Indirect functional connectivity does not predict overall survival in glioblastoma.

BACKGROUND: Lesion network mapping (LNM) is a popular framework to assess clinical syndromes following brain injury. The classical approach involves embedding lesions from patients into a normative functional connectome and using the corresponding functional maps as proxies for disconnections. However, previous studies indicated limited predictive power of this approach in behavioral deficits. We hypothesized similarly low predictiveness for overall survival (OS) in glioblastoma (GBM). METHODS: A retrospective dataset of patients with GBM was included (n = 99). Lesion masks were registered in the normative space to compute disconnectivity maps. The brain functional normative connectome consisted in data from 173 healthy subjects obtained from the Human Connectome Project. A modified version of the LNM was then applied to core regions of GBM masks. Linear regression, classification, and principal component (PCA) analyses were conducted to explore the relationship between disconnectivity and OS. OS was considered both as continuous and categorical (low, intermediate, and high survival) variable. RESULTS: The results revealed no significant associations between OS and network disconnection strength when analyzed at both voxel-wise and classification levels. Moreover, patients stratified into different OS groups did not exhibit significant differences in network connectivity patterns. The spatial similarity among the first PCA of network maps for each OS group suggested a lack of distinctive network patterns associated with survival duration. CONCLUSIONS: Compared with indirect structural measures, functional indirect mapping does not provide significant predictive power for OS in patients with GBM. These findings are consistent with previous research that demonstrated the limitations of indirect functional measures in predicting clinical outcomes, underscoring the need for more comprehensive methodologies and a deeper understanding of the factors influencing clinical outcomes in this challenging disease.

Present and Future of Immunotherapy in Patients With Glioblastoma: Limitations and Opportunities.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. Standard therapies, including surgical resection, chemoradiation, and tumor treating fields, have not resulted in major improvements in the survival outcomes of patients with GBM. The lack of effective strategies has led to an increasing interest in immunotherapic approaches, considering the success in other solid tumors. However, GBM is a highly immunosuppressive tumor, as documented by the presence of several mechanisms of immune escape, which may represent a reason why immunotherapy clinical trials failed in this kind of tumor. In this review, we examine the current landscape of immunotherapy strategies in GBM, focusing on the challenge of immunoresistance and potential mechanisms to overcome it. We discussed completed and ongoing clinical trials involving immune checkpoint inhibitors, oncolytic viruses, vaccines, and CAR T-cell therapies, to provide insights into the efficacy and outcomes of different immunotherapeutic interventions. We also explore the impact of radiotherapy on the immune system within the GBM microenvironment highlighting the complex interactions between radiation treatment and the immune response.

The role of adjuvant chemotherapy in patients with H3K27 altered diffuse midline gliomas: a multicentric retrospective study.

PURPOSE: Adult Diffuse midline glioma (DMG) is a very rare disease. DMGs are currently treated with radiotherapy and chemotherapy even if only a few retrospective studies assessed the impact on overall survival (OS) of these approaches. METHODS: We carried out an Italian multicentric retrospective study of adult patients with H3K27-altered DMG to assess the effective role of systemic therapy in the treatment landscape of this rare tumor type. RESULTS: We evaluated 49 patients from 6 Institutions. The median age was 37.3 years (range 20.1-68.3). Most patients received biopsy as primary approach (n = 30, 61.2%) and radiation therapy after surgery (n = 39, 79.6%). 25 (51.0%) of patients received concurrent chemotherapy and 26 (53.1%) patients received adjuvant temozolomide. In univariate analysis, concurrent chemotherapy did not result in OS improvement while adjuvant temozolomide was associated with longer OS (21.2 vs. 9.0 months, HR 0.14, 0.05-0.41, p < 0.001). Multivariate analysis confirmed the role of adjuvant chemotherapy (HR 0.1, 95%CI: 0.03-0.34, p = 0.003). In patients who progressed after radiation and/or chemotherapy the administration of a second-line systemic treatment had a significantly favorable impact on survival (8.0 vs. 3.2 months, HR 0.2, 95%CI 0.1-0.65, p = 0.004). CONCLUSION: In our series, adjuvant treatment after radiotherapy can be useful in improving OS of patients with H3K27-altered DMG. When feasible another systemic treatment after treatment progression could be proposed.

Impressive response to dabrafenib and trametinib plus silybin in a heavily pretreated IDH wild-type glioblastoma patient with BRAFV600E -mutant and SOX2 amplification.

Isocitrate dehydrogenase wild-type glioblastoma is the most frequent primary brain tumor in adult patients and its prognosis is still dismal with a median survival of about 1 year. BRAF V600E mutation, an important target for personalized therapy, has been identified in about 3% of these patients, but few data are available from prospective studies on the role of anti-BRAF drugs in adult glioblastoma patients. Moreover, SOX2 gene amplification and overexpression can represent an important mechanism of resistance to BRAF inhibitors by STAT3 gene activation. We present the case of a heavily pretreated 42-year-old man with BRAF V600E mutant and SOX2 amplification glioblastoma having a radiologic and metabolic [analyzed by a brain 18F-fluoro-ethyl-tyrosine([18F]FET) PET/MRI] complete response to the combination therapy with dabrafenib plus trametinib and silybin, a potent STAT3 inhibitor. The patient is currently undergoing treatment after a total of 24 months of continuation therapy with a good safety profile. In conclusion, we showed a promising activity of the personalized treatment of BRAF and MEK inhibitors in patient with BRAF V600E mutant glioblastoma; silybin can play an important role in decreasing drug resistance during BRAF inhibitor therapy, especially in patients with SOX2 amplification.

Association between thyroid function and regorafenib efficacy in patients with relapsed wild-type IDH glioblastoma: a large multicenter study.

PURPOSE: Regorafenib demonstrated encouraging results in recurrent glioblastoma patients. Some studies showed that changes in circulating thyroid hormones (fT3, fT4, fT3/fT4 ratio) can be considered as prognostic factors in patients with various types of tumors. We designed this study to investigate the relationship between baseline thyroid variables and outcome in IDH-wild type GBM patients who were treated with regorafenib. METHODS: This multicenter retrospective study included recurrent IDH-wild-type glioblastoma patients treated with regorafenib. Only patients with baseline thyroid function values (TSH, fT3, fT4, fT3/fT4 ratio) available were evaluated. RANO criteria were used to analyze neuroradiological response. Survival curves were estimated using the Kaplan-Meier method. The relationships between baseline thyroid variables (TSH, fT3, fT4, fT3/fT4) and survival (PFS, OS) were investigated with Cox regression models. RESULTS: From November 2015 to April 2022, 134 recurrent IDH-wildtype GBM patients were treated with regorafenib and 128 of these had information on baseline thyroid function value. Median follow-up was 8 months (IQR 4.7-14.0). Objective Response Rate was 9% and Disease Control Rate was 40.9%. Median PFS was 2.7 months (95%CI 2.2-3.6) and median OS was 10.0 months (95%CI 7.0-13.0). Lower baseline TSH value in the blood was correlated with a higher rate of disease progression to regorafenib (p = 0.04). Multivariable analyses suggested a non-linear relationship between PFS (p = 0.01) and OS (p = 0.03) with baseline fT3/fT4 ratio. CONCLUSION: In recurrent wild-type IDH glioblastoma patients, baseline fT3/fT4 ratio showed a non-linear relationship with survival, with different impacts across the spectrum of fT3/fT4 ratio. Moreover, baseline TSH may be a predictor of regorafenib activity.

Prolonged benefit to pembrolizumab in anaplastic oligodendroglioma patient with mismatch repair deficiency: a case report.

High-grade gliomas, including anaplastic oligodendroglioma, represent the most common malignant neoplasms of the central nervous system in the adult. The standard treatment of anaplastic oligodendroglioma consists of maximum surgical resection, radiotherapy and subsequent chemotherapy. Despite multimodal treatment, theoretically, all cases can relapse. Immune checkpoint inhibitors (ICIs) as pembrolizumab demonstrated promising results in many types of tumors, particularly in the presence of mismatch repair deficiency (MMRd). However, no ICI benefit was demonstrated in high-grade glioma prospective studies, although no biomarker was analyzed. Here, we describe an interesting case of recurrent anaplastic oligodendroglioma with MMRd, reporting a prolonged disease stability during pembrolizumab treatment.

Eslicarbazepine in patients with brain tumor-related epilepsy: a single-center experience.

PURPOSE: Brain tumor-related epilepsy (BTRE) is frequent in patients affected with glioma. Most patients have refractory seizures and require polytherapy. Promising treatment options derive from the development of novel anti-epileptic drugs (AEDs), like Eslicarbazepine (ESL), whose role in BTRE has not yet been explored. Our aim was to report a retrospective cohort of patients affected by BTRE treated with ESL as an adjunctive therapy and to discuss the potential role of this third-generation AED in this clinical context. METHODS: We analyzed a single-center, retrospectively collected cohort of patients affected by glioma and BTRE, treated with ESL as an adjunctive therapy. RESULTS: Analysis included 5 males and 3 females with age ranging from 37 to 75 years (mean = 55.5). Mean baseline Karnofsky performance status was 87.5 (range 70-100). Patients were affected by diffuse astrocytoma (3), low grade oligodendroglioma (2), anaplastic glioma (2) and glioblastoma (1). Mean follow-up was 19 months (range 6-59). Mean dose at the last follow-up was 950 mg daily. Mean weekly seizures in the month before initiation of ESL numbered 17.6 (range 0.25-50). At the last follow-up, mean weekly seizures were 2.2 (range 0-10), i.e. significantly lower than baseline (p = 0.03). The mean reduction of seizures achieved after introduction of ESL was 65%, with 6/8 patients (75%) showing a reduction of more than 50%. Two patients (25%) were seizure free. CONCLUSIONS: This single-center experience suggests that ESL may be a well-tolerated, efficacious option as an add-on drug in the treatment of BTRE.

Rapid disease progression in patient with mismatch-repair deficiency pituitary ACTH-secreting adenoma treated with checkpoint inhibitor pembrolizumab.

Secreting pituitary adenomas are tumors for which few treatment options are available, including surgical treatment and management of hormonal imbalance due to altered pituitary secretion. In case of inoperable relapse, radiotherapy or chemotherapeutic treatment can be considered; the effectiveness of these treatments, however, remains limited. In the immunotherapy era, it is necessary to select patients who can benefit from immunotherapeutic treatment. Mismatch repair deficiency is strongly associated with responsiveness to anti-PD-1 in other cancers and can be detected using immunohistochemistry for MLH1, MSH2, MHS6, and PMS2. In this case report, we report a case of rapid disease progression to pembrolizumab in a patient with a MMRd pituitary adrenocorticotropic hormone (ACTH)-secreting adenoma. For the best of our knowledge, we described for the first time, a poor efficacy of pembrolizumab in a patient with ACTH-secreting pituitary adenoma having mismatch repair deficiency probably caused by high levels of cortisol in this patient. Prospective study should be performed to assess the activity of immune checkpoint inhibitor alone or in association with temozolomide in this subsetting of pituitary adenomas.

Mismatch-Repair Protein Expression in High-Grade Gliomas: A Large Retrospective Multicenter Study.

BACKGROUND: DNA mismatch repair (MMR) is a system for repairing errors in DNA replication. Cancer cells with MMR deficiency can have immunohistochemical loss of MMR protein expression leading to a hypermutable phenotype that may correlate with anti-PD1 efficacy. Scant data exist about immunohistochemical loss of MMR protein expression in high-grade gliomas (HGG). MATERIALS AND METHODS: We performed a large multicenter retrospective study to investigate the frequency and the prognostic role of immunohistochemical loss of MMR protein expression in HGG patients; we nevertheless evaluated the association between this status and clinical or molecular characteristics. Immunohistochemical loss of MMR protein expression was recorded as partial or complete loss of at least 1 MMR protein. RESULTS: We analyzed the expression of MMR proteins in tumor tissue of 355 consecutive patients. Partial and complete immunohistochemical loss of MMR proteins was found in 43/355 samples (12.1%) and among these, 15 cases (4.2%) showed a complete loss of at the least one MMR protein. Alteration of MSH2 expression was found in 55.8%, MSH6 in 46.5%, PMS2 in 34.9%, and MLH1 in 30.2%. Alteration of MMR protein expression was statistically more frequent in anaplastic gliomas, in recurrent disease, in patients treated with temozolomide, and in IDH-mut gliomas. Immunohistochemical loss of MMR proteins was not associated with survival, adjusting for clinically relevant confounders. CONCLUSIONS: MMR protein expression status did not affect survival in HGG patients. We identified clinical and molecular characteristics correlating with immunohistochemical loss of MMR proteins expression. A large study should be performed to analyze its predictive role of immune checkpoint inhibitor efficacy in these subgroups of patients.

Knowing when to discontinue Temozolomide therapy in responding aggressive pituitary tumors and carcinomas: a systematic review and Padua (Italy) case series.

INTRODUCTION: Pituitary adenomas can show a tendency to grow, despite multimodal treatment. Temozolomide (TMZ) has been used in the last 15 years in patients with aggressive pituitary tumors. TMZ requires a careful balance of different expertise, especially for selection criteria. AREAS COVERED: We conducted: (1) a systematic review of the published literature from 2006 to 2022, collecting only cases with a complete description of patient follow-up after TMZ discontinuation; (2) a description of all patients with aggressive pituitary adenoma or carcinoma treated in Padua (Italy). EXPERT OPINION: There is considerable heterogeneity in the literature: TMZ cycles duration ranged from 3 to 47 months; the follow-up time after TMZ discontinuation ranged from 4 to 91 months (mean 24 months, median 18 months), at least a stable disease has been reported in 75% of patients after a mean 13 months (range 3-47 months, median 10 months). The Padua (Italy) cohort reflects the literature. Future directions to explore are to understand the pathophysiological mechanism of TMZ resistance escape, to develop predicting factors to TMZ treatment (especially through the delineation of the underlying transformation processes), and to further expand the therapeutic applications of TMZ (as neoadjuvant, combined with radiotherapy).

The role of radiation therapy and systemic treatments in meningioma: The present and the future.

Meningiomas are the most prevalent tumors of the central nervous system. Their standard treatment is surgery, which can be curative. Adjuvant radiotherapy treatment is reserved for newly diagnosed cases of grade II and grade III meningiomas in cases of recurrent disease or when surgery is not radical or feasible. However, around 20% of these patients cannot undergo further surgical and/or radiotherapy treatment. Systemic oncological therapy can find its place in this setting. Several tyrosine kinase inhibitors have been tested (gefitinib, erlotinib, sunitinib) with unsatisfactory or negative results. Bevacizumab has shown encouraging results in these settings of patients. Immunotherapy with immune checkpoint inhibitors has reported interesting results with modest objective response rates. Several ongoing studies are assessing different target therapies and multimodal therapies; the results are to be disclosed. Not only a better understanding of the molecular characteristics in meningiomas has allowed the gathering of more information regarding pathogenesis and prognosis, but in addition, the availability of new target therapy, immunotherapy, and biological drugs has widened the scope of potentially effective treatments in this patient population. The aim of this review was to explore the radiotherapy and systemic treatments of meningioma with an analysis of ongoing trials and future therapeutic perspectives.

Actionable molecular alterations in newly diagnosed and recurrent IDH1/2 wild-type glioblastoma patients and therapeutic implications: a large mono-institutional experience using extensive next-generation sequencing analysis.

BACKGROUND: Next-generation sequencing (NGS) panels enable the identification of alterations in cancer-related genes. This may guide a molecularly targeted strategy for the treatment of glioblastoma (GBM). MATERIAL AND METHODS: We retrospectively analysed data obtained using FoundationOne®CDx in a large cohort of IDH1/2 wild-type GBM. We aimed to 1) identify potentially actionable molecular alterations at diagnosis and/or recurrence based on ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) defined categories of targetability, 2) understand the clinical implications of NGS in terms of access to and activity of targeted therapies. RESULTS: In 442 samples, an NGS profile was available in 98.2%. The median time from diagnosis to NGS profiling was 7.4 months (interquartile range (IQR): 3.4-13.2). Although about half of the patients had at least one actionable molecular alteration, only 3.4% of them were classified as ESCAT IB-IC and 6.7% as ESCAT IIB. Only 36 patients (10.5%) received personalised treatment in clinical trials or as off-label/compassionate use from second-line (median line 3). Most patients did not receive targeted therapy due to clinical deterioration/death (49.6%). Patients treated with dabrafenib/trametinib (9 patients) had the highest disease control rate of 77% and an objective response rate of 22%, with a median progression-free survival (PFS) of 5.2 months. No complete/partial responses were seen with the other regimens. 4/9 (44.4%) patients on anti-BRAF/anti-MEK, 2/4 patients (50%) on erdafitinib and 1/1 patient on capmatinib had a PFS ratio > 1.3. One recurrent GBM patient with ROS1-GOCP fusion maintained a complete response for 11.3 months on entrectinib. CONCLUSIONS: Our study demonstrated the feasibility of NGS in GBM samples. As the number of clinically relevant targets was limited and only a small group of GBM patients were treated with targeted therapy, NGS testing should be performed in the context of clinical trials. Our results support the activity of anti-BRAF/anti-MEK, while for the other agents prospective study results are needed to draw solid conclusions.

Spinal ependymoma in adults: from molecular advances to new treatment perspectives.

Ependymomas are rare glial tumors with clinical and biological heterogeneity, categorized into supratentorial ependymoma, posterior fossa ependymoma, and spinal cord ependymoma, according to anatomical localization. Spinal ependymoma comprises four different types: spinal ependymoma, spinal ependymoma MYCN-amplified, myxopapillary ependymoma, and subependymoma. The clinical onset largely depends on the spinal location of the tumor. Both non-specific and specific sensory and/or motor symptoms can be present. Owing to diverse features and the low incidence of spinal ependymomas, most of the current clinical management is derived from small retrospective studies, particularly in adults. Treatment involves primarily surgical resection, aiming at maximal safe resection. The use of radiotherapy remains controversial and the optimal dose has not been established; it is usually considered after subtotal resection for WHO grade 2 ependymoma and for WHO grade 3 ependymoma regardless of the extent of resection. There are limited systemic treatments available, with limited durable results and modest improvement in progression-free survival. Thus, chemotherapy is usually reserved for recurrent cases where resection and/or radiation is not feasible. Recently, a combination of temozolomide and lapatinib has shown modest results with a median progression-free survival (PFS) of 7.8 months in recurrent spinal ependymomas. Other studies have explored the use of temozolomide, platinum compounds, etoposide, and bevacizumab, but standard treatment options have not yet been defined. New treatment options with targeted treatments and immunotherapy are being investigated. Neurological and supportive care are crucial, even in the early stages. Post-surgical rehabilitation can improve the consequences of surgery and maintain a good quality of life, especially in young patients with long life expectancy. Here, we focus on the diagnosis and treatment recommendations for adults with spinal ependymoma, and discuss recent molecular advances and new treatment perspectives.

Patterns of gray and white matter functional networks involvement in glioblastoma patients: indirect mapping from clinical MRI scans.

Background: Resting-state functional-MRI studies identified several cortical gray matter functional networks (GMNs) and white matter functional networks (WMNs) with precise anatomical localization. Here, we aimed at describing the relationships between brain's functional topological organization and glioblastoma (GBM) location. Furthermore, we assessed whether GBM distribution across these networks was associated with overall survival (OS). Materials and methods: We included patients with histopathological diagnosis of IDH-wildtype GBM, presurgical MRI and survival data. For each patient, we recorded clinical-prognostic variables. GBM core and edema were segmented and normalized to a standard space. Pre-existing functional connectivity-based atlases were used to define network parcellations: 17 GMNs and 12 WMNs were considered in particular. We computed the percentage of lesion overlap with GMNs and WMNs, both for core and edema. Differences between overlap percentages were assessed through descriptive statistics, ANOVA, post-hoc tests, Pearson's correlation tests and canonical correlations. Multiple linear and non-linear regression tests were employed to explore relationships with OS. Results: 99 patients were included (70 males, mean age 62 years). The most involved GMNs included ventral somatomotor, salient ventral attention and default-mode networks; the most involved WMNs were ventral frontoparietal tracts, deep frontal white matter, and superior longitudinal fasciculus system. Superior longitudinal fasciculus system and dorsal frontoparietal tracts were significantly more included in the edema (p < 0.001). 5 main patterns of GBM core distribution across functional networks were found, while edema localization was less classifiable. ANOVA showed significant differences between mean overlap percentages, separately for GMNs and WMNs (p-values<0.0001). Core-N12 overlap predicts higher OS, although its inclusion does not increase the explained OS variance. Discussion and conclusion: Both GBM core and edema preferentially overlap with specific GMNs and WMNs, especially associative networks, and GBM core follows five main distribution patterns. Some inter-related GMNs and WMNs were co-lesioned by GBM, suggesting that GBM distribution is not independent of the brain's structural and functional organization. Although the involvement of ventral frontoparietal tracts (N12) seems to have some role in predicting survival, network-topology information is overall scarcely informative about OS. fMRI-based approaches may more effectively demonstrate the effects of GBM on brain networks and survival.

Efficacy and safety of chlorpromazine as an adjuvant therapy for glioblastoma in patients with unmethylated MGMT gene promoter: RACTAC, a phase II multicenter trial.

Introduction: Drug repurposing is a promising strategy to develop new treatments for glioblastoma. In this phase II clinical trial, we evaluated the addition of chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol in patients with unmethylated MGMT gene promoter. Methods: This was a multicenter phase II single-arm clinical trial. The experimental procedure involved the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol in newly-diagnosed GBM patients carrying an unmethylated MGMT gene promoter. Progression-free survival was the primary endpoint. Secondary endpoints were overall survival and toxicity. Results: Forty-one patients were evaluated. Twenty patients (48.7%) completed 6 cycles of treatment with TMZ+CPZ. At 6 months, 27 patients (65.8%) were without progression, achieving the primary endpoint. Median PFS was 8.0 months (95% CI: 7.0-9.0). Median OS was 15.0 months (95% CI: 13.1-16.9). Adverse events led to reduction or interruption of CPZ dosage in 4 patients (9.7%). Discussion: The addition of CPZ to standard TMZ in the first-line treatment of GBM patients with unmethylated MGMT gene promoter was safe and led to a longer PFS than expected in this population of patients. These findings provide proof-of-concept for the potential of adding CPZ to standard TMZ treatment in GBM patients with unmethylated MGMT gene promoter. Clinical trial registration: https://clinicaltrials.gov/study/NCT04224441, identifier NCT04224441.

The Overall Survival and Progression-Free Survival in Patients with Advanced Adrenocortical Cancer Is Increased after the Multidisciplinary Team Evaluation.

We aimed to evaluate the role of adrenal multidisciplinary team evaluation (MTE) in affecting the overall survival (OS) and progression-free survival (PFS) in patients with adrenocortical carcinoma (ACC). We included in a retrospective monocentric study 47 patients with ACC. We divided our cohort into group 1 (without adrenal-MTE discussion, ACC diagnosis from 2004 to 2012, n = 14) and group 2 (diagnosis and beginning of treatments after 2013, all discussed in the adrenal MTE, n = 33). OS was defined by the survival between the first and the last visit, while PFS as the time from the first visit to the progression of the disease. Kaplan−Meier curves were used to compare OS and PFS between Group 1 and Group 2. Group 1stages III−IV (n = 10) presented a shorter median OS than Group 2stages III−IV (25 patients, 4 vs. 31 months, p = 0.023). Likewise, the median PFS was lower in Group 1 as compared to Group 2 (2.9 vs. 17.2 months, p < 0.001). The gain in PFS (6 months) was also confirmed in stage III-IV patients (2.9 vs. 8.7 months, respectively, for Group 1 and Group 2, p = 0.02). Group 1 presented a median PFS of 4 months, while the median PFS of Group 2 was 14.7 months (p = 0.128). In conclusion, we found a significant gain in terms of survival in patients after the MTE discussion in 2013. Therefore, ACC patients should be referred to a tertiary center, ideally from the time of diagnosis, to promptly apply all available treatments, according to the single patient's clinical history and based on multidisciplinary management.

PET/MR in recurrent glioblastoma patients treated with regorafenib: [18F]FET and DWI-ADC for response assessment and survival prediction.

OBJECTIVE: The use of regorafenib in recurrent glioblastoma patients has been recently approved by the Italian Medicines Agency (AIFA) and added to the National Comprehensive Cancer Network (NCCN) 2020 guidelines as a preferred regimen. Given its complex effects at the molecular level, the most appropriate imaging tools to assess early response to treatment is still a matter of debate. Diffusion-weighted imaging and O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography ([18F]FET PET) are promising methodologies providing additional information to the currently used RANO criteria. The aim of this study was to evaluate the variations in diffusion-weighted imaging/apparent diffusion coefficient (ADC) and [18F]FET PET-derived parameters in patients who underwent PET/MR at both baseline and after starting regorafenib. METHODS: We retrospectively reviewed 16 consecutive GBM patients who underwent [18F]FET PET/MR before and after two cycles of regorafenib. Patients were sorted into stable (SD) or progressive disease (PD) categories in accordance with RANO criteria. We were also able to analyze four SD patients who underwent a third PET/MR after another four cycles of regorafenib. [18F]FET uptake greater than 1.6 times the mean background activity was used to define an area to be superimposed on an ADC map at baseline and after treatment. Several metrics were then derived and compared. Log-rank test was applied for overall survival analysis. RESULTS: Percentage difference in FET volumes correlates with the corresponding percentage difference in ADC (R = 0.54). Patients with a twofold increase in FET after regorafenib showed a significantly higher increase in ADC pathological volume than the remaining subjects (p = 0.0023). Kaplan-Meier analysis, performed to compare the performance in overall survival prediction, revealed that the percentage variations of FET- and ADC-derived metrics performed at least as well as RANO criteria (p = 0.02, p = 0.024 and p = 0.04 respectively) and in some cases even better. TBR Max and TBR mean are not able to accurately predict overall survival. CONCLUSION: In recurrent glioblastoma patients treated with regorafenib, [18F]FET and ADC metrics, are able to predict overall survival and being obtained from completely different measures as compared to RANO, could serve as semi-quantitative independent biomarkers of response to treatment. ADVANCES IN KNOWLEDGE: Simultaneous evaluation of [18F]FET and ADC metrics using PET/MR allows an early and reliable identification of response to treatment and predict overall survival.

Regorafenib in Recurrent Glioblastoma Patients: A Large and Monocentric Real-Life Study.

Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor showing encouraging benefits in recurrent GBM patients enrolled in the REGOMA trial. We performed a large study to investigate clinical outcomes and the safety of regorafenib in a real-life population of recurrent glioblastoma patients. Patients receiving regorafenib outside clinical trials at the Veneto Institute of Oncology were retrospectively reviewed. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, prior first line therapy according to "Stupp protocol", Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. According to the original schedule, patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoints of the study were overall survival and safety. A total of 54 consecutive patients were enrolled. The median age was 56, MGMT methylated status was found in 28 out of 53 available patients (52.8%), IDH mutation in 5 (9.3%) and 22 patients were receiving steroids at baseline. The median overall survival was 10.2 months (95% CI, 6.4-13.9), the OS-12 was 43%. Age, MGMT methylation status and steroid use at baseline were not statistically significant on a multivariate analysis for OS. Patients reporting a disease control as best response to regorafenib demonstrated a significant longer survival (24.8 months vs. 6.2 months for patients with progressive disease, p = 0.0001). Grade 3 drug-related adverse events occurred in 10 patients (18%); 1 patient (2%) reported a grade 4 adverse event (rash maculo-papular). No death was considered to be drug-related. This study reported the first large "real-life" experience of regorafenib in recurrent glioblastoma. Overall, our results are close to the ones reported in the previous phase 2 study, despite the fact that we had a longer survival. We showed the encouraging activity and tolerability of this treatment in recurrent glioblastoma patients when used as a second-line treatment.

Depatuxizumab Mafodotin (Depatux-M) Plus Temozolomide in Recurrent Glioblastoma Patients: Real-World Experience from a Multicenter Study of Italian Association of Neuro-Oncology (AINO).

BACKGROUND: Depatuxizumab Mafodotin (Depatux-M; ABT-414) is an antibody-drug conjugate consisting of a specific antibody against activated EGFR and a cytotoxic agent with antimicrotubule activity. The INTELLANCE 2/EORTC 1410 phase 2 trial produced interesting results for the combination regimen of Depatux-M and temozolomide in EGFR-amplified glioblastoma patients at first recurrence. For the first time worldwide, our work investigated the clinical outcome and safety of this combination in a real-life population. MATERIALS AND METHODS: Patients were enrolled from seven AINO (Italian Association of Neuro-Oncology) Institutions. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, EGFR-amplified, one or more prior systemic therapies and ECOG PS ≤ 2. According to the original schedule, patients received Depatux-M 1.25 mg/kg every 2 weeks combined with temozolomide. The primary endpoints of the study were overall survival and safety. RESULTS: A total of 36 patients were enrolled. The median age was 57 years, ECOG PS was 0-1 in 28 patients (88%), MGMT methylated status was found in 22 (64%), 15 patients (42%) received the combined treatment as second-line therapy. The median OS was 8.04 months (95% CI, 5.3-10.7), the 12 month-OS was 37%. On univariate and multivariate analyses, the MGMT methylation status was the only factor resulting significantly associated with survival. Grade 3 ocular toxicity occurred in 11% of patients; no grade 4 ocular toxicity was reported. No death was considered to be drug-related. CONCLUSIONS: The study reported the first "real world" experience of Depatux-M plus temozolomide in recurrent glioblastoma patients. Encouraging clinical benefits were demonstrated, even though most patients were treated beyond second-line therapy. Overall, the results are close to those reported in the previous phase 2 trial. Toxicity was moderate and manageable.

Myeloid Diagnostic and Prognostic Markers of Immune Suppression in the Blood of Glioma Patients.

Background: Although gliomas are confined to the central nervous system, their negative influence over the immune system extends to peripheral circulation. The immune suppression exerted by myeloid cells can affect both response to therapy and disease outcome. We analyzed the expansion of several myeloid parameters in the blood of low- and high-grade gliomas and assessed their relevance as biomarkers of disease and clinical outcome. Methods: Peripheral blood was obtained from 134 low- and high-grade glioma patients. CD14+, CD14+/p-STAT3+, CD14+/PD-L1+, CD15+ cells and four myeloid-derived suppressor cell (MDSC) subsets, were evaluated by flow cytometry. Arginase-1 (ARG1) quantity and activity was determined in the plasma. Multivariable logistic regression model was used to obtain a diagnostic score to discriminate glioma patients from healthy controls and between each glioma grade. A glioblastoma prognostic model was determined by multiple Cox regression using clinical and myeloid parameters. Results: Changes in myeloid parameters associated with immune suppression allowed to define a diagnostic score calculating the risk of being a glioma patient. The same parameters, together with age, permit to calculate the risk score in differentiating each glioma grade. A prognostic model for glioblastoma patients stemmed out from a Cox multiple analysis, highlighting the role of MDSC, p-STAT3, and ARG1 activity together with clinical parameters in predicting patient's outcome. Conclusions: This work emphasizes the role of systemic immune suppression carried out by myeloid cells in gliomas. The identification of biomarkers associated with immune landscape, diagnosis, and outcome of glioblastoma patients lays the ground for their clinical use.