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  • 1
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    Radiation treatment of benign tumors in NF2-related-schwannomatosis: A national study of 266 irradiated patients showing a significant increase in malignancy/malignant progression
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Advances Vol. 5, No. 1 ( 2023-01-01)
    Details
    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 5, No. 1 ( 2023-01-01)
    Abstract: Radiation treatment of benign tumors in tumor predisposition syndromes is controversial, but short-term studies from treatment centers suggest safety despite apparent radiation-associated malignancy being reported. We determined whether radiation treatment in NF2-related schwannomatosis patients is associated with increased rates of subsequent malignancy (M)/malignant progression (MP). Methods All UK patients with NF2 were eligible if they had a clinical/molecular diagnosis. Cases were NF2 patients treated with radiation for benign tumors. Controls were matched for treatment location with surgical/medical treatments based on age and year of treatment. Prospective data collection began in 1990 with addition of retrospective cases in 1969. Kaplan–Meier analysis was performed for malignancy incidence and survival. Outcomes were central nervous system (CNS) M/MP (2cm annualized diameter growth) and survival from index tumor treatment. Results In total, 1345 NF2 patients, 266 (133-Male) underwent radiation treatments between 1969 and 2021 with median first radiotherapy age of 32.9 (IQR = 22.4–46.0). Nine subsequent CNS malignancies/MPs were identified in cases with only 4 in 1079 untreated (P & lt; .001). Lifetime and 20-year CNS M/MP was ~6% in all irradiated patients—(4.9% for vestibular schwannomas [VS] radiotherapy) versus & lt;1% in the non-irradiated population (P & lt; .001/.01). Controls were well matched for age at NF2 diagnosis and treatment (Males = 133%–50%) and had no M/MP in the CNS post-index tumor treatment (P = .0016). Thirty-year survival from index tumor treatment was 45.62% (95% CI = 34.0–56.5) for cases and 66.4% (57.3–74.0) for controls (P = .02), but was nonsignificantly worse for VS radiotherapy. Conclusion NF2 patients should not be offered radiotherapy as first-line treatment of benign tumors and should be given a frank discussion of the potential 5% excess absolute risk of M/MP.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    URL: Article
    DOI: 10.1093/noajnl/vdad025
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 3009682-0
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  • 2
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    Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. 12 ( 2020-12-18), p. 1840-1850
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. 12 ( 2020-12-18), p. 1840-1850
    Abstract: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ. Methods Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. Results Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. Conclusion Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa104
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 3
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    The Management and Outcomes of Patients with Extra-Pulmonary Neuroendocrine Neoplasms and Brain Metastases
    MDPI AG ; 2022
    In:  Current Oncology Vol. 29, No. 7 ( 2022-07-20), p. 5110-5125
    Details
    In: Current Oncology, MDPI AG, Vol. 29, No. 7 ( 2022-07-20), p. 5110-5125
    Abstract: Background: Brain metastases (BMs) in patients with extra-pulmonary neuroendocrine neoplasms (EP–NENs) are rare, and limited clinical information is available. The aim of this study was to detail the clinicopathological features, management and outcomes in patients with EP–NENs who developed BMs. Methods: A retrospective single-centre analysis of consecutive patients with EP–NENs (August 2004–February 2020) was conducted. Median overall survival (OS)/survival from BMs diagnosis was estimated (Kaplan–Meier). Results: Of 730 patients, 17 (1.9%) had BMs, median age 61 years (range 15–77); 8 (53%) male, unknown primary NEN site: 40%. Patients with BMs had grade 3 (G3) EP–NENs 11 (73%), G2: 3 (20%), G1: 1 (7%). Eight (53%) had poorly differentiated NENs, 6 were well-differentiated and 1 was not recorded. Additionally, 2 (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. The relative risk of developing BMs was 7.48 in patients with G3 disease vs. G1 + G2 disease (p = 0.0001). Median time to the development of BMs after NEN diagnosis: 15.9 months (range 2.5–139.5). Five patients had a solitary BM, 12 had multiple BMs. Treatment of BMs were surgery (n = 3); radiotherapy (n = 5); 4: whole brain radiotherapy, 1: conformal radiotherapy (orbit). Nine (53%) had best supportive care. Median OS from NEN diagnosis was 23.6 months [95% CI 15.2–31.3]; median time to death from BMs diagnosis was 3.0 months [95% CI 0.0–8.3] . Conclusion: BMs in patients with EP–NENs are rare and of increased risk in G3 vs. G1 + G2 EP–NENs. Survival outcomes are poor, and a greater understanding is needed to improve therapeutic outcomes.
    Type of Medium: Online Resource
    ISSN: 1718-7729
    URL: Article
    DOI: 10.3390/curroncol29070405
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2270777-3
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  • 4
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    Letter: Stereotactic Radiosurgery for Vestibular Schwannoma in Neurofibromatosis Type 2: An International Multicenter Case Series of Response and Malignant Transformation Risk
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Neurosurgery Vol. 93, No. 4 ( 2023-10), p. e98-e99
    Details
    In: Neurosurgery, Ovid Technologies (Wolters Kluwer Health), Vol. 93, No. 4 ( 2023-10), p. e98-e99
    Type of Medium: Online Resource
    ISSN: 0148-396X , 1524-4040
    URL: Article
    DOI: 10.1227/neu.0000000000002613
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1491894-8
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  • 5
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    Actinomycin D downregulates Sox2 and improves survival in preclinical models of recurrent glioblastoma
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. 9 ( 2020-09-29), p. 1289-1301
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. 9 ( 2020-09-29), p. 1289-1301
    Abstract: Glioblastoma (GBM) has been extensively researched over the last few decades, yet despite aggressive multimodal treatment, recurrence is inevitable and second-line treatment options are limited. Here, we demonstrate how high-throughput screening (HTS) in multicellular spheroids can generate physiologically relevant patient chemosensitivity data using patient-derived cells in a rapid and cost-effective manner. Our HTS system identified actinomycin D (ACTD) to be highly cytotoxic over a panel of 12 patient-derived glioma stemlike cell (GSC) lines. ACTD is an antineoplastic antibiotic used in the treatment of childhood cancers. Here, we validate ACTD as a potential repurposed therapeutic for GBM in 3-dimensional GSC cultures and patient-derived xenograft models of recurrent glioblastoma. Methods Twelve patient-derived GSC lines were screened at 10 µM, as multicellular spheroids, in a 384-well serum-free assay with 133 FDA-approved compounds. GSCs were then treated in vitro with ACTD at established half-maximal inhibitory concentrations (IC50). Downregulation of sex determining region Y–box 2 (Sox2), a stem cell transcription factor, was investigated via western blot and through immunohistological assessment of murine brain tissue. Results Treatment with ACTD was shown to significantly reduce tumor growth in 2 recurrent GBM patient-derived models and significantly increased survival. ACTD is also shown to specifically downregulate the expression of Sox2 both in vitro and in vivo. Conclusion These findings indicate that, as predicted by our HTS, ACTD could deplete the cancer stem cell population within the tumor mass, ultimately leading to a delay in tumor progression. Key Points 1. High-throughput chemosensitivity data demonstrated the broad efficacy of actinomycin D, which was validated in 3 preclinical models of glioblastoma. 2. Actinomycin D downregulated Sox2 in vitro and in vivo, indicating that this agent could target the stem cell population of GBM tumors.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa051
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 6
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    CTNI-66. THE PREOPERATIVE BRAIN IRRADIATION IN GLIOBLASTOMA (POBIG) STUDY: A NOVEL TREATMENT PARADIGM TO IMPROVE OUTCOMES?
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii88-vii88
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii88-vii88
    Abstract: The Preoperative Brain Irradiation in Glioblastoma (POBIG) study evaluates for the first time the safety, feasibility, and impact of single fraction preoperative radiotherapy in newly diagnosed glioblastoma patients. METHODS Operable patients with a radiological diagnosis of glioblastoma, by consensus of a multidisciplinary tumor board including two dedicated neuro-radiologists, are screened for the study. Anatomical and functional MRI sequences are acquired for further tumor characterization and preoperative radiotherapy planning. Radiotherapy is delivered approximately two weeks after the initial screening. Radiation targets the macroscopic and microscopic tumor region at risk of being left behind during surgery and spares at least 2cc tumor volume being debulked to safeguard unperturbed and clinically relevant tissue examination and molecular profiling. The study dose-escalates (from 8Gy to 14Gy) based on the time-to-event Continual Reassessment Methodology. Subsequently, patients undergo surgical debulking followed by postoperative fractionated radiotherapy 60Gy/30fr with concurrent temozolomide. RESULTS The first POBIG study patient underwent preoperative radiotherapy followed by a subtotal resection of a left posterior fronto-opercular tumor and completed the postoperative chemoradiotherapy. Screening, study consent, MRI imaging and analysis, radiotherapy planning and delivery until surgery can be achieved within three weeks from screening while maintaining adequate and personalized patient communication. There were no surgical or radiotherapy delays or complications. During surgery, we successfully sampled unirradiated and irradiated tumor regions. The radiotherapy field covered the whole remnant tumor, and image-guided obtained tumor samples and imaging analysis showed clear evidence of differential radiation-induced changes. CONCLUSION We successfully initiated a new treatment strategy of preoperative radiotherapy for glioblastoma patients. The first patient completed the treatment, and the study is now open for further recruitment. Paired tumor sampling and advanced imaging analysis showed promising results. The POBIG study offers a unique opportunity for a paradigm shift towards personalized treatment regimens, hopefully leading to better outcomes.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.331
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    TESSA JOWELL BRAIN MATRIX PLATFORM STUDY: PRELIMINARY ANALYSIS OF THE PRIMARY FEASIBILITY & PROCESS-CENTRED OBJECTIVE
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_3 ( 2023-09-16), p. iii8-iii9
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_3 ( 2023-09-16), p. iii8-iii9
    Abstract: The Tessa Jowell BRAIN MATRIX (ISRCTN14218060) is an ongoing platform study, collecting disease, treatment, and outcome data prospectively in glioma patients, across nine UK hospitals. We report a preliminary analysis of the primary feasibility and process-centred objectives. METHOD Primary Objective: Test the feasibility of establishing an integrated histological-molecular diagnosis using Whole Genome Sequencing (WGS) and Epigenomic Classification (EC) (‘Heidelberg Classifier’) data in NHS practice within 28 days. Primary Outcome: Time (from surgery) to integrated histological–molecular diagnosis (TTMD) using WGS and EC. Secondary Outcome: Time to completion of each node (stage) of the tissue and imaging pathway. RESULTS Data snapshot on 23-Feb-2023 confirmed 250 patients recruited. Nine nodes along the tissue & imaging pathway were defined. Twenty-one patients had completed the pathway and time to each node was calculated. Median time to complete the pathway was 404 days (range 124-653). There was a trend of improvement in TTMD in recently recruited patients. CONCLUSIONS The patient pathway from surgery to clinical feedback through a Genomic Tumour Advisory Board (GTAB) utilises NHS-accredited pathways and protocols. Delays inherent in the pathway emphasise the urgent need for infrastructure and operational delivery improvements of the NHS Genomic Medicine Service for brain cancer patients as the current timeframe is not clinically relevant for informing patient care. These data also highlight geographical inequality in accessing genomic medicine within England, across the seven Genomic Laboratory Hubs, and the devolved nations. Detailed analysis of the delays at each node will identify opportunities and solutions to inform discussions with the NHS and Genomics England.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad147.035
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2094060-9
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  • 8
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    PREOPERATIVE BRAIN IRRADIATION IN GLIOBLASTOMA (POBIG TRIAL): FEASIBILITY AND EVALUATION OF TREATMENT RESPONSE IN ENHANCING AND NON-ENHANCING REGIONS
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_3 ( 2023-09-16), p. iii1-iii1
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_3 ( 2023-09-16), p. iii1-iii1
    Abstract: Patients with glioblastoma have dismal outcomes and there is an urgent need for new treatment modalities. The POBIG trial is the first to evaluate the safety and feasibility of single-fraction preoperative radiotherapy for newly diagnosed glioblastoma. We report the results from our first dose arm. METHOD POBIG is a phase I radiotherapy dose and volume escalation trial. The first dose arm received 8Gy preoperative radiotherapy to a maximum irradiation volume of 30cm3. The irradiation field included enhancing and non- enhancing FLAIR hyperintense regions judged as highest risk for remaining as postoperative residuum. Part of the tumour remained unirradiated ( & lt;2Gy) with a margin for diagnostic sampling. Surgical resection took place within 1 week. Patients underwent diffusion/perfusion MRI scans before/after preoperative radiotherapy. RESULTS Two female and one male patient aged 61, 67 and 45 years, respectively, were enrolled. Preoperative radio- therapy was delivered at a dose of 8Gy to an irradiation volume of 7-30cm3. Near-total surgical resection was performed 2-3 days after preoperative radiotherapy treatment. Pathological examination of irradiated areas showed necrosis including fibrinoid necrosis of vessel walls. There was an increase in Ktrans permeability in both irradiated enhancing tumour (0.097,0.150) and unirradiated enhancing tumour (0.077,0.147) 24-hours after treatment. In contrast, no obvious changes were noted in irradiated (0.002,0.002) and unirradiated (0.002,0.004) non-enhancing FLAIR hyperintense regions or reference unirradiated contralateral white matter (0.000,0.000). CONCLUSIONS Preoperative radiotherapy is feasible in newly diagnosed glioblastoma. Very early radiotherapy changes manifest in enhancing tumour regardless of radiotherapy dose, evident as increased permeability and radiation- induced tumour necrosis.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad147.001
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 9
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    Prolonged Transfusion-Dependent Temozolomide-Induced Thrombocytopaenia in Glioblastoma: Risk Factors Remain Elusive
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_4 ( 2022-10-01), p. iv23-iv23
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_4 ( 2022-10-01), p. iv23-iv23
    Abstract: 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 & lt; 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 were 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; & gt;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 & lt;5 transfusions vs 75% requiring ≥ 5. Comparison of & lt; 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-resolving thrombocytopaenia remain elusive. This needs to be reflected in consent processes and in design of clinical trials.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac200.105
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 10
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    CovidNeuroOnc: A UK multicenter, prospective cohort study of the impact of the COVID-19 pandemic on the neuro-oncology service
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Advances Vol. 3, No. 1 ( 2021-01-01)
    Details
    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 3, No. 1 ( 2021-01-01)
    Abstract: The COVID-19 pandemic has profoundly affected cancer services. Our objective was to determine the effect of the COVID-19 pandemic on decision making and the resulting outcomes for patients with newly diagnosed or recurrent intracranial tumors. Methods We performed a multicenter prospective study of all adult patients discussed in weekly neuro-oncology and skull base multidisciplinary team meetings who had a newly diagnosed or recurrent intracranial (excluding pituitary) tumor between 01 April and 31 May 2020. All patients had at least 30-day follow-up data. Descriptive statistical reporting was used. Results There were 1357 referrals for newly diagnosed or recurrent intracranial tumors across 15 neuro-oncology centers. Of centers with all intracranial tumors, a change in initial management was reported in 8.6% of cases (n = 104/1210). Decisions to change the management plan reduced over time from a peak of 19% referrals at the start of the study to 0% by the end of the study period. Changes in management were reported in 16% (n = 75/466) of cases previously recommended for surgery and 28% of cases previously recommended for chemotherapy (n = 20/72). The reported SARS-CoV-2 infection rate was similar in surgical and non-surgical patients (2.6% vs. 2.4%, P & gt; .9). Conclusions Disruption to neuro-oncology services in the UK caused by the COVID-19 pandemic was most marked in the first month, affecting all diagnoses. Patients considered for chemotherapy were most affected. In those recommended surgical treatment this was successfully completed. Longer-term outcome data will evaluate oncological treatments received by these patients and overall survival.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    URL: Article
    DOI: 10.1093/noajnl/vdab014
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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