Oncolytic DNX-2401 Virus for Pediatric Diffuse Intrinsic Pontine Glioma.

BACKGROUND: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. METHODS: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. RESULTS: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. CONCLUSIONS: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).

Established and emerging uses of 5-ALA in the brain: an overview.

INTRODUCTION: 5-aminolevulinic acid (5-ALA) was approved by the FDA in June 2017 as an intra-operative optical imaging agent for patients with gliomas (suspected World Health Organization Grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue during surgery. 5-ALA fluorescence-guided surgery (FGS) has been in widespread use in Europe and other continents since 2007. METHODS: We reviewed the data available and summarize the most important known uses of 5-ALA FGS and its potential future applications. RESULTS/CONCLUSIONS: The technique has been extensively studied, and more than 300 papers have been published on this topic. Visualization of high-grade glioma tissue is robust and reproducible, and can impact the extent of tumor resection and patient outcomes. 5-ALA FGS for other kind of tumors needs further development.

Biological and clinical significance of the intratumour heterogeneity of PTEN protein expression and the corresponding molecular abnormalities of the PTEN gene in glioblastomas.

AIMS: Glioblastomas display marked phenotypic and molecular heterogeneity. The expression of the PTEN protein in glioblastomas also shows great intratumour heterogeneity, but the significance of this heterogeneity has so far received little attention. METHODS: We conducted a comparative study on paraffin and frozen samples from 60 glioblastomas. Based on PTEN immunostaining, paraffin glioblastomas were divided into positive (homogeneous staining) and both positive and negative (heterogeneous staining) tumours. DNA was extracted from manually microdissected samples from representative areas, and from frozen samples taken randomly from the same tumours. Loss of heterozygosity (LOH) of 10q23 and hypermethylation status of the PTEN promoter were studied, and the molecular findings were correlated with overall survival. RESULTS: PTEN protein was present heterogeneously in 42 cases and homogeneously in 18 cases. In homogeneous glioblastomas, no correlation was found between PTEN protein expression and the LOH of the gene. Surprisingly, in the heterogeneous glioblastomas, LOH was found significantly more frequently (P < 0.001) in PTEN-positive areas (81%) than in PTEN-negative ones (35.7%). In general, molecular results of frozen tissue were representative of the tumour. Only two cases of methylation of the PTEN promoter were identified. A significant difference was found for overall survival for LOH10q23 status (P = 0.005) and for homogeneous vs. heterogeneous tumours (P = 0.014). CONCLUSION: The expression of PTEN protein does not correlate with the abnormalities of the LOH of the gene. Interestingly, patients with glioblastomas presenting either LOH of 10q23 or heterogeneous PTEN expression have a poorer prognosis.

Factors associated with a higher rate of distant failure after primary treatment for glioblastoma.

Our purpose was to analyze the pattern of failure in glioblastoma (GBM) patients at first recurrence after radiotherapy and temozolomide and its relationship with different factors. From 77 consecutive GBM patients treated at our institution with fluorescence guided surgery and standard radiochemotherapy, 58 first recurrences were identified and included in a retrospective review. Clinical data including age, Karnofsky performance score, preoperative tumor volume and location, extend of resection, MGMT promoter methylation status, time to progression (PFS), overall survival (OS) and adjuvant therapies were reviewed for every patient. Recurrent tumor location respect the original lesion was the end point of the study. The recurrence pattern was local only in 65.5% of patients and non-local in 34.5%. The univariate and multivariate analysis showed that greater preoperative tumor volume in T1 gadolinium enhanced sequences, was the only variable with statistical signification (p < 0.001) for increased rate of non-local recurrences, although patients with MGMT methylation and complete resection of enhancing tumor presented non-local recurrences more frequently. PFS was longer in patients with non-local recurrences (13.8 vs. 6.4 months; p = 0.019, log-rank). However, OS was not significantly different in both groups (24.0 non-local vs. 19.3 local; p = 0.9). Rate of non-local recurrences in our series of patients treated with fluorescence guided surgery and standard radiochemotherapy was higher than previously published in GBM, especially in patients with longer PFS. Greater preoperative enhancing tumor volume was associated with increased rate of non-local recurrences.

Brain metastasis treatment guidelines: consensus by the Spanish Society of Neurosurgery Tumor Section.

Brain metastases are tumors that arise from a tumor cell originated in another organ reaching the brain through the blood. In the brain this tumor cell is capable of growing and invading neighboring tissues, such as the meninges and bone. In most patients a known tumor is present when the brain lesion is diagnosed, although it is possible that the first diagnose is the brain tumor before there is evidence of cancer elsewhere in the body. For this reason, the neurosurgeon must know the management that has shown the greatest benefit for brain metastasis patients, so treatments can be streamlined and optimized. Specifically, in this document, the following topics will be developed: selection of the cancer patient candidate for surgical resection and the role of the neurosurgeon in the multidisciplinary team, the importance of immunohistological and molecular diagnosis, surgical techniques, radiotherapy techniques, treatment updates of chemotherapy and immunotherapy and management algorithms in brain metastases. With this consensus manuscript, the tumor group of the Spanish Society of Neurosurgery (GT-SENEC) exposes the most relevant neurosurgical issues and the fundamental aspects to harmonize multidisciplinary treatment, especially with the medical specialties that are treating or will treat these patients.

Low grade gliomas guide-lines elaborated by the tumor section of Spanish Society of Neurosurgery.

Adult low-grade gliomas (Low Grade Gliomas, LGG) are tumors that originate from the glial cells of the brain and whose management involves great controversy, starting from the diagnosis, to the treatment and subsequent follow-up. For this reason, the Tumor Group of the Spanish Society of Neurosurgery (GT-SENEC) has held a consensus meeting, in which the most relevant neurosurgical issues have been discussed, reaching recommendations based on the best scientific evidence. In order to obtain the maximum benefit from these treatments, an individualised assessment of each patient should be made by a multidisciplinary team. Experts in each LGG treatment field have briefly described it based in their experience and the reviewed of the literature. Each area has been summarized and focused on the best published evidence. LGG have been surrounded by treatment controversy, although during the last years more accurate data has been published in order to reach treatment consensus. Neurosurgeons must know treatment options, indications and risks to participate actively in the decision making and to offer the best surgical treatment in every case.

Prognostic value of ventricular wall fluorescence during 5-aminolevulinic-guided surgery for glioblastoma.

BACKGROUND: The meaning of the ventricular wall fluorescence during 5-aminolevulinic (5-ALA)-guided surgery in patients with glioblastoma (GBM) is still unknown. The authors studied the association between ventricle fluorescence, clinical outcome and survival, and described the histopathological findings of selective biopsies from the ventricular wall. METHODS: One hundred and forty patients diagnosed of GBM underwent fluorescence-guided surgery (FGS); 65 of them were naive GBM and ventricle fluorescence during surgery was annotated prospectively. Selective biopsies were collected from the ventricular wall when possible. Clinical and radiological data were registered, including age, Karnofsky Performance Scale (KPS) score, presence of hydrocephalus, overall survival (OS), tumour volume and location (periventricular vs non-periventricular) and leptomeningeal dissemination. RESULTS: During FGS the ventricle wall was opened just when the tumour was periventricular in the preoperative MRI (45 out of 65). In 28 of them (60 %) the fluorescence extended far away from the site of opening, while in 17 it ended just in the few millimetres around the tumour. All four patients who developed hydrocephalus had periventricular tumours and the ventricle wall had been opened during surgery. Statistically significant differences were seen in OS according to periventricular location (15 m vs 33 m, P = 0.008 log rank). However, there was not significant relationship between ventricle fluorescence and hydrocephalus (P = 0.75), nor survival (14 m vs 15.5 m, P = 0.64). CONCLUSIONS: Preoperative MRI predicts if the ventricle will be opened using the 5-ALA fluorescence, according to tumour location. It does not predict, however if the ventricle wall is going to be fluorescent or not. The fluorescence of the ventricle wall is not a predictor for complications or survival. Periventricular tumour location is an independent bad prognostic factor in GBM.

Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience.

We analyzed the efficacy and applicability of surgery guided by 5-aminolevulinic acid (ALA) fluorescence in consecutive patients with glioblastoma multiforme (GBM). Thirty-six patients with GBM were operated on using ALA fluorescence. Resections were performed using the fluorescent light to assess the right plane of dissection. In each case, biopsies with different fluorescent quality were taken from the tumor center, from the edges, and from the surrounding tissue. These samples were analyzed separately with hematoxylin-eosin examination and immunostaining against Ki67. Tumor volume was quantified with pre- and postoperative volumetric magnetic resonance imaging. Strong fluorescence identified solid tumor with 100% positive predictive value. Invaded tissue beyond the solid tumor mass was identified by vague fluorescence with 97% positive predictive value and 66% negative predictive value, measured against hematoxylin-eosin examination. All the contrast-enhancing volume was resected in 83.3% of the patients, all patients had resection over 98% of the volume and mean volume resected was 99.8%. One month after surgery there was no mortality, and new or increased neurological morbidity was 8.2%. The fluorescence induced by 5-aminolevulinic can help to achieve near total resection of enhancing tumor volume in most surgical cases of GBM. It is possible during surgery to obtain separate samples of the infiltrating cells from the tumor border.

Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence.

Thirty consecutive surgical patients with glioblastoma, were operated upon using fluorescence induced by 5-aminolevulinic acid as guidance. The fluorescent quality of the tissue was used to take biopsies from the tumor center, from the invasive area around it and from adjacent normal-looking tissue. These samples were analyzed with HE, Ki-67 and nestin. Nestin expression in tissue surrounding glioblastoma cases was compared to tissue surrounding vascular lesions, metastasis and hippocampal sclerosis. The rate of gross total resection assessed by volumetric MRI was 83%. Using HE examination as the gold standard, fluorescence identified solid tumor with 100% positive predictive value, invasive areas with 97%, and normal tissue with 67% negative predictive value. Ki67 stained some cells in 69% of the non-fluorescent samples around the tumor. There was always strong nestin expression around the tumor but it was similar to control cases in non-glioma lesions with subacute expansion. 5-aminolevulinic acid fluorescence guidance is very reliable and can help to study the tumor-brain interface. Nestin expression is strong and constant in the tissue around the tumor, but is mostly an acute glial reaction, not specific of the neoplasm. Nestin staining is not recommended as a tumor stem cell marker.

Ki-67 Proliferative Activity in the Tumor Margins as a Robust Prognosis Factor in Glioblastoma Patients.

INTRODUCTION: The infiltrative margin of glioblastomas (GBM) contains proliferative tumor cells difficult to estimate radiologically as they are included in the hyperintense signal of T2 sequences and they remain in the cavity margin after tumor resection. The amount of these cells could determine overall survival (OS) of these patients. MATERIAL AND METHODS: From October 2007 to January 2010, patients whose MRI were suggestive of newly diagnosed, resectable high-grade glioma were operated using fluorescence-guided surgery (FGS). Separate samples were selectively taken from nonfluorescent white matter areas just adjacent to the border of the pale fluorescence and staining was made for Ki-67. OS was analyzed with Kaplan-Meier and Cox regression. Multivariate analysis included the following prognosis variables: age, extent of resection (EOR), O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and performance status index. RESULTS: Sample included 65 patients, comprising 37 men and 28 women, with a median Karnofsky Performance Score (KPS) of 80 (40-100) and mean age of 60 (34-78) years. Mean preoperative tumor volume was 35.8 mL. EOR was 100% in 52 patients (80%), with the lower EOR being 88%. For Ki-67, 39 patients had <5% and 26 had ≥5%. OS was 26.8 months (95% confidence interval [CI]: 18.9-28.2) for the Ki-67 low group versus 15.8 months (95% CI: 7.7-18.2) for the Ki-67 high group (p = 0.002). CONCLUSION: Proliferative activity in the normal-looking brain around the resection cavity measured with Ki-67 immunostaining is an important independent prognostic factor for GBM cases with complete resection of enhancing tumor. When complete resection is not reached, this factor is not relevant for prognosis.

Erratum: miR-425-5p, a SOX2 target, regulates the expression of FOXJ3 and RAB31 and promotes the survival of GSCs.

[This corrects the article PMC7470213.].

Clinical Profile and Results Obtained in Patients Treated by Auditory Brainstem Implants. / Perfil clínico y resultados obtenidos en los pacientes tratados mediante implante auditivo del tronco del encéfalo.

INTRODUCTION: Cochlear implants have been able to treat some types of hearing loss, but those related to cochlear nerve impairment made it necessary to find new ways to manage these deficits; leading to auditory brainstem implants (ABI). AIM: Our objective is to present the clinical profile of patients treated through an ABI and the results obtained from 1997 to 2017. MATERIAL AND METHODS: On the one hand, patients with statoacoustic nerve tumours (VIIIcranial nerve) were selected, and on the other hand, patients withoutVIII tumours with congenital malformations of the inner ear. Before and after the placement of the ABI, hearing was assessed through tonal audiometry, from which the PTA (Pure Tone Average) and the CAP (Categories of Auditory Performance) scale were obtained. RESULTS: A total of 20 patients undergoing ABI surgery were included. Eight were of tumour cause (40%) and 12 non-tumour (60%). In 15 subjects (75%) a suboccipital approach was performed and in 5 (25%) translabyrinthine. The mean of active electrodes before the implantation of Cochlear® (Nucleus ABI24) was 13/21 (61.90%) versus 8.5/12 (70.83%) of the Med-el® (ABI Med-el). An improvement in the mean PTA of 118.49dB was found against 46.55dB at 2years. On the CAP scale, values of1 were obtained in the preimplantation and of 2.57 (1-5) in the 2-year revision. CONCLUSION: The ABI is a safe option, and with good hearing results when the indication is made correctly.

miR-425-5p, a SOX2 target, regulates the expression of FOXJ3 and RAB31 and promotes the survival of GSCs.

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults and prognosis is poor despite maximum therapeutic efforts. GBM is composed of heterogeneous cell populations, among which the glioma stem-like cells (GSCs) play an important role in tumor cell self-renewal and the ability to initiate and drive tumor growth and recurrence. The transcription factor SOX2 is enriched in GSCs where it controls the stem cell phenotype, invasion and maintenance of tumorigenicity. Therefore, understanding the molecular mechanisms governed by SOX2 in GSCs is crucial to developing targeted therapies against this resistant cell population. In this study, we identified and validated a miRNA profile regulated by SOX2 in GSCs. Among these miRNAs, miR-425-5p emerged as a significant robust candidate for further study. The expression of miR-425-5p was significantly enriched in clinical GBM specimens compared with a human brain reference sample and showed a positive correlation with SOX2 expression. Using a combination of in silico analyses and molecular approaches, we show that SOX2 binds to the promoter of miR-425-5p. Loss of function studies show that repressing miR-425-5p expression in multiple GSCs inhibited neurosphere renewal and induced cell death. More importantly, miR-425-5p inhibition extended survival in an orthotopic GBM mouse model. Finally, combining several bioinformatics platforms with biological endpoints in multiple GSC lines, we identified FOXJ3 and RAB31 as high confidence miR-425-5p target genes. Our findings show that miR-425-5p is a GBM stem cell survival factor and that miR-425-5p inhibition function is a potential strategy for treating GBM.

RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.

BACKGROUND: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. METHODS: We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. RESULTS: Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with non-neoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575). CONCLUSIONS: Our data suggest that the expression of RNU6-1 in circulating exosomes could be useful for the differentiation of GBM from non-neoplastic brain lesions and PCNSL, but not from brain metastases.

Intraoperative imaging in the neurosurgery operating theatre: A review of the most commonly used techniques for brain tumour surgery. / Imagen intraoperatoria en el quirófano de neurocirugía: revisión de las técnicas más empleadas para la cirugía de los tumores cerebrales.

INTRODUCTION: New intraoperative imaging techniques, which aim to improve tumour resection, have been implemented in recent years in brain tumour surgery, although they lead to an increase in resources. In order to carry out an update on this topic, this manuscript has been drafted by a group from the Sociedad Española de Neurocirugía (Spanish Society of Neurosurgery). MATERIAL AND METHODS: Experts in the use of each one of the most-used intraoperative techniques in brain tumour surgery were presented with a description of the technique and a brief review of the literature. Indications for use, their advantages and disadvantages based on clinical experience and on what is published in the literature will be described. RESULTS: The most robust intraoperative imaging technique appears to be low- and high-field magnetic resonance imaging, but this is the technique which results in the greatest expenditure. Intraoperative ultrasound navigation is portable and less expensive, but it provides poorer differentiation of high-grade tumours and is observer-dependent. The most-used fluorescence techniques are 5-aminolevulinic acid for high-grade gliomas and fluorescein, useful in lesions which rupture the blood-brain barrier. Last of all, intraoperative CT is more versatile in the neurosurgery operating theatre, but it has fewer indications in neuro-oncology surgery. CONCLUSIONS: Intraoperative imaging techniques are used with increasingly greater frequency in brain tumour surgery, and the neurosurgeon should assess their possible use depending on their resources and the needs of each patient.

Glioblastoma treatment guidelines: Consensus by the Spanish Society of Neurosurgery Tumor Section. / Consenso sobre guías de tratamiento de los glioblastomas elaborado por el Grupo de Trabajo de Neurooncología (GTNO) de la SENEC.

INTRODUCTION: Glioblastoma (GBM) treatment starts in most patients with surgery, either resection surgery or biopsy, to reach a histology diagnose. Multidisciplinar team, including specialists in brain tumors diagnose and treatment, must make an individualize assessment to get the maximum benefit of the available treatments. MATERIAL AND METHODS: Experts in each GBM treatment field have briefly described it based in their experience and the reviewed of the literature. RESULTS: Each area has been summarized and the consensus of the brain tumor group has been included at the end. CONCLUSIONS: GBM are aggressive tumors with a dismal prognosis, however accurate treatments can improve overall survival and quality of life. Neurosurgeons must know treatment options, indications and risks to participate actively in the decision making and to offer the best surgical treatment in every case.

Correction: Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience.

[This corrects the article DOI: 10.1371/journal.pone.0217881.].

Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience.

BACKGROUND: Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. MATERIAL AND METHODS: GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m2/day of temozolomide were administered. RESULTS: Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. CONCLUSIONS: Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness.

Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models.

Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome. Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement. Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models. Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy. Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments. In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors. Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors. SIGNIFICANCE: Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs.