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1.
Cancers (Basel) ; 15(24)2023 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-38136335

RESUMO

Glioblastoma (GBM) is the most common primary malignant brain tumour, and it confers a dismal prognosis despite intensive multimodal treatments. Whilst historically, research has focussed on the evolution of GBM tumour cells themselves, there is growing recognition of the importance of studying the tumour microenvironment (TME). Improved characterisation of the interaction between GBM cells and the TME has led to a better understanding of therapeutic resistance and the identification of potential targets to block these escape mechanisms. This review describes the network of cells within the TME and proposes treatment strategies for simultaneously targeting GBM cells, the surrounding immune cells, and the crosstalk between them.

2.
Eur J Cancer ; 190: 112946, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37453240

RESUMO

BACKGROUND: In an international randomised controlled phase II study of temozolomide (TMZ) versus TMZ in combination with bevacizumab (BEV) in locally diagnosed non-1p/19q co-deleted World Health Organization grade 2 or 3 gliomas with a first and contrast-enhancing recurrence after initial radiotherapy, and overall survival at 12 months was not significantly different (61% in the TMZ arm and 55% in the TMZ + BEV arm). OBJECTIVES: Health-related quality of life (HRQoL) was a key secondary end-point in this trial, and the main objective of this study was to determine the impact of the addition of BEV to TMZ on HRQoL. METHODS: HRQoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 (version 3) and QLQ-BN20 at baseline, and then every 12 weeks until disease progression. The pre-selected primary HRQoL end-point was the QLQ-C30 global health scale, with self-perceived cognitive functioning and pain selected as secondary HRQoL issues. Analysis was undertaken using linear mixed modelling and complemented with sensitivity analyses using summary statistics. A difference was considered clinically relevant with ≥10 points difference on a 100-point scale. RESULTS: Baseline compliance was high at 94% and remained above 60% until 72 weeks, limiting the analysis to 60 weeks. Compliance was similar in both arms. We found no statistically significant or clinically significant differences between the primary HRQoL end-point in both treatment arms (p = 0.2642). The sensitivity analyses confirmed this finding. The overall test for post-baseline differences between the two treatment arms also showed no statistically or clinically significant differences regarding the selected secondary end-point scales. INTERPRETATION: The addition of BEV to TMZ in this patient group neither improves nor negatively impacts HRQoL.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Temozolomida/uso terapêutico , Bevacizumab/efeitos adversos , Qualidade de Vida , Glioma/tratamento farmacológico , Organização Mundial da Saúde
3.
Neuro Oncol ; 25(1): 123-134, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-35419607

RESUMO

BACKGROUND: Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter. METHODS: Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150-200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS. RESULTS: A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively. CONCLUSIONS: The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM.ClinicalTrials.gov NCT02617589.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Temozolomida/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Nivolumabe/uso terapêutico , Intervalo Livre de Doença , Intervalo Livre de Progressão , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Antineoplásicos Alquilantes/uso terapêutico , Metilases de Modificação do DNA/genética , Proteínas Supressoras de Tumor/genética , Enzimas Reparadoras do DNA/genética
4.
Front Oncol ; 12: 969812, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36132155

RESUMO

Background: Glioblastoma (GB) is the most severe form of brain cancer, with a 12-15 month median survival. Surgical resection, temozolomide (TMZ) treatment, and radiotherapy remain the primary therapeutic options for GB, and no new therapies have been introduced in recent years. This therapeutic standstill is primarily due to preclinical approaches that do not fully respect the complexity of GB cell biology and fail to test efficiently anti-cancer treatments. Therefore, better treatment screening approaches are needed. In this study, we have developed a novel functional precision medicine approach to test the response to anticancer treatments in organoids derived from the resected tumors of glioblastoma patients. Methods: GB organoids were grown for a short period of time to prevent any genetic and morphological evolution and divergence from the tumor of origin. We chose metabolic imaging by NAD(P)H fluorescence lifetime imaging microscopy (FLIM) to predict early and non-invasively ex-vivo anti-cancer treatment responses of GB organoids. TMZ was used as the benchmark drug to validate the approach. Whole-transcriptome and whole-exome analyses were performed to characterize tumor cases stratification. Results: Our functional precision medicine approach was completed within one week after surgery and two groups of TMZ Responder and Non-Responder tumors were identified. FLIM-based metabolic tumor stratification was well reflected at the molecular level, confirming the validity of our approach, highlighting also new target genes associated with TMZ treatment and identifying a new 17-gene molecular signature associated with survival. The number of MGMT gene promoter methylated tumors was higher in the responsive group, as expected, however, some non-methylated tumor cases turned out to be nevertheless responsive to TMZ, suggesting that our procedure could be synergistic with the classical MGMT methylation biomarker. Conclusions: For the first time, FLIM-based metabolic imaging was used on live glioblastoma organoids. Unlike other approaches, ex-vivo patient-tailored drug response is performed at an early stage of tumor culturing with no animal involvement and with minimal tampering with the original tumor cytoarchitecture. This functional precision medicine approach can be exploited in a range of clinical and laboratory settings to improve the clinical management of GB patients and implemented on other cancers as well.

5.
Cancers (Basel) ; 14(13)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35804940

RESUMO

Background: IDH-wildtype glioblastoma is the most common malignant primary brain tumour in adults. As there is limited information on prognostic factors outside of clinical trials; thus, we conducted a retrospective study to characterise the glioblastoma population at our centre. Methods: Demographic, tumour molecular profiles, treatment, and survival data were collated for patients diagnosed with glioblastoma at our centre between July 2011 and December 2015. We used multivariate proportional hazard model associations with survival. Results: 490 patients were included; 60% had debulking surgery and 40% biopsy only. Subsequently, 56% had standard chemoradiotherapy, 25% had non-standard chemo/radio-therapy, and 19% had no further treatment. Overall survival was 9.2 months. In the multivariate analysis, longer survival was associated with debulking surgery vs. biopsy alone (14.9 vs. 8 months) (HR 0.54 [95% CI 0.41−0.70]), subsequent treatment after diagnosis (HR 0.12 [0.08−0.16]) (standard chemoradiotherapy [16.9 months] vs. non-standard regimens [9.2 months] vs. none [2.0 months]), tumour MGMT promotor methylation (HR 0.71 [0.58−0.87]), and younger age (hazard ratio vs. age < 50: 1.70 [1.26−2.30] for ages 50−59; 3.53 [2.65−4.70] for ages 60−69; 4.82 [3.54−6.56] for ages 70+). Conclusions: The median survival for patients with glioblastoma is less than a year. Younger age, debulking surgery, treatment with chemoradiotherapy, and MGMT promotor methylation are independently associated with longer survival.

6.
Clin Cancer Res ; 28(11): 2440-2448, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35294545

RESUMO

PURPOSE: Despite recent advances in the molecular characterization of gliomas, it remains unclear which patients benefit most from which second-line treatments. The TAVAREC trial was a randomized, open-label phase II trial assessing the benefit of the addition of the angiogenesis inhibitor bevacizumab to treatment with temozolomide in patients with a first enhancing recurrence of World Health Organization grade 2 or 3 glioma without 1p/19q codeletion. We evaluated the prognostic significance of genome-wide DNA methylation profiles and copy-number variations on the TAVAREC trial samples. EXPERIMENTAL DESIGN: Isocitrate dehydrogenase (IDH) mutation status was determined via Sanger sequencing and IHC. DNA methylation analysis was performed using the MethylationEPIC BeadChip (Illumina) from which 1p/19q codeletion, MGMT promoter methylation (MGMT-STP27), and homozygous deletion of CDKN2A/B were determined. DNA methylation classes were determined according to classifiers developed in Heidelberg and The Cancer Genome Atlas (TCGA; "Heidelberg" and "TCGA" classifier respectively). RESULTS: DNA methylation profiles of 122 samples were successfully determined. As expected, most samples were IDH-mutant (89/122) and MGMT promotor methylated (89/122). Methylation classes were prognostic for time to progression. However, Heidelberg methylation classes determined at time of diagnosis were no longer prognostic following enhancing recurrence of the tumor. In contrast, TCGA methylation classes of primary samples remained prognostic also following enhancing recurrence. Homozygous deletions in CDKN2A/B were found in 10 of 87 IDH-mutated samples and were prognostically unfavorable at recurrence. CONCLUSIONS: DNA methylome Heidelberg classification at time of diagnosis is no longer of prognostic value at the time of enhancing recurrence. CDKN2A/B deletion status was predictive of survival from progression of IDH-mutated tumors.


Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/patologia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/patologia , Homozigoto , Humanos , Isocitrato Desidrogenase/genética , Imageamento por Ressonância Magnética , Mutação , Recidiva Local de Neoplasia/genética , Prognóstico , Deleção de Sequência
7.
Neuroradiology ; 63(12): 2047-2056, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34047805

RESUMO

PURPOSE: Surveillance of patients with high-grade glioma (HGG) and identification of disease progression remain a major challenge in neurooncology. This study aimed to develop a support vector machine (SVM) classifier, employing combined longitudinal structural and perfusion MRI studies, to classify between stable disease, pseudoprogression and progressive disease (3-class problem). METHODS: Study participants were separated into two groups: group I (total cohort: 64 patients) with a single DSC time point and group II (19 patients) with longitudinal DSC time points (2-3). We retrospectively analysed 269 structural MRI and 92 dynamic susceptibility contrast perfusion (DSC) MRI scans. The SVM classifier was trained using all available MRI studies for each group. Classification accuracy was assessed for different feature dataset and time point combinations and compared to radiologists' classifications. RESULTS: SVM classification based on combined perfusion and structural features outperformed radiologists' classification across all groups. For the identification of progressive disease, use of combined features and longitudinal DSC time points improved classification performance (lowest error rate 1.6%). Optimal performance was observed in group II (multiple time points) with SVM sensitivity/specificity/accuracy of 100/91.67/94.7% (first time point analysis) and 85.71/100/94.7% (longitudinal analysis), compared to 60/78/68% and 70/90/84.2% for the respective radiologist classifications. In group I (single time point), the SVM classifier also outperformed radiologists' classifications with sensitivity/specificity/accuracy of 86.49/75.00/81.53% (SVM) compared to 75.7/68.9/73.84% (radiologists). CONCLUSION: Our results indicate that utilisation of a machine learning (SVM) classifier based on analysis of longitudinal perfusion time points and combined structural and perfusion features significantly enhances classification outcome (p value= 0.0001).


Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Humanos , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Perfusão , Estudos Retrospectivos
8.
Small ; 17(14): e2005241, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33734595

RESUMO

Magnetic hyperthermia (MH) harnesses the heat-releasing properties of superparamagnetic iron oxide nanoparticles (SPIONs) and has potential to stimulate immune activation in the tumor microenvironment whilst sparing surrounding normal tissues. To assess feasibility of localized MH in vivo, SPIONs are injected intratumorally and their fate tracked by Zirconium-89-positron emission tomography, histological analysis, and electron microscopy. Experiments show that an average of 49% (21-87%, n = 9) of SPIONs are retained within the tumor or immediately surrounding tissue. In situ heating is subsequently generated by exposure to an externally applied alternating magnetic field and monitored by thermal imaging. Tissue response to hyperthermia, measured by immunohistochemical image analysis, reveals specific and localized heat-shock protein expression following treatment. Tumor growth inhibition is also observed. To evaluate the potential effects of MH on the immune landscape, flow cytometry is used to characterize immune cells from excised tumors and draining lymph nodes. Results show an influx of activated cytotoxic T cells, alongside an increase in proliferating regulatory T cells, following treatment. Complementary changes are found in draining lymph nodes. In conclusion, results indicate that biologically reactive MH is achievable in vivo and can generate localized changes consistent with an anti-tumor immune response.


Assuntos
Hipertermia Induzida , Nanopartículas de Magnetita , Compostos Férricos , Humanos , Hipertermia , Campos Magnéticos , Magnetismo
9.
Acta Neuropathol ; 141(6): 945-957, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33740099

RESUMO

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.


Assuntos
Astrocitoma/diagnóstico , Astrocitoma/genética , Neoplasias Encefálicas/genética , Metilação de DNA/genética , Isocitrato Desidrogenase/genética , Mutação , Neoplasias Encefálicas/diagnóstico , Humanos , Prognóstico , Taxa de Sobrevida
10.
JMIR Rehabil Assist Technol ; 7(2): e18589, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924955

RESUMO

BACKGROUND: Huntington disease (HD) is an inherited genetic disorder that results in the death of brain cells. HD symptoms generally start with subtle changes in mood and mental abilities; they then degenerate progressively, ensuing a general lack of coordination and an unsteady gait, ultimately resulting in death. There is currently no cure for HD. Walking cued by an external, usually auditory, rhythm has been shown to steady gait and help with movement coordination in other neurological conditions. More recently, work with other neurological conditions has demonstrated that haptic (ie, tactile) rhythmic cues, as opposed to audio cues, offer similar improvements when walking. An added benefit is that less intrusive, more private cues are delivered by a wearable device that leaves the ears free for conversation, situation awareness, and safety. This paper presents a case study where rhythmic haptic cueing (RHC) was applied to one person with HD. The case study has two elements: the gait data we collected from our wearable devices and the comments we received from a group of highly trained expert physiotherapists and specialists in HD. OBJECTIVE: The objective of this case study was to investigate whether RHC can be applied to improve gait coordination and limb control in people living with HD. While not offering a cure, therapeutic outcomes may delay the onset or severity of symptoms, with the potential to improve and prolong quality of life. METHODS: The approach adopted for this study includes two elements, one quantitative and one qualitative. The first is a repeated-measures design with three conditions: before haptic rhythm (ie, baseline), with haptic rhythm, and after exposure to haptic rhythm. The second element is an in-depth interview with physiotherapists observing the session. RESULTS: In comparison to the baseline, the physiotherapists noted a number of improvements to the participant's kinematics during her walk with the haptic cues. These improvements continued in the after-cue condition, indicating some lasting effects. The quantitative data obtained support the physiotherapists' observations. CONCLUSIONS: The findings from this small case study, with a single participant, suggest that a haptic metronomic rhythm may have immediate, potentially therapeutic benefits for the walking kinematics of people living with HD and warrants further investigation.

11.
JMIR Mhealth Uhealth ; 8(6): e17872, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32543446

RESUMO

BACKGROUND: Movement analysis in a clinical setting is frequently restricted to observational methods to inform clinical decision making, which has limited accuracy. Fixed-site, optical, expensive movement analysis laboratories provide gold standard kinematic measurements; however, they are rarely accessed for routine clinical use. Wearable inertial measurement units (IMUs) have been demonstrated as comparable, inexpensive, and portable movement analysis toolkits. MoJoXlab has therefore been developed to work with generic wearable IMUs. However, before using MoJoXlab in clinical practice, there is a need to establish its validity in participants with and without knee conditions across a range of tasks with varying complexity. OBJECTIVE: This paper aimed to present the validation of MoJoXlab software for using generic wearable IMUs for calculating hip, knee, and ankle joint angle measurements in the sagittal, frontal, and transverse planes for walking, squatting, and jumping in healthy participants and those with anterior cruciate ligament (ACL) reconstruction. METHODS: Movement data were collected from 27 healthy participants and 20 participants with ACL reconstruction. In each case, the participants wore seven MTw2 IMUs (Xsens Technologies) to monitor their movement in walking, jumping, and squatting tasks. The hip, knee, and ankle joint angles were calculated in the sagittal, frontal, and transverse planes using two different software packages: Xsens' validated proprietary MVN Analyze and MoJoXlab. The results were validated by comparing the generated waveforms, cross-correlation (CC), and normalized root mean square error (NRMSE) values. RESULTS: Across all joints and activities, for data of both healthy and ACL reconstruction participants, the CC and NRMSE values for the sagittal plane are 0.99 (SD 0.01) and 0.042 (SD 0.025); 0.88 (SD 0.048) and 0.18 (SD 0.078) for the frontal plane; and 0.85 (SD 0.027) and 0.23 (SD 0.065) for the transverse plane (hip and knee joints only). On comparing the results from the two different software systems, the sagittal plane was very highly correlated, with frontal and transverse planes showing strong correlation. CONCLUSIONS: This study demonstrates that nonproprietary software such as MoJoXlab can accurately calculate joint angles for movement analysis applications comparable with proprietary software for walking, squatting, and jumping in healthy individuals and those following ACL reconstruction. MoJoXlab can be used with generic wearable IMUs that can provide clinicians accurate objective data when assessing patients' movement, even when changes are too small to be observed visually. The availability of easy-to-setup, nonproprietary software for calibration, data collection, and joint angle calculation has the potential to increase the adoption of wearable IMU sensors in clinical practice, as well as in free living conditions, and may provide wider access to accurate, objective assessment of patients' progress over time.


Assuntos
Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Dispositivos Eletrônicos Vestíveis , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Reprodutibilidade dos Testes
12.
JAMA Oncol ; 6(7): 1003-1010, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437507

RESUMO

Importance: Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported. Objective: To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab. Design, Setting, and Participants: In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites. Interventions: Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death. Main Outcomes and Measures: The primary end point was overall survival (OS). Results: A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). The MGMT promoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30); P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 [18.1%]; bevacizumab, 25/165 [15.2%]), with no unexpected neurological TRAEs or deaths due to TRAEs. Conclusions and Relevance: Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types. Trial Registration: ClinicalTrials.gov Identifier: NCT02017717.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Bevacizumab/efeitos adversos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/genética , Glioblastoma/mortalidade , Glioblastoma/radioterapia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Temozolomida/uso terapêutico , Resultado do Tratamento , Proteínas Supressoras de Tumor/genética , Adulto Jovem
13.
BMC Cancer ; 20(1): 198, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164579

RESUMO

BACKGROUND: Median survival for patients with glioblastoma is less than a year. Standard treatment consists of surgical debulking if feasible followed by temozolomide chemo-radiotherapy. The immune checkpoint inhibitor ipilimumab targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and has shown clinical efficacy in preclinical models of glioblastoma. The aim of this study is to explore the addition of ipilimumab to standard therapy in patients with glioblastoma. METHODS/DESIGN: Ipi-Glio is a phase II, open label, randomised study of ipilimumab with temozolomide (Arm A) versus temozolomide alone (Arm B) after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma. Planned accrual is 120 patients (Arm A: 80, Arm B: 40). Endpoints include overall survival, 18-month survival, 5-year survival, and adverse events. The trial is currently recruiting in seven centres in the United Kingdom. TRIAL REGISTRATION: ISRCTN84434175. Registered 12 November 2018.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Ipilimumab/administração & dosagem , Temozolomida/administração & dosagem , Adulto , Idoso , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Quimiorradioterapia , Procedimentos Cirúrgicos de Citorredução , Feminino , Glioblastoma/radioterapia , Glioblastoma/cirurgia , Humanos , Ipilimumab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Temozolomida/uso terapêutico , Resultado do Tratamento , Reino Unido , Adulto Jovem
14.
Br J Cancer ; 119(10): 1171-1181, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30393372

RESUMO

Glioblastoma is the most common primary malignant brain tumour. Survival is poor and improved treatment options are urgently needed. Although immunotherapies have emerged as effective treatments for a number of cancers, translation of these through to brain tumours is a distinct challenge, particularly due to the blood-brain barrier and the unique immune tumour microenvironment afforded by CNS-specific cells. This review discusses the immune system within the CNS, mechanisms of immune escape employed by glioblastoma, and the immunological effects of conventional glioblastoma treatments. Novel therapies for glioblastoma that harness the immune system and their current clinical progress are outlined, including cancer vaccines, T-cell therapies and immune checkpoint modulators.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/imunologia , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Humanos , Imunoterapia/métodos , Radioterapia/métodos , Procedimentos Cirúrgicos Operatórios , Resultado do Tratamento , Evasão Tumoral , Microambiente Tumoral/imunologia
15.
Lancet Oncol ; 19(9): 1170-1179, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30115593

RESUMO

BACKGROUND: Bevacizumab is frequently used in the treatment of recurrent WHO grade II and III glioma, but without supporting evidence from randomised trials. Therefore, we assessed the use of bevacizumab in patients with first recurrence of grade II or III glioma who did not have 1p/19q co-deletion. METHODS: The TAVAREC trial was a randomised, open-label phase 2 trial done at 32 centres across Europe in patients with locally diagnosed grade II or III glioma without 1p/19q co-deletion, with a first and contrast-enhancing recurrence after initial radiotherapy or chemotherapy, or both. Previous chemotherapy must have been stopped at least 6 months before enrolment and radiotherapy must have been stopped at least 3 months before enrolment. Random group assignment was done electronically through the European Organisation for Research and Treatment of Cancer web-based system, stratified by a minimisation procedure using institution, initial histology (WHO grade II vs III), WHO performance status (0 or 1 vs 2), and previous treatment (radiotherapy, chemotherapy, or both). Patients were assigned to receive either temozolomide (150-200 mg/m2, orally) monotherapy on days 1-5 every 4 weeks for a maximum of 12 cycles, or the same temozolomide regimen in combination with bevacizumab (10 mg/kg, intravenously) every 2 weeks until progression. The primary endpoint was overall survival at 12 months in the per-protocol population. Safety analyses were done in all patients who started their allocated treatment. The study is registered at EudraCT (2009-017422-39) and ClinicalTrials.gov (NCT01164189), and is complete. FINDINGS: Between Feb 8, 2011, and July 31, 2015, 155 patients were enrolled and randomly assigned to receive either monotherapy (n=77) or combination therapy (n=78). Overall survival in the per-protocol population at 12 months was achieved by 44 (61% [80% CI 53-69]) of 72 patients in the temozolomide group and 38 (55% [47-69]) of 69 in the combination group. The most frequent toxicity was haematological: 17 (23%) of 75 patients in the monotherapy group and 25 (33%) of 76 in the combination group developed grade 3 or 4 haematological toxicity. Other than haematological toxicities, the most common adverse events were nervous system disorders (59 [79%] of 75 patients in the monotherapy group vs 65 [86%] of 76 in the combination group), fatigue (53 [70%] vs 61 [80%]), and nausea (39 [52%] vs 43 [56%]). Infections were more frequently reported in the combination group (29 [38%] of 76 patients) than in the monotherapy group (17 [23%] of 75). One treatment-related death was reported in the combination group (infection after intratumoral haemorrhage during a treatment-related grade 4 thrombocytopenia). INTERPRETATION: We found no evidence of improved overall survival with bevacizumab and temozolomide combination treatment versus temozolomide monotherapy. The findings from this study provide no support for further phase 3 studies on the role of bevacizumab in this disease. FUNDING: Roche Pharmaceuticals.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia , Temozolomida/administração & dosagem , Adulto , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Deleção Cromossômica , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Esquema de Medicação , Europa (Continente) , Feminino , Glioma/genética , Glioma/mortalidade , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Temozolomida/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
16.
Neuro Oncol ; 20(12): 1634-1642, 2018 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-29788497

RESUMO

Background: GSK2256098 is a novel oral focal adhesion kinase (FAK) inhibitor. Preclinical studies demonstrate growth inhibition in glioblastoma cell lines. However, rodent studies indicate limited blood-brain barrier (BBB) penetration. In this expansion cohort within a phase I study, the safety, tolerability, pharmacokinetics (PK), and clinical activity of GSK2256098 were evaluated in patients with recurrent glioblastoma. Biodistribution and kinetics of [11C]GSK2256098 were assessed in a substudy using positron-emission tomography (PET). Methods: Patients were treated with GSK2256098 until disease progression or withdrawal due to adverse events (AEs). Serial PK samples were collected on day 1. On a single day between days 9 and 20, patients received a microdose of intravenous [11C]GSK2256098 and were scanned with PET over 90 minutes with parallel PK sample collection. Response was assessed by MRI every 6 weeks. Results: Thirteen patients were treated in 3 dose cohorts (1000 mg, 750 mg, 500 mg; all dosed twice daily). The maximum tolerated dose was 1000 mg twice daily. Dose-limiting toxicities were related to cerebral edema. Treatment-related AEs (>25%) were diarrhea, fatigue, and nausea. Eight patients participated in the PET substudy, with [11C]GSK2256098 VT (volume of distribution) estimates of 0.9 in tumor tissue, 0.5 in surrounding T2 enhancing areas, and 0.4 in normal brain. Best response of stable disease was observed in 3 patients, including 1 patient on treatment for 11.3 months. Conclusions: GSK2256098 was tolerable in patients with relapsed glioblastoma. GSK2256098 crossed the BBB at low levels into normal brain, but at markedly higher levels into tumor, consistent with tumor-associated BBB disruption. Additional clinical trials of GSK2256098 are ongoing.


Assuntos
Aminopiridinas/uso terapêutico , Radioisótopos de Carbono/farmacocinética , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Ácidos Hidroxâmicos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Adulto , Idoso , Aminopiridinas/farmacocinética , Estudos de Coortes , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Ácidos Hidroxâmicos/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Distribuição Tecidual , Adulto Jovem
17.
ACS Nano ; 12(2): 1156-1169, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29341587

RESUMO

The magnetic properties and safety of dextran-coated superparamagnetic iron oxide nanoparticles (SPIONs) have facilitated their clinical use as MRI contrast agents and stimulated research on applications for SPIONs in particle imaging and magnetic hyperthermia. The wider clinical potential of SPIONs, however, has been limited by their rapid removal from circulation via the reticuloendothelial system (RES). We explored the possibility of extending SPION circulatory time using fucoidan, a seaweed-derived food supplement, to inhibit RES uptake. The effects of fucoidan on SPION biodistribution were evaluated using ferucarbotran, which in its pharmaceutical formulation (Resovist) targets the RES. Ferucarbotran was radiolabeled at the iron oxide core with technetium-99m (99mTc; t1/2 = 6 h) or zirconium-89 (89Zr; t1/2 = 3.3 days). Results obtained with 99mTc-ferucarbotran demonstrated that administration of fucoidan led to a 4-fold increase in the circulatory half-life (t1/2 slow) from 37.4 to 150 min (n = 4; P < 0.0001). To investigate whether a longer circulatory half-life could lead to concomitant increased tumor uptake, the effects of fucoidan were tested with 89Zr-ferucarbotran in mice bearing syngeneic subcutaneous (GL261) tumors. In this model, the longer circulatory half-life achieved with fucoidan was associated with a doubling in tumor SPION uptake (n = 5; P < 0.001). Fucoidan was also effective in significantly increasing the circulatory half-life of perimag-COOH, a commercially available SPION with a larger hydrodynamic size (130 nm) than ferucarbotran (65 nm). These findings indicate successful diversion of SPIONs away from the hepatic RES and show realistic potential for future clinical applications.

18.
CNS Oncol ; 6(4): 291-296, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28984141

RESUMO

BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Adolescente , Neoplasias Encefálicas/genética , Feminino , Glioma/genética , Humanos , Imidazóis/administração & dosagem , Pessoa de Meia-Idade , Mutação , Oximas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem
19.
CNS Oncol ; 6(1): 5-9, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27781490

RESUMO

Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor. Anaplastic features are found in 20-30% of cases of PXA and are associated with poor outcomes. Typical treatment is with gross total resection, followed by radiation therapy and cytotoxic chemotherapy at relapse. BRAFV600 mutations have been identified in 38-60% of patients with PXA. Several case reports and small case series have identified clinical benefit with BRAF inhibition in patients with BRAFV600-mutated PXA. We report the second published case of successful treatment with the BRAF inhibitor dabrafenib in a female patient with relapsed anaplastic PXA with a BRAFV600 mutation, and the first published case of dabrafinib treatment following intolerance to vemurafenib.


Assuntos
Antineoplásicos/uso terapêutico , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Imidazóis/uso terapêutico , Mutação/genética , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Adulto Jovem
20.
Cancer Cell ; 30(4): 578-594, 2016 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-27693047

RESUMO

Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioma/enzimologia , Isocitrato Desidrogenase/biossíntese , Ventrículos Laterais/enzimologia , Células-Tronco Neoplásicas/enzimologia , Nicho de Células-Tronco , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Metilação de DNA , Glioma/genética , Glioma/patologia , Isocitrato Desidrogenase/genética , Ventrículos Laterais/patologia , Camundongos , Camundongos Transgênicos , Mutação , Células-Tronco Neoplásicas/patologia , Transcriptoma
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