CaPaBLE - Assessing the Patient Generated Index Methodology in High Grade Glioma Patients and Caregivers

alexandrossfakianakis shared this article with you from Inoreader CaPaBLE - Assessing the Patient Generated Index Methodology in High Grade Glioma Patients and Caregivers via # Neuro-Oncology Current Issue Abstract AIMS CaPaBLE tests the feasibility and acceptability of assessing quality of life (QoL) using the patient-, or caregiver-generated index (PGI/CaGI) methodology in patients with HGG and their caregivers. METHOD CaPaBLE, (https://www.isrctn.com/ISRCTN45555598), followed patients and/or their caregivers up to 6 months. Standard measures for patients were EORTC QLQ-C30/BN20, for caregivers the CarGOQOL questionnaire. The QoL topics raised through PGI/CaGI have been coded to the most relevant domain from their respective standard measure for an initial assessment of concordance. RESULTS 36 patients, 24 caregivers recruited to study; completing an average of 3 study assessment timepoints. PGI and CaGI generated 240 and 160 topics respectively. Patient concerns most frequently coded to EORTC domain of Ro le Functioning; Caregiver concerns mostly coded to CarGOQOL domain of Burden. Other topics frequently raised by patients such as the driving and sex life, and future planning by caregivers are not specifically raised in standard questionnaires. CONCLUSION Nearly all topics raised by patients and caregivers were mapped to the domains of their respective standard QoL measure. However, almost half of all topics raised by patients and caregivers mapped to a minority of the domains included in standard measures; whilst a notable number of topics are not specifically included in standard measures at all. This raises questions regarding the efficiency and relevance of such questionnaires to patient and caregivers' daily lives. View on Web

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Hull’s Magic Box: Keeping Brain Tumour Biopsies “Alive” in the Lab Brings Research Opportunities for New Therapies and Earlier Diagnosis of Brain Tumour

alexandrossfakianakis shared this article with you from Inoreader Hull's Magic Box: Keeping Brain Tumour Biopsies "Alive" in the Lab Brings Research Opportunities for New Therapies and Earlier Diagnosis of Brain Tumour via # Neuro-Oncology Current Issue Abstract AIMS Assess/evaluate apoptosis in GBM samples maintained on a microfluidics system in response to GSK3368715 and other PRMT inhibitors, currently in clinical trials, with the ultimate goal of synergising with personalised patient care and precision medicine. Investigate the effect of treating GBM biopsies on-chip with PRMT inhibitors at the molecular level, including RNA and protein modifications. METHOD GBM biopsies are received from Hull Royal Infirmary and maintained on-chip for 8-days. They are perfused with media, at a rate of 3 μl/min, mimicking the in vivo environment and allowing real-time analysis of tumour behaviour. PRMT inhibitors, such as GSK3368715, are added to the media, in conjunction with TMZ, to determine their efficacy ex vivo using a range of techniques, such as: immunohistochemistry, cell viability assays, protein analysis and RNA-sequencing. RESULTS We show that PRMT inhibition increases apoptos is five-fold above the control, untreated GBM-on-chip samples. This is compounded by cell viability assays, which have indicated that cell viability in these post-chip tissues is reduced by 30% upon treatment with 1μM GSK3368715. Additionally, western blot analysis has indicated that PRMT inhibition with GSK3368715 appears to switch the methylation status of fused-in-sarcoma (FUS) protein in GBM biopsies. CONCLUSION These results indicate that PRMT inhibition may not only be a viable target for GBM therapy, but could also highlight a mechanism for re-sensitising MGMT-negative GBM to TMZ. This data produces an exciting argument for further research into the use of this novel inhibitor for improving prognosis for patients diagnosed with this devastating disease. View on Web

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First Line Treatment of Adult Glioblastoma Patients in England 2103-2018 from the GlioCova Project

alexandrossfakianakis shared this article with you from Inoreader First Line Treatment of Adult Glioblastoma Patients in England 2103-2018 from the GlioCova Project via # Neuro-Oncology Current Issue Abstract AIMS 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 detailed analysis of first-line treatments of adult glioblastoma (GBM) patients. METHOD We identified all adults patients diagnosed with a GBM. We focused on the first line of treatment and we defined 'maximal' first-line treatment as surgical resection followed by chemo-radiotherapy with 59-60 Gy and with at least one cycle of adjuvant chemotherapy Temozolomide. RESULTS 15,294 patients were diagnosed with a glioblastoma (60% male) with a median age of 66. 79% of patients received some treatment, with younger patients more likely to be treated (>90%, 18 - 59; < 30%, > 80). 54% underwent debulking surgery; 23%, biopsy. 14% received 'maximal' treatment and 21%, none. Patients who had no treatment had a median survival of 2 months whereas patient s who received 'maximal' treatment had a median survival of 16 months. CONCLUSION Most adult patients with a GBM in England have a histological diagnosis, and some oncological treatment. However, only 14% receive 'maximal' treatment. Of the 3222 patients who received none, some of these may have had purely private treatment; however, our dataset includes any private sector work undertaken in NHS hospitals. Survival remains poor, but outcomes in those receiving maximal treatment match those from clinical trials. However, most patients do not receive maximal treatment, and so the easiest route to improving outcomes may be optimise delivery of treatment in the 65% of patients who receive sub-maximal treatment. More information on https://blogs.imperial.ac.uk/gliocova View on Web

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Development of Novel LAT1 Targeting Small Molecules for Boron Neutron Capture Therapy (BNCT) and Potential Application for Treating Glioblastoma

alexandrossfakianakis shared this article with you from Inoreader Development of Novel LAT1 Targeting Small Molecules for Boron Neutron Capture Therapy (BNCT) and Potential Application for Treating Glioblastoma via # Neuro-Oncology Current Issue Abstract AIMS to make molecules that deliver more Boron than BPA for boron neutron capture therapy BNCT METHOD Boronated compounds were designed based on known LAT-1 substrates, synthesized using boronation techniques and purified using preparative HPLC. The compounds were formulated to achieve high concentrations when compared to BPA-fructose (BPA-F). Boronated compounds were tested for boron uptake and retention in multiple cell lines expressing either LAT1 and/or PEPT1. Compounds were further tested in multiple human xenograft models representing the cancer indication currently treatable by BNCT as well as in one syngeneic colon tumor model that may have high PEPT1 expression. Intracellular and intra tumor boron concentration were measured by ICP OES. We also synthesized 2 dipeptides and tested them in BNCT experiments with our collaborators at Kyoto University in Japan. They were tested in a CT26 mouse syngeneic model using neutrons from KURR1. RESULTS We synthesized multiple boronated compounds with better solubility than BPA (100 mg/ml v 30mg/ml in fructose). They were readily taken up in multiple cell lines and one of these compounds had longer retention than others. In competition experiments we were able to show that this compound was a superior substrate for LAT1. We also showed better BNCT results with our molecules compared to BPA. CONCLUSION BPA works for BNCT but it has limitations such as poor solubility. We made several new boronated compounds with better solubility than BPA and showed that we could deliver 2-3 x more boron in vitro and in vivo and better BNCT outcomes at KURR1. View on Web

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Photodynamics of Subependymal Giant Cell Astrocytoma (SEGA) with 5-Aminolevulinic Acid (5-ALA/Gliolan©)

alexandrossfakianakis shared this article with you from Inoreader Photodynamics of Subependymal Giant Cell Astrocytoma (SEGA) with 5-Aminolevulinic Acid (5-ALA/Gliolan©) via # Neuro-Oncology Current Issue Abstract AIMS 5-ALA (Gliolan©) is a valuable surgical tool used predominantly in high grade tumours, which utilises tissue fluorescence to improve the visualisation of the brain-tumour interface. This ensures safe maximal resection, while preserving healthy brain. While Gliolan© use in low grade tumours has previously been reported with variable results, reports of its use and success in the context of SEGA are extremely rare. This report highlights the use of Gliolan© in a patient presenting with a Subependymal Giant Cell Astrocytoma (in a background of tuberous sclerosis), facilitating maximal safe resection and preserving eloquent tissue. METHOD Tumour resection was performed with pre-operative DTI-fiber tracking and mapping. A transsulcal minimal invasive parafascicular approach (tsMIPS) was carried out with assistance of NICO BrainPath© tubular retractor system (60x13.5), neuronaviagtion, Gliolan©, intra-operative neuro monito ring (IONM), and ultrasound guidance RESULTS The tumour was found to have both bright and pale fluorescence in the cystic and solid components respectively. Resection was limited to the soft cystic component only, as the solid tumour component showed anatomical attachment to the subgenual area and the fornix. No fluorescence was perceived at the end of resection. The patient made a good recovery with no post-operative deficits. Histopathology confirmed subependymal giant cell astrocytoma (SEGA, WHO grade I). No adjuvant treatment was required CONCLUSION This reports suggests 5-ALA may be beneficial in the safe resection of SEGAs. Further studies and technological advances in the area of photodynamics, imaging, and intra-operative mapping may be helpful to fully evaluate the efficacy of 5-ALA in SEGAs and other low-grade tumours. View on Web

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Survival and Prognostic Factors in Melanoma Brain Metastasis (MBM) Treated With Stereotactic Radiosurgery (SRS)

alexandrossfakianakis shared this article with you from Inoreader Survival and Prognostic Factors in Melanoma Brain Metastasis (MBM) Treated With Stereotactic Radiosurgery (SRS) via # Neuro-Oncology Current Issue Abstract AIMS Brain metastasis is a frequent complication in melanoma, ultimately affecting 40–60% of patients with metastatic disease1. In the era of immune checkpoint and small molecule inhibitor therapy, there is a need to identify patient, tumour and treatment characteristics which may predict an improved prognosis in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM). METHOD Retrospective casenote review was carried out for all patients receiving SRS, including gammaknife and cyberknife, for MBM between 2014 – 2020 at Barts Cancer Centre. Overall survival (OS) was calculated using the Kaplan-Meier method. Differences between groups were assessed using the Log-rank (Mantel-Cox) test. RESULTS 93 patients were treated with SRS for MBM, with a median of 15 patients treated per year. The median age at treatment decision was 60 years (range 26 – 90): 59% were male; 41% female. Median num ber of lesions treated was 2 (range 1 – 15). Survival data was available for 74 patients: median overall survival for all patients was 9.5 months, with no significant survival difference by gender nor treatment year (pre-2017 vs. post-2017). However, treatment of 1-2 brain lesions carried a better prognosis compared to 3 or more lesions (median 12.2 vs. 5.7 months, p = 0.0292). CONCLUSION Initial analysis reveals an improved overall survival when fewer MBM are present. Further analyses will examine the impact of the following factors on patient survival: status of extracranial metastases, symptomatic vs. asymptomatic brain metastasis, intratumoral haemorrhage, systemic therapy pre- and post-SRS, and corticosteroid use during and after SRS. View on Web

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Local Relapse Rates for Brain Metastases Treated With Stereotactic Radiosurgery

alexandrossfakianakis shared this article with you from Inoreader Impact of the Neuro-Radiologist and Neuro-Surgeon in Contouring With the Neuro-Oncologist on Local Relapse Rates for Brain Metastases Treated With Stereotactic Radiosurgery via # Neuro-Oncology Current Issue Abstract AIMS The audit evaluates the value of MDT, including neuro-radiologist and neuro-surgeon, review of contouring carried out by a clinical oncologist in stereotactic radiosurgery (SRS). METHOD Lesions were contoured first by clinical oncologist then reviewed/edited by MDT. Iinitial contour was compared with final using Jaccard conformity and geographical miss indices. Dosimetric impact of contouring change was assessed using plan metrics to both original and final contour. The impact of contouring review on local relapse, overall survival and radio necrosis rate was evaluated with at least 24 months follow up. RESULTS 113 patients and 142 lesions treated over 22 months were identified. Mean JCI was 0.92 (0.32-1.00) and 38% needed significant editing (JCI<0.95). Mean GMI was 0.03 (0.0-0.65) and 17% showed significant miss (GMI>0.05). Resection cavities showed more changes, with lower JCI and higher GMI (p<0.05). Dosimetric analysis indicated a strong association of conformity with PTV dose metrics. Greater association was seen in resection cavity, i.e. geographical nature of a typical contouring error gives rise to greater potential change in dose. Clinical outcomes compared well with published series. Median survival was 20 months and local relapse free rate of 0.89 (0.8-0.94) at 40 months. Radio-necrosis free rate 0.9 (0.83-0.95) at 40 months with median 17 months to developing radionecrosis for those that did. CONCLUSION MDT contour review adds significant value to SRS resulting in reduced local recurrence rates. No improvement in clinical oncologist contouring over time was shown indicating a collaborative approach is needed regardless of experience of clinical oncologist - particularly for resection cavities. View on Web

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Prolonged Transfusion-Dependent Temozolomide-Induced Thrombocytopaenia in Glioblastoma: Risk Factors Remain Elusive

alexandrossfakianakis shared this article with you from Inoreader Prolonged Transfusion-Dependent Temozolomide-Induced Thrombocytopaenia in Glioblastoma: Risk Factors Remain Elusive via # Neuro-Oncology Current Issue Abstract AIMS Temozolomide-induced thrombocytopaenia is well-recognised; clinical-course varies widely. Aims: To identify risk factors for prolonged thrombocytopaenia; improve patient-care; inform trial design. METHOD Glioblastoma (GBM) patients requiring platelet transfusion were identified. (Local policy: transfuse when plt count ≤ 30 x 109/L). Inclusion criteria: First-line-standard-of-care temozolomide-chemo-radiotherapy (TMZ-CRT). Case-notes reviewed for demographics, blood-counts, radiotherapy and treatment parameters. Thrombocytopaenia grading: CTCAE V5. Date of onset measured from start of TMZ-CRT to date of platelets < 100 x 109/L, and to date of first instance of ≥ grade 3 thrombocytopaenia. Thrombocytopaenia duration: time to platelet count recovery to ≥ 100x109/L. RESULTS Between 2017-2021, 69 patients required platelet transfusion; 68/69 identified on routine monitoring. 49 patients w ere analysed (6:no CRT; 5:trial study drug; 7:≥ 2nd line treatment; 2:inadequate data). Median age: 59 (range 25-73); 61% female. First incidence of thrombocytopaenia during concurrent TMZ-CRT: 27/49 patients; during adjuvant TMZ in 22/49 (13/22 following 6-week-TMZ-CRT, 9/22 following 3-week-TMZ-CRT). In concurrent patients, median time to thrombocytopaenia: 33 days (range 23-38); median duration: 44 days (range 20-105; 5 not recovered); number of transfusions: 1-2:9 pts; 3-4:6pts; 5-7:3pts; 8-10:7pts; >10:2pts. Of 22 adjuvant patients transfused, 8/22 developed ≥G3 thrombocytopaenia post-cycle-2; 19/22 resolved after 1 or 2 transfusions. Thrombocyopaenia was associated with ≥G3 neutropaenia in 11% of patients requiring <5 transfusions vs 75% requiring ≥ 5. Comparison of < 5 vs ≥ 5 transfusion-patients did not identify differences in any demographic or treatment parameters. CONCLUSION Risk factors for prolonged TMZ-induced thrombocytopenia vs swiftly-res olving thrombocytopaenia remain elusive. This needs to be reflected in consent processes and in design of clinical trials. View on Web

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Glioma Espionage From Longitudinal CSF Proteomics

alexandrossfakianakis shared this article with you from Inoreader Glioma Espionage From Longitudinal CSF Proteomics via # Neuro-Oncology Current Issue Abstract AIMS Rapid, detailed feedback is needed to understand the individualized biological impacts of novel glioma therapies. We are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response. METHOD Global proteomic analysis of CSF was performed on the Somalogic platform – an aptamer-based technology for highly sensitive and specific analysis of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria of decrease with resection and increase with recurrence in individual paired patient samples. RESULTS Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. The HGG proteomic signature was consistently enriched in an independent validation cohort consisting of 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. Encouragingly, proteins in the HGG signature decreased in the two patients for whom CSF was collected prior to and after resection (both at POD16 and POD18) with decreased tumor burden. CONCLUSION Our data demonstrate the ability to gain detailed, individualized insights regarding glioma biology, tumor burden, and evolution through global CSF proteomics acquired from longitudinal access to gliomas via Ommaya reservoirs. View on Web

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IDHwt Glioblastomas Show Opposing Resistance Mechanisms Across Patients in Response to Standard Treatment

alexandrossfakianakis shared this article with you from Inoreader IDHwt Glioblastomas Show Opposing Resistance Mechanisms Across Patients in Response to Standard Treatment via # Neuro-Oncology Current Issue Abstract AIMS Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite aggressive treatment, a resistant tumour recurs in practically all patients. We therefore aimed to better understand the mechanisms driving this treatment resistance through investigating changes in gene expression across pairs of primary and recurrent GBM tumours. METHOD We generated or acquired bulk tumour RNA sequencing data for primary and first recurrent tumours from 107 patients who received standard treatment. Differential expression analysis between primary and recurrent samples found that the most dysregulated genes were involved in neurodevelopment and neurodifferentiation. We therefore used a publicly available ChIP-seq database to identify DNA binding factors for which binding sites are enriched in the promotors of genes with the largest expression changes from primary to recurrent. RESULTS Jumonji and AT-Rich Inter acting Domain 2 (JARID2) was the most strongly enriched for binding to promotors of dysregulated genes. 65 patients showed an up-regulation and 42 showed a down-regulation of genes bound by this protein. The same set of JARID2 bound genes were found to be dysregulated in each direction, and correlated with the largest source of variation between samples in their response to treatment. Further enrichment analyses indicated that 'Up' responders may resist treatment through reduced proliferation and increased interaction with the tumour microenvironment, whereas 'Down' responders instead rely on a shift to mesenchymal cell states. CONCLUSION These results indicate that GBM tumours can be split into two subtypes that transcriptionally reprogramme in different directions through treatment and may benefit from different treatment approaches. View on Web

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