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Correlation of MicroRNA 132 Up-regulation with an Unfavorable Clinical Outcome in Patients with Primary Glioblastoma Multiforme Treated with Radiotherapy Plus Concomitant and Adjuvant Temozolomide Chemotherapy.

ABSTRACT: BACKGROUND:MicroRNA 132 (miR-132) is dysregulated in a range of human malignancies; however, its role in glioma has not been reported. The aim of this study was to profile miR-132 expression in a cohort of patients with primary glioblastoma multiforme (GBM) treated with the Stupp regimen and to correlate microRNA levels with patient outcome. METHODS:miR-132 levels relative to RNU44 were assessed by quantitative reverse transcription-polymerase chain reaction in 43 GBMs and normal brain tissue. The cohort comprised patients less than 72 years of age with Eastern Cooperative Oncology Group (ECOG) scores between 0 and 2 who had undergone 6-week concomitant radiation and temozolomide followed by adjuvant temozolomide. Survival data were available for all cases. Tumors were characterized for O6-methylguanine-DNA methyltransferase (MGMT) methylation and isocitrate dehydrogenase (IDH) 1/2 mutation status. Associations between miR-132 expression and clinical indicators were analyzed. RESULTS:Tumor miR-132 levels ranged from 0.07- to 40.4-fold increase (mean = 5.5-fold increase) relative to normal brain. High-level miR-132 (above the mean) independently predicted for a significantly shorter overall survival (P = .008). miR-132 was a stronger prognostic indicator than ECOG score (P = .012) and age at diagnosis (P = .026) but did not correlate with MGMT methylation status or extent of tumor resection. Cox regression analysis confirmed high miR-132 as the strongest predictor of outcome (P = .010) with a hazard ratio of 2.8. CONCLUSIONS:This study identified high miR-132 expression as a biomarker of poor prognosis in patients with primary GBM treated with the Stupp regimen.

SUBMITTER: Parker NR

PROVIDER: S-EPMC3890709 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Correlation of MicroRNA 132 Up-regulation with an Unfavorable Clinical Outcome in Patients with Primary Glioblastoma Multiforme Treated with Radiotherapy Plus Concomitant and Adjuvant Temozolomide Chemotherapy.

Parker Nicole R NR Correia Nelson N Crossley Brendan B Buckland Michael E ME Howell Viive M VM Wheeler Helen R HR

Translational oncology 20131201 6

<h4>Background</h4>MicroRNA 132 (miR-132) is dysregulated in a range of human malignancies; however, its role in glioma has not been reported. The aim of this study was to profile miR-132 expression in a cohort of patients with primary glioblastoma multiforme (GBM) treated with the Stupp regimen and to correlate microRNA levels with patient outcome.<h4>Methods</h4>miR-132 levels relative to RNU44 were assessed by quantitative reverse transcription-polymerase chain reaction in 43 GBMs and normal ...[more]

PMID: 24466377

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Project description:PurposeThe survival times of glioblastoma (GB) patients after the standard therapy including safe maximal resection followed by radiotherapy plus concomitant and adjuvant temozolomide are heterogeneous. In order to define a simple, reliable method for predicting whether patients with isocitrate dehydrogenase (IDH)-wildtype GB treated with the standard therapy will be short- or long-term survivors, we analyzed the correlation of preoperative blood counts and their combined forms with progression-free survival (PFS) and overall survival (OS) in these patients.MethodsEighty-five patients with primary IDH-wildtype GB treated with the standard therapy between 2012 and 2019 were analyzed retrospectively. Cox proportional hazards models and Kaplan-Meier analysis were used to investigate the survival function of preoperative hematological parameters.ResultsPreoperative high neutrophil-to-lymphocyte ratio (NLR, >2.42), high platelet count (>236 × 109/L), and low red blood cell (RBC) count (≤4.59 × 1012/L) were independent prognostic factors for poorer OS (p = 0.030, p = 0.030, and p = 0.004, respectively). Moreover, a high NLR was an independent prognostic factor for shorter PFS (p = 0.010). We also found that, like NLR, preoperative high derived NLR (dNLR, >1.89) was of poor prognostic value for both PFS (p = 0.002) and OS (p = 0.033). A significant correlation was observed between NLR and dNLR (r = 0.88, p < 0.001), which had a similar prognostic power for OS (NLR: AUC = 0.58; 95% CI: [0.48; 0.68]; dNLR: AUC = 0.62; 95% CI: [0.51; 0.72]). Two scores, one based on preoperative platelet and RBC counts plus NLR and the other on preoperative platelet and RBC counts plus dNLR, were found to be independent prognostic factors for PFS (p = 0.006 and p = 0.002, respectively) and OS (p < 0.001 for both scores).ConclusionCheap, routinely ordered, preoperative assessments of blood markers, such as NLR, dNLR, RBC, and platelet counts, can predict the survival outcomes of patients with IDH-wildtype GB treated with the standard therapy.

Project description:The optimization of the management for elderly glioblastoma patients is crucial given the demographics of aging in many countries. We report the outcomes for a "real-life" patient cohort (i.e. unselected) comprising consecutive glioblastoma patients aged 70 years or more, treated with different radiotherapy +/- temozolomide regimens.From 2003 to 2016, 104 patients ??70 years of age, consecutively treated by radiotherapy for glioblastoma, were included in this study. All patients were diagnosed with IDH-wild type glioblastoma according to pathological criteria.Our patient cohort comprised 51 female patients (49%) and 53 male. The median cohort age was 75 years (70-88), and the median Karnofsky performance status (KPS) was 70 (30-100). Five (5%) patients underwent macroscopic complete resection, 9 (9%) had partial resection, and 90 (86%), a stereotactic biopsy. The MGMT promoter was methylated in 33/73 cases (45%). Fifty-two (50%), 38 (36%), and 14 (14%) patients were categorized with RPA scores of III, IV, and I-II. Thirty-three (32%) patients received normofractionated radiotherapy (60 Gy, 30 sessions) with temozolomide (Stupp), 37 (35%) received hypofractionated radiotherapy (median dose 40 Gy, 15 sessions) with temozolomide (HFRT?+?TMZ), and 34 (33%) HFRT alone. Patients receiving only HFRT were significantly older, with lower KPSs. The median overall survival (OS; all patients) was 5.2 months. OS rates at 12, 18, and 24 months, were 19%, 12%, and 5%, respectively, with no statistical differences between patients receiving Stupp or HFRT?+?TMZ (P?=?0.22). In contrast, patients receiving HFRT alone manifested a significantly shorter survival time (3.9 months vs. 5.9 months, P?=?0.018). In multivariate analyses, the prognostic factors for OS were: i) the type of surgery (HR: 0.47 [0.26-0.86], P?=?0.014), ii) RPA class (HR: 2.15 [1.17-3.95], P?=?0.014), and iii) temozolomide use irrespective of radiotherapy schedule (HR: 0.54 [0.33-0.88], P?<?0.02). MGMT promoter methylation was neither a prognostic nor a predictive factor.These outcomes agree with the literature in terms of optimal surgery and the use of HFRT as a standard treatment for elderly GBM patients. Our study emphasizes the potential benefit of using temozolomide with radiotherapy in a real-life cohort of elderly GBM patients, irrespective of their MGMT status.

Project description:PurposeDespite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557).MethodsSixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 μg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed.ResultsSurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients.ConclusionSurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.

Project description:Introduction Patients with glioblastoma multiforme (GBM) over age 65 represent nearly half of those diagnosed per annum. They have a different tumor markers profile, physiologic reserve, and a median survival as low as three to four months. An optimal treatment strategy in older GBM patients remains undefined, with many patients receiving radiation in 30 treatments over six weeks, a regimen based on trials originally excluding patients over age 70. Recent studies have suggested reducing the number of treatments to 10-15 over two to three weeks with similar efficacy. We present an elderly population of patients treated with six radiation treatments. Methods After IRB approval, we reviewed the electronic medical records of 20 consecutive patients over the age 60 at diagnosis with GBM, treated with maximally safe neurosurgical resection, and adjuvant hypofractionated radiation (HFRT) and temozolomide (TMZ) between 2012 and 2015. HFRT was given every other weekday for two weeks, in a total of six fractions (6 × 6 Gy to contrast-enhancing tumor +5 mm and 6 × 4 Gy to fluid-attenuated inversion recovery (FLAIR) +2 cm) with concurrent TMZ (75 mg/m2 daily), followed by adjuvant TMZ (150-200 mg/m2 in 5/28 days). The response was assessed using the Macdonald and Revised Assessment in Neuro-Oncology (RANO) criteria, radiology reports, physician notes, and tumor board consensus notes. Descriptive statistics, overall survival (OS), progression-free survival (PFS), toxicity, and steroid use were calculated and compared to the historical controls of patients treated with a six-week radiation regimen of 60 Gy in 30 fractions with TMZ. Results The median age at diagnosis was 70.5 years (range: 61 - 82 years). Median pre-radiation Karnofsky performance scale (KPS) was 60 (range: 40 - 90). The median preoperative maximum gross tumor diameter on MRI was 3.6 cm (range: 1.8 - 6 cm). Six patients (30%) had a gross total resection (GTR), eight (40%) had a subtotal resection (STR), and six (30%) had biopsy only. The median progression-free survival was five months (95% (confidence interval) CI: 2.8, 16.4) and median OS of 14 months (95% CI: 5.0, upper limit not estimable). Of the 19 patients tested for isocitrate dehydrogenase-1 (IDH), 100% were negative. Of the eight patients who had MGMT methylation status results, four (50%) were positive for O6-methylguanine-DNA methyltransferase (MGMT) methylation. In the 18 patients who completed radiation, the HFRT treatment was well tolerated without any Grade 3/4 acute toxicities. Conclusions The accelerated adjuvant course of HFRT with TMZ used for the elderly with GBM decreases radiation treatment days to six. It was well tolerated in patients over 60 years of age and provided similar OS, PFS, minimal toxicity, and decreased steroid usage compared to historical controls treated with six or even two to three weeks of radiotherapy.

Dataset Information

Correlation of MicroRNA 132 Up-regulation with an Unfavorable Clinical Outcome in Patients with Primary Glioblastoma Multiforme Treated with Radiotherapy Plus Concomitant and Adjuvant Temozolomide Chemotherapy.

Publications

Correlation of MicroRNA 132 Up-regulation with an Unfavorable Clinical Outcome in Patients with Primary Glioblastoma Multiforme Treated with Radiotherapy Plus Concomitant and Adjuvant Temozolomide Chemotherapy.

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