bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS02.5.A Alzheimer-type neuropathological changes in glioblastoma-adjacent cortex
Authors: Greutter L , Miller-Michlits Y , Klotz S , Miller-Michlits A , Roetzer-Pejrimovsky T , Baumann B , Kiesel B , Kovacs G G , Stepper P , Woehrer A 
Published: September 2022

Abstract

Background
Glioblastoma (GBM) is an aggressive type of brain cancer that is prevalent and fatal in the elderly. Age is not only the most common risk factor for brain cancer but also for neurodegenerative diseases, and previous studies have indicated an excess risk of co-occurrence of both diseases. Here, we aim to map Alzheimer (AD)-related pathology in GBM-adjacent cortex.

Material and Methods
To this end, we have screened a cohort of 99 individuals with 200 tissue samples comprising tumor and adjacent cortex, including longitudinal samples in 13 patients. The samples were provided by the Division of Neuropathology and Neurochemistry, Medical University of Vienna from 2002 to 2021. Age and tumor location were abstracted from clinical data where available. All samples were stained for A-beta, tau-AT8 and NeuN using immunohistochemistry. Whole slide scans were segmented and protein deposits were quantified with QuPath. Further statistical analyses were conducted with R. Tau pathology was recorded as neurofibrillary tangles, neuropil threads, and astroglial pathology. Likewise, amyloid pathology was assessed as plaques and/or cerebral amyloid angiopathy (CAA). For both proteins, deposits were grouped into: absent, mild, moderate, and severe.

Results
In the total cohort, median age was 67.5 ys (range 20-92 ys), the female-to-male ratio 0.68. Overall 44.4 % (n=44/99) showed any type of A-beta and/or taupathology, which was strongly correlated with age (R=0.26, p= 0.001). Among them, 38.6 % (n=17/44) had combined pathology, while 36.4 % (n=16/44) displayed pure amyloid-beta, and 25 % (n=11/44) only tau pathology. A-beta pathology comprised plaques in 74.4 % (n=29/39) and CAA in 28.2 % (n=11/29). Consistent with the spatiotemporal evolution of AD, neurofibrillary tangle load was highest in the temporal lobe (42.9 % n=21/49), while plaque load was most prevalent in the occipital lobe (62.5 % n=5/8). This pattern was accentuated in patients above age 65, while it deviated in those below age 65. Over time, the AD-type pathology increased in 38.4 % (n=5/13) and remained stable in 53.8 % (n=7/13) of recurrent tumors. Total cell densities in tumor-infiltrated cortex ranged from 474 to 7,540 cells/mm2, being similar across all lobes. Higher cell density correlated with decreased neuronal counts (R= -0.46, p&lt;0.0001) and decreased AD-load (R= -0.25, p= 0.002).

Conclusion
Collectively, our results establish frequent co-occurrence of Alzheimer disease neuropathological changes in the GBM-adjacent cortex. They prompt further investigation of shared pathogenic mechanisms and seek to raise awareness for synergistic effects on cognitive decline.
OS07.3.A Phase 1/2 clinical trial of blood-brain barrier opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin
Authors: Idbaih A , Sonabend A , Stupp R , Chinot O , Dufour H , Ducray F , Menei P , de Groot J , Desseaux C , Carpentier A 
Published: September 2022

Abstract

Background
Low intensity pulsed ultrasound (LIPU) in combination with microbubbles is a promising approach for brain drug delivery. A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of blood-brain barrier (BBB) disruption over a large volume using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy.

Material and Methods
The SonoCloud-9 device (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every 4 weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 μl/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n=3), 6 (n=3), then 9 (n=3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first 2 weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with 9 emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium (&lt;1 hr after sonication). All patients received carboplatin either after (n=21) or before (n=12) device activation to disrupt the BBB. In addition, a sub-study was performed to investigate carboplatin concentration enhancement in the peritumoral region with sonication at time of device implantation.

Results
Study accrual is complete with 38 patients enrolled and 33 patients having been implanted and received at least one sonication+carboplatin. A total of 101 sonications were performed (range=1-10 sonication sessions/patient). No DLTs were observed. A total of 14 SAEs were observed including five events considered as possibly treatment related. BBB disruption was confirmed by gadolinium enhancement after sonication. In an analysis of 60 treatments in 27 patients that had all nine emitters active, 90% of activated emitters led to BBB opening in gray and/or white matter with good repeatability of BBB opening. In 3 patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated and mature outcome results will be presented.

Conclusion
These results confirm the safety and feasibility of repeated BBB disruption using an implantable ultrasound system. LIPU substantially increases drug levels in the peritumoral brain.
OS07.7.A Rate and type of recurrence of lower-grade gliomas submitted to functional neurosurgical approach: the impact of the extent of resection
Authors: Gay L , Rossi M , Conti Nibali M , Sciortino T , Bello L 
Published: September 2022

Abstract

Background
In the last decade, different published studies enlightened the extent-of-resection (EOR) as an independent factor for progression-free-survival (PFS) in patients with lower-grade gliomas (LGG). Aim of this study was to evaluate the impact of resections extending beyond FLAIR MRI abnormalities (supratotal), and eventual predictive factors and characteristics of recurrences.

Material and Methods
We retrospectively analysed 460 patients submitted to surgery between 2007 and 2016 with a presumptive diagnosis of LGG, i.e., harbouring a mass lesion with no enhancement on contrast-administered T1-weighted MRI-sequences. All resections were performed according to functional boundaries determined by brain mapping/monitoring technique, without any patient or tumor a priori selection. The EOR was defined by analyzing pre- and post-operative volumetric FLAIR images.

Results
The median pre-operative tumor volume was 43,7 cm3. A supratotal resection (SPR) was achieved in 31.4%, a gross-total (GTR) in 41.1%, a subtotal (STR) in 27.5%. WHO grade II/III gliomas were diagnosed in 347 cases (319 IDH-mutant, 28 IDH-wildtype). Median follow-up was 60 months. SPR versus other EOR was associated to increased PFS (log rank test, p=.000) and malignant PFS (p=.000). Data were confirmed also after IDH status stratification. Rate of immediate and permanent post-op deficits among different EOR were comparable. Pre-op tumor volume, parietal and insular sites, eloquent location and dominant hemisphere tumors, and astrocytoma histology were associated to recurrence (p&lt;.05). In 95.1% of cases recurrences were peri-cavitary. Lesions invading the corpus callosum presented minor rate of relapse; recurrences were most frequently diffuse and at distant sites. After SPR most common radiological appearance of recurrence was solid, while after GTR and STR percentages of solid and diffuse patterns were similar. Occurrence of distant recurrences, away from the resection cavity, were most associated to SPR.

Conclusion
Our preliminary data suggests the dramatic impact in LGG of resections extending beyond FLAIR abnormalities on PFS and malignant PFS and on the characteristics of tumor recurrence.
OS07.8.A Prognosis in IDH-mutant glioma: the role of extent-of-resection, age and tumor grade
Authors: van der Vaart T , Wijnenga M M J , van Garderen K A , Dubbink H , French P J , Smits M , Dirven C M F , Kros J M , Vincent A P J E , van den Bent M J 
Published: September 2022

Abstract

Background
Evidence suggests that smaller residual tumor volumes after initial surgery are associated with longer survival in patients with astrocytoma, IDH-mutant, grade II. For IDH-mutant glioma of higher grade but also for oligodendroglioma, IDH-mutant, and 1p/19q codeleted, the impact on survival of more residual tumor is unclear. This could be related to the limited follow-up of patients with oligodendroglioma that typically have long overall survival. We expanded a previously published series of patients increase the duration of follow-up and the spectrum of tumor grades.

Material and Methods
Single center observational cohort study of patients with adult-type diffuse glioma, IDH-mutant, all WHO-2021 grades, from 2003 to 2021 . Molecular characteristics were assessed by next-generation targeted sequencing. Tumor volumes were calculated by semi-automatic 3D segmentation on pre- and postoperative MRI-scans. Associations between prognostic factors and survival were assessed using univariate and multivariate Cox proportional hazards models.

Results
384 patients with IDH-mutant glioma (174 oligodendroglioma, 212 astrocytoma) were followed for a median of 7 years. Median age at diagnosis was 41 years (IQR 33 - 55). Significant prognostic factors for survival were Karnofsky performance status, 1p19q-status and post-operative tumor volume. Smaller post-operative tumor volume was associated with better survival, both in astrocytoma and oligodendroglioma. Age, tumor grade and MRI-contrast enhancement were not associated with survival.

Conclusion
Lower residual tumor volume after first surgery is a strong prognostic factor in all IDH-mutant glioma subgroups, even in patients with very small residual tumor. Importantly, age and histological tumor grade were not significantly associated with survival. The data serves as further support for optimal initial resections of tumors suspected for IDH-mutant glioma, also in oligodendroglioma.
P07.05.A Implantable electrophoretic devices for local treatment of inoperable brain tumours
Authors: Ahmed M H , Naegele T , Hilton S , Malliaras G 
Published: September 2022

Abstract

Background
Glioblastoma (GBM) is the most malignant primary brain tumour in adults, with a median overall survival of fewer than 18 months after initial diagnosis. For over five decades, research has been focused on developing new anticancer therapies for GBM, including anti-neoplastic agents, molecular targeted drugs, immunotherapeutic approaches, and angiogenesis inhibiting compounds; however, the prognosis of patients has hardly improved and temozolomide remains the only chemotherapy shown to improve patient survival in randomized clinical trials. A fundamental limitation of the success of chemotherapy in brain cancer therapies is the blood-brain barrier which significantly reduces the concentration of chemotherapeutic agents delivered into a tumour.

Material and Methods
Therapeutic strategies that control drug release spatially and temporally represent a significant step forward in terms of reducing side effects and improving treatment efficacy and will thus have a significant clinical impact. Electrophoretic drug delivery devices, which use electric fields to enhance drug transport, represent one such strategy.

Results
Here, we present an implantable device that enables highly spatially selective delivery of charged drug molecules directly into brain tumours. Our device combines a microfluidic system for drug transport with embedded electrodes which enable electrophoretic transport of drug molecules into the target tissue. This allows delivery of chemotherapeutic agents without transport of bulk solvent preventing issues arising from intracranial pressure gradients. We have shown that the device can be implanted safely without any limitation. We have tested the device's capabilities to deliver a wide range of small, medium, and large chemotherapeutic agents without limitations. Currently, we are investigating the delivery of cisplatin in GBM-bearing mice.

Conclusion
While electrophoretic drug delivery was first described in the early 20th century and has been used since primarily for transdermal drug delivery, we believe that our approach is one of the first times this has been demonstrated for brain cancer therapy.
P11.37.B When to resect or biopsy for patients with supratentorial glioblastoma: a multivariable prediction model
Authors: Kommers I O , Eijgelaar R S , Barkhof F , Bouget D , Pedersen A , Ardon H , Bello L , Berger M S , Bouwknegt W , Conti Nibali M , Furtner J , Han S J , Han S J , Hervey-Jumper S , Hervey-Jumper S , Idema A J S , Kiesel B , Kloet A , Nandoe Tewarie R , Mandonnet E , Reinertsen I , Robe P A , Rossi M , Sciortino T , Solheim O , van den Brink W A , Vandertop P W , Wagemakers M , Widhalm G , Witte M G , Zwinderman A H , De Witt Hamer P C 
Published: September 2022

Abstract

Background
The prospects of a patient with suspected glioblastoma may rely heavily on the indication for surgical resection versus biopsy only. Biopsy percentages vary considerably across hospitals and guidelines for treatment of glioblastoma lack criteria for surgical decision-making. To identify patient and tumor characteristics associated with the decision to resect or biopsy a glioblastoma and to develop and validate a prediction model for decision support.

Material and Methods
Clinical data and pre-operative MRI scans were collected for adults who underwent first-time surgery for supratentorial glioblastoma from a registry-based cohort study of 12 hospitals from the Netherlands, Germany, France, Italy, and the United States between 1st of January 2007 and 31st of December 2011. The main outcome was the type of surgical procedure: surgical resection or biopsy only. Predictors were patient- and tumor-related characteristics. Radiological factors were extracted from MRI using an automated tumor segmentation method. A prediction model was constructed using multivariable logistic regression analysis. The model was cross-validated and externally validated with a leave-one-hospital-out approach.

Results
Out of 1053 patients treated for glioblastoma, 28% underwent biopsy only. Biopsy rates varied from 15-40% across hospitals. The prediction model showed excellent discrimination with an average area under the curve of 0.86. Of the patient-related characteristics, younger age was associated more with resection and Karnofsky Performance Score of 60 or less with biopsy. Of the tumor-related characteristics, a location in the right hemisphere, unifocality, no tumor midline crossing, and no involvement of the cortical spinal tract, were associated with resection, as well as a high expected resectability index, a location in the right occipital lobe, and a higher percentage of tumor in Schaefer’s dorsal or ventral attention, limbic, and default networks. External validation proved acceptable to outstanding discrimination with areas under the curve ranging between 0.79 and 0.92 for hospitals.

Conclusion
A prediction model is presented and validated to support the decision to resect or to biopsy a patient with a suspected supratentorial glioblastoma. In this prediction model, tumor-related characteristics were more informative than patient-related factors. This may support surgical decision-making for individual patients, or facilitate comparisons of patient cohorts between surgeons or institutions.
P11.64.A Long-term follow up and translational data from the ReoGlio phase Ib trial of GM-CSF and intravenous pelareorep (Reovirus) alongside standard of care in GBM
Authors: Short S , Kendall J , West E , Chalmers A , McBain C , Melcher A , Collinson F , Phillip R , Brown S , Samson A 
Published: September 2022

Abstract

BACKGROUND
We previously reported safety data from a phase Ib, open-label study of intravenous oncolytic virus pelareorep with GM-CSF alongside standard chemoradiotherapy in newly diagnosed glioblastoma confirming that the combination is well tolerated. We now report on long-term follow up and analysis of translational samples from tumour and blood in a subset of patients.

METHODS
15 patients with newly diagnosed GBM were treated with GM-CSF 50μg subcutaneously on days 1-3 and intravenous pelareorep on days 4-5 in weeks 1 and 4 of chemoradiotherapy, and subsequently in week 1 of each adjuvant temozolomide course: 7 patients received 1x1010TCID50 (dose level 1); 8 received 3x1010TCID50 (dose level 2). The primary objective was to determine the maximum tolerated dose of pelareorep and GM-CSF with standard chemoradiotherapy. Following a protocol amendment we also collected survival data in all patients up to August 2021. Serial blood samples were taken from three patients, at baseline, during chemoradiotherapy and in the first adjuvant cycle. Peripheral blood mononuclear cells were analysed for immune checkpoint expression by flow cytometry, RNAseq gene expression and T-cell receptor clonality, whilst plasma cytokines were quantified by Luminex.

RESULTS
This combination was well tolerated with 87% of patients completing treatment as planned. Survival data analysis showed that median OS was 12.6 months in dose level 1 and 16.1 months in dose level 2, median OS for all patients was 13.1 months. The 24-month survival estimate for all patients was 25.0%, 16.7% for dose level 1 and 33.3% for dose level 2. One patient in dose level 1 remains alive at 43 months post registration without further treatment. Laboratory data showed that pelareorep infusion resulted in inflammatory cytokine and chemokine secretion, immune checkpoint modulation, and upregulation of inflammatory pathways. There was also increased peripheral clonal tumour-specific T-cell proliferation following pelareorep infusion.

CONCLUSION
Although based on small numbers, these long-term follow up data suggest this may be an active combination in a subset of GBM patients. Translational data confirm that pelareorep potentially activates tumour-targeting immune pathways in GBM, with consequential immune checkpoint modulation. These data support a combination clinical trial of pelareorep, radiotherapy and immune checkpoint blockade in GBM.
P11.68.A Hemangiopericytoma, case series and clinic-pathological analysis
Authors: Redaelli V , Calatozzolo C , Marucci G , Pinzi V , Gaviani P , Botturi A , Simonetti G , Mattei L , Pollo B , Silvani A 
Published: September 2022

Abstract

Background
Hemangiopericytoma (HPC) is an extremely rare aggressive tumor of mesenchymal origin, which constitutes less than 1% of primary tumors of the central nervous system. Typically it occurs in young adults (mean age at diagnosis 30-50 years). Initially described as gemmangiomas, was first called hemangiopericytoma in 1942 but it was considered as a variant of meningioma until 1993 when it was finally recognized as a distinct clinical-pathological entity by the World Health Organization (WHO). In 2016, there was the unification of both HPC and Solitary Fibrous Tumor (SFT) in a single spectrum of rare and thick mesenchymal tumors due to the identification, in both tumoral types, of a molecular alteration called NAB2-STAT6 fusion.

Material and Methods
The present study is a case series of patients that received a pathological diagnosis of SFT/HPC at our Institute from 1981 to 2020. Clinical data included: demographic data, tumor characteristics and treatment modality. Hystological diagnosis and immunohistochemistry allowed to confirm diagnosis, based on the 2016 WHO classification. Haematoxylin staining was completed with immunohistochemistry with primary antibodies for STAT 6 and evaluation of presence of tumor necrosis. Statistical analysis was conducted considering age at first diagnosis, treatment modality, extent of tumor resection, presence of necrosis in histological analysis compared to PFS-1, OS and relapses number.

Results
The case series was composed by 82 patients (46 men and 36 women) with median age of 43 (± 20) that accede to our Institute from 1981 to 2020. Our statistical analysis showed significative correlation between age, extend of tumor resection and presence of necrosis with OS and relapses number.

Conclusion
Hemangiopericytoma is a very rare cerebral tumors, and for this reason large case series are not disposable in literature. In our study we collected all disposable data of every patient with pathological diagnosis of SFT/HPC acceded to our hospital in the long period of 39 years in the aim to verify the presence of significative correlations. We observed strong correlation between tumor resection and presence of necrosis in tumor tissue with prognosis parameters (OS and number of relapses). This result it could be important to conduct the decisional process about treatment after surgical resection, considering also pathological features, rather than only surgical resection.