bluuebunny/crossref_metadata_2025_split huggingface dataset:
P14.94 Mitochondrial DNA copy number in new onset and recurrent glioblastoma and its effect on radiation resistance and patient survival
Authors: Sravya P , Nimbalkar V P , Kanuri N N , Rao S , Arivazhagan A , Somanna S , Kondaiah P , Santosh V 
Published: September 2019

Abstract

BACKGROUND
Recent evidence shows that mitochondrial DNA (mtDNA) content is responsible for radiation resistance in various cancers, but not evaluated in glioblastoma(GBM).Hence,we studied the role of mtDNA content in GBM pathogenesis and treatment response.

MATERIAL AND METHODS
Archived FFPE tissues of newly diagnosed GBM(n=130), recurrent GBM (n=32 pairs) and non-neoplastic control brain(n=30) with available clinical details were utilized for the study. Immunohistochemistry, Sanger’s sequencing, methylation specific PCR and fluorescent in-situ hybridization were used to study IDH, ATRX and TERT promoter mutations, MGMT promoter methylation and EGFR amplification. mtDNA content was analyzed using quantitative real time PCR (relative quantification) and was calculated using the formula 2- ΔΔCTx100. Malignant glioma cell lines U87 and LN229 were used to study the difference in mtDNA content following radiation exposure.LN229 cell line was subjected to mtDNA depletion by incubation with ethidium bromide for 4 days.The parent and mtDNA depleted LN229 cell lines were then assessed for sensitivity to radiation and Temozolomide(TMZ) therapy using MTT assay.

RESULTS
mtDNA content was lower than control brain tissue(mean mtDNA content 19.6) in all cases studied,with significantly lower content in older patients(p=0.04).Lower mean mtDNA content was seen in IDH wild type, MGMT unmethylated and EGFR amplified tumors when compared to their counterparts(p=1.06).Survival analysis using Cox regression showed that lower mtDNA copy number is associated with higher risk and hence poorer prognosis(p=0.047).Paired tumor analysis was performed in 32 patients with recurrence of whom only 19 had received radiation therapy (RT).The mean mtDNA content was higher at recurrence as compared to the primary tumor in those who received RT(mean at diagnosis 20.1; mean at recurrence 49.3, p=0.02) while no significant difference was observed in those who did not receive RT. U87 and LN229 cell lines exposed to radiation (0, 2, 4 and 6Gy) showed an increase of 8% and 25% in mtDNA content, respectively, after 6Gy radiation exposure.LN229 parent cells showed a radiation dose dependent decline in cell viability(86% at 2Gy, 68% at 4Gy and 50% at 6Gy).The mtDNA depleted LN229 cells were 100% viable at 0, 2 and 4 Gy and 82% viable at 6Gy.The IC50 of TMZ in parent LN229 cells was 69.3 µM while in the mtDNA depleted cells,it was 100.8 µM. Conclusion:Our study shows that lower mtDNA content is associated with poorer survival in GBM.RT increased the mtDNA content in both patient samples and malignant glioma cell lines.mtDNA depleted LN229 lines are more radio-chemo resistant than parent LN229 lines,thus showing that lower mtDNA content leads to treatment resistance.Hence,we establish the significant role of mtDNA content in the pathogenesis and treatment resistance of GBM.
P14.107 Rapid early progression of glioblastoma is not related to cortical/neural stem cells regions
Authors: Jancalek R , Kazda T , Belanova R , Pospisil P , Burkon P , Hynkova L , Slampa P , Lakomy R 
Published: September 2019

Abstract

BACKGROUND
Rapid early progression (REP) of glioblastoma after surgery is quite often observed on pre-radiotherapy MR scan. Clinical and molecular biomarkers indicating increased risk of this REP may be of high clinical need. Subventricular brain zone (SVZ) and hippocampal regions are supposed to harbor astrocyte-like neural stem cells with tumors arising from these transformed SVZ stem cells dreaded to be of higher risk of REP. Lim′s et al classification of initial glioblastoma location related to these neural stem cells regions was predictive for invasive and multifocal tumor phenotype. The aim of this retrospective single-institutional study is to evaluate the relations of this Lim classification on REP in unselected cohort of glioblastoma patients.

MATERIAL AND METHODS
Patients treated by radiotherapy between 2014–2017 were grouped as follows: Lim1 (SVZ+⋯SVZ/hippocampal involvement and Cortex+⋯cortex involvement), Lim2 (SVZ+ and Cortex-), Lim3 (SVZ- and Cortex+) and Lim4 (SVZ- and Cortex-). Some patients were indicated to Stupp regimen. REP was defined on pre-radiotherapy MR as new distant lesion, progression of residuum, or new enhancement in postsurgery cavity.

RESULTS
In total, 144 patients were analyzed (94 men, mean age 59 years). 47 patients (30.5%) were treated according to Stupp regimen. Lim1 classification was presented in 74 (48%) patients, Lim2 in 22 (14.3%), Lim3 in 50 (32.5%) and Lim4 in 8 (5.2%) patients. Cortical structures (Lim1 and Lim3) were involved in 124 (80.5%) patients. Median overall survival was significantly better in patients treated according to Stupp regimen (23.3 vs. 8.6 months, p&lt;0.001) and in those without REP (18.5 vs. 10.2 months, p=0.001). REP was presented in 52% of 95 evaluable patients who underwent both post-surgery and pre-radiotherapy MR scans and there was no significant impact of time to start of radiotherapy. No significant relation between REP and Lim classification was observed (REP in 23/47 Lim1, in 8/13 Lim2, in 16/31 Lim3 and in 2/4 Lim4 patients).

CONCLUSION
Initial location of enhancing glioblastoma is not predictive for REP. Patients experiencing REP have significantly worse overall survival and modification of their management represents urgent unmet clinical need. Molecular and clinical biomarkers indicating increased risk of REP are needed. Supported by Ministry of Health of the Czech Republic, grant No. 18-03-00469.
P14.123 Neurological complications related to checkpoints inhibitors
Authors: Esparragosa I , Valenti-Azcarate R , Moreno-Ajona D , Gallego Perez de Larraya J 
Published: September 2019

Abstract

BACKGROUND
Currently, immunotherapy is part of the therapeutic arsenal for oncological treatment. Indeed, the need for new medications has led to the development of immune checkpoint inhibitors. Despite favourable oncological outcomes, these treatments have been associated with immune-related adverse events. Although infrequent, neurological toxicities have been reported. Early recognition is crucial for improvement of functional outcome and requires a multidisciplinary approach.

OBJECTIVE
To describe a case series of patients with neurological complications related to checkpoint inhibitors.

PATIENTS AND METHODS
We identified six oncological patients who presented immunomediated neurological complications, derived from the use of checkpoints inhibitors. Five cases were men. Ages ranged from 58 to 73 years. Nivolumab, alone or combined, was the most commonly associated drug (4/6). Underlying diseases included lung carcinoma (2/6), melanoma (2/6), renal carcinoma (1/6) and ovarian adenocarcinoma (1/6). An acute demyelinating sensory-motor polyneuropathy and an acute axonal sensory polyneuropathy were documented in two and one case, respectively. In these, the cerebrospinal fluid analysis revealed albuminocytologic dissociation. All three cases improved after treatment with intravenous immunoglobulins (0.4 g/Kg a day for five days). The latter and another case were diagnosed of aseptic meningitis after cerebrospinal fluid lymphocytic pleocytosis was found. High fever was also associated with lower extremities areflexia, weakness and ataxia. Methylprednisolone (1g/day for five days) was administered. One case of necrotizing inflammatory myositis with high levels of creatine kinasa, confirmed by muscular biopsy, involving cervical weakness and ptosis, was effectively treated with Methylprednisolone (1g/day for five days) follow by oral prednisone tapering. An anti-Yo related pancerebellar syndrome was the only case with a fatal outcome despite treatment.

CONCLUSION
The increasingly frequent use of immunotherapy in the treatment of cancer may lead to an increase in neurological complications. These include a broad spectrum of syndromes with peripheral nervous system predominantly susceptible. Early identification of these and appropriate management of drug-related toxicity are required. Immune-modulating therapies are particularly beneficial.
P14.124 EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with standard temozolomide-based radiochemotherapy versus standard temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma
Authors: Roth P , Reijneveld J , Gorlia T , Dhermain F , De Vos F , Vanlancker M , O’Callaghan C , Le Rhun E , van den Bent M , Mason W , Weller M 
Published: September 2019

Abstract

BACKGROUND
The standard of care for patients with newly diagnosed glioblastoma includes maximal debulking surgery followed by radiotherapy (RT), and concomitant as well as maintenance therapy with the alkylating agent, temozolomide (TMZ). However, the prognosis remains poor and novel treatment strategies are urgently needed. Targeting the proteasome has been considered a promising anti-cancer approach for several years. Marizomib is a novel, irreversible and pan-proteasome inhibitor, which crosses the blood-brain barrier and has been assessed in phase I trials in patients with newly diagnosed or recurrent glioblastoma.

MATERIAL AND METHODS
EORTC 1709/CCTG CE.8 is a randomized, controlled, open label phase III superiority trial. Patients with histologically confirmed newly diagnosed glioblastoma and a performance status >70 are eligible. Patients are randomized in a 1:1 ratio to receive standard of care (TMZ/RT→TMZ) alone or TMZ/RT→TMZ plus marizomib. The study aims at enrolling 750 patients. Stratification factors include study site, age, performance status and extent of resection. The primary objective of this trial is to compare overall survival in patients receiving marizomib in addition to standard of care with those receiving standard treatment only. The testing strategy specifies the determination of this objective in the intent-to-treat population as well as the subgroup of patients with MGMT-unmethylated tumors. Secondary endpoints include progression-free survival, safety, neurocognitive function and quality of life. A translational research program has been set up. The study will be activated at approximately 50 EORTC sites across Europe, 25 sites in Canada and additional sites in the US. Patient recruitment started in June 2018 and as of April 29, 2019, a total of 164 patients have been randomized. An update on the enrolment status will be provided at the EANO meeting. ClinicalTrials.gov Identifier: NCT03345095
P14.127 From next generation sequencing and comparative genomic hybridization to personalised medicine for adult primary brain tumors: the profiler trial
Authors: Bonneville-levard A , Frappaz D , Pissaloux D , Wang Q , Perol D , Blay J , Meyronet D 
Published: September 2019

Abstract

BACKGROUND
Personalized anti-tumoral therapies may currently be proposed on the basis of immuno-histochemistry, but also next-generation sequencing and comparative genomic hybridization. ProfiLER trial explored the feasibility, efficacy and the impact of molecular profiling for patients with solid or hematological advanced cancers including brain tumors.

MATERIAL AND METHODS
Patients with primary brain tumors, pre-treated with at least one line of anti-cancer treatment, could be included in this multicentric prospective trial. A molecular profile (next-generation sequencing and comparative genomic hydridization) was established on fresh or archived sample. Weekly molecular tumor board analysed results to propose as far as possible a molecular targeted therapy.

RESULTS
between February 2013 and December 2015, 141 patients with primary brain tumor were enrolled. One hundred five samples were further analyzed as 30 samples were excluded, and 6 are on-going. The rate of screen failure was 16/33 for stereotactic biopsy (49%) versus 11/104 (11%) for removal. The main representative histologic type of tumors were glioblastoma (n=46, 43,8%), low grade glioma (n=26, 24,8%), high grade glioma (n=12, 11,4%) and atypical and anaplastic meningioma (n=8, 7,6%). Median delay between the diagnostic of the primitive tumor and the inclusion in ProfiLER study was 2.7 years (0.2 - 29 years). Median delay between the consent and the results of the multidisciplinary meeting was 2.8 months (1–7.1 months). Forty-three patients (41%) presented at least one “druggable molecular alteration”. The most frequently altered genes were CDKN2A (n=18, 29%), EGFR (n=12, 20%), PDGFRa (n=8, 13%), PTEN (n=8, 13%), CDK4 (n=7, 11%), KIT (n=6, 10%), PIK3CA (n=5, 8%), MDM2 (n=3, 5%). Sixteen patients could not have a proposition of specific treatment due to death before MBT (n=5, 31.3%), lack of available clinical trials (n=9, 56%), or ambiguous results (n=2, 12.5%). Among the 27 patients (26%) for whom a specific therapy has been proposed, only six patients ultimately received a medical targeted therapy (everolimus n=3, erlotinib n=1, ruloxitinib n=1, sorafenib n=1). Four patients discontinued the treatment for toxicity, the 2 others for clinical progression.

CONCLUSION
routine high-throughput sequencing is feasible for brain tumors but delays should be reduced to be able to propose targeted therapies to patients fit enough to benefit from experimental treatment. Macroscopic surgery is the best way to obtain workable samples. Specific panel genes for neurologic tumors should be developed, as well as change of practices concerning exclusion criteria in clinical trials.
P14.129 Predicting glioblastoma invasion using multiparametric MRI and a bi-level machine learning approach
Authors: Li C , Liu P , Wei Y , Li Y , Schönlieb C , Price S J 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma is characterized by its extensive infiltration into the brain parenchyma, which poses challenges to accurate treatment volume targeting. Current treatment planning is based on the contrast-enhancing images. Tumor invasion, however, is well known beyond the contrast enhancement. Although deep learning shows potential in delineating tumor invasion based on multiparametric MRI, it requires large amount of training data. Image inpainting may reconstruct the lost image information based on image structure and requires less training data. The purpose of this study is to investigate whether a bi-level deep learning approach could integrate conventional neural network (CNN) and image inpainting to delineate tumor invasion based on the multiparametric MRI.

MATERIAL AND METHODS
A total of 115 patients (mean age 59.3 yrs, range 22 - 76 yrs, 87 males) with supratentorial de novo glioblastoma were recruited for maximal safe tumor resection. Post-operative temozolomide chemoradiotherapy was performed following the Stupp protocol. The Response Assessment in Neuro-oncology criteria was used to evaluate patient response. All MRI sequences were pre-operatively acquired using a 3T scanner, including T2-weighted, post-contrast T1-weighted, FLAIR, dynamic susceptibility contrast (DSC) and diffusion tensor imaging (DTI). The isotropic (p) and anisotropic (q) maps were generated from DTI. The relative cerebral blood volume (rCBV), mean transit time (MTT) and relative cerebral blood flow (rCBF) were generated from the DSC images after the leakage correction. All images were coregistered to post-contrast T1W images. Contrast-enhancing (CE) and non-enhancing (NE) regions were semi-automatically segmented and validated by an experienced neuro-radiologist. A tissue segmentation was performed using the FAST (FMRIB’s Automated Segmentation Tool) to segment the normal-appearing brain excluding the above both tumor regions and were classified into three tissue types (grey matter, white matter and CSF). A CNN model was applied to build a classification function between the CE region and the three normal-appearing tissue types based on the multi-parametric MRI. A bespoke inpainting scheme was then applied to predict the tumor invasion area in the NE region. Kaplan-Meier and Cox proportional regression were used to evaluate the significance of the predicted volume.

RESULTS
The volumes of the contrast-enhancing tumor is 53.6 ± 33.8 cm3. The predicted invasive volume in the non-enhancing region is 31.0 ± 17.7 cm3.The multivariate model shows that the predicted volume was significantly associated with OS (HR = 0.97, P= 0.006). The patient subgroup with a higher predicted volume showed significantly better OS (P= 0.009) and PFS (P= 0.021).

CONCLUSION
The proposed bi-level deep learning approach may effectively integrate multiparametric MRI for predicting tumor invasio.
High-resolution MRI demonstrates that more than 90% of small intracranial melanoma metastases develop in close relationship to the leptomeninges
Authors: Lasocki Arian , Khoo Chloe , Lau Peter K H , Kok David L , Mcarthur Grant A 
Published: September 2019

AbstractBackgroundDespite classic teaching that intracranial metastases typically arise at the gray–white matter junction, small intracranial melanoma metastases (IMM) are frequently observed at the interface between the cortex and leptomeninges (ie, “corticomeningeal interface”), suggesting possible leptomeningeal origin.MethodsMRI brain examinations of melanoma patients treated at a specialist oncology center from July 2015 to June 2017 were retrospectively reviewed. The MRI examination on which IMM were first visible was identified, utilizing 1 mm volumetric postcontrast imaging prior to local therapy. Individual metastases (up to 10 per patient) were assessed for the presence of leptomeningeal contact, as well as their number, size, and morphology. Lesions ≥10 mm in long axis were excluded, in order to examine early metastatic disease.ResultsSeventy-five patients had evidence of IMM. Fifteen patients had only lesion(s) measuring ≥10 mm at diagnosis, leaving 60 patients. One hundred ninety-two individual metastases were examined (median 2 per patient; interquartile range, 1–4), 174 (91%) demonstrating leptomeningeal contact. A nodular morphology was observed in 154 of 192 (82%), 32 (17%) were ovoid but elongated along the cortex, and 6 (3%) were linear. Only 3 patients (5%) also exhibited a “classic” linear leptomeningeal disease appearance.ConclusionsMost IMM measuring between 2 and 9 mm in diameter are corticomeningeal nodules. These data raise the hypothesis that deeper parenchymal extension of IMM occurs secondarily. If the leptomeninges provide a preferential site for establishment of IMM, further investigation of the underlying biology of this phenomenon may provide opportunities for novel therapeutic strategies for patients with IMM.Key Points1. Most small IMM develop at the corticomeningeal interface, rather than the gray‒white junction.2. This suggests that the pia mater provides a preferential site for establishment of IMM.3. Deeper brain parenchymal extension may occur secondarily.
Proton pump inhibitors and histamine-2 receptor antagonists on the risk of pancreatic cancer: a systematic review and meta-analysis
Authors: Laoveeravat P , Thavaraputta S , Vutthikraivit W , Suchartlikitwong S , Mingbunjerdsuk T , Motes A , Nugent K , Rakvit A , Islam E , Islam S 
Published: September 2019

Abstract

Background
Proton pump inhibitors (PPI) and histamine-2 receptor antagonists (H2RA) have been widely used for multiple purposes. Recent studies have suggested an association between these medications and the risk of pancreatic cancer. However, the results have been inconclusive.

Aim
We, therefore, conducted a study to assess the risk of developing pancreatic cancer in patients who used PPI and H2RA.

Design
A systematic review and meta-analysis.

Methods
A literature search was performed using MEDLINE and EMBASE databases from inception through February 2019. Studies that reported risk ratio comparing the risk of pancreatic cancer in patients who received PPI or H2RA versus those who did not receive treatments were included. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effect generic inverse variance method. Sensitivity analysis, excluding one study at a time, was performed.

Results
After screening abstracts from the searching methods, seven studies (six case–control studies and one cohort study) were included in the analysis with total 546 199 participants. Compared to patients who did not take medications, the pooled RR of developing pancreatic cancer in patients receiving PPI and H2RA were 1.73 (95% CI: 1.16–2.57) and 1.26 (95% CI: 1.02–1.57), respectively. However, the sensitivity analysis of PPI changed the pooled RR to 1.87 (95% CI: 1.00–3.51) after a study was dropped out. Likewise, H2RA sensitivity analysis also resulted in non-significant pooled RR.

Conclusions
This meta-analysis did not find the strong evidence for the associations between the use of PPI and H2RA and pancreatic cancer.
Is axial psoriatic arthritis distinct from ankylosing spondylitis with and without concomitant psoriasis?
Authors: Feld Joy , Ye Justine Yang , Chandran Vinod , Inman Robert D , Haroon Nigil , Cook Richard , Gladman Dafna D 
Published: September 2019

Abstract

Objective
The aim of this study was to compare patients with ankylosing spondylitis with psoriasis (ASP) and without psoriasis (AS), to axial PsA (axPsA) patients.

Methods
Two adult cohorts were recruited from the AS clinic: ASP and AS. These two cohorts were compared with two adult cohorts recruited from the PsA clinic: axPsA (radiographic sacroiliitis: ⩾bilateral grade 2 or unilateral grade 3 or 4); and Peripheral PsA. All patients were followed prospectively according to the same protocol. The demographic, clinical and radiographic variables were compared. Adjusted means were used to account for varying intervals between visits. A logistic regression was performed and adjusted for follow-up duration.

Results
There were 477 axPsA patients, 826 peripheral PsA, 675 AS and 91 ASP patients included. AS patients were younger (P &lt; 0.001), more male and HLA-B*27 positive (76%, 72% vs 64%, P ⩽ 0.001, 82%, 75%, vs 19%, P = 0.001). They had more back pain at presentation (90%, 92% vs 19%, P = 0.001), worse axial disease activity scores (bath ankylosing spondylitis disease activity index: 4.1, 3.9 vs 3.5 P = 0.017), worse back metrology (bath ankylosing spondylitis metrology index: 2.9, 2.2 vs 1.8, P &lt; 0.001), worse physician global assessments (2.4, 2.2 vs 2.1, P &lt; 0.001), were treated more with biologics (29%, 21% vs 7%, P = 0.001) and had a higher grade of sacroiliitis (90%, 84% vs 51%, P &lt; 0.001). Similar differences were detected in the comparison of ASP to axPsA and in a regression model.

Conclusion
AS patients, with or without psoriasis, seem to be different demographically, genetically, clinically and radiographically from axPsA patients. axPsA seems to be a distinct entity.