had an independent impact on OS: 21.5 Mo. (Group A) vs. 10.1 Mo. (Group C). Moreover, we described TET1-deletions on Chr. 10 in 90.1% of cases, which was not previously described in IDH-wt GBM. Bi-allelic TET1 deletions (32.7%) with concurrent EGFR-amplification had a significant impact on patient’s outcome (OS 12.2 Mo. vs. 17.6 Mo.; p=0.013).

Conclusion

Although GBM signatures showed subtle association with AAO, our data provides no evidence for an age-specific molecular pattern. The vast amount of detected alterations regardless of AAO underlines the overall heterogeneity of IDH-wt GBM. The cause of better prognosis at younger age remains unclear on a molecular explanatory approach. Finally, a bi-allelic deletion of TET1 may represent a relevant alteration in IDH-wt GBM.