HDAC inhibitors (HDACi) hold great potential as anticancer therapies due to their ability to regulate the acetylation of both histone and non-histone proteins, which is frequently disrupted in cancer and contributes to the development and advancement of the disease. Additionally, HDACi have been shown to enhance the cytotoxic effects of DNA-damaging agents such as radiation and cisplatin. In this study, we found that histone deacetylase inhibits valproic acid (VPA), synergized with PARP1 inhibitor (PARPi), talazoparib (BMN-673), and alkylating agent, and temozolomide (TMZ) to induce DNA damage and reduce glioblastoma multiforme. At the molecular level, VPA leads to a downregulation of FANCD2 and RAD51, and the eradication of glioblastoma cells. The results of this study indicate that combining HDACi with PARPi could potentially enhance the treatment of glioblastoma, the most aggressive type of cancer that originates in the brain. Full article

Standard treatment for glioblastoma multiforme (GBM) is surgery followed by radiotherapy plus concurrent chemotherapy with daily temozolomide (TMZ), and six subsequent TMZ 5/28-day cycles. Research has focused on identifying more effective alternatives to the current protocol, including extension of the number of adjuvant TMZ cycles. We performed a retrospective analysis of all GBM patients treated in our hospital (160 patients, 2011–2020). Median follow-up was 16.0 months. Analysis of prognostic factors was performed with a particular focus on the benefit of extending TMZ chemotherapy. Improved survival correlated with younger age, female gender, good performance status, absence of cognitive dysfunctions, no steroid use, and total tumor resection. Median progression-free survival (PFS) was 12 months and median overall survival (OS) was 20.0 months for the entire cohort. Median OS by adjuvant TMZ was 10.0 months if no adjuvant chemotherapy given (group 0), 15.0 months for patients that did not complete six TMZ cycles (group A), 24.0 months for those that did (group B), and 29.0 months for patients having received more than six cycles (group C) (p < 0.0001). At the three-year mark, 15.9% patients were alive in group A, 24.4% in group B and 38.1% in group C. Carefully selected GBM patients may derive benefit from extending the standard adjuvant chemotherapy beyond six TMZ cycles, but more data is required. Full article

The onco-functional balance in neuro-oncology requires maximizing tumor removal while rigorously preserving patients’ neurological status. When postoperative worsening prevents the implementation of oncologic treatments, palliative care service offers an individualized path for symptom and psychosocial distress relief. Here, we report on a series of 25 patients operated on for malignant brain tumor who did not undergo adjuvant treatments after neurosurgery; they represented 3.9% of the whole institutional surgical series. These patients were significantly older and had a lower preoperative Karnofsky performance status than the whole cohort. Importantly, in 22 out of 25 (88%) cases, a surgical complication occurred, leading to clinical worsening in 21 patients. For the end of life, the majority of patients chose a hospice care facility (72%). While a careful selection of brain tumor patients candidate to neurosurgery is required, palliative care service provided invaluable help in coping with patients’ and caregivers’ needs. Full article

Purpose. For recurrent high-grade gliomas (HGG), no standard therapeutic approach has been reported; thus, surgery, chemotherapy, and re-irradiation (re-RT) may all be proposed. The aim of the study was to evaluate safety and efficacy of re-RT by radiosurgery or fractionated stereotactic radiotherapy (SRS/FSRT) in association to chemotherapy in patients with recurrent HGG. Material/Methods: All patients with histological diagnosis of HGG that suffered by recurrent disease diagnosed by magnetic resonance imaging (MRI), according to Response Assessment in Neuro-Oncology (RANO) criteria, after primary/adjuvant chemo-radiotherapy treatment and underwent to re-RT by SRS/FSRT were included in the analysis. Second-line chemotherapy was administered. Outcomes were evaluated by neurological examination and brain MRI performed 1 month after re-RT and then every 2–3 months. Results: From November 2019 to September 2021, 30 patients presenting recurrent HGG underwent re-RT. Median dose was 24 Gy (range 15–36 Gy), and median fractions was 5 (range 1–6). Twenty-one patients (70%) had RPA class ≤ IV. One patient had a histological diagnosis of anaplastic oligodendroglioma, 24 patients (80%) were affected by glioblastoma (GBM) including 3 cases of multifocal form, and 5 patients (17%) by anaplastic astrocytoma. Median time between primary/adjuvant RT and disease recurrence was 8 months. In six cases (20%) re-operation was performed, and in most cases (87%), a second line of systemic therapy was administrated. At a median follow-up time from recurrence of 13 months (range 6–56 months), 10 patients (33%) were alive: 2 patients with partial response disease, 7 patients with stable disease, and 1 patient with out-field progression disease. Of the 20 patients who died (67%), 15 (75%) died for progression disease and 5 (25%) for other causes (3 due to septic event, 1 due to thrombo-embolic event, and 1 due to car accident). Median OS and PFS after recurrence were 12.1 and 11.2 months. Six-month and one-year OS were, respectively, 81% and 51%. No acute or late neurological side effects grade ≥ 2 and no case of radio-necrosis were reported. One patient experienced, after reintervention and during Regorafenib treatment (administered 40 days after surgery), dehiscence of the surgical wound. In three cases, grade 2 distal paresthesia was reported. Grade 3–4 hematologic toxicity occurred in seven cases. Three case of grade 5 toxicities during chemotherapy were reported: three septic events and one thrombo-embolic event. Conclusion. Re-RT with SRT/FSRT in association with second-line systemic therapy is a safe and feasible treatment for patients with HGG recurrence. Validation of these results by prospective studies is needed. Full article

Background: The multi-disciplinary tumor board (MTB) is essential to quality cancer care and currently recommended to offer the best personalized clinical approach, but little has been published regarding MTBs in neuro-oncology (nMTBs). The aim of the present paper is to describe our nMTB, to evaluate its impact on clinical management decisions, and to assess the role of neuroradiologists. Methods: The retrospective evaluation of the cases discussed at our nMTB from March 2017 to March 2020. From the electronic records, we extracted epidemiological, clinical and other specific data of nMTB. From the radiological records, we calculated data relating to the number, time for revision, and other specifications of MRI re-evaluation. Statistical analysis was performed. Results: a total of 447 discussions were analyzed, representing 342 patients. The requests for case evaluations came from radiation oncologists (58.8%) and neurosurgeons (40.5%), and were mainly addressed to the neuroradiologist (73.8%). The most frequent questions were about the treatment’s changes (64.4%). The change in patient treatment was reported in 40.5% of cases, 76.8% of these were based on the neuroradiologic assessment. A total of 1514 MRI examinations were re-evaluated, employing approximately 67 h overall. The median of the MRI exams reviewed per patient was 3 (min–max 1–12). Conclusions: Our study supported that the multidisciplinary approach to patient care can be particularly effective in managing brain tumors. A review by an expert neuroradiologist impacts patient management in the context of nMTBs, but has costs in terms of the time and effort spent preparing for it. Full article

Aim: To test inter-fraction reproducibility, intrafraction stability, technician aspects, and patient/physician’s comfort of a dedicated immobilization solution for Brain Linac-based radiation therapy (RT). Methods: A pitch-enabled head positioner with an open-face mask were used and, to evaluate inter- and intrafraction variations, 1–3 Cone-Beam Computed Tomography (CBCT) were performed. Surface Guided Radiation Therapy (SGRT) was used to evaluate intrafraction variations at 3 time points: initial (i), final (f), and monitoring (m) (before, end, and during RT). Data regarding technician mask aspect were collected. Results: Between October 2019 and April 2020, 69 patients with brain disease were treated: 45 received stereotactic RT and 24 conventional RT; 556 treatment sessions and 863 CBCT’s were performed. Inter-fraction CBCT mean values were longitudinally 0.9 mm, laterally 0.8 mm, vertically 1.1 mm, roll 0.58°, pitch 0.59°, yaw 0.67°. Intrafraction CBCT mean values were longitudinally 0.3 mm, laterally 0.3 mm, vertically 0.4 mm, roll 0.22°, pitch 0.33°, yaw 0.24°. SGRT intrafraction mean values were: i_, m_, f_ longitudinally 0.09 mm, 0.45 mm, 0.31 mm; i_, m_, f_ laterally 0.07 mm, 0.36 mm, 0.20 mm; i_, m_, f_ vertically 0.06 mm, 0.31 mm, 0.22 mm; i_, m_, f_ roll 0.025°, 0.208°, 0.118°; i_, m_, f_ pitch 0.036°, 0.307°, 0.194°; i_, m_, f_ yaw 0.039°, 0.274°, 0.189°. Conclusions: This immobilization solution is reproducible and stable. Combining CBCT and SGRT data confirm that 1 mm CTV-PTV margin for Linac-based SRT was adequate. Using open-face mask and SGRT, for conventional RT, radiological imaging could be omitted. Full article

Background: Glioblastoma (GBM) is a very poor-prognosis brain tumor. To date, maximal excision followed by radiochemotherapy, in 30 fractions, is the standard approach. Limited data are present in the literature about hypofractionated radiotherapy (hypo-RT) in GBM poor prognosis patients. Thus, this retrospective study was conducted to evaluate efficacy and toxicity of hypo-RT with simultaneous integrated boost (SIB) in association with temozolomide (TMZ) in this patient setting. Methods: Poor-prognosis GBM patients underwent surgery (complete, subtotal or biopsy) followed by SIB-hypo-RT and concomitant/adjuvant TMZ. The prescription dose was 40.05 Gy (15 fractions) with a SIB of 52.5 Gy (3.5 Gy/fraction) on surgical cavity/residual/macroscopic disease. Volumetric modulated arc therapy was performed. Results: From July 2019 to July 2021, 30 poor-prognosis patients affected by GBM were treated by SIB-hypo-RT; 25 were evaluated in the present analysis due to a minimum follow up of 6 months. The median age and KPS were 65 years and 60%, respectively. At the median follow-up time of 15 months (range 7–24), median and 1-year overall survival and progression-free survival were 13 months and 54%, and 8.4 months and 23%, respectively. No acute or late neurological side effects of grade ≥ 2 were reported. Grade 3–4 hematologic toxicity occurred in three cases. Conclusion: SIB-hypo-RT associated with TMZ in poor-prognosis patients affected by GBM is an effective and safe treatment. Prospective studies could be warranted. Full article

Brain biopsy is the gold standard in order to establish the diagnosis of unresectable brain tumors. Few studies have investigated the long-term outcomes of biopsy patients. The aim of this single-institution-based study was to assess the concordance between radiological and histopathological diagnoses, and the long-term patient outcome. Ninety-three patients who underwent brain biopsy in the last 5 years were analyzed. We included patients treated with stereotactically guided needle, open, and neuroendoscopic biopsies. Most patients (86%) received needle biopsy. Gliomas and primary brain lymphomas comprised 88.2% of cases. The diagnostic yield was 95.7%. Serious complication and death rates were 3.2% and 2.1%, respectively. The concordance rate between radiological and histological diagnoses was 93%. Notably, the positive predictive value of radiological diagnosis of lymphoma was 100%. Biopsy allowed specific treatment in 72% of cases. Disease-related neurological worsening was the main reason that precluded adjuvant treatment. Adjuvant treatment, in turn, was the strongest prognostic factor, since the median overall survival was 11 months with vs. 2 months without treatment (p = 0.0002). Finally, advanced molecular evaluations can be obtained on glioma biopsy specimens to provide integrated diagnoses and individually tailored treatments. We conclude that, despite the huge advances in imaging techniques, biopsy is required when an adjuvant treatment is recommended, particularly in gliomas. Full article

Angiogenesis has long been implicated as a crucial process in GBM growth and progression. GBM can adopt several strategies to build up its abundant and aberrant vasculature. Targeting GBM angiogenesis has gained more and more attention in anti-cancer therapy, and many strategies have been developed to interfere with this hallmark. However, recent findings reveal that the effects of anti-angiogenic treatments are temporally limited and that tumors become refractory to therapy and more aggressive. In this review, we summarize the GBM-associated neovascularization processes and their implication in drug resistance mechanisms underlying the transient efficacy of current anti-angiogenic therapies. Moreover, we describe potential strategies and perspectives to overcome the mechanisms adopted by GBM to develop resistance to anti-angiogenic therapy as new potential therapeutic approaches. Full article

Diffuse intrinsic pontine glioma (DIPG) is a type of intrinsic brainstem glial tumor that occurs primarily in the pediatric population. DIPG is initially diagnosed based on clinical symptoms and the characteristic location on imaging. Histologically, these tumors are characterized by a heterogenous population of cells with multiple genetic mutations and high infiltrative capacity. The most common mutation seen in this group is a lysine to methionine point mutation seen at position 27 (K27M) within histone 3 (H3). Tumors with the H3 K27M mutation, are considered grade 4 and are now categorized within the H3 K27-altered diffuse midline glioma category by World Health Organization classification. Due to its critical location and aggressive nature, DIPG is resistant to the most eradicative treatment and is universally fatal; however, modern advances in the surgical techniques resulting in safe biopsy of the lesion have significantly improved our understanding of this disease at the molecular level. Genomic analysis has shown several mutations that play a role in the pathophysiology of the disease and can be targeted therapeutically. In this review, we will elaborate on DIPG from general aspects and the evolving molecular landscape. We will also review innovative therapeutic options that have been trialed along with new promising treatments on the horizon. Full article

Efficient transdisciplinary cooperation promotes the rapid discovery and clinical application of new technologies, especially in the competitive sector of oncology. In this review, written from a clinical-scientist point of view, we used glioblastoma—the most common and most aggressive primary brain tumor as a model disease with a largely unmet clinical need, despite decades of intensive research—to promote transdisciplinary medicine. Glioblastoma stem-like cells (GSCs), a special tumoral cell population analogue to healthy stem cells, are considered largely responsible for the progression of the disease and the mediation of therapy resistance. The presented work followed the concept of translational science, which generates the theoretical backbones of translational research projects, and aimed to close the preclinical gap between basic research and clinical application. Thus, this generated an integrated translational precision medicine pipeline model based on recent theoretical and experimental publications, which supports the accelerated discovery and development of new paths in the treatment of GSCs. The work may be of interest to the general field of precision medicine beyond the field of neuro-oncology such as in Cancer Neuroscience. Full article

Glioblastoma is the most common malignant brain tumor in adults. The current management relies on surgical resection and adjuvant radiotherapy and chemotherapy. Despite advances in our understanding of glioblastoma onset, we are still faced with an increased incidence, an altered quality of life and a poor prognosis, its relapse and a median overall survival of 15 months. For the past few years, the understanding of glioblastoma physiopathology has experienced an exponential acceleration and yielded significant insights and new treatments perspectives. In this review, through an original R-based literature analysis, we summarize the clinical presentation, current standards of care and outcomes in patients diagnosed with glioblastoma. We also present the recent advances and perspectives regarding pathophysiological bases as well as new therapeutic approaches such as cancer vaccination and personalized treatments. Full article

Glioblastoma, as the most aggressive brain tumor, is associated with a poor prognosis and outcome. To optimize prognosis and clinical therapy decisions, there is an urgent need to stratify patients with increased risk for recurrent tumors and low therapeutic success to optimize individual treatment. Radiogenomics establishes a link between radiological and pathological information. This review provides a state-of-the-art picture illustrating the latest developments in the use of radiogenomic markers regarding prognosis and their potential for monitoring recurrence. Databases PubMed, Google Scholar, and Cochrane Library were searched. Inclusion criteria were defined as diagnosis of glioblastoma with histopathological and radiological follow-up. Out of 321 reviewed articles, 43 articles met these inclusion criteria. Included studies were analyzed for the frequency of radiological and molecular tumor markers whereby radiogenomic associations were analyzed. Six main associations were described: radiogenomic prognosis, MGMT status, IDH, EGFR status, molecular subgroups, and tumor location. Prospective studies analyzing prognostic features of glioblastoma together with radiological features are lacking. By reviewing the progress in the development of radiogenomic markers, we provide insights into the potential efficacy of such an approach for clinical routine use eventually enabling early identification of glioblastoma recurrence and therefore supporting a further personalized monitoring and treatment strategy. Full article