bluuebunny/crossref_metadata_2025_split huggingface dataset:
P06.17.A OPTIC NEUROPATHY RELATED TO IMMUNE CHECKPOINT INHIBITORS: A CASE SERIES
Authors: Cuzzubbo S , Philippakis E , Baroudjian B , Ursu R , Lebbé C , Coutourier A , Carpentier A F 
Published: September 2023

Abstract

BACKGROUND
Immune checkpoint inhibitors (ICIs) are associated with a broad spectrum of neurotoxicities. ICI-related optic neuritis have been rarely reported and poorly described. However, their knowledge is essential to promptly recognise and manage them since a persisted visual decline is reported in approximately half of the patients. A systemic steroid treatment has been correlated to a better prognosis.

MATERIAL AND METHODS
We report a retrospective series of patients with an ICI-related optic neuritis, referred to our departments between 2018 and 2022, with the aim to describe their clinical and para-clinical features and the outcome. Other causes of optical neuropathy were excluded by blood analysis and brain MRI.

RESULTS
We identified three melanoma patients who developed an ICI-related optic neuropathy. They were treated with combined ipilimumab with nivolumab (n=2) or pembrolizumab monotherapy (n =1). The symptoms occurred after a delay of 43-196 days from ICI initiation and consisted of bilateral painless reduction of visual acuity, associated with colored scotomas in one case and conjunctival erythema in another case. Ophthalmological examination found a bilateral papilledema in all the patients, associated with a panuveitis in one case (patient #1). The presence of papilledema was verified by fundus fluorescein angiography and optic coherence tomography (OCT). Visual evoked potential confirmed a bilateral involvement of optical nerves in two cases, and was normal in the third case, which was thus consistent with a papillitis. ICIs were stopped in patients #1 and #2 and oral steroids started in patient #1. Both patients experienced a complete recovery within 2 weeks from steroids onset and 24 weeks from the last ICI dose, respectively. Given the quick and spontaneous improvement of both symptoms and ophthalmological exam, ICI was continued with the same regimen in patient #3, and the optic neuropathy progressively improved until complete recovery 3 months later. ICI treatment was reintroduced in patient #2 after four months, with no recurrence of the optical neuritis until the last follow up (5 years).

CONCLUSION
As reported in other series of immune-related optic neuropathies, a bilateral optic nerve involvement with painless decline of vision and papilledema was the most common presentation. Unlike other reports, all the patients of this series experienced a favorable outcome, with total recovery of vision and normalization of the ophthalmological exam. The recovery seems more rapid if patient receive steroids. We reintroduced or continued the ICI in two patients, with no recurrence of optic neuritis, thus suggesting that ICI treatment discontinuation is not mandatory in case of non-severe optical neuropathies. However, a careful analysis of the benefit/risk ratio should be done on a case-by-case basis.
P07.06.A PATIENT-DERIVED GLIOBLASTOMA MINIATURE AND CANCER STEM CELL SUICIDE-INDUCING NANO-AWAKENER BASED ON IT
Authors: Yoon S , Baek S , Yoo S , Jo E , Lee D , Shim J , Choi R , Park J , Moon J , Kim E , Chang J , Lee J , Park J , Sung H , Kang S 
Published: September 2023

Abstract

BACKGROUND
Patient-specific anti-tumor therapies can evolve by vitalizing the mother tissue-like cancer niche, cellular profile, genetic signature, and drug responsiveness. This evolution elucidated a key mechanism along with the development of the cancer therapy. The present study aimed to meet these clinical demands by approaching the direct culture of GBM patient tissues with a 1 mm post-punching diameter in a 3D microchannel network chip (“GBM miniature”).

MATERIAL AND METHODS
Hence, we directly cultured of GBM patient tissue (1 mm diameter) in a microchannel network chip (GBM miniature) to preserve mother tissue-like characteristic signatures and microenvironment. When chemoradiation therapy were administered within 1 day, the responsiveness of the tissue in the chip mirroring the clinical outcomes. The characteristics of migrating cells from GBM miniature were analyzed, and peptides that target these migrating CSCs were searched for. And, by attaching this CSC peptide to the nanovesicle, the therapeutic effect was confirmed in GBM miniature.

RESULTS
Upon testing within 1 day, the tissue chip reflected patient drug responsiveness as seen in the clinic. As the tissue chip culture was continued, the intact GBM signature was getting lost, and the outward migration of stem cells from the tissue origin increased, indicating a leaving-home effect on the family dismantle. Nanovesicle production using GBM stem cells enabled self-chasing of the cells that escaped the temozolomide effect owing to quiescence. The anti-PTPRZ1 peptide display and temozolomide loading to nanovesicles awaked stem cells from the quiescent stage to death.

CONCLUSION
This research proposes a GBM patient avatar platform and mechanism-learned nanotherapy for translation.
P07.08.A DEVISING AN EXOSOMES CONTROLLED-RELEASE HYDROGEL FOR GLIOBLASTOMA THERAPY
Authors: HE Z , Meng Z , Wang G 
Published: September 2023

Abstract

BACKGROUND
An efficient therapeutic method for glioblastoma hasn’t been founded. Nowadays, the combination of tumor surgery resection and chemoradiotherapy show limited outcomes even implanting a drug-loaded wafer on the tumor resection cavity during the surgery. Although Local drug delivery improves the adverse effects of intravenous chemotherapy drug injection, the low efficiency of drug transmembrane transportation still leads to poor therapeutic outcomes. Meanwhile, the stiff wafer is not able to perfectly match the irregular shape of the resection cavity. Recently, drug-loaded nanoparticles coated by tumor-derived exosomes applied in tumor-targeting drug delivery were frequently reported. The unique feature of tumor-homing, immune evasion of tumor-derived exosomes was used to improve the delivery efficiency, however, the therapeutic efficiency is weakened by liver filtration and the blood-brain barrier.

MATERIAL AND METHODS
For enhancing the therapeutic efficacy and compatibility of tumor resection cavity, in this project, a novel injectable hydrogel carrying DOX-loaded nanoparticles coated by tumor-derived exosomes, called Exo-DMSNs@CS, for intra-operative therapy of glioblastoma was devised. The doxorubicin-loaded nanoparticles encapsulated by tumor-derived exosomes (Exo-DMSNs) were integrated into body-temperature sensitive chitosan hydrogel, then injected into the tumor resection cavity and gelation along the shape. By passing the blood-brain barrier, the therapeutic efficacy can be improved by elevating the delivery efficiency induced by the released tumor-targeting Exo-DMSNs.

RESULTS
The hydrogel Exo-DMSNs@CS was successfully fabricated and contained features of thermosensitive, in vivo controlled releasing, in vitro tumor-targeting, and biocompatible. For simulating the scenario of intra-operative therapy, the Exo-DMSNs@CS was evaluated in the mice orthotopic GBM resection model. The decreased relapse speed and extended survival showed in the Exo-DMSNs@CS compared to DMSNs@CS demonstrated that the tumor-exosomes improve the prognosis of the mice. Moreover, the acceptable side effect was also confirmed.

CONCLUSION
The Eco-DMSNs@CS is suitable for therapy with better efficiency compared to traditional local drug delivery. This research provides a new strategy for glioblastoma patients and data support for similar product devising.
P08.03.A CAREGIVERS OF ADULT NEURO-ONCOLOGICAL PATIENTS: UNMET NEEDS AND RELEVANT PROBLEMS - A PROSPECTIVE STUDY
Authors: Spieker M , Rapp M , Rieger D , Bombach P , Kurz S , Tatagiba M , Sabel M , Tabatabai G , Renovanz M 
Published: September 2023

Abstract

BACKGROUND
The diagnosis of a brain tumor represents high burden for patients’ caregivers. Psychosocial screening tools for caregivers adapted to neuro-oncological tumor entities are urgently required but do not exist. To bridge this gap, we aim to develop a problem list in terms of a holistic need assessment tailored to their unmet needs of caregivers for an application in combination to the NCCN distress thermometer scale.

MATERIAL AND METHODS
First, items of high relevance for the caregivers were identified on basis of retrospective analyses. Second, we prospectively conducted an assessment in two centers: in the first center, caregivers filled out a questionnaire (center A), in the second center, the questionnaire was applied as qualitative interview with caregivers (center B). We performed a qualitative content analysis applying inductive/deductive categorizations of the reports.

RESULTS
The qualitative interviews included n=11 main questions and up to 4 subquestions focusing on changes in everyday life, relationship, social live, emotional, physical, financial, spiritual problems and support needs. A total of 47 caregivers were assessed (n=25 in center A via questionnaire, n=22 in center B via interviews) during outpatient visits. Most of the caregivers wished for psychological support (27/47, 57%), first contact with psycho-oncologists after first diagnosis (25/47, 53%) or in case of a clinical deterioration (28/47, 59%). Strategies for problem solving (26/47, 55%) and finding sources of strength (22/47, 47%) were most important regarding needed support. Changes in everyday life’ were reported by 87% of caregivers (41/47), including constraints/organization of (medical) appointments (24/47, 51%) or constant availability required for the partner (20/47, 43%). Also, 70% (33/47) put their own interests last or adapt their leisure activities. In the qualitative interviews (Center B), additional items indicating caregiver burden were identified: “dealing with psychological problems of the patient” (3/22, 16%), “different coping strategies among patient and caregiver” (4/22, 18%). Emotional problems, particularly depressive symptoms were addressed more profoundly in the qualitative interviews (“loss of interest and feelings of sadness”, 4/22, 18%).

CONCLUSION
The interviews reflected the unmet needs of brain tumor caregivers and allow for the targeted assessment of the specific burdens. Furthermore, we were able to gather more in-depth information per qualitative interviews.
P09.02.B THE RELATIONSHIP BETWEEN SYMPTOMS AND THE SOCIAL DETERMINANTS OF HEALTH AMONG THE PRIMARY BRAIN TUMOR POPULATION: A SYSTEMATIC REVIEW
Authors: Stockdill M L , Johnson M , Karim Z , Cooper D , Armstrong T S , King A L 
Published: September 2023

Abstract

BACKGROUND
Social determinants of health (SDoH) account for up to half of all health outcomes in the general population, but their impact on symptoms is less understood, especially in rare cancers such as primary brain tumors (PBT).

MATERIAL AND METHODS
We reviewed the literature and examined the relationship between SDoH and mood and neurocognitive symptoms in the PBT population. PubMed, EMBASE, and CINAHL identified 3,006 publications. SDoH were defined using PROGRESS criteria (Place of residence, Race/ethnicity, Occupation, Gender, Religion, Education, Socioeconomic status, Social capital). Two individuals screened and assessed study bias.

RESULTS
Of 3,006 abstracts identified, 150 full text articles were assessed for eligibility and 48 studies were included with a total sample of 28,454 PBT participants. 27 studies were cross-sectional with the majority from single institutions in the US (12), Germany (10), or Netherlands (5). Sample sizes varied from 27 to 15,320. 22 studies examined the relationship with 1 of the PROGRESS categories and no study examined all 8. 4 studies measured place of residence, 2 race/ethnicity, 13 occupation, 43 gender, 1 religion, 18 education, 4 socioeconomic status, and 15 social capital. 37 studies reported on mood related symptoms with 20 focused on depression, 14 anxiety, and 11 distress. 15 studies assessed neurocognitive symptoms, while 4 assessed both mood and neurocognition. Among studies assessing neurocognition, 1 found a relationship with place of residence and socioeconomic status, 7 out of 10 reported a relationship with education, and 7 of 11 found no relationship with gender. None examined race/ethnicity or religion. Disparate results were found related to occupation. Among the 37 studies assessing mood, results were disparate except for place of residence, which related rural residence to depressive symptoms. Bias assessment revealed that 61% of the studies were fair in quality, 31% poor, and 8% good indicating the majority of studies had evidence of bias.

CONCLUSION
Most studies were descriptive or exploratory and lacked comprehensive inclusion of SDoH, which limited the opportunity to perform meta-analysis. This is the first systematic review examining the relationship of symptoms in the PBT population and SDoH to date. Future studies should use standardized collection of SDoH, reduce study bias, and encourage inclusion of diverse samples to identify gaps for the development of future interventions.
P10.01.A A PATIENT-DERIVEDEX VIVO ORGANOID MODEL ALLOWS EVALUATION OF TUMOR TREATING FIELDS (TTFIELDS) EFFECTS ON GLIOBLASTOMA, ANAPLASTIC EPENDYMOMA AND OLIGODENDROGLIOMA SAMPLES
Authors: Nickl V , Schulz E , Salvador E , Trautmann L , Diener L , Kessler A F , Monoranu C M , Ernestus R , Löhr M , Hagemann C 
Published: September 2023

Abstract

BACKGROUND
The use of TTFields, which are alternating electric fields of low intensity (1-3 V/cm) and intermediate frequency (100-500 kHz), has shown its clinical efficacy in the treatment of newly diagnosed glioblastoma (GBM) patients at 200 kHz. Nevertheless, more knowledge is required for the prediction of individual tumors’ responsiveness to treatment. Recently, we developed patient-derived three-dimensional GBM tissue culture models to screen patient tumors for TTFields treatment susceptibility. Here, we extended these models to brain tumors beyond GBM, namely anaplastic ependymoma (AE) and oligodendroglioma. We cultured tumor-organoids as microtumors on murine organotypic hippocampal slice cultures (OHSCs) and subjected them to TTFields at 200 kHz.

MATERIAL AND METHODS
We prepared OHSCs by slicing the brains of mice 5-8 days postpartum to a thickness of 350 µm using a vibratome and culturing them for 14 days. We obtained organoids from freshly resected tumor tissue from three GBM, one AE, and one oligodendroglioma patient, each. The organoids were cultured for 14 days as well and then stained with carboxyfluorescein succinimidyl ester. Next, we placed the organoids onto the OHSCs and administered TTFields at 200 kHz and 1.5 V/cm for 72 h using the inovitro™ laboratory research system. We quantified microtumor growth by fluorescence imaging.

RESULTS
The three tumor entities, in particular organoids from GBM, AE and oligodendroglioma, grew as microtumors after being placed onto OHSCs. TTFields treatment at 200 kHz led to significantly decreased microtumor size of the three analysed GBM samples as well as the AE sample. However, the oligodendroglioma microtumor size was not significantly reduced.

CONCLUSION
Based on clinical experience, we expected that TTFields lead to a reduction in microtumor size. However, to our knowledge, we were the first to apply TTFields to patient-derived AE and oligodendroglioma samples. The lack of TTFields-effects on the latter might be due to different inter-patient sensitivity or suboptimal TTFields frequency. Nevertheless, our work is proof of principle that an organoid-based patient-derived 3D tissue culture model could be used to evaluate effects of TTFields on different brain tumor entities.
P10.07.A A CLINICALLY COMPATIBLEIN VITRODRUG-SCREENING PLATFORM IDENTIFIES THERAPEUTIC VULNERABILITIES IN PRIMARY CULTURES OF BRAIN METASTASES
Authors: Jeising S , Trübel J , Felsberg J , Picard D , Wolter M , Kaulich K , Häberle L , Esposito I , Steinmann J , Cornelius J , Beez T , Rapp M , Sabel M , Nickel A , Remke M , Reifenberger G , Qin N 
Published: September 2023

Abstract

BACKGROUND
Approximately 20% of cancer patients (including lung, melanoma, breast, renal, and colorectal cancer patients) develop brain metastases. Current systemic therapies often show limited efficacy for brain metastasis treatment and support palliative care only.

MATERIAL AND METHODS
In this preclinical study, short-term cultured primary cancer cells from brain metastasis patients were molecularly characterized using next-generation sequencing and functionally evaluated using high-throughput in vitro drug screening to identify pharmacological treatment sensitivities.

RESULTS
Next-generation sequencing identified matched genetic alterations between brain metastasis tissues and corresponding patient-derived cultured cancer cells. Mutant allele frequencies indicated that short-term cultures of cancer cells reflect the existence of distinct subpopulations of cancer cells within brain metastases. This indicates that our short-term cultured primary brain metastasis cells are suitable models for recapitulating heterogeneity in the sensitivity of tumor cells to anti-cancer drugs. Employing our in-house high-throughput in vitro drug screening platform, we additionally screened primary cultures from the brain metastasis patients for response to 267 anticancer compounds, and integrated the molecular and high-throughput drug screening data sets.

CONCLUSION
Our preclinical study thus provides proof-of-concept for combining molecular profiling with in vitro drug screening for improved prediction of therapeutic vulnerabilities in brain metastasis patients. This approach could advance the use of patient-derived cancer cells in clinical practice and might eventually facilitate decision-making for personalized drug treatment.
P10.08.B PI3K INHIBITION FOR SENSITIZING CANCER CELLS TO TUMOR TREATING FIELDS (TTFIELDS)
Authors: Klein-Goldberg A , Voloshin T , Zemer-Tov E , Paz R , Somri-Gannam L , Volodin A , Koren L , Wainer-Katsir K , Haber A , Dor-On E , Giladi M , Weinberg U , Palti Y 
Published: September 2023

Abstract

BACKGROUND
Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. TTFields therapy is approved for treatment of adult patients with glioblastoma (GBM) or unresectable pleural mesothelioma. Clinical trials are underway in other solid tumors, including ovarian cancer and non-small cell lung carcinoma (NSCLC). The objective of this study is to identify possible mechanisms involved in reduced sensitivity of cancer cell to TTFields, and explore strategies to circumvent them.

MATERIAL AND METHODS
GBM U-87 MG, ovarian cancer A2780, and NSCLC H1299 cells were treated with continuous long-term application of TTFields (1.7 V/cm RMS, 200 or 150 kHz, 6 or 13 days, specific conditions depending on cell line). Changes in signaling pathways were examined for cells following 3 days of treatment with Luminex multiplex assay, followed by Western blot validation for specific pathway markers. In vivo validation was performed in ovarian cancer (MOSE-L), hepatocellular carcinoma (N1-S1), and NSCLC (LL/2) tumor sections from animals treated with TTFields utilizing immunohistochemistry. Next, efficacy of TTFields concomitant with relevant inhibitors was evaluated in vitro and in mice inoculated orthotopically with ovarian cancer cells (MOSE-L). Tumor volume was measured at study end by luciferin signal detection using the In Vivo Imaging System (IVIS).

RESULTS
TTFields inflicted a cytotoxic effect on the cancer cells that increased over time, though with moderately reduced sensitivity following prolonged treatment application. PI3K/AKT signaling pathway was shown to be activated in treated cells, with the amplitude of AKT phosphorylation increasing over time. AKT phosphorylation was also demonstrated in tumor sections of animals treated with TTFields. Experiments performed with concomitant PI3K/AKT pathway inhibitors sensitized the cells to TTFields, enhancing cytotoxicity in vitro and treatment efficacy in vivo.

CONCLUSION
PI3K/AKT signaling pathway is involved in cancer cell reduced sensitivity to TTFields, and inhibition of this pathway sensitizes cancer cells to TTFields.
P10.18.B JUGLONE AS A NOVEL EPIGENETIC DRUG FOR GLIOBLASTOMA
Authors: Barciszewska A , Belter A , Gawrońska I , Giel-Pietraszuk M , Naskręt-Barciszewska M Z 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is the most common and aggressive primary brain tumor and one of the human malignancies with the highest mortality. Standard approaches for GBM, including, gross total resection, radiotherapy, and chemotherapy, cannot destroy all the cancer cells and, despite advances in its treatment, the prognosis for GBM remains poor. The, until now, the most successful chemotherapy with temozolomide (TMZ) for brain gliomas is not fully effective, and therefore new therapeutic strategies for GBM are needed. We found that juglone (J), which exhibits cytotoxic, anti-proliferative, and anti-invasive effects on various cells could be a promising agent for GBM therapy.

MATERIAL AND METHODS
We analyzed the effects of juglone alone and in combination with temozolomide on glioblastoma cell lines. In addition to the analysis of cell viability and cell cycle, we looked at the epigenetic effects of these compounds on cancer cells. We estimated the total DNA methylation in T98G, U138, U118, and HaCaT lines after treatment with different J and J/TMZ concentrations and incubation time using TLC separation of radioactively labeled nucleotides. The combination treatment with J and TMZ was evaluated with total DNA methylation analysis and 8-oxo-dG (oxidative stress marker) estimation using EC detection.

RESULTS
We noticed concentration and time-dependent changes in total DNA methylation. The highest increase was observed for the T98G cell line at the incubation time of 24hrs. Normal cell line (HaCaT) did not present significant changes. TMZ alone induced a lowering of DNA methylation, but juglone diminished that effect. J induces minute oxidative stress in low concentrations, but is quite high and rapid at concentrations over 50uM, concomitantly with none/slight decrease in DNA methylation. However, the combination of J/TMZ in increasing concentrations diminished the oxidative stress effect.

CONCLUSION
Our results strongly suggest that a combination of juglone and temozolomide can be applied for better GBM treatment. At certain incubation times and concentrations, juglone increases DNA methylation, which is a positive therapeutic effect in oncogenesis. Small doses of J keep a low level of 8-oxo-dG with an increase in DNA methylation. The combination of J/TMZ in high concentrations of both drugs decreases the oxidative stress effect of chemotherapy. The study was supported by OPUS 19 (2020/37/B/NZ5/03249) grant from the National Science Center, Poland.