Αρχειοθήκη ιστολογίου

Κυριακή 2 Οκτωβρίου 2022

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

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

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

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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.
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Local Relapse Rates for Brain Metastases Treated With Stereotactic Radiosurgery

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

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

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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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Tecovirimat therapy for severe monkeypox infection: Longitudinal assessment of viral titers and clinical response pattern – A first case‐series experience

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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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Development of chemiluminescent lab‐on‐fiber immunosensor for rapid point‐of‐care testing of anti‐SARS‐CoV‐2 antibodies and evaluation of longitudinal immune response kinetics following three‐dose inactivation virus vaccination

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Developing reliable, rapid, and quantitative point-of-care testing (POCT) technology of SARS-CoV-2 specific antibodies and understanding longitudinal vaccination response kinetics are highly required to restrain the ongoing Coronavirus Disease 2019 (COVID-19) pandemic. We demonstrate a novel portable, sensitive, and rapid chemiluminescent lab-on-fiber detection platform for detection of anti-SARS-CoV-2 antibodies: the c-LOFI. Using SARS-CoV-2 Spike S1 RBD protein functionalized fiber bio-probe, the c-LOFI can detect anti-SARS-CoV-2 IgG and IgM antibodies with high sensitivity based on their respective HRP labeled secondary antibodies. The limits of detection of anti-SARS-CoV-2 IgG and IgM antibodies were 0.6 ng/mL and 0.3 ng/mL, respectively. The c-LOFI was successfully applied for direct detection of anti-SARS-CoV-2 antibodies in whole blood samples with simple dilution, which can serve as a finger prick test to rapidly detect antibodies. Furthermore, the l ongitudinal immune response (>12 months) kinetics following three-dose inactivated virus vaccines was evaluated based on anti-SARS-CoV-2 IgG detection results, which can provide importance significance for understanding the immune mechanism against COVID-19 and identify individuals who may benefit from the vaccination and booster vaccination. The c-LOFI has great potential to become a sensitive, low-cost, rapid, high-frequency POCT tool for the detection of both SARS-CoV-2 specific antibodies and other biomarkers.

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Partial laryngectomy for naïve pT3N0 laryngeal cancer: Systematic review on oncological outcomes

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Abstract

The first aim was to define the oncologic outcomes of open partial laryngectomy (OPL) in naïve pT3 laryngeal cancer. The second aim was to analyze the outcomes after OPL versus total laryngectomy (TL). A literature search was conducted in three databases (MEDLINE, EMBASE, and Cochrane Library) until January 2022. In 805 patients treated with OPL, 5-year OS, DSS, DFS and LFS were 80.5% (95% CI 70.6–87.6), 83.4% (95% CI 75.7–89), 77.4% (95% CI 66.3–85.7) and 77.9% (95% CI 68.7–85), respectively. Three articles compared TL versus OLP: 5-year OS, DSS and DFS risk difference were 0.100 (95% CI −0.092 to 0.291), 0.067 (95% CI −0.085 to 0.220) and 0.018 (95% CI −0.164 to 0.201) respectively. OPL for selected pT3 laryngeal cancer is able to guarantee a high percentage of oncological success. Accurate patient selection is of utmost importance to differentiate advanced disease amenable to conservative surgery.

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Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome

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Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome

The brains of 8-week-old wildtype (WT) mice (left) and mice carrying mutations (D1113H) in the ADAR1 gene (right) probed for expression of Interferon Stimulated Gene 15 (ISG-15) using In situ hybridization (red). WT mice show little to no expression of ISG-15 while ADAR1 mutant mouse brain shows a broad and chaotic distribution of expression throughout the brain (8 of many foci circled).


Abstract

Chronic inflammation is frequently invoked as a mechanism of neurodegeneration and yet inflammatory cell infiltrates are seldom seen in brains of these disorders. Different disciplines utilize different technologies and methodologies to describe what is immunologically defined as the innate immune response (IIR). We examined murine models of the human neurodegenerative disease Aicardi–Gutiérrez Syndrome, where an IIR is initiated by aberrant RNA metabolism secondary to a mutation in adenosine deaminase acting on RNA gene (ADAR1). We previously showed that these mice demonstrated a deficit in RNA editing that lead to MDA-5 mediated RNA sensing pathway activation of the IIR with massive interferon stimulated gene transcription and translation. As early as 2 weeks of age, in situ hybridization demonstrated that different central nervous system (CNS) cell lineages expressed very high levels of distinct interferon stimulated genes (ISGs) in the absence of interferon and absence of immune cell infiltrates. We have expanded these studies to more completely describe the breadth of ISG expression systemically and in CNS using double label in situ hybridization. Within the CNS aberrant ISG expression was mostly limited to neurons, microglia, ependyma, choroid plexus, and endothelial cells with little expression in oligodendroglia and astrocytes except for STAT1. Wild type controls showed a similar pattern of ISG expression but only in aged mice and at levels minimally detectable by in situ hybridization. Despite months of elevated ISG expression in mutant mice, there was essentially no inflammatory infiltrate, no interferon production and minimal glial reaction. Histomorphological neurodegenerative pathology of ventricular dilatation and deep gray matter mineralization were evident in mutant mice 8–13 months of age but this did not show a spatial relationship to ISG expression. This IIR without immune cell infiltration leads to neurodegeneration through non-c anonical pathways that may accentuate normal aging pathways.

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