bluuebunny/crossref_metadata_2025_split huggingface dataset:
P02.06.B Calvarial metastases: overview of the different entities and the pre-, intra- and postoperative course
Authors: Hunziker S , Nasi-Kordishti I , Tatagiba M 
Published: September 2022

Abstract

Background
Calvarial metastases are most often in cancer with systematic bony metastatic disease. Calvarial metastases occur via hematogenous spread, retrograde seeding through Batson’s venous plexus, or direct extension. A variety of different primary tumours can cause calvarial metastases. The lesions can be palpable on the skin, cause local swelling and, depending on the location, neurological deficits can also occur. The aim of this research is to present an overview of the different entities and the neurosurgical management.

Material and Methods
Retrospectively, all patients who underwent surgery on a calvarial metastasis in our department between 2004 and 2021 (n=22) were identified. Data on the morphological and histological findings as well as the pre-, intra- and postoperative course were gathered and analysed.

Results
Swelling (n=14), cosmetically disturbing (n=9), pain (n=6), neurological deficits (n=4), epilepsy (n=3) and B-symptoms (n=1) were the main complaints. 7 had no symptoms at the time of diagnosis. There was a side preference with most of the lesions occurring on the right (n=13), less on the left (n=5) or bilateral (n=4). Calvarial metastases are divided in primary lesions, originating in the bone and secondary lesions infiltrating the bone. The majority of lesions originated from the bone except two, which wer secondary infiltrating the bone. 20 were not limited to the bone, infiltrating adjacent tissue (skin 70%, dura 85%, brain 35%). 18 lesions were osteolytic except four, where no further description was provided. Intraoperatively, craniectomy or in case of biopsy a craniotomy was performed. 70% of cases required Dural plastic. Depending on history and location the operative approach was biopsy (n=1), extended (n=6), subtotal (n=1) or complete (n=14) resection. Intraoperative major bleeding occurred in 15 % of cases, all with macroscopic high vascularization; hemodynamically relevant (n=1), requiring LAE (n=1). Histologically most common were adenocarcinoma of the lung (n=5), mamma (n=3), prostate (n=2), sigma (n=1), rectum (n=1) and gastric (n=1). Melanoma (n=3), neuroblastoma (n=1) and clear cell renal carcinoma (n=2) were less common. Other rare primaries were carcinoma of the parotid (n=1), SCLC (n=1) and follicular thyroidal cancer (n=1). Postoperatively, further treatment was initiated depending on the primary tumour.
Conclusion:
Above mentioned clinical symptoms or the staging of a cancer leads to the diagnosis of calvarial metastasis. Preoperative imaging shows localisation and the degree of infiltration into adjacent tissues. Imaging results and the clinical symptoms determine the surgical strategy. But definitive diagnosis can only be made by histological analysis. After surgery, the histology, the extension of the primary tumour and the clinical condition of the person influence the kind of further treatment initiated.
P02.07.B Patient-derived glioblastoma organoids: Elucidating the mechanisms of glioblastoma therapeutic resistance in the context of tumor microenvironment
Authors: Habič A , Majc B , Porčnik A , Bošnjak R , Mlakar J , Lah Turnšek T , Breznik B , Novak M 
Published: September 2022

Abstract

Background
Intratumoral heterogeneity plays an important role in glioblastoma (GB) resistance to standard therapy consisting of irradiation and chemotherapy with temozolomide (TMZ). However, classical in vitro GB models fail to represent the complex cellular composition of tumors in vivo, which hinders relevant examination of GB therapeutic response. To overcome these limitations, we studied the effects of irradiation and TMZ in a novel patient-derived organoid model.

Material and Methods
We established a patient-derived GB organoid model by a protocol recently published by Jacob et al. Original tumor tissue and tissue-derived organoids were compared by immunofluorescence staining of selected cell type markers and qPCR analysis of expression levels of a panel of selected target genes, including 15 genes defining GB subtypes. To analyze GB therapeutic response, organoids from 11 patients were exposed to a single dose of irradiation (10 Gy), one-week treatment with TMZ (50 µM) or their combination. The effects of therapy were assessed by viability and invasion assays. Expression levels of a number of genes related to GB subtypes, epithelial-mesenchymal transition, stemness, DNA damage responses, cell cycle, cytokines, and cell markers of the tumor microenvironment (TME) were compared between treated organoids and untreated controls. In addition, the heterogeneity of the TME and its responses to treatment were investigated by spatially resolved transcriptomics with in situ sequencing (ISS) methodology.

Results
Organoids recapitulate inter-patient variability and reflect the cellular composition and gene expression levels of the tumor tissue from which they were derived. GB stem cells and differentiated cancer cells are present in organoids along with various cells of the TME, e.g., macrophages and microglia, lymphocytes, and endothelial cells. Irradiation and TMZ showed no significant effects on organoid viability and invasion. However, some target genes were differentially expressed in the treated organoids, such as E3 ubiquitin-protein ligase MDM2 and cyclin-dependent kinase inhibitor 1A (CDKN1A). To our knowledge, we are the first to apply spatially resolved transcriptomics (ISS) to formalin-fixed, paraffin-embedded sections of (un)treated GB organoids. Our results elucidate the role of the TME in GB therapeutic response and shed light on potential mechanism underlying GB therapy resistance.

Conclusion
Patient-derived GB organoids recapitulate the key characteristics and complex composition of patient’s tumor tissue, providing a valuable platform for studies of GB therapeutic response and resistance.
P02.10.A CRISPR/Cas9 deletion of SOX2 Regulatory Region 2 (SRR2) decreases SOX2 malignant activity in glioblastoma
Authors: Saenz-Antoñanzas A , Moncho-Amor V , Elúa-Pinín A , Rizzoti K , Lovell-Badge R , Matheu A 
Published: September 2022

Abstract

Background
SOX2 is a transcription factor associated with stem cell activity in several tissues. SOX2 expression is elevated in a large proportion of cancers, such as glioblastoma (GB), the most common malignant primary brain tumor in adults. SOX2 acts as a relevant driver of GB progression and high levels are associated with the population of tumor initiating cells and poor patient outcome. Transcriptional regulation of SOX2 is complex and not fully understood. The SOX2 regulatory region 2 (SRR2) is located downstream of the SOX2 coding region and mediates SOX2 expression by the association of p21CIP1 and p27KIP1 to SRR2. In this study we dissected the role of SRR2 on SOX2 activity in GB.

Material and Methods
We deleted SRR2 (SRR2del) by CRISPR/Cas9 technology in U373 GB cells. We analyzed the expression of SOX2 and performed in vitro functional experiments. We accomplished rescue experiments overexpressing SOX2 in SRR2del cells and we studied the link between SOX2, p21CIP1 and p27KIP1. Finally, we carried out an in vivo carcinogenesis assay by the injection of SRR2del cells in immunodeficient mice.

Results
We report that the deletion of SRR2 in GB cells leads to a reduction of SOX2 expression, which was accompanied with an impairment of cell growth and proliferation as well as with a reduction of self-renewal capacity in vitro. These data reveal that SRR2 is required for SOX2 expression and that its deletion results in impaired tumorigenic capacity of GB cells. These effects correlated with an increased expression of p21CIP1 and p27KIP1 together with high levels of p53 in SRR2del cells. On the contrary, SRR2del cells presented decreased levels of stem cell markers, supporting the idea that SRR2 is necessary for the SOX2-mediated regulation of stemness pathways. Furthermore, ectopic overexpression of SOX2 in SRR2del cells restored SOX2 expression as well as proliferation and stem cell properties, indicating that the expression and the oncogenic activity of SOX2 is regulated by SRR2. Additionally, our xenograft models revealed that the lack of SRR2 impairs tumor initiation and growth in vivo. Tumors derived from SRR2del cells were significantly smaller compared to controls and exhibit low levels of SOX2, Ki67 and BMI1 but high levels of p21CIP1 and p27KIP1.

Conclusion
Our data confirm that the SRR2 regulates SOX2 expression and reveal that SRR2 deletion reduces SOX2 levels and halts malignant activity driven by SOX2 in GB.
P02.11.B An hypothesis generating study of MRI-Derived Radiomics on tumor and microenvironment tissue heterogeneity to guide post-operative management of glioblastoma: toward personalized radiation treatment volume delineation
Authors: Cannatà M , Russo R , Beghella Bartoli F , Palumbo I , Tran H , Votta C , Lupattelli M , Boldrini L , Dinapoli N , Camilli F , Balducci M , Gambacorta M , Valentini V , Aristei C , Sabatino G , Pignotti F , Gaudino S , Chiesa S 
Published: September 2022

Abstract

Background
The glioblastoma’s bad prognosis is primarily due to intra-tumor heterogeneity, demonstrated from several studies that collected molecular biology, cytogenetic data and more recently radiomic features for a better prognostic stratification.The GLIFA project (GLIoblastoma Feature Analysis) is a multicentric project planned to investigated the role of radiomic analysis in GBM management, to verify if radiomic features in the tissue around the resection cavity which may guide the radiation target volume delineation.

Material and Methods
We retrospectively analyze from three centers radiomic features extracted from 90 patients with total or near total resection, who completed the standard adjuvant treatment and for whom we had post-operative images available for features extraction.The Manual segmentation was performed on post gadolinium T1w MRI sequence by 2 radiation oncologist reviewed by a neuroradiologist, both with at least 10 years of experience. The Region of interest (ROI) considered for the analysis were: the surgical cavity +/- post-surgical residual mass (CTV_cavity); the CTV a margin of 1.5 cm added to CTV_cavity and the volume resulting from subtracting the CTV_cavity from the CTV was defined as CTV_Ring. Radiomic analysis and modelling were conducted in RStudio. Z-score normalization was applied to each radiomic feature. A radiomic model was generated using the 226 features extracted from the Ring to perform a binary classification and predict the PFS at 6 months (statistical, morphological and textural features). A 3-fold cross-validation repeated five times was implemented for internal validation of the model.

Results
Two-hundred and seventy ROIs were contoured. The proposed radiomic model was given by the best fitting logistic regression model, and included the following 3 features: F_cm_merged.contrast, F_cm_merged.info.corr.2, F_rlm_merged.rlnu. A good agreement between model predicted probabilities and observed outcome probabilities was obtained (p-value of 0.49 by Hosmer and Lemeshow statistical test). The ROC curve of the model reported an AUC of 0.78 (95% CI: 0.68 - 0.88).

Conclusion
This is the first hypothesis-generating study who applies a radiomic analysis focusing on healthy tissue ring around the surgical cavity on post-operative MRI. This study provides a preliminary model for a decision support tool for a customization of the radiation target volume in GBM patients in order to achieve a margin reduction strategy.
P03.03.A STEREOBRAIN: Stereotactic radiosurgery versus whole-brain radiotherapy in patients with 4-10 brain metastases - a non-randomized controlled trial
Authors: Niyazi M , Bodensohn R , Kaempfel A , Forbrig R , Garny S , Corradini S , Belka C 
Published: September 2022

Abstract

Background
Since the JLGK0901 study described non-inferiority of stereotactic radiosurgery (SRS) of 5-10 compared to 2-4 brain metastases in 2014, it has been widely discussed if SRS should replace whole brain radiotherapy (WBRT) in 5 - 10 brain metastases though lacking randomized evidence. At our department, WBRT has been the treatment of choice in 4-10 brain metastases until 2017. This paradigm was entirely changed to include patients within the STEREOBRAIN trial (DRKS00014694). We designed this prospective controlled single arm trial to systematically introduce SRS to 4 to 10 brain metastases comparing this new treatment regimen with the former approach. We aimed at showing a survival benefit of this novel treatment paradigm.

Material and Methods
Inclusion criteria were 4-10 brain metastases, largest diameter 2.5 cm, all histologies except SCLC, germ cell tumors, lymphoma, and ECOG ≤ 2. The retrospective WBRT cohort was identically selected from consecutive patients from 2012 to 2017 in a 1:2 fashion. At a significance level of 5%, a total number of 99 events (deaths) across the two groups allows to detect an increase in median OS from 6 months (retrospective WBRT cohort) to 11 months (SRS) considered clinically relevant (and corresponding to a hazard ratio of 0.55 assuming exponential distributions of survival times within groups) with a power of 80%. Propensity-score matching was performed to take confounders into account given the inherent bias caused by different treatment periods. Multiple brain mets SRS was performed using a single-isocenter technique.

Results
Patients were recruited from 2017 - 2020 and end of F/U was July 1st 2021. Forty patients were recruited to the SRS cohort and 70 patients were eligible within the WBRT cohort (81 events altogether). Median follow-up, OS and intracranial progression free survival were 21.6 months (95%-CI 19.8-NA), 10.4 months (95%-CI 9.3-NA) and 7.1 months (95%-CI 3.9-14.2) for the SRS-cohort, and 61.4 months (95% 54.6-NA), 6.5 months (95%-CI 4.9-10.4) and 5.9 months (95%-CI 4.1-8.8) for the WBRT-cohort, respectively. The Cox-model yielded a trend for improved survival within the SRS-cohort, HR 0.65 (95%-CI 0.4-1.1); p=0.076. After optimal propensity score matching, OS was significantly superior for the SRS-cohort (HR 0.53 (95%-CI 0.32-0.86), p=0.01). No grade III toxicities were observed in the SRS-cohort.

Conclusion
Despite all limitations of a historical control and missing the target number of events, there was a clear signal of improved survival with SRS compared to WBRT for patients with 4-10 metastases. Whether adapted WBRT (hippocampal sparing, simultaneous integrated boost) or SRS is to be preferred needs to be investigated in the future.
P03.05.A Radiation-induced leukoencephalopathy (RIL) in glioma: unique injury dynamics following proton vs photon beam radiotherapy
Authors: Winter S F , Gardner M , Parsons M W , Grassberger C , Bussière M , Kaul D , Boehmerle W , Endres M , Shih H A , Dietrich J 
Published: September 2022

Abstract

Background
White matter injury after brain-directed radiotherapy (RT), aka radiation-induced leukoencephalopathy (RIL), is common in brain tumor patients. Differentiation from progressive disease can be challenging. Dosimetric advantages of protons (PRT) over photons (XRT) minimize radiation to healthy brain tissue, potentially limiting radiotoxic sequelae including RIL. We characterized RIL during periods of progression-free survival (PFS) in glioma patients irradiated with either PRT or XRT, hypothesizing that PRT would result in reduced RIL outside of the target field.

Material and Methods
34 patients (19 male; mean age = 40.10y) with grade 2/3 gliomas and a history of partial cranial RT were stratified by RT modality [XRT (n=17) vs PRT (n=17)] and matched on 11 criteria [age, sex, tumor type/location/laterality, mutational status (IDH; 1p19q deletion), concurrent/adjuvant chemotherapy, radiation dose/fractions] for retrospective analysis. RIL development was characterized longitudinally for up to 3 years post-RT via analysis of serial MRI T2/FLAIR sequences. A novel RIL scoring system with embedded Fazekas scale was designed to quantify injury severity at both global (whole brain) and hemispheric levels.

Results
Matched groups did not differ significantly on any demographic or clinical characteristics. Median PFS post-RT was 4.7 (XRT) and 5.1 (PRT) years. The novel RIL scoring system was reliable (intraclass correlation coefficient &gt;0.9). There was a significant increase in global RIL in both XRT [F(3, 57)=8.63, p&lt; .001] and PRT [F(3, 61)=4.69, p&lt; .005] groups over time, relative to baseline (1-month post-RT). A majority [62% (XRT) and 72% (PRT)] developed moderate or severe RIL within 3 years, with the ipsilesional hemisphere more severely affected. Analysis of RIL injury dynamics (i.e., average % change between 1 and 3 years post-RT) at hemispheric level identified radiation modality-specific differences: XRT resulted in greater contralesional hemispheric injury than PRT [F(1, 31)=4.32, p&lt;.05]. This effect was not observed in ipsilesional hemispheres.

Conclusion
RIL is common in glioma patients and quantifiable by characteristic imaging features, including early onset post-RT, greater ipsilesional injury burden, and progression over time. RIL injury dynamics appear to be radiation modality-specific, whereby XRT causes greater delayed injury in the remote, contralesional hemisphere. These findings may reflect dosimetric differences between protons and photons. The impact of such sequelae on cognitive function is subject of current investigation.
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

Abstract

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

Abstract

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.&lt;Bookmark(28)&gt;