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Background: Glioblastoma (GBM), the most common malignant brain tumor, is associated with devastating outcomes. IPAX-1 was a multicenter, open-label, single-arm phase I study to evaluate carrier-added 4-L-[131I]iodo-phenylalanine ([131I]IPA) plus external radiation therapy (XRT) in recurrent GBM. Methods: A total of 10 adults with recurrent GBM who had received first-line debulking surgery plus radio-chemotherapy, were randomized to a single-dose regimen (1f; 131I-IPA 2 GBq before XRT); a fractionated parallel dose regimen (3f-p; 3 131I-IPA 670 MBq fractions, in parallel with second-line XRT), or a fractionated sequential dose regimen (3f-s; 3 131I-IPA 670 MBq fractions before and after XRT). Metabolic tumor responses were determined using O-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography, while single-photon emission computed tomography was used to guide [131I]IPA tumor dosimetry. Results: All dose regimens were well tolerated. Organ-absorbed radiation doses in red marrow (0.38 Gy) and kidney (1.28 Gy) confirmed no radiation-based toxicity. Stable disease was observed in 4 of the 9 patients at 3 months post-treatment (3-month follow-up [FU], 1 patient did not reach protocol-mandated end of study), yielding a response rate of 44.4%. At the 3-month FU, 6 patients demonstrated metabolic stable disease. Median progression-free survival was 4.3 months (95% confidence interval [CI]: 3.3-4.5), while median overall survival was 13 months (95% CI: 7.1-27). Conclusions: Single or fractionated doses of [131I]IPA plus XRT were associated with acceptable tolerability and specific tumor targeting in patients with recurrent GBM, warranting further investigation.
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PURPOSE: We present results of a retrospective population-based investigation of patterns of care and outcome of glioblastoma patients in Austria. PATIENTS AND METHODS: In this nation-wide cooperative project, all Austrian glioblastoma patients newly diagnosed between 2014 and 2018 and registered in the ABTR-SANOnet database were included. Histological typing used criteria of the WHO classification of CNS tumors, 4th edition 2016. Patterns of care were assessed, and all patients were followed until the end of 2019. RESULTS: 1,420 adult glioblastoma cases were identified. 813 (57.3%) patients were male and 607 (42.7%) female. Median age at diagnosis was 64 years (range: 18-88). Median overall survival (OS) was 11.6 months in the total cohort and 10.9 months in patients with proven IDH-wildtype. Median OS in the patient group ≤ 65 years receiving postoperative standard of care therapy was 16.1 months. In the patient group > 65 years with postoperative therapy, median OS was 11.2 months. Follow-up ≥ 5 years identified 13/264 (4.9%) long-term survivors. Brain tumor surgery frequently was assisted by 5-aminolevulinic acid (5-ALA) fluorescence (up to 55%). Postoperative treatment was initiated around one month after surgery (median: 31 days) following standardized protocols in 1,041/1,420 (73.3%) cases. In 830 patients (58.5%), concomitant radiochemotherapy was started according to the established standard of care. Treatment in case of progressive disease was considerably variable. 170/1,420 patients (12.0%) underwent a second surgical procedure, 467 (33.0%) received systemic treatment after progression, and 173 (12.2%) were re-irradiated. CONCLUSION: Our data illustrate and confirm nation-wide translation of effective standard of care to Austrian glioblastoma patients in the recent past. In the case of progressive disease, highly variable therapeutic approaches were used, most frequently accompanied by anti-angiogenic therapy. Long-term survival was observed in a minor proportion of mostly younger patients who typically had gross total tumor resection, a favorable postoperative ECOG score, and standard of care therapy.
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BACKGROUND AND OBJECTIVES: In high-grade glioma (HGG) surgery, intraoperative MRI (iMRI) has traditionally been the gold standard for maximizing tumor resection and improving patient outcomes. However, recent Level 1 evidence juxtaposes the efficacy of iMRI and 5-aminolevulinic acid (5-ALA), questioning the continued justification of iMRI because of its associated costs and extended surgical duration. Nonetheless, drawing from our clinical observations, we postulated that a subset of intricate HGGs may continue to benefit from the adjunctive application of iMRI. METHODS: In a prospective study of 73 patients with HGG, 5-ALA was the primary technique for tumor delineation, complemented by iMRI to detect residual contrast-enhanced regions. Suboptimal 5-ALA efficacy was defined when (1) iMRI detected contrast-enhanced remnants despite 5-ALA's indication of a gross total resection or (2) surgeons observed residual fluorescence, contrary to iMRI findings. Radiomic features from preoperative MRIs were extracted using a U2-Net deep learning algorithm. Binary logistic regression was then used to predict compromised 5-ALA performance. RESULTS: Resections guided solely by 5-ALA achieved an average removal of 93.14% of contrast-enhancing tumors. This efficacy increased to 97% with iMRI integration, albeit not statistically significant. Notably, for tumors with suboptimal 5-ALA performance, iMRI's inclusion significantly improved resection outcomes (P-value: .00013). The developed deep learning-based model accurately pinpointed these scenarios, and when enriched with radiomic parameters, showcased high predictive accuracy, as indicated by a Nagelkerke R2 of 0.565 and a receiver operating characteristic of 0.901. CONCLUSION: Our machine learning-driven radiomics approach predicts scenarios where 5-ALA alone may be suboptimal in HGG surgery compared with its combined use with iMRI. Although 5-ALA typically yields favorable results, our analyses reveal that HGGs characterized by significant volume, complex morphology, and left-sided location compromise the effectiveness of resections relying exclusively on 5-ALA. For these intricate cases, we advocate for the continued relevance of iMRI.
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Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing.
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Big Data , Glioblastoma , Humanos , Aprendizado de Máquina , Doenças Raras , Disseminação de InformaçãoRESUMO
PURPOSE: The treatment of oligodendroglioma consists of tumor resection and radiochemotherapy. The timing of radiochemotherapy remains unclear, and predictive biomarkers are limited. EXPERIMENTAL DESIGN: Adult patients diagnosed with isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted CNS WHO grade 2 and 3 oligodendroglioma at the Medical University of Vienna and the Kepler University Hospital Linz (Austria) in 1992 to 2019 were included. Progression-free (PFS) and overall survival (OS) between early postoperative treatment and initial observation were compared using propensity score-weighted Cox regression models. DNA methylation analysis of tumor tissue was performed using Illumina MethylationEPIC 850k microarrays. RESULTS: One hundred thirty-one out of 201 (65.2%) patients with CNS WHO grade 2 and 70 of 201 (34.8%) with grade 3 oligodendroglioma were identified. Eighty-three of 201 (41.3%) patients underwent early postoperative treatment, of whom 56 of 83 (67.5%) received radiochemotherapy, 15 of 84 (18.1%) radiotherapy (RT) only and 12 of 83 (14.5%) chemotherapy only. Temozolomide-based treatment was administered to 64 of 68 (94.1%) patients, whereas RT + procarbazine, lomustine (CCNU), and vincristine (PCV) were applied in 2 of 69 (3.5%) patients. Early treatment was not associated with PFS [adjusted hazard ratio (HR) 0.74; 95% CI, 0.33-1.65, P = 0.459] or OS (adjusted HR: 2.07; 95% CI, 0.52-8.21, P = 0.302) improvement. Unsupervised clustering analysis of DNA methylation profiles from patients receiving early treatment revealed two methylation clusters correlating with PFS, whereas no association of clustering with O6-methylguanine methyltransferase (MGMT) promoter methylation, CNS WHO grade, extent of resection, and treating center could be observed. CONCLUSIONS: In this retrospective study, early postoperative treatment was not associated with improved PFS/OS in oligodendroglioma. The potentially predictive value of whole-genome methylation profiling should be validated in prospective trials.
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Neoplasias Encefálicas , Oligodendroglioma , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Metilação de DNA , Humanos , Isocitrato Desidrogenase/genética , Lomustina , Metiltransferases/genética , Oligodendroglioma/genética , Oligodendroglioma/cirurgia , Procarbazina/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Temozolomida/uso terapêutico , Vincristina , Organização Mundial da SaúdeRESUMO
Introduction: In this post hoc analysis we compared various response-assessment criteria in newly diagnosed glioblastoma (GB) patients treated with tumor lysate-charged autologous dendritic cells (Audencel) and determined the differences in prediction of progression-free survival (PFS) and overall survival (OS). Methods: 76 patients enrolled in a multicenter phase II trial receiving standard of care (SOC, n = 40) or SOC + Audencel vaccine (n = 36) were included. MRI scans were evaluated using MacDonald, RANO, Vol-RANO, mRANO, Vol-mRANO and iRANO criteria. Tumor volumes (T1 contrast-enhancing as well as T2/FLAIR volumes) were calculated by semiautomatic segmentation. The Kruskal-Wallis-test was used to detect differences in PFS among the assessment criteria; for correlation analysis the Spearman test was used. Results: There was a significant difference in median PFS between mRANO (8.6 months) and Vol-mRANO (8.6 months) compared to MacDonald (4.0 months), RANO (4.2 months) and Vol-RANO (5.4 months). For the vaccination arm, median PFS by iRANO was 6.2 months. There was no difference in PFS between SOC and SOC + Audencel. The best correlation between PFS/OS was detected for mRANO (r = 0.65) and Vol-mRANO (r = 0.69, each p < 0.001). A total of 16/76 patients developed a pure T2/FLAIR progressing disease, and 4/36 patients treated with Audencel developed pseudoprogression. Conclusion: When comparing different response-assessment criteria in GB patients treated with dendritic cell-based immunotherapy, the best correlation between PFS and OS was observed for mRANO and Vol-mRANO. Interestingly, iRANO was not superior for predicting OS in patients treated with Audencel.
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INTRODUCTION: Adult brainstem gliomas (BSGs) are rare central nervous system tumours characterized by a highly heterogeneous clinical course. Median survival times range from 11 to 84 months. Beyond surgery, no treatment standard has been established. We investigated clinical and radiological data to assess prognostic features providing support for treatment decisions. METHODS: 34 BSG patients treated between 2000 and 2019 and aged ≥ 18 years at the time of diagnosis were retrospectively identified from the databases of the two largest Austrian Neuro-Oncology centres. Clinical data including baseline characteristics, clinical disease course, applied therapies, the outcome as well as neuroradiological and neuropathological findings were gathered and analysed. The tumour apparent diffusion coefficient (ADC), volumetry of contrast-enhancing and non-contrast-enhancing lesions were determined on magnetic resonance imaging scans performed at diagnosis. RESULTS: The median age at diagnosis was 38.5 years (range 18-71 years). Tumour progression occurred in 26/34 (76.5%) patients after a median follow up time of 19 months (range 0.9-236.2). Median overall survival (OS) and progression-free survival (PFS) was 24.1 months (range 0.9-236.2; 95% CI 18.1-30.1) and 14.5 months (range 0.7-178.5; 95% CI 5.1-23.9), respectively. Low-performance status, high body mass index (BMI) at diagnosis and WHO grading were associated with shorter PFS and OS at univariate analysis (p < 0.05, log rank test, respectively). ADC values below the median were significantly associated with shorter OS (14.9 vs 44.2 months, p = 0.018). CONCLUSION: ECOG, BMI, WHO grade and ADC values were associated with the survival prognosis of BSG patients and should be included in the prognostic assessment.
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Neoplasias Encefálicas , Glioma , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/patologia , Tronco Encefálico/patologia , Glioma/diagnóstico por imagem , Glioma/terapia , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto JovemRESUMO
BACKGROUND: No systemic treatment has been established for meningioma progressing after local therapies. METHODS: This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. RESULTS: Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. CONCLUSIONS: Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.
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Neoplasias Encefálicas , Neoplasias Meníngeas , Meningioma , Adulto , Neoplasias Encefálicas/induzido quimicamente , Neoplasias Encefálicas/tratamento farmacológico , Intervalo Livre de Doença , Humanos , Neoplasias Meníngeas/tratamento farmacológico , Meningioma/tratamento farmacológico , Qualidade de Vida , Trabectedina/efeitos adversos , Trabectedina/uso terapêutico , Organização Mundial da SaúdeRESUMO
Background: Primary CNS lymphoma is a highly aggressive and rare type of extranodal non-Hodgkin lymphoma. Although, new therapeutic approaches have led to improved survival, the management of the disease poses a challenge, practice patterns vary across institutions and countries, and remain ill-defined for vulnerable patient subgroups. Material and Methods: Using information from the Austrian Brain Tumor Registry we followed a population-based cohort of 189 patients newly diagnosed from 2005 to 2010 through various lines of treatment until death or last follow-up (12-31-2016). Prognostic factors and treatment-related data were integrated in a comprehensive survival analysis including conditional survival estimates. Results: We find variable patterns of first-line treatment with increasing use of rituximab and high-dose methotrexate (HDMTX)-based poly-chemotherapy after 2007, paralleled by an increase in median overall survival restricted to patients aged below 70 years. In the entire cohort, 5-year overall survival was 24.4% while 5-year conditional survival increased with every year postdiagnosis. Conclusion: In conclusion, we show that the use of poly-chemotherapy and immunotherapy has disseminated to community practice to a fair extent and survival has increased over time at least in younger patients. Annually increasing conditional survival rates provide clinicians with an adequate and encouraging prognostic measure.
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Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Adolescente , Adulto , Idoso , Áustria/epidemiologia , Neoplasias Encefálicas/mortalidade , Feminino , Seguimentos , Humanos , Linfoma não Hodgkin/mortalidade , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Sistema de Registros/estatística & dados numéricos , Rituximab/uso terapêutico , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. PATIENTS AND METHODS: TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. RESULTS: Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69-1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48-1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37-1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52-1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). CONCLUSION: There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. IMPLICATIONS FOR PRACTICE: Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.
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Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Neoplasias Encefálicas/patologia , Método Duplo-Cego , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de SobrevidaRESUMO
Dendritic cells (DCs) are antigen-presenting cells that are capable of priming anti-tumor immune responses, thus serving as attractive tools to generate tumor vaccines. In this multicentric randomized open-label phase II study, we investigated the efficacy of vaccination with tumor lysate-charged autologous DCs (Audencel) in newly diagnosed glioblastoma multiforme (GBM). Patients aged 18 to 70 years with histologically proven primary GBM and resection of at least 70% were randomized 1:1 to standard of care (SOC) or SOC plus vaccination (weekly intranodal application in weeks seven to 10, followed by monthly intervals). The primary endpoint was progression-free survival at 12 months. Secondary endpoints were overall survival, safety, and toxicity. Seventy-six adult patients were analyzed in this study. Vaccinations were given for seven (3â»20) months on average. No severe toxicity was attributable to vaccination. Seven patients showed flu-like symptoms, and six patients developed local skin reactions. Progression-free survival at 12 months did not differ significantly between the control and vaccine groups (28.4% versus 24.5%, p = 0.9975). Median overall survival was similar with 18.3 months (vaccine: 564 days, 95% CI: 436â»671 versus control: 568 days, 95% CI: 349â»680; p = 0.89, harzard ratio (HR) 0.99). Hence, in this trial, the clinical outcomes of patients with primary GBM could not be improved by the addition of Audencel to SOC.
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Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.
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Metilação de DNA/genética , Genoma Humano/genética , Glioblastoma/genética , Recidiva Local de Neoplasia/genética , Mapeamento Cromossômico , Progressão da Doença , Epigênese Genética , Feminino , Heterogeneidade Genética , Glioblastoma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Recidiva Local de Neoplasia/patologiaRESUMO
Background: Meningiomas are mostly benign tumors tending to progress to higher-grade lesions. Mutations in the telomerase reverse transcriptase (TERT) gene promoter are comparably rare in meningioma, but were recently suggested to predict risk of recurrence and progression. Here we have analyzed a cohort of World Health Organization grades I-III meningiomas regarding the impact of TERT promoter mutations on patient prognosis and in vitro cell propagation feasibility. Methods: From 110 meningioma patients, 128 tissue samples were analyzed for the TERT promoter mutations C228T and C250T by direct sequencing. Of the 128 samples, 121 were tested for cell propagation in vitro. Telomerase activity, TERT mRNA expression, and telomere lengths were investigated by telomeric repeat amplification protocol assay, reverse transcription PCR, and quantitative PCR, respectively. Impact of the E-twenty-six (ETS) transcription factor inhibitor YK-4-279 on cell viability and TERT promoter activity was analyzed. Results: TERT promoter mutations were found in 5.5% of all samples analyzed and were associated with a significantly upregulated telomerase activity and TERT mRNA expression (P < 0.0001 both). Regarding telomere lengths, no significant difference between the TERT promoter wild-type and mutated subgroups was detected. Patients with TERT promoter mutated tumors exhibited significantly shorter overall survival (P = 0.0006; 53.8 vs 115.6 mo). The presence of TERT promoter mutations but not telomerase activity or TERT mRNA expression predicted indefinite cell growth in vitro. TERT promoter mutated meningioma cells were hypersensitive against the ETS transcription factor inhibitor YK-4-279, inducing a distinct downregulation of TERT promoter activity. Conclusion: TERT promoter mutations drive meningioma aggressiveness, resulting in reduced patient survival, but might also open novel therapeutic options for progressive disease.
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Biomarcadores Tumorais/genética , Neoplasias Meníngeas/patologia , Meningioma/patologia , Mutação , Recidiva Local de Neoplasia/patologia , Regiões Promotoras Genéticas , Telomerase/genética , Linhagem Celular Transformada , Seguimentos , Humanos , Indóis , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/cirurgia , Meningioma/genética , Meningioma/cirurgia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
BACKGROUND: Expression of the telomerase reverse transcriptase (TERT) might be altered by activating mutations of the rs2853669 polymorphism within the promoter region. Here we investigate the impact of these genomic alterations on telomerase activation and dissect their prognostic potential in glioblastoma (GBM). METHODS: The respective TERT promoter region was sequenced in 126 GBM tissues and compared with clinical parameters and glioma biomarkers MGMT promoter methylation and IDH1 mutation. TERT mRNA expression, telomerase activity, and telomere lengths were determined by reverse transcriptase PCR, TRAP assay, and real-time PCR, respectively. RESULTS: Seventy-three percent of GBM patients harbored TERT promoter mutations associated with enhanced telomerase activity and TERT mRNA expression but reduced telomere lengths (P < .001 for all). Patients with mutated tumors exhibited significantly shorter overall survival in the entire cohort (11.5 vs 23.1 months; P < .0001) and in the primary GBM patient subgroup lacking IDH1 mutations (n = 120; P = .0084). This prognostic impact was confined to younger patients (aged <65 years), while the negative prognostic power of enhanced age at diagnosis was limited to those patients lacking TERT promoter mutations. Presence of the common single nucleotide polymorphism rs2853669, disrupting an endogenous Ets2 transcription factor-binding site, was associated with improved survival exclusively in patients with a wild-type TERT promoter. On the contrary, the shortest mean overall survival was detected in those patients harboring both an activating TERT promoter mutation and homozygous rs2853669 alleles. CONCLUSION: In summary, TERT promoter mutations are powerful prognosticators for worse course of disease in human GBM patients but their prognostic value is influenced by the rs2853669 polymorphism and age at diagnosis.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Glioblastoma/diagnóstico , Glioblastoma/genética , Telomerase/genética , Fatores Etários , Idoso , Biomarcadores Tumorais , Neoplasias Encefálicas/mortalidade , Intervalo Livre de Doença , Feminino , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Regiões Promotoras GenéticasRESUMO
PURPOSE: Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RTâTMZ) has been studied in retrospective and single-arm prospective studies, applying temozolomide continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen. EXPERIMENTAL DESIGN: Patients with glioblastoma at first progression after TMZ/RTâTMZ and at least two maintenance temozolomide cycles were randomized to Arm A [one week on (120 mg/m(2) per day)/one week off] or Arm B [3 weeks on (80 mg/m(2) per day)/one week off]. The primary endpoint was median time-to-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR. RESULTS: Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome in both arms for median TTF [A: 1.8 months; 95% confidence intervals (CI), 1.8-3.2 vs. B: 2.0 months; 95% CI, 1.8-3.5] and overall survival [A: 9.8 months (95% CI, 6.7-13.0) vs. B: 10.6 months (95% CI, 8.1-11.6)]. Median TTF in patients with MGMT-methylated tumors was 3.2 months (95% CI, 1.8-7.4) versus 1.8 months (95% CI, 1.8-2) in MGMT-unmethylated glioblastoma. Progression-free survival rates at 6 months (PFS-6) were 39.7% with versus 6.9% without MGMT promoter methylation. CONCLUSIONS: Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation.
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Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/genética , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina/análogos & derivados , Glioblastoma/genética , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética , Adulto , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Metilação de DNA/genética , Dacarbazina/administração & dosagem , Intervalo Livre de Doença , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Regiões Promotoras Genéticas/genética , Modelos de Riscos Proporcionais , Temozolomida , Adulto JovemRESUMO
AIM: We aimed to characterize angiogenesis and proliferation and their correlation with clinical characteristics in a large brain metastasis (BM) series. METHODS: Ki67 proliferation index, microvascular density (MVD) and hypoxia-inducible factor 1 alpha (HIF-1 alpha) index were determined by immunohistochemistry in BM and primary tumour specimens. RESULTS: Six hundred thirty-nine BM specimens of 639 patients with lung cancer (344/639; 53.8%), breast cancer (105/639; 16.4%), melanoma (67/639; 10.5%), renal cell carcinoma (RCC; 52/639; 8.1%) or colorectal cancer (CRC; 71/639; 11.1%) were available. Specimens of the corresponding primary tumour were available in 113/639 (17.7%) cases. Median Ki67 index was highest in CRC BM and lowest in RCC BM (P < 0.001). MVD and HIF-1 alpha index were both highest in RCC BM and lowest in melanoma BM (P < 0.001). Significantly higher Ki67 indices, MVD and HIF-1 alpha indices in the BM than in matched primary tumours were observed for breast cancer, non-small cell lung cancer (NSCLC) and CRC. Correlation of tissue-based parameters with overall survival in individual tumour types showed a favourable and independent prognostic impact of low Ki67 index [hazard ratio (HR) 1.015; P < 0.001] in NSCLC BM and of low Ki67 index (HR 1.027; P = 0.008) and high angiogenic activity (HR 1.877; P = 0.002) in RCC. CONCLUSION: Our data argue for differential pathobiological and clinical relevance of Ki67 index, HIF1-alpha index and MVD between primary tumour types in BM patients. An independent prognostic impact of tissue-based characteristics was observed in patients with BM from NSCLC and RCC, supporting the incorporation of these tissue-based parameters into diagnosis-specific prognostic scores.
Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Neovascularização Patológica/mortalidade , Neovascularização Patológica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Proliferação de Células , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Antígeno Ki-67/análise , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Modelos de Riscos ProporcionaisRESUMO
PURPOSE: Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)-binding fusion protein, in glioblastoma. EXPERIMENTAL DESIGN: Patients (N = 91) with glioblastoma at first or second progression were randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N = 84 (26 patients rRT, 58 patients rRT+APG101)] were balanced. RESULTS: Progression-free survival at 6 months (PFS-6) rates were 3.8% [95% confidence interval (CI), 0.1-19.6] for rRT and 20.7% (95% CI, 11.2-33.4) for rRT+APG101 (P = 0.048). Median PFS was 2.5 (95% CI, 2.3-3.8) months and 4.5 (95% CI, 3.7-5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27-0.88; P = 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36-1.01; P = 0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06-0.58) for treatment with APG101, suggesting a potential biomarker. CONCLUSIONS: CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker.
Assuntos
Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptor fas/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores , Terapia Combinada , Esquema de Medicação , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prognóstico , Qualidade de Vida , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Resultado do Tratamento , Carga Tumoral , Adulto Jovem , Receptor fas/administração & dosagem , Receptor fas/efeitos adversosRESUMO
Glioblastoma has a poor prognosis accompanied by debilitating neurological symptoms and impaired quality of life. Effective treatment strategies are needed, beyond the current standard of care (SOC), to improve outcomes. Glioblastomas are highly vascularized with elevated levels of VEGF, representing an appropriate target for selective therapies. The role of the anti-VEGF agent bevacizumab in newly diagnosed and recurrent glioblastoma is not fully clear at this time. Although bevacizumab has demonstrated improvements in progression-free survival in newly diagnosed and recurrent glioblastoma, there remain challenges in assessing disease progression after antiangiogenic treatment. The bevacizumab mechanism of action suggests a rationale for continuing bevacizumab treatment through multiple lines of therapy, strengthened by longer progression-free and overall survival observed with bevacizumab continuation beyond progression in a Phase III study in metastatic colorectal cancer and in pooled analyses of Phase II trials in glioblastoma. A novel study (randomized, double-blind, Phase IIIb; TAMIGA [MO28347]) aims to evaluate whether continuing bevacizumab plus lomustine (as second-line therapy) and SOC (third line and beyond) improves survival compared with placebo plus lomustine and then placebo plus SOC in patients with glioblastoma who progressed after first-line bevacizumab plus SOC.