bluuebunny/crossref_metadata_2025_split huggingface dataset:
P03.10.B A successful case of Histiocytic sarcoma
Authors: Bonzano E , Colombo S , Mantovani L , Di Liberto R , Filippi A 
Published: September 2022

Abstract

Background
Histiocytic sarcoma (HS) is an extremely rare malignant neoplasm accounting for less than 1% of all hemato-lymphoid neoplasms. Sixty percent of all cases are metastatic at presentation and the prognosis is really poor. Currently, there are limited treatment options for HS, and no standard treatment can be recommended. Surgery and/or chemotherapy are the most commonly employed treatment modalities for HS, while radiotherapy seems to be an effective option in patients with localized lesions.

Material and Methods
A 48-year-old woman admitted to our hospital for a drug-resistant neck pain. Her medical record review was relevant for hypothyroidism in replacement therapy, hystero-adnexectomy for fibromatosis (2 years ago), anxiety-depressive syndrome. A Brain and Head-and-Neck Magnetic Resonance Imaging (MRI) showed a left expansive osteolytic occipito-cervical vertebral lesion at level C1-C2, measuring 3.4cm x 2.3 cm x 2.6 cm. The mass was completely resected on July 12,2021 and pathological and immunohistochemical staining confirmed the diagnosis of HS with positive immunohistochemistry for CD163, CD4, CD68, CD14, CD45 / LCA; weak expression of S100 and focal positivity for lysozyme; Ki67 = 45%.On August 10, 2021 a 18F-FDG PET/CT imaging of the total body did not reveal any distal metastases. On August 13, 2021 a bone marrow aspirate showed no neoplastic cells. She underwent to an adjuvant chemotherapy regimen that consisted of ifosfamide administered as an infusion with bolus carboplatin, and etoposide (ICE). On August 28,2021 a concomitant radiotherapy is given, with a total dose of 45 Gy delivered in 15 fractions plus a sequential boost to 54 Gy.Results: VMAT was used to deliver a conformal RT plan. The patient tolerated the entire treatment very well, with a Grade 1 dysphagia immediately after the completion of radiotherapy, with a complete resolution about a week later. At last Brain Head-and-Neck RMN and 18F-FDG PET/CT on March 28, 2022 there is no evidence of recurrent disease.

Conclusion
The favorable outcome of our patient with combined chemotherapy and radiotherapy should promote future research to explore treatment protocols in patients with localized or favorable subtypes of HS.For patients with a good PS, young age, long life expectancy, advanced RT techniques may be used to customize safe treatment.
P04.01.B High impact of ITGB1 on Pi3K/AKT expression in medulloblastoma
Authors: Zhu S , Cheng Z , Wu Z , Wang J 
Published: September 2022

Abstract
Medulloblastoma, an embryonal tumor of the cerebellum, is one of the most frequent malignant brain tumors. Despite the increasing use of genetic variation in treatment stratification, high-risk patients characterized by light meningeal spread, TP53 mutations, or MYC amplification still have poor survival. Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, which can be considered as a master regulator for cancer. In tissue samples obtained from medulloblastoma patients, the significant upregulation of PI3K/AKT was associated with a lifting expression level of integrin β1(ITGB1). To understand the underlying mechanism, we investigated the effect of ITGB1 on the PI3K/AKT pathway in medulloblastoma cell lines. Transfection of this ITGB1 reduced proliferation and invasion of several medulloblastoma cell lines and inhibit epithelial-mesenchymal transition. In addition, knocking down ITGB1 expression can significantly inhibit the activation of PI3K/AKT signaling pathway. In conclusion, ITGB1 may selectively activation the pathophysiological effect of aberrant PI3K/AKT expression and serve as a targeted approach for medulloblastoma therapy.
P04.02.A Integrated diagnosis and therapeutic decision of pediatric nervous system tumors using a comprehensive genomic profiling test
Authors: Azevedo A , Roque R , Passos J , Nunes S , Migueis J , Faria C , Sagarribay A , Serpa A , Roque L , Mafra M , Salgado D 
Published: September 2022

Abstract

Background
Nervous system tumors (NST) are one of the leading causes of cancer-related death in children. Next-generation sequencing has enabled the identification of an increasing number of genetic markers, allowing for a more accurate diagnosis, and may help guide clinicians towards a more specific therapeutic approach.

Material and Methods
Retrospective cohort study of pediatric and young adult patients with NST analyzed with FoundationOneHeme® (FOH) panel from March 2020 to April 2021. This panel was requested, in addition to previously performed pathological reviews and routine genetic tests, in order to obtain more accurate diagnoses and/or possible therapeutic targets.

Results
Fifty NST were analyzed with FOH panel, corresponding to 49 patients. Median age at NST diagnosis was 13 years (range 0-23 years); 50% were females. Initial diagnoses were: 10 pilocytic astrocytomas, 10 diffuse gliomas, 5 ependymomas, 6 mixed neuronal-glial tumors, 7 embryonal tumors, 3 meningeal tumors, 5 peripheral nervous system tumors (PNST) and 4 other types of tumors. There was a change in the final integrated diagnosis after performing the FOH panel in 10 patients (1 pilocytic astrocytoma, 3 diffuse gliomas, 4 mixed neuronal-glial tumors and 1 PNST). In thirty patients, at least one possible therapeutic target was identified: in 5 patients the target therapies are approved for the patients’ tumor type; in 20 patients, target therapies are approved for the same mutations in other tumor types; and in 30 patients target therapies are still being evaluated in ongoing clinical trials. After the results of the FOH panel were known, the previous therapeutic approach was changed in 15 patients, but in only 4 this was attributed to the new genomic findings.

Conclusion
Comprehensive genomic profiling tests can improve diagnostic accuracy and allow for a more reliable approach to the management of pediatric patients with nervous system tumors. Although in most patients there was no immediate therapeutic application of the potential targets found, the genomic data obtained could be very useful to patients who may have tumor progressions in the future.
P05.03.B Application of rapid cytology in intraoperative diagnosis of primary central nervous system lymphoma
Authors: Liwen H , Xingfu W , Limei Z 
Published: September 2022

Abstract

Background
To assesment the value of rapid cytological diagnosis in primary central nervous system lymphoma (PCNSL) surgery.

Material and Methods
A total of 213 PCNSL specimens from the First Affiliated Hospital of Fujian Medical University between 2012 to 2022 were included, 1-2mm3 was taken from the tissues diagnosed for intraoperative pathology and made into cell smears, rapid cytological diagnosis was performed after 95% ethanol fixation and H&E staining, most of the remaining tissues were diagnosed by frozen section. With the results of paraffin section pathological diagnosis as the control standard, compared the accuracy of rapid cytology and frozen tissue section and their combined diagnosis.

Results
Cytological smears can reveal microscopic structures within the cells under a microscope, furthermore, it can avoid the formation of artifacts or deformation of cells when frozen due to excessive water in brain tissue. Compared with paraffin section pathological diagnosis, the diagnostic accuracy of rapid cytology was 151cases (70.89%) , that of frozen tissue section was 175 cases (82.16%) , and that of the combination of the two methods was 187 cases (87.79%) . There were 26 cases (12.21%) in which neither method could give a definite conclusion intraoperatively and only depended on the results of paraffin tissue sections.

Conclusion
Rapid cytology alone is less accurate in diagnosing PCNSL than frozen sections alone. However, the combination of the two diagnosis can improve the accuracy of intraoperative diagnosis of PCNSL and correct some errors that may occur when only relying on frozen section diagnosis. It is especially suitable for stereotactic biopsy surgery or cases with very little tissue, as well as primary medical units without frozen section machine and other equipment.
P06.01.A Deconvolution of immunotherapy-treated glioblastoma identifies cellular heterogeneity and plasticity at the single-cell level
Authors: Hendriksen J D , Flynn A , Maarup S B , Poulsen H S , Lassen U , Weischenfeldt J 
Published: September 2022

Abstract

Background
Glioblastoma is the most aggressive cancer originating in the brain with an average survival of 15 months. One of the characteristics of glioblastoma is the high level of intra-tumour heterogeneity (ITH), but the composition and complexity at the single-cell level is poorly understood. Here, we aimed to assess the effects and consequences of immune checkpoint inhibitor (ICI) on the cellular and molecular heterogeneity of glioblastoma tumours using at the single cell level.

Material and Methods
In collaboration with the phase I trials unit at Rigshospitalet, we performed paired molecular analysis of glioma cells from primary and relapse surgery after ICI treatment. Samples were analysed using single-cell RNA sequencing (scRNA-seq) as well as bulk RNA sequencing and whole exome DNA sequencing.

Results
In an effort to trace cellular lineages we developed and refined methods to a identify copy number changes using scRNA-seq. To this end, we identified clonal and subclonal tumour cell populations in each sample. We found high levels of ITH prior to treatment, both with respect to the glioblastoma subtype enrichment and the cell type-specific gene expression. Using expression-based cell-type classification, we found defined recurrent cell-type populations present at both surgery time points. The immune checkpoint treatment had consequences on the cellular phenotypes and proportions of tumour cells, suggesting a level of plasticity in the neoplastic cells. Moreover, we identified examples of clonal dynamics and sweeps following ICI treatment, pointing to potential treatment response and resistance in these population.

Conclusion
In summary, we pursued single cell-focused analysis of ICI treated glioblastoma patients to study the cellular and molecular heterogeneity within and between glioblastoma patients, which pointed to recurrent patterns of cellular responses following ICI treatment.
P06.02.B Advanced CAR-T cell against orthotopic glioblastoma mouse model
Authors: Hwang K , Nam K M , Kwon J E , Ji S Y , Han J H , Seo T W , Choi Y N , Kim K , Jeon S , Choi K , Kong S , Kim C Y 
Published: September 2022

Abstract

Background
The adoptive and engineered chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in treating hematologic cancers; however, this success has yet to be extrapolated to solid tumors such as glioblastoma multiforme (GBM). The purpose of this study was to evaluate the survival efficacy using advanced CAR-T cells in orthotopic GBM mouse model.

Material and Methods
Advanced CAR-T cell, which reprograms the patient’s T-cells with a transgene encoding part of interleukin-7 receptor-α (ΔIL7Rα) domain in addition to the CD3ζ signaling domain and 4-1BB costimulatory domain in the advanced CAR gene to exhibit excellent in vivo persistence and anti-tumor effect of advanced CAR-T cells. In addition to the advanced CAR gene, TGF-beta converter is introduced, which converts the inhibitory signal of TGF-beta, an immunosuppressive cytokine overexpressed in the hostile tumor microenvironment, into the activation signal of the cytokine IL-18 in advanced CAR-T cells.DAY9 NSG mice bearing orthotopically xenografted GBM cell lines (1 × 105 U251MG expressing IL13Rα2) were randomized to 8 experimental groups. Each experimental group was intravenously injected with only once with different subtype advanced CAR-T cells (Td ~ 47.3% of 5 × 106) and monitored for survival.

Results
Among treatment groups, mice treated with advanced CAR-T cells of TGF-β converter subtype demonstrated a statistically significant increase in survival (p=0.042, 95%CI, 0.375-0.981) compared with other subtypes. In DAY9 orthotopic GBM mouse model, we showed that a single I.V. injection of advanced CAR-T cells targeting IL13Rα2-specific tumor achieved survival benefit.

Conclusion
This study is the first report to show statistically significant survival benefit in DAY9 orthotopic GBM mouse model using a single I.V. injection of advanced CAR-T cells, yet merits further clinical trials in real world of clinical setting.
P06.04.B Efficacy of Podoplanin-CAR-T Cells inex vivo Patient Derived Glioblastoma Organoids
Authors: Diener L , Goedert N , Schulz T , Monoranu C , Ernestus R , Hagemann C , Löhr M , Nerreter T , Dufner V 
Published: September 2022

Abstract

Background
Glioblastoma (GBM) is the most prevalent malignant brain tumor in adults. Recent immunotherapeutic approaches led to promising effects both in vitro and in preclinical animal models. However, tumor heterogeneity, antigen escape mechanisms and complex interactions with the tumor microenvironment (TME) hinder their clinical breakthrough. Thus, patient derived ex vivo models are needed to test new therapeutical approaches. Genetically modified T cells expressing a chimeric antigen receptor (CAR) hold enhanced affinity for tumor associated antigens. As Podoplanin (PDPN) shows stable and increased expression in GBM, it is a suitable target antigen. When activated, CAR-T cells initiate the triad of cytokine release, T cell proliferation and target cell apoptosis. We evaluated the performance of PDPN-CAR-T cells in GBM patient derived organoids (PDO).

Material and Methods
PDOs were generated from freshly resected GBM tissue and could be cultured successfully up to several months. We assessed PDPN expression of PDOs via immunohistochemistry (IHC) prior to treatment. PDPN-CAR T cells were generated from peripheral blood mononuclear cells of healthy donors via lentiviral transduction and expansion. The transduction rate was assessed by flow cytometry prior to application. PDOs treated with untransduced T cells served as controls. PDOs were incubated with a preset number of PDPN-CAR T cells at a E:T ratio of 1:4 and were examined microscopically to register morphological disintegration after 48h. Immunofluorescence staining was conducted to detect proliferating CD4+ CART cells (CD4+/ Ki67+) after 72h and cytokine release of IFN-γ was determined via ELISA after 20h.

Results
In total, PDOs from three patients were treated with PDPN-CART cells. All of them expressed the antigen according to IHC staining. All incubated PDOs presented clear disintegration of the circular organoid shape up to total dissolving, whereas control PDOs stayed intact. CD4+ CART cells showed extensive proliferation at a mean rate of 79.8% ± 6,59% which was significant for two PDOs in comparison to control PDOs (p = 0.48, p &lt; 0.01). PDPNCART cells exhibited significantly elevated IFN-γ release in all PDOs (p &lt; 0.01).

Conclusion
We here describe PDPN as a promising target and proved effectiveness of PDPN-CAR-T cells in an ex vivo 3D model. Additional ex vivo models like tumor slice cultures might be crucial to evaluate effectiveness of CAR-T cell therapy. PDPN-CAR-T cells should be tested in these ex vivo as well as in vivo GBM models alone and in a combined approach with CARs targeting additional antigens in order to overcome tumor heterogeneity.
P06.05.A Repeated intracranial administration of ipilimumab and nivolumab in patients with recurrent glioblastoma (rGB): A multi-cohort adaptive phase I clinical trial
Authors: Geens W , Schwarze J K , Awada G , Tijtgat J , Lescrauwet L , Geeraerts X , Vaeyens F , Cras L , Van Binst A , Everaert H , Michotte A , Cauwenbergh T , Bruneau M , Forsyth R , Tuyaerts S , Neyns B , Duerinck J 
Published: September 2022

Abstract

Background
Perioperative intracerebral (iCE) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with IV NIVO was shown to be feasible, safe and associated with an encouraging survival benefit (Duerinck et al. JITC 2021). In subsequent cohorts, combination of iCE administration with biweekly intracavitary (iCA, via an Ommaya reservoir) administration of increasing doses of IPI and NIVO was investigated.

Methods
Three cohorts were defined according to resectability and postoperative treatment schedule. Patients (pts) in cohort-A and -C underwent a maximal safe resection, pts in cohort-B stereotactic biopsy only. All pts received iCE administration of 10 mg NIVO and 5 mg IPI at the end of the surgical intervention, after which an OR was implanted and an additional 10mg of NIVO and IPI (1, 5 or 10 mg) was administered iCA in cohort-C. All pts received biweekly postoperative NIVO 10 mg IV and iCA administrations of NIVO (3 dose levels were investigated in cohorts-A and -B: 1, 5, or 10 mg) for up to a maximum of 24w postoperatively. In cohort-C, 10 mg of NIVO was complemented with IPI (1, 5, or 10 mg). NGS and RNA gene expression profiling was performed on all tissue samples.

Results
In total, 44 pts were included (A: n= 16, B: n= 16, C: n= 12 recruitment ongoing). All pts in cohort-A and -B are off study treatment. All pts received the predefined dose of iCE IPI/NIVO and at least one administration of the predefined iCA dose. AE were infrequent and mostly not immune-related. Most common AE were fatigue(n=37), headache(n=25), confusion(n=18) and postoperative fever(n=15). Bacterial colonization of the Ommaya port occurred in 6 pts, subacute neurological deterioration requiring corticosteroids in 8 pts. There were no grade 5 AEs. Median PFS was 13w for cohort-A, 5w in cohort-B and 13w in cohort-C. Median OS is 43weeks in A, 29w in B and is not yet reached in cohort-C after median follow-up of 23w. OS did not differ significantly between study cohorts. OS of pts who underwent surgical resection (cohorts-A and -C) compared favorably to a historical cohort of 469 Belgian patients with rGB (treated in three prospective phase II clinical trials and a large multicenter early acces program for bevacizumab).

Conclusions
iCE followed by repeated iCA administrations of increasing doses of NIVO with/without IPI in rGB is feasible and safe without dose limiting AEs. A potential survival benefit seems restricted to pts amenable to surgical resection.
P06.08.B Radiation therapy enhances anti-tumor activity of a MET CAR T-based immunotherapy for glioblastoma
Authors: Hovhannisyan L , Aebersold D M , Medova M , Ochsenbein A F , Maher J , Zimmer Y 
Published: September 2022

Abstract

Background
Glioblastoma is the most frequent primary brain tumor with dismal prognosis after standard treatment with surgery, and chemoradiation (the Stupp protocol). After a decade of failed clinical trials, tumor-treating fields have been first to show the added benefit of improved overall survival compared to the Stupp protocol (20.9 months vs 16.0 months). However, GBM remains a devastating disease, with almost inevitable recurrence, and limited options for second-line therapy. Radiation therapy (RT), is a standard therapy option for GBM, and it is used in most GBM cases affecting tumor through induction of DNA-damage. Recently, RT has been investigated as a mediator of T cell-based therapies in the context of immunosuppressive GBM microenvironment. The findings have shown promise in combination of T cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapies, in improving the tumor infiltration, and penetration with immune cells. MET is a relevant oncogene in the context of GBM, being involved in stem-like properties, radiation response and resistance․ Hence, MET appeared to be a plausible target for combination with RT. In our research, we use MET-targeting CAR T cells (MET-CAR T cells) combined with radiation, and hypothesize synergistic interaction for GBM treatment.

Material and Methods
We used adherent (2D) and stem-like (3D) human GBM cell lines with different levels of MET expression. For MET-CAR T cell generation we did retrovirus-mediated transduction of activated human T cells and sorted the CAR-positive cells. We co-cultured MET-CAR T cells with GBM cells with or without RT, and assessed the killing and cytokine production in CAR T cells.

Results
Our results indicated that 5Gy radiation combined with MET-CAR T cells increases their potential in tumor cell killing. We observed increased CAR T cells effect at lower CAR T to target cells ratios when combined with radiation, even when radiation treatment did not lead to a significant decrease in viability. This phenomenon was similar across different types of cell lines (adherent, stem-like), different levels of MET expression, and different sensitivity to CAR T cells. We investigated the underlying mechanisms via intracellular cytokine measurement. We observed the most prominent response in TNF-α-expression. We also observed an increase in Granzyme B expression in co-culture with some of the GBM cell lines, especially in CD8+ subpopulation of CAR T cells. IFN-gamma expression increased in some adherent glioma cell lines but not in stem-like cell lines.

Conclusion
In conclusion, our data demonstrates the potency of MET-CAR T cells against GBM, and increased efficiency when combined with radiation. The suggested mechanism is the increased activation of T cells in TNF-α-dependent-manner. To validate these results we are testing our setup in an orthotopic mouse GBM model.
P07.03.A Advances in Robotic Navigated Laser Craniotomy. An in-vivo non-recovery animal study
Authors: Winter F , Beer D , Morawska M , Dorfer C , Roessler K 
Published: September 2022

Abstract

Background
We previously described a new frameless stereotactic intervention using robotic guided laser beam for depth electrode placement. This study tested the feasibility of a new cutting strategy for angulated precision bone channels as well as improved cut-through detection using optical coherence tomography (OCT) and a new generation of co-axial live video feed.

Material and Methods
Preoperative CT scans were performed to plan trajectories for bone channels angulated 45, 60, and 90° relative to the surface. The animals were prepared under general anesthesia by a trained veterinarian conforming European requirements and Good Laboratory Practice regulations. A new cutting strategy was implemented consisting of two circular paths and three different ablation phases. After cut-through detection bolts and depth electrodes were inserted. Before termination ad-hoc planned laser craniotomies were performed to evaluate possible cortex damage.

Results
70 robotic guided laser beam precision bone channels were cut in four pig specimens. Bolts and depth electrodes were implanted solely guided by the trajectory given by the laser precision channels. The new cutting strategy showed no irregularities for either cylindrical (n=38, 45°=10, 60°14, 90°=14) or anti-conical (n=33, 45°=11, 60°=13, 90°=9) bone channels. Angulation and hole diameter showed no significant difference between cylindrical and anti-conical cutting strategies. The updated co-axial camera live video feed in addition to OCT reliably detected cut-through in 80% of cases. Insertion of bolts with firm fit was achieved in 94% of bone channels. All four anesthesia protocols showed no irregularities. No unintended damage to the cortex was detected after laser guided craniotomy.

Conclusion
The new cutting strategy showed promising results in 70 precision bone channels for angulated cylindrical and anti-conical channels in a large in-vivo non-recovery animal study. OCT signal and a new co-axial camera proved its feasibility for cut-through detection. Robotic guided laser beam techniques proved its feasibility for the placement of depth electrodes and might be a suitable option to optimize the burr hole for biopsies.