Current treatment guidelines for the management of recurrent glioblastoma (rGBM) are far from definitive, and the prognosis remains dismal. Despite recent advancements in the pharmacological and surgical fields, numerous doubts persist concerning the optimal strategy that clinicians should adopt for patients who fail the first lines of treatment and present signs of progressive disease. With most recurrences being located within the margins of the previously resected lesion, a comprehensive molecular and genetic profiling of rGBM revealed substantial differences compared with newly diagnosed disease. In the present comprehensive review, we sought to examine the current treatment guidelines and the new perspectives that polarize the field of neuro-oncology, strictly focusing on progressive disease. For this purpose, updated PRISMA guidelines were followed to search for pivotal studies and clinical trials published in the last five years. A total of 125 articles discussing locoregional management, radiotherapy, chemotherapy, and immunotherapy strategies were included in our analysis, and salient findings were critically summarized. In addition, an in-depth description of the molecular profile of rGBM and its distinctive characteristics is provided. Finally, we integrate the above-mentioned evidence with the current guidelines published by international societies, including AANS/CNS, EANO, AIOM, and NCCN.

Background: High-grade gliomas are aggressive and life-threatening brain tumors. At the time of recurrence, the patients and their families need to decide on future treatment. None of the treatment options are curative, and tradeoffs between benefits and harms must be made. This study aimed to explore the patients’ and family members’ decisional needs when making the decision. Methods: We performed semi-structured individual interviews with patients and family members to explore their experiences during the decision making. A phenomenological hermeneutical analysis was conducted. Results: A total of 15 patients and 14 family members aged 22-79 years participated in the study. Most of the family members were partners to the patient. The findings were centered around three interrelated and concurrently occurring themes: (I) A patient- and family-centered decision making, including the subtheme of being a supportive family member; (II) Balanced information and a trustful professional encounter; and (III) The value of hope. We found that both the patients and family members preferred to be involved in the decision making and that a trustful relationship with the surgeon, balanced and tailored information, and sufficient time to make the decision were essential. The experience of hope had a significant influence on patients’ decisions. Conclusion: This study found that patient and family involvement, balanced information, and hope were the primary decisional needs of patients and family members at the time of recurrent high-grade glioma. Patients and family members can have different decisional needs, making individual needs assessment essential to decisional support.

Purpose: Glioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of cancer stem cells (CSCs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here, we identify CD70 as a potential therapeutic target for recurrent GBM CSCs.Experimental design: In the current study, we identified the relevance and functional influence of CD70 on primary and recurrent GBM cells, and further define its function using established stem cell assays. We use CD70 knockdown studies, subsequent RNAseq pathway analysis, andin vivoxenotransplantation to validate CD70’s role in GBM. Next, we developed and tested an anti-CD70 chimeric antigen receptor (CAR)-T therapy, which we validatedin vitroandin vivousing our established preclinical model of human GBM. Lastly, we explored the importance of CD70 in the tumor immune microenvironment (TIME) by assessing the presence of its receptor, CD27, in immune infiltrates derived from freshly resected GBM tumor samples.Results: CD70 expression is elevated in recurrent GBM and CD70 knockdown reduces tumorigenicityin vitroandin vivo. CD70 CAR-T therapy significantly improves prognosisin vivo. We also found CD27 to be present on the cell surface of multiple relevant GBM TIME cell populations, notably putative M1 macrophages and CD4 T cells.Conclusion: CD70 plays a key role in recurrent GBM cell aggressiveness and maintenance. Immunotherapeutic targeting of CD70 significantly improves survival in animal models and the CD70/CD27 axis may be a viable polytherapeutic avenue to co-target both GBM and its TIME.

Background: Sonodynamic therapy (SDT) is an emerging ultrasound-based treatment modality for malignant gliomas which combines ultrasound with sonosensitizers to produce a localized cytotoxic and modulatory effect. Tumor-specificity of the treatment is achieved by the selective extravasation and accumulation of sonosensitizers in the tumor-bearing regions. The aim of this study is to demonstrate the safety of low-intensity ultrasonic irradiation of healthy brain tissue after the administration of FDA-approved sonosensitizers used for SDT in experimental studies in an in vivo large animal model.Methods: In vivo safety of fluorescein (Na-Fl)- and 5 aminolevulinic acid (5-ALA)-mediated low-intensity ultrasound irradiation of healthy brain parenchyma was assessed in two sets of four healthy swine brains, using the magnetic resonance imaging (MRI)-guided Insightec ExAblate 4000 220 kHz system. After administration of the sonosensitizers, a wide fronto-parietal craniotomy was performed in pig skulls to allow transmission of ultrasonic beams. Sonication was performed on different spots within the thalamus and periventricular white matter with continuous thermal monitoring. Sonication-related effects were investigated with MRI and histological analysis.Results: Post-treatment MRI images acquired within one hour following the last sonication, on day one, and day seven did not visualize any sign of brain damage. On histopathology, no signs of necrosis or apoptosis attributable to the ultrasonic treatments were shown in target areas.Conclusions: The results of the present study suggest that either Na-FL or 5-ALA-mediated sonodynamic therapies under MRI-guidance with the current acoustic parameters are safe towards healthy brain tissue in a large in vivo model. These results further support growing interest in clinical translation of sonodynamic therapy for intracranial gliomas and other brain tumors.

Background: A significant proportion of glioblastoma (GBM) patients are considered for repeat resection, but evidence regarding best management remains elusive. Our aim was to measure the degree of clinical uncertainty regarding reoperation for patients with recurrent GBM. Methods: We first performed a systematic review of agreement studies examining the question of repeat resection for recurrent GBM. An electronic portfolio of 37 pathologically confirmed recurrent GBM patients including pertinent magnetic resonance images and clinical information was assembled. To measure clinical uncertainty, 26 neurosurgeons from various countries, training backgrounds, and years’ experience were asked to select best management (repeat surgery, other nonsurgical management, or conservative), confidence in recommended management, and whether they would include the patient in a randomized trial comparing surgery with nonsurgical options. Agreement was evaluated using κ statistics. Results: The literature review did not reveal previous agreement studies examining the question. In our study, agreement regarding best management of recurrent GBM was slight, even when management options were dichotomized (repeat surgery vs. other options; κ=0.198 [95% confidence interval: 0.133-0.276]). Country of practice, years’ experience, and training background did not change results. Disagreement and clinical uncertainty were more pronounced within clinicians with (κ=0.167 [0.055-0.314]) than clinicians without neuro-oncology fellowship training (κ=0.601 [0.556-0.646]). A majority (51%) of responders were willing to include the patient in a randomized trial comparing repeat surgery with nonsurgical alternatives in 26/37 (69%) of cases. Conclusion: There is sufficient uncertainty and equipoise regarding the question of reoperation for patients with recurrent glioblastoma to support the need for a randomized controlled trial.

Objective: The aim of this study was to evaluate the efficacy of Gamma Knife radiosurgery (GKRS) as a salvage therapy for high-grade glioma in our center. Methods: A total of 167 patients with malignant glioma were treated with GKRS in our Gamma Knife Center between January 2013 and December 2017; 140 patients (85 males and 55 females) were followed up and enrolled in our study. A single lesion was found in 110 cases, and multiple lesions were found in 30 cases; 108 cases received a single therapy, and in 32 cases, at least 2 GKRSs were performed. The median tumor volume was 13.5 cm³. The mean radiation dosage was 14.35 Gy (range, 6–18 Gy). MRI was performed regularly. The RANO criteria and Cox analysis were used to evaluate the therapeutic efficiency. Results: Follow-up MRI showed the local control rate was 61.4% at 3 months after GKRS, 25.0% at 6 months, and 7.1% at 12 months. The mean and median progression-free survival (PFS) periods were 8.6 (95% CI, 6.3–11.0) and 4 (95% CI, 3.5–4.5) (range, 1–60) months, respectively. The overall survival (OS) after GKRS was 3–62 months, with a mean of 16.7 (95% CI, 14.6–18.9) months, and the median survival was 13 (95% CI, 12.1–13.9) months. The 1-, 2-, and 5-year survival rates were 51.4, 10.0, and 2.9%, respectively. No severe complications occurred. Cox regression showed that glioma pathology was closely related to prognosis (p < 0.05). The Karnofsky Performance Score had little influence on PFS (p > 0.05) but influenced OS significantly (p < 0.05). Conclusion: GKRS can be used to effectively treat malignant brain glioma and can therefore be used as an alternative treatment option.

There are only few studies comparing differences in the outcome of primary versus secondary gliosarcoma. This study aimed to review the outcome and survival of patients with primary or secondary gliosarcoma following surgical resection and adjuvant treatment. The data were also matched with data of patients with primary and secondary glioblastoma (GBM). Treatment histories of 10 patients with primary gliosarcoma and 10 patients with secondary gliosarcoma were analysed and compared. Additionally, data of 20 patients with primary and 20 patients with secondary GBM were analysed and compared. All patients underwent surgical resection of the tumour in our department. Follow-up data, progression-free survival (PFS), and median overall survival (mOS) were evaluated. The median PFS in patients with primary gliosarcoma was significantly higher than in patients with secondary gliosarcoma (p = 0.037). The 6-month PFS rates were 80.0% in patients with primary and 30.0% in patients with secondary gliosarcoma. Upon recurrence, five patients with primary gliosarcoma and four patients with secondary gliosarcoma underwent repeat surgical resection. The mOS of patients with primary gliosarcoma was significantly higher than that of patients with secondary gliosarcoma (p = 0.031). The percentage of patients surviving at 1-year/2-year follow-up in primary gliosarcoma was 70%/20%, while it was only 10%/10% in secondary gliosarcoma. When PFS and mOS of primary gliosarcoma was compared to primary GBM, there were no statistically differences (p = 0.509; p = 0.435). The PFS and mOS of secondary gliosarcoma and secondary GBM were also comparable (p = 0.290 and p = 0.390). Patients with primary gliosarcoma have a higher PFS and mOS compared to those with secondary gliosarcoma. In the case of tumour recurrence, patients with secondary gliosarcoma harbour an unfavourable prognosis with limited further options. The outcome of patients with primary or secondary gliosarcoma is comparable to that of patients with primary or secondary GBM.

Background: The current standard treatment for glioblastoma (GBM) is maximal safe surgical resection followed by radiation and chemotherapy. Unfortunately, the disease will invariably recur even with the best treatment. Although the literature suggests some advantages in reoperating patients harboring GBM, controversy remains. Here, we asked whether reoperation is an efficacious treatment strategy for GBM, and under which circumstances, it confers a better prognosis. Methods: We retrospectively reviewed 286 consecutive cases of newly diagnosed GBM in a single university hospital from 2008 to 2015. We evaluated clinical and epidemiological parameters possibly influencing overall survival (OS) by multivariate Cox regression analysis. OS was calculated using the Kaplan–Meier method in patients submitted to one or two surgical procedures. Finally, the survival curves were fitted with the Weibull model, and survival rates at 6, 12, and 24 months were estimated. Results: The reoperated group survived significantly longer (n = 63, OS = 20.0 ± 2.3 vs. 11.4 ± 1.0 months, P< 0.0001). Second, the multivariate analysis revealed an association between survival and number of surgeries, initial Karnofsky Performance Status, and age (all P< 0.001). Survival estimates according to the Weibull regression model revealed higher survival probabilities for reoperation compared with one operation at 6 months (83.74 ± 3.42 vs. 63.56 ± 3.59, respectively), 12 months (64.00 ± 4.85 vs. 37.53 ± 3.52), and 24 months (32.53 ± 4.78 vs. 12.02 ± 2.36). Conclusion: Our data support the indication of reoperation for GBM, especially for younger patients with good functional status. Under these circumstances, survival can be doubled at 12 and 24 months.

Objective: The purpose of this study was to investigate the possible benefit of repeat surgery on overall survival for patients with recurrent glioblastoma multiforme (GBM). Methods: We performed a retrospective analysis of data from patients who presented with recurrent GBM over a 5-year period (n = 157), comparing baseline characteristics and survival for patients who had at least 1 new tumor resection followed by chemotherapy (reoperation group, n = 59) and those who received medical treatment only (no-reoperation group, n = 98) for recurrence. Results: The baseline characteristics of the two groups differed in terms of WHO performance status (better in the reoperation group), mean age (60 years in the reoperation group vs. 65 years in the no-reoperation group), mean interval to recurrence (3 months later in the reoperation group than in the no-reoperation group) and more gross total resections in the reoperation group. Nevertheless, the patients in the reoperation group had a higher rate [32.8%] of sensorimotor deficits than those of the no-reoperation group [14.2]. There was no significant difference in sex; tumor localization, side, or extent; MGMT status; MIB-1 labeling index; or Karnofsky Performance Status [KPS] score. After adjustment for age, the WHO performance status, interval of recurrence, and extent of resection at the first operation, multivariate analysis showed that median survival was significantly better in the reoperation group than in the no-reoperation group (22.9 vs. 14.61 months, P< 0.05). After a total of 69 repeat operations in 59 patients (10 had 2 repeat surgeries), we noted 13 temporary and 20 permanent adverse postoperative events, yielding a permanent complication rate of 28.99% (20/69). There was also a statistically significant (P = 0.029, Student's t-test) decrease in the mean KPS score after reoperation (mean preoperative KPS score of 89.34 vs. mean postoperative score of 84.91). Conclusion: Our retrospective study suggests that repeat surgery may be beneficial for patients with GBM recurrence who have good functional status (WHO performance status 0 and 1), although the potential benefits must be weighed against the risk of permanent complications, which occurred in almost 30% of the patients who underwent repeat resection in this series.

Diffusion magnetic resonance (MR) characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-vascular endothelial growth factor (VEGF) therapy; however, its use in large volume recurrence has not been evaluated. To determine if diffusion MR characteristics can predict survival outcomes in patients with large volume recurrent glioblastoma treated with bevacizumab or repeat resection. A total of 32 patients with large volume (>20 cc or > 3.4 cm diameter) recurrent glioblastoma treated with bevacizumab and 35 patients treated with repeat surgery were included. Pretreatment tumor volume and apparent diffusion coefficient (ADC) histogram analysis were used to phenotype patients as having high (>1.24 μm2/ms) or low (<1.24 μm2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor. In bevacizumab and surgical cohorts, volume was correlated with overall survival (Bevacizumab: P = .009, HR = 1.02; Surgical: P = .006, HR = 0.96). ADCL was an independent predictor of survival in the bevacizumab cohort (P = .049, HR = 0.44), but not the surgical cohort (P = .273, HR = 0.67). There was a survival advantage of surgery over bevacizumab in patients with low ADCL (P = .036, HR = 0.43) but not in patients with high ADCL (P = .284, HR = 0.69). Pretreatment diffusion MR imaging is an independent predictive biomarker for overall survival in recurrent glioblastoma with a large tumor burden. Large tumors with low ADCL have a survival benefit when treated with surgical resection, whereas large tumors with high ADCL may be best managed with bevacizumab.

Background: Shared decision making (SDM) has proven to be a valuable approach in different patient populations when treatment decisions are called for. Along the disease trajectory of high-grade glioma (HGG), patients are presented with a series of treatment decisions. At the same time, HGG patients often experience cognitive deterioration and reduced decision-making capacity. This study aimed to review the current knowledge about shared decision making from the perspective of the HGG patient. Methods: Systematic searches were performed in MEDLINE, CINAHL, PsycINFO, and EMBASE. Studies were reviewed against the inclusion criteria and assessed for methodological quality. Descriptive data from the included studies were extracted and a narrative synthesis of the findings was performed. Results: The searches resulted in 5051 original records. Four studies involving 178 HGG patients fulfilled the inclusion criteria. The narrative synthesis revealed that most HGG patients in the included studies appreciated an SDM approach and that sufficient information and involvement increased patients’ emotional well-being. The use of a patient decision aid showed the potential to increase knowledge, decrease uncertainty, and affect the treatment decision making of HGG patients. Conclusion: The results indicate that many HGG patients prefer an SDM approach and that SDM can lead patients toward improved emotional well-being. The evidence is weak, however, and firm conclusions and practice guidelines concerning SDM in HGG patients cannot be made. Future research is warranted to improve decision support for HGG patients.

Background: At present, the treatment of recurrent glioblastoma is extremely challenging. In this study, we used a novel three-dimensional non-coplanar template (3DNPT) combined with open MR to guide ¹²⁵I seed implantation for recurrent glioblastoma. The aim of this study was to evaluate the feasibility, accuracy, and effectiveness of this technique. Methods: Twenty-four patients of recurrent glioblastoma underwent 3DNPT with open MR-guided ¹²⁵I brachytherapy from August 2017 to January 2019. Preoperative treatment plan and 3DNPT were made according to enhanced isovoxel T1-weighted MR images. ¹²⁵I seeds were implanted using 3DNPT and 1.0-T open MR imaging guidance. Dosimetry verification was performed after brachytherapy based on postoperative CT/MR fusion images. Preoperative and postoperative dosimetry parameters of D90, V100, V200, conformity index (CI), external index (EI) were compared. The objective response rate (ORR) at 6 months and 1-year survival rate were calculated. Median overall survival (OS) measured from the date of brachytherapy was estimated by Kaplan-Meier method. Results: There were no significant differences between preoperative and postoperative dosimetry parameters of D90, V100, V200, CI, EI (P > 0.05). The ORR at 6 months was 75.0%. The 1-year survival rate was 58.3%. Median OS was 12.9 months. One case of small amount of epidural hemorrhage occurred during the procedure. There were 3 cases of symptomatic brain edema after brachytherapy treatment, including grade three toxicity in 1 case and grade two toxicity in 2 cases. The three patients were treated with corticosteroid for 2 to 4 weeks. The clinical symptoms related to brain edema were significantly alleviated thereafter. Conclusions: 3DNPT combined with open MR-guided ¹²⁵I brachytherapy for circumscribed recurrent glioblastoma is feasible, effective, and with low risk of complications. Postoperative dosimetry matched the preoperative treatment plan. The described method can be used as a novel implantation technique for ¹²⁵I brachytherapy in the treatment of recurrent gliomas. Trial registration: The study was approved by the Institutional Review Board of Shandong Provincial Hospital Affiliated to Shandong University (NSFC:NO.2017–058), registered 1st July 2017.

Recurrence of glioblastoma (GB) is inevitable. As the optimal management for recurrent glioblastoma continues to evolve, clear treatment guidelines for are lacking. Existing literature does not clarify the role that second surgery plays in the treatment of these patients. Although few studies report that second surgery is beneficial in select patients and leads to longer overall survival (OS), other studies have demonstrated the limited impact that repeat surgery has on the eventual patient outcome. Maximal safe resection (high extent of resection—EOR) has been proven to improve the OS at reoperation, even when undertaken for cases where the first surgery achieved only a limited EOR. Karnofsky Performance Score (KPS) and age at presentation are valuable prognostic factors that predict better OS and aid in better patient selection for surgical management. The true value of reoperation versus systemic treatment, their effects the patient’s QoL and the added increase in overall survival is better judged after detailed investigation by means of a prospective, randomized trial.

Malignant glial tumors (gliomas) are the second (after cerebral stroke) cause of death from diseases of the central nervous system. The current routine therapy, involving a combination of tumor resection, radio-, and chemo-therapy, only modestly improves survival. Sonodynamic therapy (SDT) has been broadly defined as a synergistic effect of sonication applied in combination with substances referred to as “sonosensitizers”. The current review focuses on the possibility of the use of tumor-seeking sonosensitizers, in particular 5-aminolevulinic acid, to control recurring gliomas. In this application, SDT employs a principle similar to that of the more widely-known photodynamic therapy of superficially located cancers, the difference being the use of ultrasound instead of light to deliver the energy necessary to eliminate the sensitized malignant cells. The ability of ultrasound to penetrate brain tissues makes it possible to reach deeply localized intracranial tumors such as gliomas. The major potential advantage of this variant of SDT is its relative non-invasiveness and possibility of repeated application. Until now, there have been no clinical data regarding the efficacy and safety of such treatment for malignant gliomas, but the preclinical data are encouraging.

Los tumores primarios del sistema nervioso representaron aproximadamente el 1,4 % de los nuevos diagnósticos de cáncer en 2015 y causan el 2,6 % de las muertes por cáncer. Estos tienen una mayor implicación clínica en la población infantil y en adultos jóvenes; y su incidencia disminuye con la edad. Los tumores más frecuentes en los adultos incluyen meningiomas, gliomas y tumores pituitarios. En este artículo se hace una revisión actualizada sobre la epidemiología de los tumores primarios del sistema nervioso, así como las principales características y actualizaciones en el manejo de los tumores más prevalentes en la población adulta.

Deciding whether to re-operate patients with intracranial tumor recurrence or remnant is challenging, as the data on safety of repeated procedures is limited. This study set out to evaluate the risks for morbidity, mortality, and complications after repeated operations, and to compare those to primary operations. Retrospective observational two-center study on consecutive patients undergoing microsurgical tumor resection. The data derived from independent, prospective institutional registries. The primary endpoint was morbidity at 3 months (M3), defined as significant decrease on the Karnofsky Performance Scale (KPS). Secondary endpoints were mortality, rate and severity of complications according to the Clavien–Dindo Grade (CDG). 463/2403 (19.3%) were repeated procedures. Morbidity at M3 occurred in n = 290 patients (12.1%). In univariable analysis, patients undergoing repeated surgery were 98% as likely as patients undergoing primary surgery to experience morbidity (OR 0.98, 95% CI 0.72–1.34, p = 0.889). In multivariable analysis adjusted for age, sex, tumor size, histology and posterior fossa location, the relationship remained stable (aOR 1.25, 95% CI 0.90–1.73, p = 0.186). Mortality was n = 10 (0.4%) at discharge and n = 95 (4.0%) at M3, without group differences. At least one complication occurred in n = 855, and the rate (35.5% vs. 35.9%, p = 0.892) and severity (CDG; p = 0.520) was similar after primary and repeated procedures. Results were reproduced in subgroup analyses for meningiomas, gliomas and cerebral metastases. Repeated surgery for intracranial tumors does not increase the risk of morbidity. Mortality, and both the rate and severity of complications are comparable to primary operations. This information is of value for patient counseling and the informed consent process. The online version of this article (10.1007/s11060-018-03058-y) contains supplementary material, which is available to authorized users.

The aim of this retrospective study was to evaluate survival outcomes in well-performing, mainly, young patients receiving a sequence of all available therapeutic options for relapsed glioblastoma, including re-irradiation.

Glioblastomas (GBM) are localized in only less than 1% of patients in the cerebellum. Therefore, tumor characteristics, survival, and the efficacy of therapies are not yet well defined. The present study aims to characterize the molecular features of cerebellar GBM (GBMc) in 8 patients treated with contemporary modality in our institution.

GBM is one of the most common and aggressive brain tumors. Surgery and adjuvant chemoradiation have succeeded in providing a survival benefit. Although most patients will eventually experience local recurrence, the means to fight recurrence are limited and prognosis remains poor. In a disease where local control remains the major challenge, few trials have addressed the efficacy of local treatments, either surgery or radiation therapy. The present article reviews recent advances in the biology, imaging and biomarker science of GBM as well as the current treatment status of GBM, providing new perspectives to the problem of local recurrence.