bluuebunny/crossref_metadata_2025 huggingface dataset:
P03.07.A MRI signature in preoperative imaging predicts mesenchymal stem cell features and radioresistance in primary glioblastoma stem cell cultures
Authors: Eckert F , Ganser K , Bender B , Schittenhelm J , Noell S , Stransky N , Hoffmann E , Zips D , Huber S , Paulsen F
Published: September 2022

Background

Recently, a molecular signature describing the mesenchymal / proneural features of primary stem-cell-enriched glioblastoma cultures was identified correlating with invasiveness, radiation sensitivity and patient-outcome. However, generating and characterizing primary cultures is time-consuming and this might hamper translation into clinical concepts. The aim of this study was to evaluate the use of standard preoperative MR imaging (T1ce and T2FLAIR sequences) to predict the molecular signature and thus enable the development of clinical treatment concepts based on the molecular properties of the individual tumors.

Material and Methods

For 16 patients, for whom primary stem cell enriched cultures had been characterized for their mesenchymal / proneural signature and radiation sensitivity, tumor volume (hyperintense volume in T1ce), necrosis (hypointense volume inside the tumor volume) and edema (hyperintense volume in T2FLAIR) were contoured for volumetric analysis. Volume parameters were used to calculate ratios (edema/tumor and necrosis/tumor) and a MRI signature, which was then correlated with molecular parameters and patient outcome stratified by MGMT promoter methylation.

Results

As expected, the prognosis of patients with MGMT-promoter-methylated tumors was better (n.s.) compared to those with unmethylated MGMT promoters. Neither molecular nor imaging data were significantly different between these subgroups. In the subgroup of patients with unmethylated MGMT promoter, volumetric imaging parameters correlated with the molecular signature and cellular radiation sensitivity of the stem cell enriched cultures. This association was much weaker in the subgroup with methylated MGMT promoter.

Conclusion

In the subgroup of patients with unmethylated MGMT promoter, volumetric parameters on preoperative standard MR imaging might hint at the molecular properties of the respective tumor and its radiation sensitivity. This might be a clinically applicable method to stratify treatment according to molecular stem cell subtype without tissue culture and molecular analysis.
P03.09.A Proton beam therapy for adults medullobastoma
Authors: Frakulli R , Ni N , Schmidt L , Guntrum F , Kramer P , Frisch S , Glas M , Timmermann B
Published: September 2022

Background

Although Medulloblastoma (MB) is the most common primary malignant intracranial tumor in childhood, in adults it is extremely rare. Therefore, available data is scarce and experience with radiation and proton beam therapy (PBT) is very limited. The treatment typically includes tumour resection, irradiation of the craniospinal axis (CSI) followed by a boost, +/- concomitant chemotherapy, and maintenance therapy. Herein, we present our preliminary analysis of outcome and toxicity after PBT.

Material and Methods

Patients ≥ 18 years with primary MB treated with PBT between January 2017 and March 2020 enrolled in the prospective registry study (DRKS00004384) were evaluated in this analysis. Within the registry, adverse events were documented according to CTCAE v4.0 before, during, and after PT. The overall survival (OS), local control (LC) and higher-grade toxicity (≥ grade 3) were analyzed.

Results

A total of 19 patients (13 males, 6 females) with a median age of 23 years (range, 18.5- 39 years) were included in this study. Histopathology type were classic, desmoplastic /extensive nodularity or anaplastic MB in 52.6%, 26.3% and 21.1 % of patients, respectively. Complete tumor resection was performed in 57.8 % of patients. 68.4 % of patients had local disease without any metastases. Median total CSI dose was 35.2 Gy(RBE) (range, 23.4-40 Gy) with a median single dose of 1.6 Gy(RBE) (range, 1-1.8 Gy). All patients received either boost to the posterior fossa (57.9%) or to the tumor bed only (42.1%). The median total tumor dose was 18.8 Gy(RBE) (range, 54-68 Gy). Concomitant chemotherapy was given to 63.1% of patients. The median follow-up time after first diagnosis was 28.2 months (range, 8-56 months). No higher-grade acute or late adverse event was documented so far. One patient developed local disease progression. Another patient deceased due to an acute pulmonary embolism during maintenance chemotherapy without evidence of disease. The 3-year LC and OS rate were 89 % and 94 %, respectively.

Conclusion

Early results display good feasibility and high tumor control of PT in adult patient with MB. Results will need to be confirmed in larger cohort with longer follow-up time.
P03.10.B A successful case of Histiocytic sarcoma
Authors: Bonzano E , Colombo S , Mantovani L , Di Liberto R , Filippi A
Published: September 2022

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

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

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

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

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

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

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 < 0.01). PDPNCART cells exhibited significantly elevated IFN-γ release in all PDOs (p < 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

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

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

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.
P07.06.B The Impact of Using Intraoperative Ultrasound on Surgical Resection of High-Grade Glioma: A Systematic Review and Meta-Analysis
Authors: Solomou G , Christou A , Gillespie C S , Khouli O , Plaha P
Published: September 2022

Background

Despite operative and adjuvant therapies, high-grade glioma (HGG) remains incurable, with the extent of surgical resection being one of the modalities that can improve patient survival. Enabling maximal safe and minimising post-operative neurological morbidity is a key aim of surgical resection. Numerous intraoperative surgical adjuncts are used at surgery and intraoperative ultrasound (IoUS), is one such adjunct. IoUS is a cost-effective, easy to use, repeatable surgical adjunct, safe for the patient and potentially available in all centres. Although it’s commonly used, no up to date systematic review exists collating and quantifying the level of evidence, delineating its impact on the extent of surgical resection.

Material and Methods

A systematic review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The study was registered with the PROSPERO database (CRD42022300034). Keywords across Medline/PubMed and Embase between 1996 and November 2021 were used. We included articles with adult supratentorial, histopathologically confirmed HGG patients aimed for resection, evaluating the correlation of IoUS use and gross-total resection (GTR). Meta-analyses were conducted according to the statistical heterogeneity between the studies using the Open Meta Analyst software.

Results

2942 articles were identified of which 16 were qualitative assessed and 10 used for quantitative meta-analysis. In qualitative assessment, a mean 4.63/8 Newcastle-Ottawa-Scale score was found for studies with no cohorts (no use of IoUS) and a mean score of 6/9, for studies including exposed versus non-exposed cohorts. The RCT was of moderate quality according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool. A pooled analysis across 10 studies of HGG aimed for resection with the use of IoUS, led to GTR achieved in 168/365 cases, resulting in an overall GTR rate of 51.1% (95% CI, 33.9%-68.3%, p<0.001), with great heterogeneity across studies (93.02% p<0.001). In a subgroup meta-analysis of 3 studies of HGG aimed for complete resection only, GTR was achieved in 43/62 cases, yielding a 72.7% GTR rate (95% CI 41.6%-100%, p<0.001) with significant heterogeneity across studies (I2 92.1%, p<0.001). In 4 case-controlled studies, a total of 43.6% (48/110) GTR rate was achieved when IoUS was used versus 24.7% (65/263) when IoUS was not used, resulting in an odds ratio = 2.009 (95% CI 1.157-3.490, p <0.001) for achieving GTR.

Conclusion

The meta-analysis showed a high GTR rate (72.7%) when HGG were aimed for complete resection and a two-fold probability of achieving GTR when IoUS is used than not used.
P07.07.A Fluorescence lifetime imaging for improved visualization of 5-ALA fluorescence during biopsies of suspected brain tumors
Authors: Millesi M
Published: September 2022

Background

Stereotactic brain tumor biopsies represent a standard neurosurgical technique enabling a precise histopathological tumor diagnosis which is of utmost importance for optimal further treatment allocation. However, non-diagnostic biopsies are not uncommon in routine clinical practice. To overcome this shortcoming, serial biopsies or intraoperative histopathology are typically performed prolonging the operating times and potentially increasing the risk of complications. Recently, the value of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence for visualization of diagnostic tumor tissue was demonstrated in navigation-guided brain tumor biopsies. However, a not negligible proportion of brain tumors lack visible fluorescence. In some of these tumors, a subvisual concentration of PpIX could be detected by spectroscopic analysis. Thus, detection of such subvisual PpIX accumulation in tumor samples in biopsies by the new “Fluorescence Lifetime Imaging” (FLIM) technique might lead to further improvement of this approach.

Material and Methods

Patients that underwent navigation-guided biopsy of a suspected brain tumor were eligible for inclusion in this study. After administration of 5-ALA, the tissue samples were checked for visible fluorescence during the navigation-guided stereotactic biopsy with a sterile microscope. In each sample the observed fluorescence signal was documented. Additionally, the tissue samples were investigated ex-vivo by FLIM for detection of PpIX accumulation. In each case, a histopathological diagnosis was established according to the WHO classification of CNS tumors.

Results

A total number of 20 tissue samples could be retrieved in 16 patients with suspected brain tumors. The biopsy with assistance of 5-ALA was feasible in all patients and no relevant side effects occurred. Visible PpIX fluorescence could be observed in 75% of cases. In contrast, 25% of samples did not show visible fluorescence. In one specimen, no fluorescence signal could be evaluated as the sample was covered by too much blood. However, significant accumulation of PpIX could be detected by FLIM in all samples in which evaluation was possible (n=19). A final histopathological diagnosis was feasible in all patients.

Conclusion

Fluorescence Lifetime Imaging is a promising new technique for improved detection of brain tumor tissue during navigation-guided biopsies. Thus, this new technique might lead in future to reduced operating times and complication rate by minimizing the cases that need serial biopsies or intraoperative histopathology.
P07.08.B Surgical management of recurrent lower-grade gliomas: analysis of oncological and functional outcomes and associated factors
Authors: Gay L , Rossi M , Sciortino T , Conti Nibali M , Simonelli M , Navarria P , Rudà R , Soffietti R , Bello L
Published: September 2022

Background

Presently, there are no clear evidence-based recommendations for the surgical management of progressive or recurrent lower-grade gliomas (LGGs). In our work, we evaluated the oncological (PFS, OS) and functional (neurological, neuropsychological, quality of life evaluation) outcomes of a series of LGGs treated in a 5-year period. The aim was to identify clinical, imaging, and molecular factors, associated with better outcomes, to be implemented in the treatment decision making process.

Material and Methods

In our retrospective analysis, 738 recurrent LGGs were included (follow-up 7.9 years; IQR:6-9); 550 were surgically treated, 495 with open resection (with brain mapping techniques), and 55 with tumor biopsy (with frameless stereotactic technique).

Results

Overall, 521 patients (70.6%) recurred. Of those treated with open resection 63.5% relapsed. Tumor progression was histologically confirmed in 72.5% of cases, no valuable tumor (effect of treatment) in 27.5% of cases (particularly in cases previously treated with RT and CHT), histo-molecular conversion (astrocytoma instead of oligodendroglioma diagnosis) in 7.5% of cases, malignant transformation in 38.7% of cases. Among the clinical (patient functional status, previous PFS, previous EOR, previous CHT and duration of CHT, previous RT), imaging (type of recurrence, i.e. typical versus atypical, speed of growth, contrast enhancement), and molecular (IDH, codeletion, ATRX, MGMT, tumor grade, CDNK status) factors analyzed, longest PFS of recurrent tumors was associated with patient functional status, previous PFS, previous EOR, speed of growth (>6 mm/year), atypical type of recurrence, tumor grade, presence of codeletion, and CDNK status. Best functional outcome associated with surgical resection, EOR, and tumor grade; worst functional outcome with RT and malignant transformation. Longest OS associated with previous EOR, surgical resection, tumor grade, presence of co-deletion. Malignant transformation was associated to previous EOR. Among patients submitted solely to tumor biopsy, changes in MGMT methylation status and in IDH status were observed in 65.3% and 5% of cases, respectively. Modification in IDH status was associated with atypical (distant) type of recurrence. New histo-molecular profile helped in the treatment decision making process.

Conclusion

Surgical resection of recurrent LGGs is associated with longer PFS and OS. Tumor biopsy should be considered, when surgery considered unfeasible, to tailor adjuvant treatment.
P07.10.B Preoperative brain mapping using transcranial magnetic stimulation applied to brain tumour resection surgery
Authors: Brugada-Bellsolà F , Lucente G , Teixidor Rodríguez P , Garcia-Armengol R , Hostalot Panisello C , Tardáguila Serrano M , González Crespo A , Pastor Cabeza M , Menéndez Girón S , Domínguez Alonso C
Published: September 2022

Background

Brain oncological surgery must pursue maximal tumour resection to achieve oncological benefits while preserving acceptable neurological function. Neuromonitoring techniques and brain mapping have been developed over the last decades to intraoperatively assess the exact location of neurological functions and secure their preservation. However, the fact that they cannot offer preoperative information and require in some cases the patient’s collaboration during displeasing awake surgeries raised the interest during last years on noninvasive techniques offering preoperative functional information. Navigated transcranial magnetic stimulation (nTMS) is a noninvasive technique able to create small magnetic fields and electrically stimulate brain cortex, emulating the effect obtained by cortical direct electrical stimulation (DES). It is a promising tool for performing pre-operative cortical brain mapping.

Material and Methods

We performed a unicenter prospective descriptive study including patients diagnosed with intra axial brain tumours neighboring cortical zones apparently implicated in motor and/or language functions who were planned for surgical resection. We performed preoperative nTMS (SofTaxic Neuro navigation system 3.0, EMS, Bologna) in all of them to define the location of these functions.

Results

Between November 2020 and December 2021 we included 18 patients (11 men, 7 women) with a mean age of 56 years (range 29-71). Location (8 temporal, 6 frontal, 3 parietal and 1 insular) and laterality (12 left, 6 right) of the brain tumours were registered. In all cases, cortical brain motor mapping with nTMS was performed with positive results, obtaining a mean anteroposterior diameter of the motor cortex of 22,75 mm. In 11 cases language mapping was also performed, detecting a total of 40 cortical language positive sites (31 frontal, 9 temporal) in those patient’s left hemispheres. No relevant side effects were noticed after nTMS performance. Definitive pathological results after surgery revealed high-grade glioma in 15 cases and low-grade glioma in 3.

Conclusion

nTMS is a recent noninvasive technique that allows the realization of preoperative cortical brain mapping. The information provided by this technique is of extreme value to better define surgical candidates and to plan brain tumour resection surgeries, according to functional cortical sites identified. The available literature describes its applications, mainly in localizing motor and language cortices, showing good concordance with intraoperative cortical DES, which is still the gold standard technique for brain mapping. Its integration in the pre-operative brain tumour assessment offers important advantages without adding relevant morbidity.
P07.11.A Impact of awake craniotomy on extent-of-resection and performance in glioma: a retrospective, propensity-score matched cohort study
Authors: Schnitzler S J P , van der Vaart T , van Garderen K , van den Bent M J , Vincent A J P E
Published: September 2022

Background

The goal of awake craniotomy is to safely optimize the extent-of-resection in patients with glioma. Lower postoperative tumor volume is associated with better overall survival, emphasizing the importance of optimal surgical resection. Awake craniotomy causes less postoperative neurological deficits than surgery under general anesthesia, however, it is unclear whether awake craniotomy leads to lower postoperative tumor volume compared with general anesthesia in presumed lower grade glioma.

Methods

Retrospective, matched cohort study in patients with astrocytoma, IDH-mutant grade 2 and 3, oligodendroglioma, IDH-mutant, and 1p/19q-codeleted grade 2 and 3, and low-grade glioma, IDH-wildtype (now designated glioblastoma, IDH-wildtype), who underwent resection with awake craniotomy or under general anesthesia between 2003 and 2021 at Erasmus MC Brain Tumor Center. Pre- and postoperative tumor volumes were measured by semi-automatic 3D MRI-segmentation. First, we performed a multivariate logistic regression to assess which factors predicted selection for awake craniotomy. Thereafter, matching based on propensity score was attempted. Outcome variables were postoperative tumor volume, resection percentage and Karnofsky Performance Status (KPS) 3 months after surgery.

Results

We identified 181 awake craniotomy-patients and 135 general anesthesia-patients. Awake craniotomy-patients were younger, in better condition, more often male, with tumors more often in eloquent areas, in the left side of the brain and non-contrast enhancing. When performing matching without replacement, only 68 awake craniotomy-patients could be matched with 68 general anesthesia-patients, underscoring the imbalance in the dataset. Matching with replacement yielded a matched dataset of 181 awake craniotomy-patients with 60 general anesthesia-patients with adequate matching on most baseline variables, except for eloquent area (47% for awake craniotomy and 21.7% for general anesthesia, p < 0.001). In this matched dataset, median postoperative volume in awake craniotomy was 5.8 mL (IQR 0 - 92.8) vs 12.2 mL (IQR 0 - 90.1) in general anesthesia (p-value = 0.114). Resection percentages did not differ between the awake craniotomy- and general anesthesia-groups. KPS scores at 3 months after surgery did not differ between awake craniotomy and general anesthesia (p = 0.15).

Conclusion

Postoperative tumor volume was not lower in awake craniotomy-patients than in general anesthesia-patients. Neither were resection percentage and KPS scores at 3 months after surgery significantly different between the groups. Adequate matching was only obtainable using replacement, underscoring the risk of bias in unmatched datasets. These data should be interpreted with care, given the retrospective nature, potential residual confounding and potential lack of generalizability due to unmatched normal resection patients.
P08.05.B Communication in the context of glioblastoma treatment: what matters most to patients and caregivers
Authors: Boele F W , Butler S , Nicklin E , Pointon L , Short S C , Murray L
Published: September 2022

Background

Given the poor prognosis of glioblastoma, with short survival times regardless of treatment, it is critical that the benefits and risks of treatments are clearly discussed with patients and family caregivers. The respective value of quantity versus quality of life varies for each individual. Yet, effective communication can be complicated by emotional responses following diagnosis, patients’ neurocognitive deficits, and sometimes, lower health literacy. We aimed to investigate patient and caregiver experiences and preferences around glioblastoma treatment communication.

Material and Methods

Semi-structured qualitative interviews were conducted with adult glioblastoma patients and their caregivers, interviewed as dyads or individuals. Purposive sampling was used to capture views across the entire disease trajectory. Interviews were recorded, transcribed verbatim, and analysed for common themes. Analysis is ongoing and will be completed by June 2022, with preliminary findings described below.

Results

In total, 15 glioblastoma patients and 13 caregivers took part, 8 as dyads. Five main themes were found. 1) Communication experiences. A rush to get treatment underway can limit adequate communication. Patients and caregivers described that risks of treatment were clearly explained, but perceived it as ‘the only option’. 2) Communication preferences. Balanced and sensitive communication of prognostic information was desired, with uncertainty providing hope as well as being a burden. Patients and caregivers can have different information and support needs, requiring separate and proactive communication. 3) What matters most. Participants valued feeling involved, having clear and reliable information and support from the treatment team, and developing a personable relationship. In terms of treatment goals, they valued extending life with good quality of life. 4) Decision-making. Participants emphasised the importance of being involved in decisions, involving caregivers, and following treatment team advice. While faced with extremely limited treatment options, they valued having a sense of control over declining, pausing or stopping treatment. 5) Impact of Covid-19. In general, patients described limited impact of the measures taken during the pandemic (e.g., masks, telephone consultations), whilst caregivers highlighted specific issues around not being able to support patients in emergencies, expressing/reading nonverbal cues, or fully participating in telephone consultations.

Conclusion

Glioblastoma patients and caregivers value sensitive, comprehensive and comprehensible communication around treatment risks and benefits, and supportive care. Involving and supporting caregivers is critical.
P08.06.A Work resumption following lower-grade glioma surgery: a multicenter cohort study
Authors: Kommers I O , van Genderen M N G , Eijgelaar R S , Witte M G , de Haan Y , Ille S , Mandonnet E , Krieg S M , Barkhof F , de Witt Hamer P C
Published: September 2022

Background

Patients with lower-grade glioma (LGG) are often of working age. For LGG patients post-surgical work resumption is at risk from treatment including resective surgery. However, little is known on determinants of returning to work. In this study we examined determinants of post-surgical work resumption after nine months using patient- and tumor-related characteristics, such as tumor and resection cavity locations.

Material and Methods

This retrospective multicenter cohort study included adults with supratentorial WHO grade II and III gliomas who underwent a first-time surgery in Paris, Munich or Amsterdam between 2011 and 2016. Patient-related characteristics included age, sex, patient condition, received treatments, classification of work type and skill level. Presurgical tumors and postsurgical resection cavities were manually segmented on MRI and registered to standard brain space. These segmentations were mapped to Schaefer, XTRACT and Harvard-Oxford atlas parcellations of cortical, white matter and grey nuclei structures. Predictors of postsurgical return to work were examined in multivariable logistic regression and Bayesian hurdle regression models.

Results

The cohort consisted of 219 patients. Before surgery 192 (88%) patients were able to work, and after surgery 119 (62%) resumed work. Independent predictors of returning to work were male sex (OR = 3.21, CI = 1.44 - 7.46, p = 0.005) and lower age (per 1 year older, OR = 0.96, CI = 0.92 - 0.99, p = 0.029). No associations were found between work resumption and locations of the tumor or resection cavity.

Conclusion

Many patients are able to work before and many return to work after first-time LGG surgery. Inability to resume work is exclusively associated with patient-related characteristics and not with tumor or resection locations. This novel information may inform patient counseling.