Mesenchymal stem cells as natural biofactories for exosomes carrying miR-124a in the treatment of gliomas

Abstract

Background

MicroRNAs (miRs) are promising new therapeutics for glioblastoma. However, which miRs are most effective against glioblastomas and how these miRs should be delivered are major unanswered problems.

Methods

To identify potent antiglioma miRs, we selected 8 miRs based on a literature search and screened them against a panel of glioma stem cell (GSC) lines, representing all of the glioblastoma subtypes defined by The Cancer Genome Atlas. To address delivery, we tested the hypothesis that ex vivo cultured bone marrow–derived mesenchymal stem cells (MSCs) can package miRs into exosomes and that these engineered exosomes can systemically deliver antiglioma miRs to glioblastomas.

Results

Of the screened miRs, we identified miR-124a as the most effective antiglioma agent against GSCs. We then transduced MSCs with lentivirus vectors containing miR-124a and isolated vesicles from the medium. Electron microscopy, western blotting, and Nanosight proved that the isolated vesicles were exosomes. Quantitative PCR documented that these exosomes contained high levels of miR-124a, which was not present in control exosomes. In vitro treatment of GSCs with exosomes containing miR-124a (Exo-miR124) resulted in a significant reduction in viability and clonogenicity of GSCs compared with controls. In vivo treatment of mice harboring intracranial GSC267 with systemically delivered Exo-miR124 resulted in 50% of animals living long term. No evidence of tumor was present on histological analysis of the survivors. Mechanistic studies showed that miR-124a acts by silencing Forkhead box (FOX)A2, resulting in aberrant intracellular lipid accumulation.

Conclusion

MSCs can be used as natural biofactories to produce Exo-miR124, which is an effective antiglioma agent worthy of further clinical evaluation.

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A proposed framework of supportive and palliative care for people with high-grade glioma

Abstract

Background

Patients with malignant high-grade glioma (HGG) have significant supportive and palliative care needs, yet few tailored guidelines exist to inform practice. This study sought to develop an HGG framework of supportive and palliative care informed by needs reported by patients, families, and health care professionals (HCPs).

Methods

This study integrates a mixed-methods research program involving: (i) exploring experiences through systematic literature review and qualitative study (10 patients, 23 carers, and 36 HCPs); and (ii) an epidemiological cohort study (N = 1821) describing care of cases of HGG in Victoria, Australia using linked hospital datasets. Recommendations based on these studies were developed by a multidisciplinary advisory committee for a framework of supportive and palliative care based on the findings of (i) and (ii).

Results

Key principles guiding framework development were that care: (i) aligns with patient/family caregiver needs according to illness transition points; (ii) involves continuous monitoring of patient/family caregiver needs; (iii) be proactive in response to anticipated concerns; (iv) includes routine bereavement support; and (v) involves appropriate partnership with patients/families. Framework components and resulting activities designed to address unmet needs were enacted at illness transition points and included coordination, repeated assessment, staged information provision according to the illness transition, proactive responses and referral systems, and specific regular inquiry of patients' and family caregivers' concerns.

Conclusion

This evidence-based, collaborative framework of supportive and palliative care provides an approach for patients with HGG that is responsive, relevant, and sustainable. This conceptual framework requires evaluation in robust clinical trials.

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Clinical characteristics associated with postoperative seizure control in adult low-grade gliomas: a systematic review and meta-analysis

Abstract

Background

Epilepsy is the most common symptom in patients with supratentorial low-grade gliomas (LGGs), which adversely affects the patient's quality of life. Poor seizure control with anti-epileptic therapy is an indication for surgery in these patients. Recent studies have sought to identify predictors of postoperative seizure control after surgical resection of LGG; gross total resection was shown to be a significant predictor in this respect. However, the prognostic value of other factors is not clear.

Methods

We performed a systematic review and meta-analysis of 23 studies with a combined study population of 2641 patients with LGG, in order to identify potential factors associated with favorable postoperative seizure control. Data were extracted on age and sex of patient, tumor location, tumor histology, type of seizure, seizure duration, extent of resection, and imaging characteristics.

Results

Patients ≥45 years of age achieved better postoperative seizure control (risk ratio [RR], 0.89; 95% CI, 0.81–0.99). Focal seizures were associated with poor seizure control (RR, 1.32; 95% CI, 1.18–1.49) compared with generalized seizures (RR, 0.77; 95% CI, 0.68–0.87). Prolonged history of seizures (≥1 y) had a negative impact on postoperative seizure control (RR, 1.22; 95% CI, 1.10–1.34). Gross total resection was superior to subtotal resection with respect to postoperative seizure control (RR, 0.68; 95% CI, 0.63–0.73).

Conclusions

This systematic review and meta-analysis identified predictors of postoperative seizure control in patients undergoing surgical resection of LGGs. Our results provide a reference for clinical treatment of LGG-related epilepsy.

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A recombinant lentiviral PDGF-driven mouse model of proneural glioblastoma

Abstract

Background

Mouse models of glioblastoma (GBM), the most aggressive primary brain tumor, are critical for understanding GBM pathology and can contribute to the preclinical evaluation of therapeutic agents. Platelet-derived growth factor (PDGF) signaling has been implicated in the development and pathogenesis of GBM, specifically the proneural subtype. Although multiple mouse models of PDGF-driven glioma have been described, they require transgenic mice engineered to activate PDGF signaling and/or impair tumor suppressor genes and typically represent lower-grade glioma.

Methods

We designed recombinant lentiviruses expressing both PDGFB and a short hairpin RNA targeting Cdkn2a to induce gliomagenesis following stereotactic injection into the dentate gyrus of adult immunocompetent mice. We engineered these viruses to coexpress CreERT2 with PDGFB, allowing for deletion of floxed genes specifically in transduced cells, and designed another version of this recombinant lentivirus in which enhanced green fluorescent protein was coexpressed with PDGFB and CreERT2 to visualize transduced cells.

Results

The dentate gyrus of injected mice showed hypercellularity one week post-injection and subsequently developed bona fide tumors with the pathologic hallmarks of GBM leading to a median survival of 77 days post-injection. Transcriptomic analysis of these tumors revealed a proneural gene expression signature.

Conclusion

Informed by the genetic alterations observed in human GBM, we engineered a novel mouse model of proneural GBM. While reflecting many of the advantages of transgenic mice, this model allows for the facile in vivo testing of gene function in tumor cells and makes possible the rapid production of large numbers of immunocompetent tumor-bearing mice for preclinical testing of therapeutics.

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miR miR on the wall, who’s the most malignant medulloblastoma miR of them all?

Abstract

microRNAs (miRNAs) have wide-ranging effects on large-scale gene regulation. As such, they play a vital role in dictating normal development, and their aberrant expression has been implicated in cancer. There has been a large body of research on the role of miRNAs in medulloblastoma, the most common malignant brain tumor of childhood. The identification of the 4 molecular subgroups with distinct biological, genetic, and transcriptional features has revolutionized the field of medulloblastoma research over the past 5 years. Despite this, the growing body of research on miRNAs in medulloblastoma has largely focused on the clinical entity of a single disease rather than the molecular subgroups. This review begins by highlighting the role of miRNAs in development and progresses to explore their myriad of implications in cancer. Medulloblastoma is characterized by increased proliferation, inhibition of apoptosis, and maintenance of stemness programs—features that are inadvertently regulated by altered expression patterns in miRNAs. This review aims to contextualize the large body of work on miRNAs within the framework of medulloblastoma subgroups. The goal of this review is to stimulate new areas of research, including potential therapeutics, within a rapidly growing field.

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Acute toxicity of intraoperative radiotherapy and external beam-accelerated partial breast irradiation in elderly breast cancer patients

Abstract

Background and purpose

We investigated the acute toxicity of accelerated partial breast irradiation using external beam (EB-APBI) or intraoperative radiotherapy (IORT) techniques in elderly breast cancer patients.

Materials and methods

Women ≥ 60 years with unifocal breast tumors of ≤ 30 mm were eligible for this prospective multi-center cohort study. IORT was applied with electrons following lumpectomy (23.3 Gy). EB-APBI was delivered using 3D-CRT or IMRT in 10 daily fractions of 3.85 Gy within 6 weeks after surgery. Acute toxicity was scored using the CTCAE v3.0 at 3 months after treatment. Patient-reported symptoms were analyzed using visual analogue scales (VAS) for pain and fatigue (scale 0–10), and single items from the EORTC QLQ-C30 and Breast Cancer questionnaires.

Results

In total, 267 (IORT) and 206 (EB-APBI) patients were available for toxicity analysis. More patients experienced ≥ grade 2 CTCAE acute toxicity in the IORT group (10.4% IORT and 4.9% EB-APBI; p = 0.03); grade 3 toxicity was low (3.3% IORT and 1.5% EB-APBI; ns); and no grade 4 toxicity occurred. EB-APBI patients experienced less fatigue direct postoperatively (EORTC p < 0.00, VAS p < 0.00). After 3 months only pain, according to the VAS scale, was significantly worse in the EB-APBI group (p < 0.00).

Conclusion

Acute toxicity after IORT and EB-APBI treatment is acceptable.

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Prognostic role of high sensitivity C-reactive protein and interleukin-6 in glioma and meningioma patients

Abstract

High sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) can be important prognostic indicators of brain tumor patients. We investigated the association of circulating IL-6 and hsCRP concentrations with discharge outcomes and survival of glioma and meningioma patients. One-hundred and sixty-three (115 women; median age 57 years) patients admitted for meningioma (n = 94), high-grade glioma (n = 48) and low-grade glioma (n = 21) surgery were enrolled in this prospective cohort study. Serum samples were collected within 24 h of admission. Discharge outcome was evaluated using the Glasgow Outcome Scale (unfavorable outcome = score from 1 to 3). Follow-up continued until November, 2016. Elevated IL-6 (≥ 2 pg/ml) and hsCRP (≥ 1 mg/l) concentrations were present in 25 and 35% of brain tumor patients, respectively. Elevated IL-6 concentrations were associated with unfavorable outcome at hospital discharge, adjusting for brain tumor histological diagnosis, patient age and gender (OR 2.39, 95% CI 0.97–5.91, p = 0.05). Elevated hsCRP concentrations were not associated with discharge outcome (p = 0.13). In multivariate Cox regression analyses adjusted for patient age, gender, extent of tumor resection and adjuvant treatment, elevated IL-6 concentration was associated with greater mortality risk in high-grade glioma patients (OR 2.623; 95% CI 1.129–5.597; p = 0.01), while elevated hsCRP concentration was associated with greater mortality risk in meningioma patients (OR 3.650; 95% CI 1.038–12.831; p = 0.04). Elevated IL-6 concentration is associated with greater unfavorable outcome risk in brain tumor patients and with greater mortality in high-grade glioma patients, while elevated hsCRP concentration is associated with greater mortality in meningioma patients.

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