bluuebunny/crossref_metadata_2025_split huggingface dataset:
P10.13.B Repurposing neuroleptics to treat brain metastases: Clozapine as a novel therapy for melanoma brain metastases
Authors: Wikerholmen T , Taule E , Thorsen F A , Sundstrøm T 
Published: September 2022

Abstract

Background
Around half of advanced melanoma patients develop brain metastases (BM) and survival is still measured in months. Current treatments, although increasingly effective, are not sufficient for this patient group, necessitating development of new therapeutic options. Drugs targeting BM specifically are a scarcity. However, utilizing drug repurposing, i.e. novel uses of drugs already approved for other medical conditions, may broaden available therapy options. Medications used to treat psychosis can penetrate an intact blood-brain barrier and it has been shown that patients with schizophrenia have lower incidences of certain cancer types than the rest of the population. Still, little is known on antitumor effects of neuroleptics on BM. We have preliminary data showing that the antipsychotic drug clozapine effectively inhibits growth of human melanoma brain metastasis (MBM) cell lines in vitro.

Material and Methods
We used the H1, H2, H3 and H10 MBM cell lines, as well as normal human astrocytes (NHA). Monolayer viability and IncuCyte studies were performed to determine IC50 doses. Cell migration was measured by a scratch wound assay. Apoptosis was studied by flow cytometry. Colony formation assays were performed using 2D clonogenic assays and 3D soft agar models. A protein array was used to find signaling proteins potentially affected by clozapine. The effect of clozapine on the normal brain was assessed, using a novel brain organoid model developed from fetal rat brains.

Results
A viability screening using 6 different neuroleptics showed that clozapine was most effective in inhibiting MBM cell viability, while NHA tolerated the same doses. MBM cells exhibited a dose-dependent inhibition of cell proliferation, migration, clonogenic formation and 3D growth. Flow cytometry demonstrated that apoptosis was a major mechanism of cytotoxicity. The protein array showed that CCL3, IL8 and VEGF were downstream targets of clozapine. These results are currently being confirmed by western blots. Doses significantly above MBM IC50 doses did not affect viability of brain organoids. Currently, a partnership with the Dept. of Chemistry (UiB) has been initiated to develop and test novel clozapine derivates, to find a more effective derivative with a larger therapeutic window and lesser side effects.

Conclusion
Clozapine shows promise as a novel agent for use in cancer therapy due its favorable tolerability, small molecular size and established clinical safety.
P11.04.A Observational, prospective multicenter study on the role of body mass index (BMI) in the development of thrombotic complications in cancer patients with PICC: preliminary results
Authors: Simonetti G , Gammone M , Bersani A , Garofalo R , Anghileri E , Botturi A , Gaviani P , Redaelli V , Silvani A 
Published: September 2022

Abstract

Background
Peripherally inserted central catheters (PICC) became widespread and changed substantially the approach to the patients venous system. They guarantee, both in hospital and at home, a stable and safe vascular access to administer irritants or vesicants therapies. However, the benefit provided may occasionally be affected by relevant thrombotic complications especially in patients with hypercoagulability such as oncological patients. Among the identification of independent risk factors, the role of a BMI&gt;25 kg/m2 is now emerging in literature with conflicting results.

Material and Methods
Oncological patients with PICC were included in this multicenter prospective study. We evaluated clinical data, BMI, KPS, steroid therapies and anticoagulants at the time of PICC positioning and at regular intervals.

Results
A total of 51 patients were analyzed. The median KPS was 90 (range 80-100), and the median ECOG was 1 (range 0-3). The most common tumors were represented by: lymphomas both Hodgkin and non-Hodgkin (38%), lymphatic and myeloid leukemia (35%), neurooncological tumors including glioblastoma, primary central nervous system lymphoma, anaplastic astrocytoma and meningioma (15%), other solid cancer (breast, gastroesophageal, rectal cancer) (12%).55% patients were at first diagnoses, 12% were at the first recurrence, and the remaining were at the second or third recurrence. No malpositioning were registered. 18% of patients were on anticoagulant/antiplatelet therapy, 67% were treated with steroids. Concerning BMI, 39% was normal weight, 43% overweight and 10% obese, only 2% was considered underweight. Overall, 8% of patients developed PICC related thrombosis within a median time of 68 days (49-87) after PICC implantation mainly occurred in upper right extremity insertion sites. We therefore assessed the incidence of PICC related thromboembolic events in the groups, with 4% of event registered in the cohort of patients overweight/obese, and 14% of events in the cohort of patients with normal weight/underweight.

Conclusion
Preliminary analysis does not allow to draw firm conclusions. It will therefore be necessary to reach the sample size for achieve generalizable results and confirm the risk of developing thromboembolic events in overweight/obese patients. Meanwhile, an accurate anamnesis and a physical evaluation with particular attention to the presence of malnutrition, both over nutrition and undernutrition, could help to identify potential oncological patients at risk of developing PICC related thrombosis.
P11.21.B Distinct age-related molecular and clinical features inIDH-Wildtype Glioblastoma
Authors: Richter S , Stasik S , Schackert G , Thiede C , Krex D , Juratli T A 
Published: September 2022

Abstract

Background
The incidence of IDH-wildtype Glioblastomas (IDH-wt GBM) are highest amongst the elderly. However, IDH-wt GBM can occur in younger patients, subsequently associated with a relatively better prognosis. We aimed for comprehensive molecular characterization of IDH-wt GBM in a cohort with large range of Age at onset (AAO) to investigate age-related molecular patterns with potential impact on clinical tumor features and patients′ outcome.

Material and Methods
We performed Whole Exome Sequencing (WES) on 55 patients with IDH-wt GBM. Sanger Sequencing was utilized for the TERT-promotor region as well as selected candidate genes to validate the results of the WES. Moreover, Progression-free- and Overall survival (PFS, OS) data, clinical- and tumor features were collected.

Results
The patients’ median AAO was 58 yrs. (range: 22.9-70.8 yrs.). We divided our study cohort into three subgroups based on AAO quartiles for further analysis: Group A: 22.9-40.4 yrs. (Q1), Group B: 44.5-71.0 yrs. (Q2-3) and Group C: 72.7-79.8 yrs. (Q4). The median OS for all patients was 15.9 months with a PFS of 9.5 months. The median tumor volume at initial presentation was 43.8 cm3 and correlated with AAO: 63.6 cm3 (Group A) vs. 41.2 cm3 (Group C).We identified a median of 32 mutations per tumor. Exome and Sanger sequencing detected frequent alterations on TERT-promoter (76.4%) and EGFR (90.9% gain, 50.1% amplification, 29.1% mutation). Chromosome 7 gain (92.7%) and Chromosome 10 deletion (85.5%) occurred significantly less in younger patients (Group A vs. Groups B/C; p=0.037, p=0.013). However, other individual alterations did not correlate with AAO. Via clustering of various alterations (e.g. TP53, PDGFRA, ATRX), we found an association between a proneural GBM signature and younger AAO (p=0.036). AAO itself had an independent impact on OS: 21.5 Mo. (Group A) vs. 10.1 Mo. (Group C). Moreover, we described TET1-deletions on Chr. 10 in 90.1% of cases, which was not previously described in IDH-wt GBM. Bi-allelic TET1 deletions (32.7%) with concurrent EGFR-amplification had a significant impact on patient’s outcome (OS 12.2 Mo. vs. 17.6 Mo.; p=0.013).

Conclusion
Although GBM signatures showed subtle association with AAO, our data provides no evidence for an age-specific molecular pattern. The vast amount of detected alterations regardless of AAO underlines the overall heterogeneity of IDH-wt GBM. The cause of better prognosis at younger age remains unclear on a molecular explanatory approach. Finally, a bi-allelic deletion of TET1 may represent a relevant alteration in IDH-wt GBM.
P11.22.A Prognostic and predictive relevance of immunohistochemically determined p53 mutation in glioblastoma
Authors: Kempter J , Gempt J , Wiestler B , Combs S E , Schlegel J , Liesche-Starnecker F , Schmidt-Graf F 
Published: September 2022

Abstract

Background
It can be expected that molecular biomarkers will increasingly affect clinical decisions and lead to the development of more personalized therapies in glioblastoma (GBM) in the future. In several other tumor entities TP53 gene mutation or p53 immunoreactivity (IR) serve as a prognostic marker, significantly affecting overall survival (OS) and progression-free survival (PFS). Such an association has not yet sufficiently been demonstrated in GBM. However, there are known prognostic markers in GBM, notably MGMT promotor methylation (mMGMT) which also serves as an important predictive marker leading to a better response to temozolomide chemotherapy. Our aim was to evaluate retrospectively if p53 mutation determined via immunohistochemistry (IHC) could act as a prognostic or predictive marker in GBM.

Material and Methods
Tumor samples of 195 treatment-naïve patients with IDHwt GBM that had been stained with the p53 antibody DO-7 were subdivided into 2 different groups by p53 IHC. Samples were considered as p53mut when strong p53 IR was detected in ≥10% of all tumor cells and as p53wt when in &lt;10%. Treatment, further molecular and survival data were gathered retrospectively for all patients. Statistical analyses were performed with SPSS.

Results
The frequency of p53mut was 36.4% (71/195). p53mut tumors showed a significantly higher IR with Ki-67 proliferation marker (p=0.005) and p53wt seemed to be associated with multifocal primary tumor localization, though not statistically significant (p=0.107). There was no significant difference between p53wt and p53mut regarding gender, age, extent of resection, adjuvant therapy, occurrence of seizures, mMGMT or ATRX loss. The p53 status was not associated with OS or PFS. Factors that univariately led to significantly longer OS and PFS were younger age, unilateral or unifocal primary tumor localization, gross-total resection, higher Karnofsky Performance Status (KPS), mMGMT and adjuvant treatment via Stupp regimen instead of radiotherapy alone, the latter being significantly better than best supportive care. In multivariate survival analyses only age &lt;65 years, the Stupp regimen more than radiotherapy alone and KPS ≥80% significantly prolonged both OS and PFS. Unifocal primary tumor localization led to longer OS and mMGMT led to longer PFS independently. The p53 status did not significantly affect the response to different adjuvant therapy regimens neither concerning OS nor PFS.

Conclusion
Based on our study, p53 IR has no prognostic or predictive significance in IDHwt GBM. There have been previous studies with similar and others with contradicting results. Remarkable is the discordance of the used IR thresholds between different studies. Further studies should aim to revalidate the staining threshold and improve the concordance between TP53 gene sequencing and p53 IHC in IDHwt GBM.
P11.26.A STAT3 expression in brain metastases from breast cancer: correlations with different molecular subtypes and clinical outcome
Authors: Pellerino A , Bruno F , Mo F , Bertero L , Bellini E , Beano A , Montemurro F , Valiente M , Rudà R , Soffietti R 
Published: September 2022

Abstract

Background
STAT3 expression in peritumoral reactive astrocytes (RA) of brain metastases (BM) may favor a pro-metastatic environment. The aim of the study was to evaluate in a retrospective cohort of surgically resected BM from breast cancer (BC) the expression of pSTAT3 in RA of peritumoral tissue of BM, identify different patterns of expression according to molecular subtypes, and correlate with intracranial progression-free survival (i-PFS).

Material and Methods
Patients with histologically proven BM diagnosis from BC were identified from the biobank of Pathology Unit of University of Turin and Spanish national BrM network (RENACER). pSTAT3 expression was evaluated and scored in RA of peritumoral tissue using GFAP and STAT3 immunohistochemistry, according to Priego et al. (Nat Med 2018). Data on histological diagnosis, molecular subtypes, and i-PFS were retrieved by chart review. Intracranial progression was defined based on MRI reports.

Results
Eighty-five BM specimens from BC of 85 female patients with a median age of 54 years (range 30-81 years) were available for analysis. Immunohistochemistry for GFAP and pSTAT3 was feasible in 68/85 (80%). Fifteen out of 68 patients (21.1%) had BM from luminal BC, 27/68 (39.7%) from HER2-positive BC, and 26/68 (39.2%) from TNBC. Fifty-six out of 68 (82.4%) showed positive staining of pSTAT3 in peritumoral RA, of which 9/68 (13.3%) scored with 3, 26/68 (38.2%) with 2, and 21/68 (30.9%%) with 1, while pSTAT3 expression was negative (score 0) in 12/68 (17.6%). High pSTAT3 expression (score 2-3) was observed in 17/27 (62.9%) BM from HER2-positive BC and in 15/26 (57.7%) BM from TNBC, while most of BM from luminal BC (12/15 - 80%) had low or absent pSTAT3 (score 0-1) (p=0.021). Overall i-PFS was 16 months (range 7-41): low pSTAT3 BM (score 0-1) had a median i-PFS of 21 months versus 12 months for high pSTAT3 BM (score 2-3). A shorter median i-PFS was observed in high pSTAT3 BM from TNBC (4 months) as compared with low pSTAT3 BM (11 months). Conversely, i-PFS of high pSTAT3 BM (7 months) was similar to low pSTAT3 BM (6 months) in HER2-positive BC.

Conclusion
pSTAT3 expression in RA of peritumoral tissue of BM from TNBC and HER2-positive BC is higher than in BM from luminal BC. Of note, patients with high pSTAT3 BM from TNBC progressed earlier in comparison with those with low pSTAT3, suggesting that pSTAT3 expression has an influence on the outcome.
P11.43.B The impact of neutrophils-to-lymphocytes ratio on survival in patients affected by brain metastases and treated with Gamma Knife Radiosurgery
Authors: Gagliardi F , Snider S , Roncelli F , Pompeo E , De Domenico P , Klungtvedt V , Barzaghi L , Bulotta A , Lazzari C , Del Vecchio A , Mortini P 
Published: September 2022

Abstract

Background
The Neutrophil-to-Lymphocyte ratio (NLR) is a biomarker for host systemic inflammation. Elevated NLR may result from neutrophilia, lymphopenia or both and is associated with poor prognosis and treatment responses in various malignant tumors, such as breast, gastric, colorectal and lung cancer. It was found that in patients treated with GK-SRS for brain metastases (BM) from non-small cell lung cancer (NSCLC), median survival was significantly longer in patients with NLR &lt; 5 at the time of radiosurgery and after treatment (within 1 month from SRS). High percentage of neutrophils, low percentage of lymphocytes and elevated platelet-to-lymphocyte ratio were predictive of poor OS in patients with brain metastases. Further evidences are needed to support and better define these findings.

Material and Methods
We retrospectively examined 111 consecutive patients with BMs from NSCLC (95 patients) and melanoma (16 patients) treated with GK-SRS. A total of 695 lesions were treated (median lesion number per patient 6; range 1-18), the median volume was 0.108 cc (range 0.004-33.44 cc).
NLR was calculated using N/L, where N and L, respectively, refer to peripheral blood neutrophils (N) and lymphocyte (L) counts at the timepoint nearest to the SRS treatment. Kaplan-Meier analysis described the survival time according to NLR. Univariable and multivariable Cox regression analyses were used to confirm the impact of NLR on overall survival.

Results
Median (IQR) age at diagnosis of brain metastases was 64 yrs (55-70), median (IQR) NLR was 6.7 (1.3-32), and median (IQR) overall survival was 13.5 months (1-42). At univariable Cox-regression analyses, lower NLR was associated with improved overall survival (HR: 1.05; p=0.004). Total number of lymphocytes, neutrophils and monocytes were not associated with improved overall survival (all p&gt;0.1). At multivariable Cox regression analyses, after adjusting for patient age, sex and the use of DEX therapy, NLR represented an independent predictor of overall survival (HR: 1.06; p=0.003).

Conclusion
NLR represents an independent prognostic factor in patients affected by BMs from NSCLC and melanoma. Inflammation and immunity may play a critical role in these patients. Further analysis examining more specific neutrophils or lymphocytes subsets may increase our understanding of cancer etiology and progression.
P11.47.B A description of inpatient admissions of adult glioblastoma patients in England 2103 - 2018 from the GlioCova project
Authors: Le Calvez K , Mauricaite R , Williams M 
Published: September 2022

Abstract

Background
The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Here we present early analysis of inpatient admissions of adult glioblastoma (GBM) patients.

Material and Methods
We identified all adults patients diagnosed with a GBM and extracted all the inpatient admissions for 1 night or more after the date of diagnosis. We focused on number and length of admissions, variation in those numbers, and place of discharge.

Results
Between 2013 and 2018, 15,294 patients were diagnosed with a glioblastoma in England (60% male) with a median age of 66, of whom, 12,441 (61% male) were admitted overnight with a total of 49,384 admissions post-diagnosis. Half of these patients were less than 64 at the time of their admission. The mean number of post-diagnosis admissions was 4, with a mean length of stay of 9.5 days. However, for half of the admissions, patients stayed 5 days or less in hospital (IQR = 10). Most of the procedures done were treatment-related, such as surgery for which patients stayed an average of 6.3 days (median = 4; IQR = 5). Patients who were admitted for non-treatment reasons stayed on average almost 10 days (median = 5; IQR = 11). Fewer than 3,000 admissions resulted in a patient death (5.5% of all admissions), whereas over 23,000 admissions for 10,426 patients ended with patients being discharged at home. About 2,000 patients were discharged to another hospital, hospice or a nursing home.

Conclusion
Most of the patients diagnosed with a glioblastoma will be admitted at some point after their diagnosis. Although the average length of stay is not that long, there is a considerable tail of longer-staying patients, for whom improved services and support might enable quicker discharge. To our knowledge, this is the first time inpatient admissions in adult brain patients are being looked at.GlioCova is supported by the Imperial/NIHR BRC, and the members of the GlioCova EAG. This work uses data provided by patients and collected by the NHS as part of their care and support.More information on the Gliocova project can be found on https://blogs.imperial.ac.uk/gliocova.
P11.51.B Initial temozolomide monotherapy without radiotherapy might be of limited benefit in the treatment of astrocytoma, IDH-mutant, CNS WHO grade 2 and 3
Authors: Weller J , Katzendobler S , Blobner J , Quach S , Egensperger R , Suchorska B , Thon N , Weller M , Tonn J 
Published: September 2022

Abstract

Background
The role of temozolomide chemotherapy alone in isocitrate dehydrogenase (IDH-) mutant astrocytomas has not been conclusively determined. Radiotherapy might be superior to temozolomide alone. Recent studies have linked temozolomide therapy with poor clinical course and induction of hypermutation in IDH-mutant gliomas.

Material and Methods
In this retrospective, single-center study, 183 patients with astrocytoma, IDH-mutant, CNS WHO grade 2 or 3 according to WHO 2021 and diagnosed between 2000 and 2019 were included. Patients initially monitored by means of a wait-and-scan strategy, or treated with radiotherapy alone, or receiving temozolomide alone after histological sampling through biopsy or tumor resection were studied. Patient-related, clinical and imaging data were correlated with progression-free and overall survival. A matched-pair analysis accounting for post-surgical tumor volume was conducted.

Results
No significant differences in median age and clinical status at diagnosis was seen. WHO grades were balanced between patients treated with radiotherapy and temozolomide, but the proportion of WHO grade 2 gliomas was higher in the wait-and-scan cohort. Radiotherapy was associated with significantly longer overall survival than temozolomide (in years, 14.4 vs 10.7; p=0.02) and longer progression-free survival than temozolomide (in years, 6.2 vs 3.4, p=0.02) and wait-and-scan strategies (in years, 6.2 vs 4; p=0.03). Comparing wait-and-scan with temozolomide, survival was significantly longer in the wait-and-scan cohort (in years, not reached vs 10.7, p&lt;0.0001). An analysis of WHO grade 2 astrocytomas only also showed superior survival in the wait-and-scan cohort as compared to temozolomide (p=0.02). Of note PFS was similar overall and in WHO grade 2 astrocytomas.

Conclusion
The results suggest superiority of radiotherapy alone over temozolomide alone or wait-and-scan strategies in IDH-mutant WHO grade 2 and 3. Recent study results indicating that temozolomide might compromise prognosis in some IDH-mutant gliomas might be supported by our data, although caution in interpretation of retrospective data is required. The potential negative effects may only be apparent in the long-term.
P11.62.A The link between gliomas infiltrationandwhite matter architecture investigated with electron microscopy and diffusion tensor imaging
Authors: Latini F , Fahlström M , Beháňová A , Sintorn I , Hodik M , Staxäng K , Ryttlefors M 
Published: September 2022

Abstract

Background
Diffuse low-grade gliomas (DLGG) display different preferential locations in eloquent and secondary associative brain areas. The reason for this tendency is still unknown. We hypothesized that the intrinsic architecture and water diffusion properties of the white matter bundles in these regions may facilitate gliomas infiltration.

Material and Methods
Magnetic resonance imaging of sixty-seven diffuse low-grade gliomas patients were normalized to/and segmented in MNI space to create three probabilistic infiltration weighted gradient maps according to the molecular status of each tumor group (IDH mutated, IDH wild-type and IDH mutated/1p19q co-deleted). Diffusion tensor imaging (DTI)- based parameters were derived for five major white matter bundles, displaying regional differences in the grade of infiltration, averaged over 20 healthy individuals acquired from the Human connectome project (HCP) database. Transmission electron microscopy (TEM) was used to analyze fiber density, fiber diameter and g-ratio in 100 human white matter regions, sampled from cadaver specimens, reflecting areas with different gliomas infiltration in each white matter bundle. Histological results and DTI-based parameters were compared in anatomical regions of high- and low grade of infiltration (HIF and LIF) respectively.

Results
We detected differences in the white matter infiltration of five major white matter bundles in three groups. IDHm infiltrated left fronto-temporal subcortical areas. IDHwt were detected in the posterior-temporal and temporo-parietal regions bilaterally. IDHm/1p19q infiltrated anterior subcortical regions of the frontal lobes bilaterally. Regional differences within the same white matter bundles were detected by both TEM- and DTI analysis linked to different topographical variables. Our multimodal analysis showed that HIF regions, common to all the groups, displayed a smaller fiber diameter, lower FA and higher RD compared with LIF regions.

Conclusion
Our results suggest that the both morphological features and diffusion parameters of the white matter may be different in regions linked to the preferential location of DLGG.