bluuebunny/crossref_metadata_2025_split huggingface dataset:
P08.01.A Evaluation of a multimodal rehabilitative palliative care programme for patients with high-grade glioma and their family caregivers
Authors: Nordentoft S , Dieperink K , Johansson S , Jarden M , Piil K 
Published: September 2022

Abstract

Background
When a family member is diagnosed with high-grade glioma, it not only affects the patient, but also the entire family. Due to an intense disease- and treatment trajectory and a complex symptom burden, patients often depend on support from their family caregivers. Family caregivers struggle to adjust to a change in family roles. Hence, proper information and supportive care are essential for patients and family caregivers to help them manage their changed life situations.

Material and Methods
This was a longitudinal multi-methods study applying qualitative interview data and quantitative survey data to explore and evaluate the programme. A multimodal rehabilitative palliative care programme was designed by a multidisciplinary cross-sectoral team of clinical specialists and researchers. The purpose was to provide patients and family caregivers with information and facilitate the exchange of perspectives and experiences among peers e.g. on daily living and family function. Additionally, to provide participants with strategies to manage this life transition

Results
Adult patients with high-grade glioma (n = 17) and their family caregivers (n = 16) completed a 4-day residential programme and a 2-day follow-up programme 3 months later. Qualitative data were collected during focus group interviews (n = 4) with patients and caregivers. Participants responded to self-developed questionnaires after each programme, scoring all sessions for relevance and satisfaction on a 5-point Likert scale (0, not relevant/satisfied; 5, very relevant/highly satisfied). Three themes emerged in the focus group interviews: 1) meeting peers strengthens social well-being, 2) the value of information and focusing on individual needs, and 3) accepting life as an unpredictable passage. The mean overall satisfaction score was 4.80 (standard deviation [SD], 0.55) for the initial 4-day programme and 4.28 (SD, 0.83) for the follow-up programme.

Conclusion
The multimodal rehabilitative palliative care programme addressed unmet patient and caregiver needs and may have the potential to enhance family function or coping mastery. The programme was feasible, and all sessions received high scores for satisfaction and relevance, as well as positive evaluations. Qualitative findings confirmed the value of individualized information and peer interactions. In particular, peer-to-peer interventions for family caregivers may address individual support needs, including sharing experiences and strengthening social well-being.
P08.02.B The Clinical Frailty Scale as predictor of overall survival after resection of high-grade glioma
Authors: Klingenschmid J , Krigers A , Pinggera D , Kerschbaumer J , Thomé C , Freyschlag C F 
Published: September 2022

Abstract

Background
The Clinical Frailty Scale (CFS) describes the general level of fitness or frailty and is widely used in geriatric medicine, intensive care and orthopaedic surgery. This study was conducted to analyze, whether CFS could be used for patients with high-grade glioma.

Material and Methods
Patients harboring high-grade gliomas, undergoing first resection at our center between 2015 and 2020 were retrospectively evaluated. Patients’ performance was assessed using the Rockwood Clinical Frailty Scale and the Karnofsky Performance Scale (KPS) preoperatively and 3-6 months postoperatively.

Results
289 patients were included. Pre- as well as postoperative median frailty was 3 CFS points (IqR 2-4) corresponding to “managing well”. CFS strongly correlated with KPS preoperatively (r = -0.85; p &lt; 0.001) and at the 3-6 months follow-up (r = -0.90; p &lt; 0.001). The reduction of overall survival (OS) was 54% per point of CFS preoperatively (HR 1.54, CI95% 1.38-1.70; p &lt; 0.001) and 58% at the follow-up (HR 1.58, CI95% 1.41-1.78; p &lt; 0.001), comparable to KPS. Patients with IDH mutation showed significantly better preoperative and follow-up CFS and KPS (p &lt; 0.05). Age and performance scores correlated only mildly with each other (r = 0.21⋯0.35; p &lt; 0.01), but independently predicted OS (p &lt; 0.001 each).

Conclusion
CFS seems to be a reliable tool for functional assessment of patients suffering from high-grade glioma. CFS includes non-cancer related aspects and therefore is a contemporary approach for patient evaluation. Its projection of survival can be equally estimated before and after surgery. IDH-mutation caused longer survival and higher functionality.
P08.04.B The Clinical Frailty Scale is superior to the Karnofsky Performance Status as predictor of overall survival in patients with surgical treatment of brain metastases
Authors: Krigers A , Pichler N , Kerschbaumer J , Demetz M , Klingenschmid J , Thomé C , Freyschlag C F 
Published: September 2022

Abstract

Background
The Clinical Frailty Scale (CFS) evaluates patients’ level of frailty on a scale from 1 (very fit) to 9 (terminally ill) and is commonly used in geriatric medicine, intensive care and orthopaedics but not in patients harboring neuro-oncological diseases. Our study was conducted to reveal if the usage of CFS generates more reliable prediction of overall survival in patients after brain metastases resection rather than Karnofsky Performance Status (KPS).

Material and Methods
All patients which were operated for brain metastatic disease at our department from 2005-2019 were included. CFS and KPS were retrospectively assessed for the timepoints pre- and postoperatively as well during follow-up 3-6 months after resection.

Results
205 patients with mean follow-up of 22.8 months (CI95% 18.4-27.1) were evaluated. Mean estimated OS was 32.1 months (CI95% 25.0-39.1). CFS showed a median of 3 points (IqR 2-4) at all 3 assessment-points which means patients were “managing well”. Median KPS was 80 preoperative (IqR 80-90) and 90 (IqR 80-100) postoperative as well as on follow-up after 3-6 months. CFS strongly correlated with KPS: preoperatively (r=-0.92; p&lt; 0.001), postoperatively (r=-0.85; p&lt;0.001) and at follow-up (r=-0.93; p&lt;0.001). In the same time, CFS pre- and postoperatively showed only weak correlation with CFS at follow-up after 3-6 months (r=0.30, p&lt;0.001; and r=0.37, p&lt;0.001, correspondingly). In multivariate integrated Cox regression model, the CFS predicted the expected reduction of OS superior to KPS at all 3 assessment-points. One point increase of preoperative CFS represented 30% additional hazard to decease (HR=1.30, CI95% 1.15-1.46; p&lt;0.001), correspondingly postoperative CFS provides 39% (HR=1.39, CI95% 1.25-1.54; p&lt;0.001) and at follow-up 42% of hazard (HR= 1.42, CI95% 1.27-1.59; p&lt;0.001). In case of KPS, decrease of 10 points resulted in additional hazards to decease of 26% (HR=0.974/point, CI95% 0.962-0.987; p&lt;0.001) postoperatively 14% (HR=0.986/point, CI95% 0.978-0.993; p&lt;0.001) and 31% (HR=0.969/point, CI95% 0.959-0.978; p&lt;0.001) at follow-up.

Conclusion
CFS is a feasible and reliable performance scoring in patients undergoing brain metastasis resection, that provides better OS prediction as compared to KPS. Whereas, CFS at follow-up after 3-6 months specifies the expected OS most accurately. Due to weak correlation between CFS preoperatively vs. postoperatively and in 3-6 months, initial frailty does not predict the patients’ postoperative frailty score.
P08.07.A Long-term multidimensional assessment of fatigue and fatigue as predictor of survival in patients with brain metastases after Gamma Knife radiosurgery
Authors: Verhaak E , Schimmel W , Butterbrod E , Sitskoorn M , Hanssens P , Gehring K 
Published: September 2022

Abstract

Background
The aim of this study was to assess long-term multidimensional fatigue and (change in) fatigue as predictor for survival in patients with brain metastases (BM) up to 21 months after Gamma Knife radiosurgery (GKRS).

Material and Methods
Patients with 1 to 10 BM, expected survival &gt;3 months, and Karnofsky Performance Status ≥70 were included. Fatigue was measured with the Multidimensional Fatigue Inventory (MFI). Linear mixed models were used to evaluate fatigue up to 21 months after GKRS. Fatigue before GKRS and changes in fatigue in the first three months after GKRS were evaluated as predictors for survival duration.

Results
Patients with BM experienced significantly higher levels of fatigue on all subscales prior to GKRS (n=92) compared to Dutch controls (n=104), all p’s≤.001. Over 21 months, levels of physical fatigue increased significantly (p=.001), and levels of mental fatigue decreased significantly (p=.004). Between pre-GKRS and 3 months, there was a significant increase in levels of general (p&lt;.001) and physical fatigue (p&lt;.001), followed by stable fatigue scores between 3 (n=67) and 6 (n=53) months, 6 and 12 (n=34) months and 12 and 21 (n=21) months. Minimal clinically important (MCI) increases in general (p=.023, time ratio=0.61) and in physical fatigue (p=.008, time ratio=0.56) from pre-GKRS to 3 months thereafter were independent negative predictors of survival time (i.e., an MCI increase in these domains predicted a reduction of 39% and 44% respectively in survival time compared to stable or decreased fatigue).

Conclusion
Results indicate that up to 21 months after GKRS fatigue is a persistent problem in patients with BM. Except for an increase in general and physical fatigue up to 3 months after treatment, fatigue remained stable up to 21 months after GKRS. In addition, an MCI increase in general or physical fatigue within three months after GKRS may be related to worse survival outcome.
P08.09.A Improving support for family carers: Creating a cross-sector collaborative working group
Authors: Nicklin E , Jopson J , Boele F 
Published: September 2022

Abstract

Background
Family carers of people with brain tumours and other progressive neurological conditions have unique but overlapping support needs. This is because caring can be particularly challenging due to patients’ cognitive issues, behavioural changes, and neuropsychiatric symptoms. We undertook stakeholder engagement work to bring together family carers, academics, service providers and policy makers to form a working group and highlight opportunities for improvement of family carer (FC) support.

Material and Methods
Sixteen stakeholders (academics, carers, charity representatives, clinicians and policy makers) participated in two one-hour online workshops (N=8 in each). Workshops started with introductions, an outline of meeting objectives, and a specially created animated video introducing the topic. A structured discussion followed, focusing on current FC support and barriers in accessing support. Finally, we covered blue-sky thinking exercises, with attendees describing their ideal vision of FC support in the future; and how the group can work together to improve support. Workshop findings were integrated into a position statement.

Results
The position statement covers five pillars for joint action. 1) Collaboration, coordination, and co-design - current support is fragmented. Better collaboration is needed between the social care sector, the third sector, and healthcare systems, to stop struggling FCs falling through the net. 2) Valuing carers - there is a need to acknowledge and enhance the awareness of FC contributions, e.g. through co-producing research publications highlighting the value FCs bring. 3) Redefine personalised medicine- carer support needs are varied and no one size fits all. Personalised care is key to identify specific needs of carers arising from aspects of diversity, such as ethnicity and age. 4) Flexible evidence-based support- we need to build a better evidence-base for FC support; and prioritise evidence-based support. This is especially important given the scarcity of funds and resources for FCs. 5) Promotion of current support services- many FCs do not know where to get support locally. More research can help to identify barriers and facilitators to support carers’ access to formal support.
Conclusion:
To improve support for FCs, we need to move away from fragmented approaches and move towards a more collaborative approach with carers at the centre. Our collective vision is that future support is based on what matters to them as individuals and what is effective in meeting their needs. We strive to provide flexible, accessible, responsive and inclusive support for FCs, and invite other carers, service providers, academics and policymakers to join our effort.
P08.10.B Family-centred care in neuro-oncology: a longitudinal mixed-methods feasibility study
Authors: Piil K , Locatelli G , Laegaard Skovhus S , Tolver A , Jarden M 
Published: September 2022

Abstract

Background
A diagnosis of a malignant brain tumour represents a fearful event for patients, often followed by severe physical, cognitive, emotional, and psychosocial impairments. In turn, being a family member and an informal caregiver of a person with an oncological disease is also a burdensome experience. Family and network can influence patient outcomes, and family-centred intervention may help both patients and caregivers to face illness-related issues. However, studies aiming at implementing family-centered interventions in patients with high grade glioma (HGG) and their families are scarce. Therefore, this study aims to understand how patients with HGG and their families experienced the course of illness and investigate the impact of family and network consultations (FNCs) on both of them.

Material and Methods
We adopted a quasi-experimental feasibility study using a longitudinal mixed-methods design. The intervention consisted of three FNCs delivered over a 1-year period. Quantitative data on physical activity level, anxiety, depression, family functioning, perceived nursing support, symptom burden and interference on daily living, caregiver burden and quality of life were collected at four time points. Qualitative data on patients’ and families’ perspectives on the intervention were explored through telephone interviews.

Results
A total of 21 patients with HGG and 47 family members were included in the study. Patients mean age was 66 years and they were mainly male (86%), married and living with the patient (95%), and retired (54%). Caregivers mean age was 47 years, and they were mainly female (62%), children of the cared person (47%), and employed (55%). The integration of quantitative and qualitative data showed that many variables improved over time (e.g., symptom interference in patients, family functioning in caregivers, quality of life) or remained stable (e.g., anxiety and depression), apart from physical functioning and symptom burden that worsened. Families described FNCs as a valuable strategy to holistically address the needs and concerns of the entire family and to strengthen the family dialogue and union.

Conclusion
FNCs can be a valuable strategy to implement family-centred care practices. However, advanced nursing competencies are required to provide optimal family-centred care. Plus, the intervention should be personalized and based on the needs of each family.
P10.01.A Reversible blood-brain barrier (BBB) disruption by Tumor Treating Fields (TTFields) in a human 3Din vitro model
Authors: Salvador E , Kessler A F , Köppl T , Schönhärl S , Burek M , Tempel Brami C , Voloshin T , Giladi M , Ernestus R , Löhr M , Förster C , Hagemann C 
Published: September 2022

Abstract

Background
Drug delivery to the central nervous system (CNS) is often impeded by the restrictive nature of the blood brain barrier (BBB). Since many therapeutic molecules are not able to traverse this barrier, the development of new methods to disrupt the BBB is of paramount importance. Tumor Treating Fields (TTFields) are alternating electric fields of low intensity (1-3 V/cm) and intermediate frequency (100-300 kHz), which are approved and effective for the treatment of glioblastoma at a frequency of 200 kHz. We recently demonstrated that TTFields at lower frequencies are able to transiently induce BBB permeability in in vitro and in vivo murine models. Here, we explored whether the transient opening of the BBB by TTFields in our murine systems also translates to a human cell-based 3D model.

Material and Methods
A three-dimensional BBB model was established by co-culturing primary human brain microvascular endothelial cells (HBMVEC) on a transwell insert together with human pericytes on the bottom of a well-plate. The model was treated with TTFields at 100-300 kHz for 2496 h using the inovitro™ TTFields Lab Bench System (Novocure®). Afterwards, the cells recovered for 24-96 h. In order to analyze the effects of TTFields on barrier integrity and compromise, transendothelial electrical resistance (TEER) of the HBMVEC monolayer was measured before the start of TTFields treatment, immediately after TTFields cessation, as well as 24-96 h after TTFields treatment. Permeability of the barrier was assessed by visualizing the movement of FITC-dextran through the HBMVEC monolayer. In addition, changes in expression and localization of the tight junction protein (TJP) claudin-5 (Cl-5) after application of TTFields were analyzed by fractionated Western-blotting and immunofluorescence (IF) staining, respectively.

Results
Application of TTFields at all investigated frequencies significantly decreased TEER across the HBMVEC monolayer after as early as 24 h, with the strongest effects seen after 72 h at a TTFields frequency of 100 kHz. TTFields treatment delocalized TJP Cl5 from the cell boundaries to the cytoplasm as evidenced by Western-blots and IF stainings. Restoration of the cell barrier was already measurable as early as 24 h after TTFields cessation and a complete recovery was evident after 48 h.

Conclusion
These results in a human 3D in vitro model confirm our previous observations from mouse models that TTFields could transiently open the BBB. These fundamental pre-clinical data demonstrate the feasibility of facilitating drug delivery to the CNS via concomitant application of TTFields. This method opens up the prospect of improved drug-based treatment of devastating CNS diseases such as GBM if these results could be translated to the clinical setting in the future.
P10.03.B Insights into the development of tunable brain implants for local chemotherapy
Authors: Waldherr L , Handl V , Abrahamsson T , Arbring Sjöström T , Seitanidou M , Erschen S , Honeder S , Tomin T , Birner-Grünberger R , Ghaffari Tabrizi-Wizsy N , Ropele S , Ücal M , Nowakowska M , Schäfer U , Patz S , Simon D , Schindl R 
Published: September 2022

Abstract

Background
Glioblastomas (GBMs) remain an unmastered medical challenge. Poor delivery and systemic toxicity of many chemotherapeutic agents limit their therapeutic success in GBM treatment. Bioelectronic implants for local chemo drug delivery can optimize drug concentrations at the tumor site, duration of treatment and tumor suppression, while systemic effects remain at an acceptable low level. We present miniature bioelectronic devices for drug delivery able to administer chemotherapeutics via electric control with high spatiotemporal precision.1 The drug delivery is based on the electro migration of drug molecules in an ion selective matrix towards a target of choice. These bioelectronic devices, called chemotherapeutic ion pumps (chemoIPs), can be used for triggered drug release of chemotherapeutics that are usually shielded by the blood brain barrier.

Material and Methods
The performance of chemoIPs is studied in different brain tumor models with increasing complexity (cell culture and different in vivo models). With chemoIPs it is possible to constantly administer drugs with highest precision (delivery rates at pmol*min-1 precision) towards cell culture spheroids, ex ovo-grown tumors and in vivo brain tumors

Results
The treatment efficiency was analyzed via flow cytometry quantifying apoptosis and cell cycle arrest, as well as immune-histochemical analysis for apoptosis. ChemoIP treatment is able to trigger the disintegration of targeted tumor spheroids, and is able to inhibit the tumor growth of ex ovo-grown glioblastomas significantly. Furthermore, the proteomes of neurons and glioblastoma cells were recorded via proteomics, which showed that only GBM cells are harmed by the chemotherapeutic treatment, but not neurons. In parallel, can follow the pharmacokinetics of the chemoIP-mediated drug administration via drug quantification using mass spectrometry and compare it to computer simulations in different tumor models.

Conclusion
The here exemplified electrically-driven drug delivery via chemoIPs is a drug administration method that can serve as basis for further implant development, which has the potential to increase the efficacy of chemotherapy due to highly-targeted and locally-controlled drug delivery.
P10.04.A The development of a potent, tumour-specific heptamethine cyanine dye-palbociclib conjugate with novel mechanisms of action for the treatment of glioblastoma
Authors: Cooper E A , Choi P J , Schweder P , Correia J , Turner C , Faull R , Denny W A , Dragunow M , Jose J , Park T I 
Published: September 2022

Abstract

Background
Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-cancer agents for brain tumours is challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery

Material and Methods
We conjugated palbociclib, a cyclin-dependent kinase 4/6 inhibitor to the HMCD, MHI 148 for the treatment of GBM. Patient-derived GBM cell lines were established from surgically resected biopsy GBM tissue.

Results
High-throughput drug screening revealed an almost 100-fold increase in cytotoxicity of the palbociclib-MHI 148 conjugate compared to palbociclib alone. Moreover, the palbociclib-MHI 148 conjugate was synergistic with radiation, but not with temozolomide. Further analysis revealed the palbociclib-MHI 148 conjugate was superior to other cyclin-dependent kinase inhibitors in vitro. The shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI 148 prompted further investigation. We revealed that palbociclib-MHI 148-dependent inhibition of cell-cycle progression resulted in increased DNA damage. This preceded increased transcription of key extrinsic apoptosis genes and caused a time-dependent upregulation of TNFR1 endocytosis-dependent cell death signalling. Notably, inhibition of endocytosis and siRNA knockdown of TNFR1 prevented palbociclib-MHI 148-induced cell death.
Conclusion:
These results highlight a novel mechanism of action of palbociclib when conjugated to MHI-148 that induced autocrine-driven TNFR1-mediated apoptosis. In addition, we highlight the potential application of HMCDs in repurposing tyrosine kinase inhibitors, to overcome the current limitations preventing the expansion of second-line treatment options for GBM.