bluuebunny/crossref_metadata_2025_split huggingface dataset:
P14.03.A DO GLIOMA PATIENTS PRODUCE AUTO-ANTIBODIES FOR GLIOMA-SPECIFIC PHOSPHO-PROTEIN MODIFICATIONS
Authors: Zeneyedpour L , Stingl C , Kros J M , Sillevis Smitt P A E , Luider T M 
Published: September 2023

Abstract

BACKGROUND
Many studies have shown that dysregulation of protein phosphorylation plays an important role in the development of cancer. Aberrantly phosphorylated peptides can be derived from dysregulated cell signaling pathways in various cancers and may serve as tumor-specific antigens and might be promising targets for cancer immunotherapy. Several techniques are available to purify immunoglobulins (IgG) from plasma or other body fluids using affinity to immobilized binders In contrast, Melon Gel resin retains non-IgG proteins and hence allows enrichment of IgG directly from the sample without affinity binding. We have developed a technique for the detection of auto-antibodies in HGG.

MATERIAL AND METHODS
To perform an Ab-peptide binding assay, we used a phospho-peptide library (a mixture of phospho-peptides obtained after phospho-enrichment of enzymatically digested fresh-frozen GBM tissue) and three plasma samples from HGG patients and a healthy donor as source of IgG. After mixing of the plasma samples with the phospho-peptide library the IgG purification was performed using the Melon Gel resin. We separated possible unbound peptides using a 30 kDa-molecular-weight (MW) filter device. The high MW fraction, containing IgGs and IgG-peptide complexes were acidified and precipitated to release Ab-bound peptides. Subsequently, the IgG-bound peptides were measured and identified in a mass spectrometer.

RESULTS
Performing the developed Ab-peptide binding assay using the HGG and healthy plasma samples combined with the GBM phospho-peptide library, we detected EGFR phospho-peptide GSHQIS[+80]LDNPDYQQDFFPK (S1166) in three of four IgG-bound fractions of samples incubated with HGG plasma and not in the corresponding unbound fractions. This result indicates the presence of auto-antibodies against EGFR phospho-peptide S1166 in the plasma of the three HGG patients. A contrasting result was obtained in the donor sample, where the EGFR peptide was detected almost exclusively in the unbound fraction. With the use of Avastin as negative control instead of plasma, the EGFR peptide S1166 was solely found in the unbound fraction.

CONCLUSION
An antibody-peptide-antigen complex enrichment with Melon Gel was successfully applied to find auto-antibodies that recognize disease-related phospho-peptides. This method has the potential to detect the putative presence of auto-antibodies without knowledge of the antigen. We demonstrated in a proof of concept the presence of auto-antibodies against an EGFR phospho-peptide in plasma of HGG patients. This antibody-peptide binding assay could potentially be further applied to other types of cancer to find targets for therapeutic interventions.
P14.11.B A MULTICENTER STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND WITH SYSTEMIC MICROBUBBLE OSCILLATORS FOR BLOOD-BRAIN BARRIER DISRUPTION FOR LIQUID BIOPSY IN GLIOBLASTOMA (LIBERATE)
Authors: Ahluwalia M S , DeGroot J , Lee J , Mogilner A , Schwartz T , Burns T , Shah B , McDermott M , Bettegowda C , Ozair A , Khosla A A , Sahgal A , Mishra M , Achrol A , Lipsman N , Woodworth G 
Published: September 2023

Abstract

BACKGROUND
Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) levels in blood due to the blood-brain barrier (BBB). This results in challenges to the identification of blood-based biomarkers and the development of novel biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with intravenously administered microbubble oscillators non-invasively causes BBB disruption (BBBD). This clinical trial aimed to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM.

METHODS
LIBERATE is a prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating the safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged 18-80 years with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being included. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered intravenous oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using a 220 kHz LIFU device is performed with real-time acoustic feedback for effective cavitation. Before and after the procedure, phlebotomies and MRI brain are performed to evaluate outcomes. The primary study endpoint is defined, per subject, as the ratio between their cfDNA level in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to a ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in cfDNA sample from 1-hour post-LIFU sample and biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N=50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hours, and 3 hours to determine the time of greatest yield, (3) correlation of MRI parameters related to grading of BBBD and biomarkers positive in cfDNA from post-LIFU blood samples.

RESULTS
Patient enrollment commenced in 2022, and 8 patients have been recruited by 04/11/2023.

CONCLUSION
Findings from this trial will be critical to liquid biopsy in GBM (Clinical trial information: NCT05383872).
P14.13.B DECODING GLIOBLASTOMA: SIM4ULATING TUMOUR MICROENVIRONMENT TO DETECT NOVEL BIOMARKERS USING ORGAN-ON-CHIP MODELS
Authors: Bayona C , Randelovic T , Wrona M , Salafranca J , Ochoa I 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is the most common malignant primary brain tumour in adults, with a survival rate of 14 months even after current treatment. There are two major limitations in understanding how the tumour works and what markers could facilitate its diagnosis. On the one hand, the great heterogeneity is responsible for the ineffectiveness of treatments. This underlines the importance of developing more complex models that can simulate different elements of the tumour microenvironment of GBM, including hypoxic gradients that lead to the generation of the characteristic necrotic core. On the other hand, the diagnostic techniques currently used have their inherent limitations and entail serious risks for the patients. Therefore, the development of diagnostic markers that allow real-time monitoring of tumour status without posing a very high risk, could improve diagnosis and treatment of patients with GBM.

METHODS
Our approach consisted on a gas impermeable and pillarless microfluidic device composed of a central chamber, where U-251 MG cells were highly dense seeded in a collagen matrix, and two side channels that provided oxygen and nutrients to the cells. The device was used to generate the necrotic region characteristic of glioblastoma, then, the medium that flowed through the lateral channels in contact with the cells was collected on different days of necrotic core formation and analysed by solid-phase microextraction system coupled with gas chromatography-mass spectrometry. This technique was used to detect the presence of differential volatile organic compounds (VOCs) secreted by tumour cells in different microenvironments.

RESULTS
The microfluidic device enabled the generation of an in vitro glioblastoma tumour microenvironment characterised by a necrotic zone in the centre of the tumour mass after seven days of cell culture. This allowed the study of VOCs in different microenvironment conditions, and showed that devices with a necrotic core exhibited a much more complex VOC footprint. Among the compounds detected were some types of aldehydes, phenols and nitrogen compounds. Clinical validation of the GBM VOC profile is ongoing.

CONCLUSION
Our impermeable and pillarless device has allowed us to simulate elements of the tumour microenvironment that are difficult to reproduce with other models, such as central necrotic zones surrounded by cells with nutrient availability. In addition, it offers a promising advance in the characterisation of the metabolic fingerprint of glioblastoma that bring us closer to real-time monitoring of the disease with less invasive methods than those currently used.
P15.05.B THE IMPACT OF IOMRI ON GLIOBLASTOMA RESECTION AND CLINICAL OUTCOMES IN A STATE-OF-THE-ART NEURO-ONCOLOGICAL SETUP
Authors: Schwendner M , Zhang W , Ille S , Wiestler B , Meyer B , Krieg S M 
Published: September 2023

Abstract

BACKGROUND
Intraoperative magnetic resonance imaging (ioMRI) is applied to improve the extent of resection in patients suffering from primary brain tumors, especially glioblastoma (GBM). While some older randomized trials reported data on safety and feasibility, ioMRI’s actual impact in a modern neurosurgical setting has not been sufficiently investigated. We therefore aimed to evaluate the effect of ioMRI on tumor resection and progression-free survival (PFS) in GBM patients in a modern high-volume center.

MATERIAL AND METHODS
Patients undergoing ioMRI for resection of supratentorial GBM were prospectively included between March 2018 and June 2020. In all cases, ioMRI was performed after complete macroscopic tumor resection. The extent of resection (EOR) was determined by volumetric analysis. Gross total resection (GTR) was defined as EOR ≥95%. Furthermore, progression-free survival (PFS) was analyzed through univariate and multivariate Cox proportional regression analysis.

RESULTS
Overall, 172 patients were enrolled in this study. The mean EOR increased from 93·9% on ioMRI to 98·3% (p&lt;0·0001) on postoperative MRI, with residual tumor volume decreasing from 1·3 ± 4·2 cm3 to 0·6 ± 2·5 cm3(p=0·0037). The GTR rate increased from 78·5% to 93·0% (p=0·0002). Logistic regression revealed recurrent GBM (odds ratio [OR] =3·047, 95% confidence interval [CI] 1·165-7·974, p=0·023) and tumor volume less than 15 cm3 (OR=3·031, 95% CI 1·062-8·651, p=0·038) as independent risk factors leading to STR. Tumor resection performed additionally after ioMRI lead to equally long PFS compared to patients with complete tumor removal achieved before ioMRI (HR=0·898, 95%CI 0·543-1·483, p=0·67).

CONCLUSION
ioMRI serves as a valuable tool in a modern neurosurgical setting, severely decreasing residual tumor volume. ioMRI considerably helps to achieve comparable PFS even in cases, where an unexpected tumor residual is found on ioMRI after initial resection.
P15.15.B DIFFUSE ADULT-TYPE GLIOMA INFILTRATION DEFINED ON FET-PET
Authors: Harat M , Miechowicz I , Rakowska J , Zarębska I , Małkowski B 
Published: September 2023

Abstract

BACKGROUND
O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET is a valuable tool in glioma imaging used to the definition of biopsy site, monitoring of treatment response and differentiation of treatment-related changes from glioma progression The physiological uptake within reactive astrogliosis may limits FET-PET ability to precisely define glioma extent. For the implementation of FET-PET into clinical trials, a methodological PET standardization is urgently needed to enable more precise and reproducible FET PET quantification. The primary aim of our study was to define a glioma infiltration using threshold based method between astrogliosis and tumoral tissue in FET-PET.

RESULTS
Astrogliosis presented similar uptake to grade 2 glioma samples. Standard threshold method (1,6x uptake in contralateral brain) in PET aquisiton 40-60 minutes post injection is effective but the accuracy decrease outside contrast enhancement within FLAIR to 56% sensitivity and 41% specificity. Adding second aquisition increased sensitivity within FLAIR to 71%. Finally, using tumor-to-plexus ratio, it is possible to differentiate astrogliosis and grade 2, and achieve sensitivity of 73% and specificty of 84% within FLAIR or 90% sensitivity with 61% specificity. ROC curves are significantly different related to method used with best results specific to new strategy.

CONCLUSION
Determining glioma extent using standard threshold method in PET or FLAIR is limited. Improving is possible with dual aquisition and/or different tumor to background ratio. This may largely improve delineation of glioma for surgery or radiotherapy.
P15.17.B DYNAMIC FDG PET AS A PREDICTOR OF SURVIVAL IN PATIENTS WITH GLIOMAS
Authors: Moosa S , Ramanathan P , Qureshi Z , Kundu B , Quigg M 
Published: September 2023

Abstract

BACKGROUND
The neuroimaging characteristics of treatment-related necrosis (TRN) induced by chemotherapy and radiotherapy mimic those of tumor progression (TPR). This can make it challenging for clinicians to deliver prognoses for patients with gliomas and subsequently optimize their treatment regimens. In this study, we evaluate the utility of dynamic FDG (dFDG) PET, which provides information about dynamic metabolic changes, for predicting survival in patients who have undergone treatment for gliomas.

MATERIAL AND METHODS
Clinical and radiographic information were obtained for 21 adult patients with known or suspected recurrent gliomas and had radiographic worsening reported on MRI within 6 months of completion of radiation and chemotherapy. All patients underwent dFDG PET imaging, and the prognostic significance of rate constants from the suspected tumor region were analyzed using Cox regressions.

RESULTS
Based on dFDG PET imaging, higher values of the k3 rate constant predicted a hazard ratio of 6.7 of death within 12 months of diagnosis. Hazard ratios of the k1 and k2 parameters were not significant in prediction of 12-month survival.

CONCLUSION
The k3 kinetic parameter of dFDG PET imaging, a marker for glucose uptake and metabolism, is predictive of 12-month survival in glioma patients who have questionable tumor progression. Clinicians can use this information to estimate the likelihood of TPR versus TRN in patients with gliomas and subsequently tailor their treatment plans based upon expected survival.
P16.05.B SAFETY AND EFFICACY OF INTRA-CSF BIOLOGIC AGENTS IN TREATMENT OF NEOPLASTIC MENINGITIS
Authors: Trifoi M , Appiah A , Sichinga K , Aregawi D , Glantz M 
Published: September 2023

Abstract

BACKGROUND
Neoplastic meningitis (NM) is an increasingly frequent, profoundly morbid, and almost invariably fatal complication of solid and hematologic malignancies. Despite multimodal therapy, median survival in randomized trials is approximately 4 months. Biologic agents are widely utilized in management of extra-CSF disease, but often have limited ability to penetrate the CSF. Intra-CSF administration of biologic agents has not been widely investigated. We describe the safety and efficacy of tumor-specific, intra-CSF biologic therapy in a large group of patients with neoplastic meningitis.

MATERIAL AND METHODS
We queried the database of a large, international neoplastic meningitis registry (NeMeRe) to identify patients with neoplastic meningitis who received at least one dose of neoplastic meningitis-directed therapy with a biologic agent. Detailed patient demographic, treatment, toxicity and outcome data was extracted and analyzed for the first 140 consecutive patients treated at our institution.

RESULTS
These 140 patients received an intrathecal biologic agent as part of a histology- and molecular profile-directed intraventricular chemotherapy treatment approach. Agents included rituximab (58 patients with lymphoma, 224 cycles), trastuzumab (42 patients with malignant primary brain tumors, 211 cycles; 15 patients with breast cancer, 149 cycles; 1 patient with esophageal cancer, 9 cycles), panitumumab (4 patients with lung cancer, 9 cycles), nivolumab (1 patient with melanoma, 5 cycles; 2 patients with breast cancer, 2 cycles; 2 patients with GBM 12 cycles; 2 patients with lung cancer, 4 cycles; 2 patients with gastric adenocarcinoma, 17 cycles; 2 patients with renal clear cell carcinoma, 17 cycles; 1 patient with AML, 2 cycles; 1 patient with multiple myeloma, 8 cycles) and alpha-interferon (10 patients with melanoma, 31 cycles; 2 patients with renal clear cell carcinoma, 18 cycles). Grade I/II toxicity occurred in 5.8% of rituximab, 3.2% of trastuzumab, 0% of panitumumab, 16.3% of nivolumab, and 3.2% of alpha-interferon containing cycles. There was no grade III toxicity. Median survivals in patients with lymphomatous meningitis (304 days), solid tumor NM from primary brain tumors (243 days), HER2 -positive breast cancer (not reached, &gt;315 days), lung cancer (192 days), and melanoma (307 days) were encouraging. No difference in survival was seen between patients with and without treatment-related toxicity in any histologic group.

CONCLUSION
This large registry-based cohort study suggests that rituximab, trastuzumab, panitumumab, nivolumab, and alpha interferon may be safely administered into the CSF as part of a multi-agent intra-CSF treatment regimen. Survival, while very tentative, is encouraging. A prospective, multi-center evaluation of these agents in patients with neoplastic meningitis is warranted.
P16.07.B PROSPECTIVE DOUBLE ARM PHASE 2 RANDOMIZED TRIAL FOR PATIENTS WITH MULTIPLE BRAIN METASTASIS AND/OR LEPTOMENINGEAL CARCINOMATOSIS: COMPARISON OF WHOLE BRAIN RADIATION THERAPY (WBRT) ALONE AND WBRT PLUS SILIBININ
Authors: Clerici E , Navarria P , Bellu L , Marini B , Lobefalo F , Scorsetti M 
Published: September 2023

Abstract

BACKGROUND
Occurrence of brain metastases (BMs) is increasing given availability of Magnetic Resonance Imaging (MRI) able to detect also small brain lesions, and most effective systemic therapy able to better control extra-cranial disease. Estimated 20% of patients with cancer will develop BMs. In case of limited brain metastases, radiosurgery or hypofractionated radiosurgery is treatment of choice. A subgroup of patients characterized by extensive brain disease and/or leptomeningeal carcinomatosis can require whole brain radiotherapy (WBRT). Since the 1950s, WBRT has been the most treatment used for patients with multiple BMs, given its effectiveness in palliation, widespread availability, and ease to deliver. However, the median overall survival (OS) recorded is restricted to 3 months, on the average. A better understanding of molecular and cellular mechanisms underlying brain metastasis might be expected to lead of improvements in overall survival. Recent studies demonstrated that active signal transducer and activator of transcription 3 (STAT3) in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis, even at advanced stages of colonization. Silibinin is a natural polyphenolic flavonoid isolated from seed extracts of herb milk thistle. It has been shown to impair STAT3 activation, and in preclinical studies, show an anticancer effects in vitro and in vivo. Based on this background, we designed a double arm phase 2 randomized trial evaluating the benefit of Silibinin associated to WBRT respect to WBRT alone. Primary endpoint is OS, secondary endpoints are toxicity in term of corticosteroid therapy use, brain failure (BF) and progression free survival (PFS).

MATERIAL AND METHODS
Forty-four patients will be enrolled in two years. Patients with histological or cytological confirmation of solid tumor malignancy, clinical indication for WBRT and Karnofsky performance status (KPS) ≥60 will be enrolled. In arm A experimental, WBRT is concomitant to Silibinin, in arm B control, WBRT alone will be administered. In both arms, total dose of radiotherapy is 30 Gy in 10 fractions. Quality of life and use of corticosteroids will be evaluated first, last day of RT, and during follow-up. Outcome will be evaluated by MRI or CT at 2 months after RT, and every 3 months thereafter.

RESULTS
From March 2023, 6 patients were enrolled, 2 patients in Arm A and 4 in arm B. Primary histology was breast cancer in 3 patients and non small cell lung cancer in 3. In arm A, 1 patients dismissed RT for worsening of general conditions related to rapid lung progression.

CONCLUSION
WBRT with or without Silibinin was well tolerated, no acute toxicities or increase of corticosteroids were observed.
P17.12.B FEASIBILITY OF PROLYL OLIGOPEPTIDASE (PREP) AS TUMOR BIOMARKER IN GLIOBLASTOMA PATIENTS: A PILOT STUDY
Authors: Casili G , Caffo M , Scuderi S , Basilotta R , Lanza M , Filippone A , Paterniti I , Campolo M , Cuzzocrea S , Esposito E 
Published: September 2023

Abstract

BACKGROUND
Prolyl oligopeptidase (PREP) is a serine protease that hydrolyzes biologically active oligopeptides on their carboxyl side. PREP has been connected with multiple physiological and pathological conditions. Moreover, increased PREP activities have been found in tumors, although its involvement in the modulation of cancer mechanism is still unclear. Thus, the identification of PREP and clarification of its clinical significance are important for improving the diagnosis and treatment of brain tumors. The purpose of this study was to analyze the expression of PREP and its diagnostic and prognostic value in patients with Glioblastoma (GBM). Materials and

METHODS
In this study, GBM patients and controls were enrolled and clinical data and PREP expression, from serum and biopsies, were collected. The relationships between PREP, Protein phosphatase 2A (PP2A), STAT3 and Transforming growth factor-β (TGF- β) were also analyzed from clinical data.

RESULTS
Our study found that PREP was significantly upregulated in the serum samples and in biopsy from GBM patients compared with controls. This upregulation was negatively correlated with survival, but significantly correlated with age and Mindbomb Homolog-1 Index (MIB1). Also, PREP expression was inversely correlated with tumor suppressor PP2A in biopsy from GBM patients, while PREP protein levels resulted to be positively correlated with STAT3 and TGF-β protein expression.

CONCLUSION
s: The detection of PREP in serum and biopsies have the potential to serve as diagnostic and prognostic biomarker in GBM patient. The findings may provide diagnostic and therapeutic target for GBM.