Κυριακή 2 Οκτωβρίου 2022

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

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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.
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Neurosurgically-Applied Chemotherapy for Childhood Brain Tumours Arising in the Posterior Fossa Using a Biodegradable Paste

alexandrossfakianakis shared this article with you from Inoreader
Abstract
AIMS
This project aims to develop a local drug delivery system for treatment of childhood medulloblastoma (MB) and atypical teratoid/rhabdoid tumours (AT/RT), malignant brain neoplasms occurring in the posterior fossa for which prognoses remains poor. Our goal is to repurpose drug compounds reported as effective against MB and AT/RT, but which either cannot cross the blood-brain-barrier (BBB) or have not been assessed for localised delivery. We have developed a novel intra-cavity drug delivery system, consisting of polymer microparticles made from poly(DL-lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) which will be employed to release drugs over several weeks.
METHOD
Cell toxicity assays were undertaken using drugs of interest against an in vitro panel of relevant MB and AT/RT cell lines. PLGA/PEG paste incorporating the drugs were prepared and release kinetics assessed.
RESULTS
IC50 values of the drugs were assessed across all cell lines and a range of potencies were observed, with optimum conditions identified as dual treatments of PG545 (heparanse inhibitor) with CHIR99021 (glycogen synthase kinase-3 inhibitor) for MB and ribavirin (anti-viral) with CHIR99021 for AT/RT. Importantly, it was noted that the drugs retained their cytotoxicity following release from PLGA/PEG. Furthermore, release kinetics were finely tuned through careful control of the composition through addition of excipients and encapsulation of drugs in nanoparticles, and a library of formulations were prepared.
CONCLUSION
A local drug delivery system for MB and AT/RT has been developed and an optimum formulation, based upon in vitro cell assays and release kinetics, has been identified for in vivo efficacy studies in orthotopic models.
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Palliative Carboplatin Chemotherapy in Previously Treated High-Grade Glioma: Real-World Efficacy and Safety

alexandrossfakianakis shared this article with you from Inoreader
Abstract
AIMS
Effective third-line chemotherapy options for patients after temozolomide (TMZ) and nitrosourea-based chemotherapy for high-grade glioma (HGG) are not well defined. The use of carboplatin is limited due to uncertainly around its effectiveness and tolerability.
METHOD
Patients with HGG treated with single-agent carboplatin chemotherapy between 2005-2021 were identified from our institutional database. Patient and treatment-related details were acquired from electronic hospital records. SPSS Statistics for Windows, (Version 23.0, IBM Corp.) was used for data analysis.
RESULTS
A total of 16 HGG patients were identified. This included 9 glioblastoma (GBM) and 3 anaplastic astrocytomas (AA). These 12 patients were used for further analysis. The median age was 48 (22-73) years. All patients initially received a flat dose of 450 mg intravenous carboplatin every 3-4 weeks. All had previously received high dose RT (54-60 G y), and temozolomide and lomustine-based chemotherapy. Carboplatin was used as 3rd or 4th line treatment. The median number of cycles given was 3 (range: 1-12). Five had rapid decline in performance status after 1-3 cycles. Five patients required dose/ cycle length adjustment due to grade 1 or 2 haematological toxicity. Other than cumulative fatigue, no other >/= grade 2 toxicities were reported. None required inpatient management for treatment toxicities. Median progression-free survival on carboplatin was 3 months (range 1-11 months) and overall survival was 8 months (range 1–26 months).
CONCLUSION
Carboplatin is a viable treatment option for HGG with acceptable toxicity rates. However, careful patient selection remains key to attaining maximum benefit.
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Brain Tumour Diagnosis and Relationships Among Patients: A Social Science Perspective on Changing Tumour Classification

alexandrossfakianakis shared this article with you from Inoreader
Abstract
AIMS
Peer-to-peer relationships between people with a brain tumour are critical to how they cope with illness. These are often premised on shared diagnoses. However, as molecular genetic/epigenetic markers revise tumour classification, the terms of such relationships could also change. We explore these relationships and the potential repercussions for patients whose diagnoses are revised according to new tumour classification.
METHOD
We draw on two UK-based ethnographic studies of brain tumour care. The first examined how patients navigated complex healthcare systems (2014-2016); the second explored changing classification and personalised medicine (2020-2021). Both involved repeated qualitative interviews with patients, families, clinicians and classification experts, and observations of routine care. Here, we focus on interviews and observations with patients (N=29).
RESULTS
Patients described how peer-to-peer relati onships helped them understand their condition, envision their futures, find solidarity, navigate medical decisions, and access non-standard treatments. Many described the importance of finding people who shared their diagnosis. One patient, whose diagnosis was revised to a less aggressive tumour years after being first diagnosed, described how a radical change in prognosis challenged her relationships with peers, and contributed to significant survivor guilt as she outlived them.
CONCLUSION
Our findings confirm the importance of peer-to-peer relationships for patients. They suggest how changing tumour classification could have significant unforeseen social and psychological impacts for patients, including survivor guilt, by changing the nature of such relationships. We speculate that this will become more common in an era of personalised medicine and when breakthroughs in cancer understanding are more rapidly integrated in routine care.
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Exploring a Link Between Alzheimer’s and Glioma by Investigating SORL1 Network

alexandrossfakianakis shared this article with you from Inoreader
Abstract
AIMS
Use bioinformatics methods to identify and validate associated proteins and genes in the SORL1 network. Generate a bank of patient derived cells in association with the Royal Preston Hospital BTNW tissue bank. Explore identified targets from the bioinformatics in patient derived cells.
METHOD
Proteins and genes associated with SORL1 and SORLA were identified on GeneCards. Connectivity mapping of known and predicted interactions linked to SORL1 was explored in STRING. For clinical validation differential expression was investigated by comparing genomic data from GTEX and TCGA, available at Xenabrowser. For survival analysis Kaplan-Meier curves were generated on cBioPortal. The five most differently expressed novel targets are taken forward for laboratory experiments using western blots for protein quantification and immunocytochemistry to identify and visualise target proteins.
RESULTS
A total of 73 genes (30 from GeneCards and 43 from STRING) were obtained. 63 genes from the generated SORL1-related network were shown to be differentially expressed whilst 40 were significantly different between low-surviving patients and high-surviving patients. The top five associated proteins are CKAP4, CTNND1, FN1, HSPA12A and SORCS3. CKAP4, CTNND1 and FN1 are highly expressed in both glioma and glioblastoma, but low expressed in healthy tissue. HSPA12A is low expressed in cancerous brain tissue and highly expressed in healthy samples. SORCS3 is differentially expressed in healthy samples and glioma, but significantly low expressed glioblastoma.
CONCLUSION
This project provides insight into SORL1 molecular relationships and function in tissue, cultured cells and serum from a patient cohort including demographics, disease progression and site.
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Stereotactic Radiosurgery for Brainstem Metastases

alexandrossfakianakis shared this article with you from Inoreader
Abstract
AIMS
Limited data exists on outcomes following SRS for brainstem metastases (BSM). The purpose of this audit was to explore the use of SRS using Cyberknife for BSM at a single centre; reporting rates of toxicity and survival outcomes.
METHOD
Patients undergoing SRS for BSM from 2013 to 2021 were identified from a prospective database. Clinical characteristics were collected including; gender, age, histology and KPS. The use of previous WBRT, the volume and the dose delivered to the BSM were also recorded. All target volumes were peer reviewed by a neuro-radiologist.
RESULTS
41 patients with a BSM were identified. The median age was 62 years (range 35-78). Histology was lung 15 (36.6%), breast 13 (31.7%) and other 13(31.7%). The median brainstem target volume was 0.36cc (range 0.01 – 5.63cc). 32 patients had single fraction (dose range 14.5 to 18Gy) and 9 patients had 3 fractions (dose range 17-24Gy). 7 patients had p revious WBRT. Median overall survival was 242 days (range 19-1213). A radiological response or stable disease was seen in 26 out of 30 patients with post SRS imaging available for review. 2 patients developed a 6th nerve palsy. 12 patients required a prolonged course of dexamethasone. No statistically significant relationship was observed between patient age, brainstem lesion size or fractionation and the need for prolonged use of dexamethasone but there was a trend with lung cancer patients requiring prolonged dexamethasone (p=0.06).
CONCLUSION
Brainstem SRS is viable option with an acceptable late toxicity profile. Updated information on survival and local control will be presented.
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Tecovirimat therapy for severe monkeypox infection: Longitudinal assessment of viral titers and clinical response pattern – A first case‐series experience

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Tecovirimat is the only antiviral with conditional and emergency approval for treatment of monkeypox by the European Medicines Agency. We present longitudinal virologic data of three patients with severe monkeypox treated with Tecovirimat. These patients presented with underlying comorbidities (ulcerative colitis; acute syphilis; HIV infection) and higher baseline monkeypox viremia compared to patients with less severe disease courses. Tecovirimat was well-tolerated, and clinical improvement was observed. In median viremia decreased by more than 2 logs within one week of therapy.

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