Response assessment of GBM during immunotherapy by delayed contrast treatment response assessment maps.

Introduction: Assessing the treatment response of glioblastoma multiforme during immunotherapy (IT) is an open issue. Treatment response assessment maps (TRAMs) might help distinguish true tumor progression (TTP) and pseudoprogression (PsP) in this setting. Methods: We recruited 16 naïve glioblastoma patients enrolled in a phase II trial consisting of the Stupp protocol (a standardized treatment for glioblastoma involving combined radiotherapy and chemotherapy with temozolomide, followed by adjuvant temozolomide) plus IT with dendritic cells. Patients were followed up till progression or death; seven underwent a second surgery for suspected progression. Clinical, immunological, and MRI data were collected from all patients and histology in case of second surgery. Patients were classified as responders (progression-free survival, PFS > 12 months), and non-responders (PFS ≤ 12), HIGH-NK (natural killer cells, i.e., immunological responders), and LOW-NK (immunological non-responders) based on immune cell counts in peripheral blood. TRAMs differentiate contrast-enhancing lesions with different washout dynamics into hypothesized tumoral (conventionally blue-colored) vs. treatment-related (red-colored). Results: Using receiver operating characteristic (ROC) curves, a threshold of -0.066 in VBlue/VCE (volume of the blue portion of tumoral area/volume of contrast enhancement) variation between values obtained in the MRI performed before PsP/TTP and at TTP/PSP allowed to discriminate TTP from PsP with a sensitivity of 71.4% and a specificity of 100%. Among HIGH-NK patients, at month 6 there was a significant reduction compared to baseline and month 2 in median "blue" volumes. Discussion: In conclusion, in our pilot study TRAMs support the discrimination between tumoral and treatment-related enhancing features in immunological responders vs. non-responders, the distinction between PsP and TTP, and might provide surrogate markers of immunological response.

Quality assessment of the MRI-radiomics studies for MGMT promoter methylation prediction in glioma: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the methodological quality and diagnostic accuracy of MRI-based radiomic studies predicting O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in gliomas. METHODS: PubMed Medline, EMBASE, and Web of Science were searched to identify MRI-based radiomic studies on MGMT methylation in gliomas published until December 31, 2022. Three raters evaluated the study methodological quality with Radiomics Quality Score (RQS, 16 components) and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis Or Diagnosis (TRIPOD, 22 items) scales. Risk of bias and applicability concerns were assessed with QUADAS-2 tool. A meta-analysis was performed to estimate the pooled area under the curve (AUC) and to assess inter-study heterogeneity. RESULTS: We included 26 studies, published from 2016. The median RQS total score was 8 out of 36 (22%, range 8-44%). Thirteen studies performed external validation. All studies reported AUC or accuracy, but only 4 (15%) performed calibration and decision curve analysis. No studies performed phantom analysis, cost-effectiveness analysis, and prospective validation. The overall TRIPOD adherence score was between 50% and 70% in 16 studies and below 50% in 10 studies. The pooled AUC was 0.78 (95% CI, 0.73-0.83, I2 = 94.1%) with a high inter-study heterogeneity. Studies with external validation and including only WHO-grade IV gliomas had significantly lower AUC values (0.65; 95% CI, 0.57-0.73, p < 0.01). CONCLUSIONS: Study RQS and adherence to TRIPOD guidelines was generally low. Radiomic prediction of MGMT methylation status showed great heterogeneity of results and lower performances in grade IV gliomas, which hinders its current implementation in clinical practice. CLINICAL RELEVANCE STATEMENT: MGMT promoter methylation status appears to be variably correlated with MRI radiomic features; radiomic models are not sufficiently robust to be integrated into clinical practice to accurately predict MGMT promoter methylation status in patients with glioma before surgery. KEY POINTS: • Adherence to the indications of TRIPOD guidelines was generally low, as was RQS total score. • MGMT promoter methylation status prediction with MRI radiomic features provided heterogeneous diagnostic accuracy results across studies. • Studies that included grade IV glioma only and performed external validation had significantly lower diagnostic accuracy than others.

Distinctive electro-clinical, neuroimaging and histopathological features of temporal encephaloceles associated to epilepsy.

OBJECTIVE: Encephaloceles (ENCs) may cause clinical complications, including drug-resistant epilepsy that can be cured with epilepsy surgery. METHODS: We describe clinical, diagnostic, and neuropathological findings of 12 patients with temporal ENC and epilepsy evaluated for surgery and compare them with a control group of 26 temporal lobe epilepsy (TLE) patients. RESULTS: Six patients had unilateral and 6 bilateral temporal ENCs. Compared to TLEs, ENCs showed i) later epilepsy onset, ii) higher prevalence of psychiatric comorbidities, iii) no history of febrile convulsions, and iv) ictal semiology differences. Seven patients had MRI signs of gliosis, and 9 of intracranial hypertension. Interictal EEG analysis in ENCs demonstrated significant differences with controls: prominent activity in the beta/gamma frequency bands in frontal regions, interictal short sequences of low-voltage fast activity, and less frequent and more localized interictal epileptiform discharges. Ictal EEG patterns analyzed in 9 ENCs showed delayed and slower contralateral spread compared to TLEs. All ENCs that underwent surgery (7 lobectomies and 1 lesionectomy) are in Engel class I. Neuropathological examination revealed 4 patterns: herniated brain fragments, focal layer I distortion, white matter septa extending into the cortex, and altered gyral profile. CONCLUSIONS AND SIGNIFICANCE: The described peculiarities might help clinicians to suspect the presence of largely underdiagnosed ENCs.

Case report: Multiple brain intravascular papillary endothelial hyperplasia: incidence, diagnostic challenges, and management approach.

Multiple hemorrhagic brain lesions are mainly diagnosed based on clinico-radiological features integrated with histological data. Intravascular papillary endothelial hyperplasia (IPEH), or Masson's tumor, is a very rare entity, particularly when localized in the brain. In this study, we describe a case of multiple recurrent brain IPEHs and provide details on the diagnostic phase, therapeutic approaches, and related challenges. A 55-year-old woman presented with a relapsing neurological deficit. Brain magnetic resonance imaging (MRI) revealed a hemorrhagic right frontal-parietal lesion. When new neurological symptoms occurred, subsequent MRI scans detected more bleeding cerebral lesions. She underwent a series of single hemorrhagic lesion debulking. For any samples that underwent histopathological examination, the first results were not informative; the second and the third results revealed hemangioendothelioma (HE); and the fourth results led to the IPEH diagnosis. Interferon alpha (IFN-α) and subsequently sirolimus were prescribed. Both were well tolerated. Clinical and radiological features remained stable 43 months after starting sirolimus therapy and 132 months after the first diagnosis. To date, 45 cases of intracranial IPEH have been reported, mostly as single lesions without parenchymal location. They are usually treated by surgery and sometimes by radiotherapy upon recurrence. Our case is notable for two main reasons: because of the consecutive recurrent multifocal exclusively cerebral lesions and the therapeutic approach we used. Based on multifocal brain recurrence and good performance, we propose pharmacological therapy, including IFN-α and sirolimus, to stabilize IPEH.

Development of A Radiomic Model for MGMT Promoter Methylation Detection in Glioblastoma Using Conventional MRI.

The methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter is a molecular marker associated with a better response to chemotherapy in patients with glioblastoma (GB). Standard pre-operative magnetic resonance imaging (MRI) analysis is not adequate to detect MGMT promoter methylation. This study aims to evaluate whether the radiomic features extracted from multiple tumor subregions using multiparametric MRI can predict MGMT promoter methylation status in GB patients. This retrospective single-institution study included a cohort of 277 GB patients whose 3D post-contrast T1-weighted images and 3D fluid-attenuated inversion recovery (FLAIR) images were acquired using two MRI scanners. Three separate regions of interest (ROIs) showing tumor enhancement, necrosis, and FLAIR hyperintensities were manually segmented for each patient. Two machine learning algorithms (support vector machine (SVM) and random forest) were built for MGMT promoter methylation prediction from a training cohort (196 patients) and tested on a separate validation cohort (81 patients), based on a set of automatically selected radiomic features, with and without demographic variables (i.e., patients' age and sex). In the training set, SVM based on the selected radiomic features of the three separate ROIs achieved the best performances, with an average of 83.0% (standard deviation: 5.7%) for accuracy and 0.894 (0.056) for the area under the curve (AUC) computed through cross-validation. In the test set, all classification performances dropped: the best was obtained by SVM based on the selected features extracted from the whole tumor lesion constructed by merging the three ROIs, with 64.2% (95% confidence interval: 52.8-74.6%) accuracy and 0.572 (0.439-0.705) for AUC. The performances did not change when the patients' age and sex were included with the radiomic features into the models. Our study confirms the presence of a subtle association between imaging characteristics and MGMT promoter methylation status. However, further verification of the strength of this association is needed, as the low diagnostic performance obtained in this validation cohort is not sufficiently robust to allow clinically meaningful predictions.

Carcinomatosis under control by osimertinib in EGFR and TP53 mutated lung adenocarcinoma.

INTRODUCTION: Approximately 25%-30% of patients with non-small cell lung cancer (NSCLC) develop central nervous system (CNS) metastases during the course of the disease; this percentage is higher in patients with epidermal growth factor receptor (EGFR) mutations. Leptomeningeal metastases, infrequent in the advanced setting, have a particularly dismal prognosis. Osimertinib, a third-generation EGFR inhibitor, can provide effective and durable response in this setting. CASE DESCRIPTION: We present a 62-year-old man with progressive vomiting, headache, short-term memory impairment, and left lower limb hyposthenia. Computed tomography (CT) showed bilateral lung nodules, multiple lymphadenopathies, liver and bone metastases, and CNS and leptomeningeal dissemination, including multiple parenchymal nodules located at supra- and infratentorial brain. Bone needle biopsy documented TTF1+ lung adenocarcinoma. Whole brain radiotherapy (WBRT) and symptomatic treatments were started. Next-generation sequencing reported deletion of exon 19 of EGFR and mutation 8 of TP53. Osimertinib 80 mg was promptly started and WBRT interrupted. Some days after the patient experienced repetitive seizures and neurologic worsening, antiepileptic drugs and dexamethasone were implemented, with gradual improvement. Radiologic evaluation, including brain MRI and thorax-abdominal CT, showed partial response on CNS as well as extracranial sites, which was sustained. CONCLUSIONS: First-line treatment with osimertinib can be safe and effective in EGFR-mutated NSCLC even in presence of multiple negative predictive factors (poor Performance Status, diffuse leptomeningeal involvement, TP53 comutation), suggesting that deferring local treatments can be feasible in this setting, allowing the patient to maintain a good quality of life.

High tumor mutational burden and T-cell activation are associated with long-term response to anti-PD1 therapy in Lynch syndrome recurrent glioblastoma patient.

BACKGROUND: Glioblastomas (GBMs) in patients harboring somatic or germinal mutations of mismatch-repair (MMR) genes exhibit a hypermutable phenotype. Here, we describe a GBM patient with increased tumor mutational burden and germline MMR mutations, treated using anti-PD1 therapy. METHODS: A woman with newly diagnosed GBM (nGBM) was treated by surgery, radiotherapy, and temozolomide. The tumor recurred after 13 months leading to a second surgery and treatment with nivolumab. Whole-exome sequencing was performed on the nGBM, recurrent GBM (rGBM), and blood. Immune infiltration was investigated by immunohistochemistry and the immune response in the blood during treatment was analyzed by flow cytometry. RESULTS: High density of infiltrating CD163 + cells was found in both GBM specimens. Large numbers of CD3 + and CD8 + T cells were homogeneously distributed in the nGBM. The infiltration of CD4 + T cells and a different CD8 + T cell density were observed in the rGBM. Both GBM shared 12,431 somatic mutations, with 113 substitutions specific to the nGBM and 1,683 specific to the rGBM. Germline variants included pathogenic mutation in the MSH2 (R359S) gene, suggesting the diagnosis of Lynch syndrome. Systemic immunophenotyping revealed the generation of CD8 + T memory cells and persistent activation of CD4 + T cells. The patient is still receiving nivolumab 68 months after the second surgery. CONCLUSIONS: Our observations indicate that the hypermutator phenotype associated with germinal mutations of MMR genes and abundant T-cell infiltration contributes to a durable clinical benefit sustained by a persistent and robust immune response during anti-PD1 therapy.

Gliomatosis cerebri (GC) or GC-like? A picture to be reconsidered in neuro-oncology based on large retrospective analysis of GC series.

INTRODUCTION: Gliomatosis cerebri (GC), defined until 2016 as a distinct astrocytic glioma entity, has been removed from the 2016 World Health Organization classification of tumors of the central nervous system. However, its identity is still debated. MATERIALS AND METHODS: We retrospectively present 122 patients, including a subgroup with histology confirmation (n = 75, cohort b). RESULTS: Radiological features showed extension limited to 3 lobes in 31%; bilateral, midline, and basal ganglia and subtentorial involvement in 95%, 52%, 84%, and 60%, respectively; and contrast enhancement in 59.5%. Perioperative mortality occurred in 4%. Histology concluded for grades II, III, and IV, respectively, in 31%, 35%, and 22% (not specified in 12%). Thirty-one percent had isocitrate dehydrogenase (IDH) 1 mutation. Treatments included radiotherapy in 51.2% and chemotherapy in 74.5%. Median overall survival was 17 months. Negative prognostic factors for survival were older age, poorer Karnofsky Performance Scale (KPS), subtentorial, midline and disseminated disease, and lack of chemotherapy, at univariate analysis. At multivariate analysis, KPS ≥ 80, chemotherapy, and subtentorial and disseminated disease remained prognostic (p < 0.0001). For cohort b, same prognostic factors were confirmed, except for midline location, at univariate analysis; at multivariate analysis, only KPS ≥ 80 and chemotherapy remained prognostic (p < 0.0001). CONCLUSION: We described clinical, neuroimaging, management, and histomolecular features of one of the largest GC series. We identified KPS ≥ 80, radiological pattern as subtentorial localization and dissemination, and chemotherapy as prognostic factors, at multivariate analysis. Planning prospective study, associated to focused genetic assays, could help to clarify if GC has specific features that may result in the identification as a separate entity from other gliomas.

In vivo 2-hydroxyglutarate-proton magnetic resonance spectroscopy (3 T, PRESS technique) in treatment-naïve suspect lower-grade gliomas: feasibility and accuracy in a clinical setting.

Isocitrate dehydrogenase 1/2 (IDH1/2) mutations are often detected in lower-grade gliomas (LGG) and result into 2-hydroxyglutarate (2HG) synthesis. Prior studies showed that 2HG can be detected in vivo using magnetic resonance spectroscopy (MRS), but its accuracy and translational impact are still under investigation. PURPOSE: To investigate the clinical feasibility of MRS for in vivo detection and quantification of 2HG on consecutive treatment-naïve suspect LGG patients and to compare MRS accuracy with tissue IDH1/2 analysis. METHODS: MRS spectra at 3 T were acquired with 1H-MRS single-voxel PRESS 2HG-tailored sequences with TE 30 (group 1) or TE 97 (groups 2A and B). Voxel sizes were 1.5 × 1.5 × 1.5 cm3 for group 1 (n = 13) and group 2A (n = 14) and 2 × 2 × 2 cm3 for group 2B (n = 32). Multiple metabolites' concentrations were analyzed with LCModel. Tumors were assessed for IDH status and main molecular markers. 2HG levels in urine/blood were measured by liquid chromatography-mass spectrometry. RESULTS: The larger voxel TE 97 sequence resulted in highest specificity (100%), sensitivity (79%), and accuracy (87%). Urine and blood 2HG did not result predictive. CONCLUSION: Our data confirm that 2 × 2 × 2-cm3 voxel TE 97 MRS shows high accuracy for 2HG detection, with good sensitivity and 100% specificity in distinguishing IDH mutant gliomas. Main limits of the technique are small tumor volume and low cellularity. Integrating 2HG-MRS with other metabolites may help non-invasive diagnosis of glioma, prognostic assessment, and treatment planning in clinical setting.

Advanced MRI Assessment during Dendritic Cell Immunotherapy Added to Standard Treatment Against Glioblastoma.

Evaluating changes induced by immunotherapies (IT) on conventional magnetic resonance imaging (MRI) is difficult because those treatments may produce inflammatory responses. To explore the potential contribution of advanced MRI to distinguish pseudoprogression (PsP) and true tumor progression (TTP), and to identify patients obtaining therapeutic benefit from IT, we examined aMRI findings in newly diagnosed glioblastoma treated with dendritic cell IT added to standard treatment. We analyzed longitudinal MRIs obtained in 22 patients enrolled in the EUDRACT N° 2008-005035-15 trial. According to RANO criteria, we observed 18 TTP and 8 PsP. Comparing MRI performed at the time of TTP/PsP with the previous exam performed two months before, a difference in cerebral blood volume ΔrCBVmax ≥ 0.47 distinguished TTP from PsP with a sensitivity of 67% and specificity of 75% (p = 0.004). A decrease in minimal apparent diffusion coefficient rADCmin (1.15 vs. 1.01, p = 0.003) was observed after four vaccinations only in patients with a persistent increase of natural killer cells (response effectors during IT) in peripheral blood. Basal rADCmin > 1 was independent predictor of longer progression free (16.1 vs. 9 months, p = 0.0001) and overall survival (32.8 vs. 17.5 months, p = 0.0005). In conclusion, rADC predicted response to immunotherapy and survival; Apparent Diffusion Coefficient (ADC) and Cerebral Blood Volume (CBV) modifications over time help differentiating PsP from TTP at onset.

A novel lecithin-based delivery form of Boswellic acids as complementary treatment of radiochemotherapy-induced cerebral edema in patients with glioblastoma multiforme: a longitudinal pilot experience.

BACKGROUND: Glioblastoma multiforme (GBM) is an extremely challenging neurological disease for which the development of more effective therapeutic options and of adjuvant/complementary treatment is needed. We investigated the effects of an innovative phytosome-based delivery form of boswellic acids extract (Monoselect AKBA™) on radiochemotherapy-induced cerebral edema in patients with primary GBM. METHODS: Patients with de novo GBM treated with surgery, radiotherapy and chemotherapy with temozolomide were enrolled in this longitudinal study and received boswellia-based product 4500 mg/die for a maximum of 34 weeks. Cerebral edema was assessed at 4, 12, 22 and 34 weeks post-surgery, together with steroids consumption and patients' psychological status. RESULTS: A total of 20 patients were included in the study. The percentage of patients with reduced edema was constant during the study, while the percentage of those with reduced or stable edema tended to increase over time. Of note, two patients achieved a considerable reduction in brain edema, which led to a more favorable and beneficial surgical resection. In addition, a good percentage of patients assumed a stable/reduced steroids dose or were dexamethasone free during the study. Lastly, patients' QoL and psychological state were maintained throughout the study. CONCLUSIONS: Complementary treatment with Monoselect AKBA™ might exert a beneficial effect in reducing radiochemotherapy-induced cerebral edema, thanks to the anti-inflammatory properties of the boswellia serrata extract. The reduction in brain edema might diminish dexamethasone assumption, thus minimizing steroids-induced side effects, and in few cases may allow a complete surgical excision of the tumor mass.

Expansion of effector and memory T cells is associated with increased survival in recurrent glioblastomas treated with dendritic cell immunotherapy.

BACKGROUND: The efficacy of dendritic cell (DC) immunotherapy as a single therapeutic modality for the treatment of glioblastoma (GBM) patients remains limited. In this study, we evaluated in patients with GBM recurrence the immune-mediated effects of DC loaded with autologous tumor lysate combined with temozolomide (TMZ) or tetanus toxoid (TT). METHODS: In the phase I-II clinical study DENDR2, 12 patients were treated with 5 DC vaccinations combined with dose-dense TMZ. Subsequently, in eight patients, here defined as Variant (V)-DENDR2, the vaccine site was preconditioned with TT 24 hours before DC vaccination and TMZ was avoided. As a survival endpoint for these studies, we considered overall survival 9 months (OS9) after second surgery. Patients were analyzed for the generation of effector, memory, and T helper immune response. RESULTS: Four of 12 DENDR2 patients reached OS9, but all failed to show an immunological response. Five of eight V-DENDR2 patients (62%) reached OS9, and one patient is still alive (OS >30 months). A robust CD8+ T-cell activation and memory T-cell formation were observed in V-DENDR2 OS>9. Only in these patients, the vaccine-specific CD4+ T-cell activation (CD38+/HLA-DR+) was paralleled by an increase in TT-induced CD4+/CD38low/CD127high memory T cells. Only V-DENDR2 patients showed the formation of a nodule at the DC injection site infiltrated by CCL3-expressing CD4+ T cells. CONCLUSIONS: TT preconditioning of the vaccine site and lack of TMZ could contribute to the efficacy of DC immunotherapy by inducing an effector response, memory, and helper T-cell generation.

Survival gain in glioblastoma patients treated with dendritic cell immunotherapy is associated with increased NK but not CD8+ T cell activation in the presence of adjuvant temozolomide.

In a two-stage phase II study, 24 patients with first diagnosis of glioblastoma (GBM) were treated with dendritic cell (DC) immunotherapy associated to standard radiochemotherapy with temozolomide (TMZ) followed by adjuvant TMZ. Three intradermal injections of mature DC loaded with autologous GBM lysate were administered before adjuvant TMZ, while 4 injections were performed during adjuvant TMZ. According to a two-stage Simon design, to proceed to the second stage progression-free survival (PFS) 12 months after surgery was expected in at least 8 cases enrolled in the first stage. Evidence of immune response and interaction with chemotherapy were investigated. After a median follow up of 17.4 months, 9 patients reached PFS12. In these patients (responders, 37.5%), DC vaccination induced a significant, persistent activation of NK cells, whose increased response was significantly associated with prolonged survival. CD8+ T cells underwent rapid expansion and priming but, after the first administration of adjuvant TMZ, failed to generate a memory status. Resistance to TMZ was associated with robust expression of the multidrug resistance protein ABCC3 in NK but not CD8+ T cells. The negative effect of TMZ on the formation of T cell-associated antitumor memory deserves consideration in future clinical trials including immunotherapy.

Brain Gliomas: Multicenter Standardized Assessment of Dynamic Contrast-enhanced and Dynamic Susceptibility Contrast MR Images.

Purpose To evaluate the feasibility of a standardized protocol for acquisition and analysis of dynamic contrast material-enhanced (DCE) and dynamic susceptibility contrast (DSC) magnetic resonance (MR) imaging in a multicenter clinical setting and to verify its accuracy in predicting glioma grade according to the new World Health Organization 2016 classification. Materials and Methods The local research ethics committees of all centers approved the study, and informed consent was obtained from patients. One hundred patients with glioma were prospectively examined at 3.0 T in seven centers that performed the same preoperative MR imaging protocol, including DCE and DSC sequences. Two independent readers identified the perfusion hotspots on maps of volume transfer constant (Ktrans), plasma (vp) and extravascular-extracellular space (ve) volumes, initial area under the concentration curve, and relative cerebral blood volume (rCBV). Differences in parameters between grades and molecular subtypes were assessed by using Kruskal-Wallis and Mann-Whitney U tests. Diagnostic accuracy was evaluated by using receiver operating characteristic curve analysis. Results The whole protocol was tolerated in all patients. Perfusion maps were successfully obtained in 94 patients. An excellent interreader reproducibility of DSC- and DCE-derived measures was found. Among DCE-derived parameters, vp and ve had the highest accuracy (are under the receiver operating characteristic curve [Az] = 0.847 and 0.853) for glioma grading. DSC-derived rCBV had the highest accuracy (Az = 0.894), but the difference was not statistically significant (P > .05). Among lower-grade gliomas, a moderate increase in both vp and rCBV was evident in isocitrate dehydrogenase wild-type tumors, although this was not significant (P > .05). Conclusion A standardized multicenter acquisition and analysis protocol of DCE and DSC MR imaging is feasible and highly reproducible. Both techniques showed a comparable, high diagnostic accuracy for grading gliomas. © RSNA, 2018 Online supplemental material is available for this article.

MRI in Glioma Immunotherapy: Evidence, Pitfalls, and Perspectives.

Pseudophenomena, that is, imaging alterations due to therapy rather than tumor evolution, have an important impact on the management of glioma patients and the results of clinical trials. RANO (response assessment in neurooncology) criteria, including conventional MRI (cMRI), addressed the issues of pseudoprogression after radiotherapy and concomitant chemotherapy and pseudoresponse during antiangiogenic therapy of glioblastomas (GBM) and other gliomas. The development of cancer immunotherapy forced the identification of further relevant response criteria, summarized by the iRANO working group in 2015. In spite of this, the unequivocal definition of glioma progression by cMRI remains difficult particularly in the setting of immunotherapy approaches provided by checkpoint inhibitors and dendritic cells. Advanced MRI (aMRI) may in principle address this unmet clinical need. Here, we discuss the potential contribution of different aMRI techniques and their indications and pitfalls in relation to biological and imaging features of glioma and immune system interactions.

Advanced MRI may complement histological diagnosis of lower grade gliomas and help in predicting survival.

MRI grading of grade II and III gliomas may have an important impact on treatment decisions. Occasionally,both conventional MRI (cMRI) and histology fail to clearly establish the tumour grade. Three cMRI features(no necrosis; no relevant oedema; absent or faint contrast enhancement) previously validated in 196 patients with supratentorial gliomas directed our selection of 68 suspected low-grade gliomas (LGG) that were also investigated by advanced MRI (aMRI), including perfusion weighted imaging (PWI), diffusion weighted imaging(DWI) and spectroscopy. All the gliomas had histopathological diagnoses. Sensitivity and specificity of cMRI preoperative diagnosis were 78.5 and 38.5 %, respectively, and 85.7 and 53.8 % when a MRI was included, respectively. ROC analysis showed that cut-off values of 1.29 for maximum rCBV, 1.69 for minimum rADC, 2.1 for rCho/Cr ratio could differentiate between LGG and HGG with a sensitivity of 61.5, 53.8, and 53.8 % and a specificity of 54.7, 43 and 64.3 %, respectively. A significantly longer OS was observed in patients with a maximum rCBV<1.46 and minimum rADC>1.69 (80 vs 55 months, p = 0.01; 80 vs 51 months, p = 0.002, respectively). This result was also confirmed when cases were stratified according to pathology (LGG vs HGG). The ability of a MRI to differentiate between LGG and HGG and to predict survival improved as the number of a MRI techniques considered increased. In a selected population of suspected LGG,classification by cMRI underestimated the actual fraction of HGG. aMRI slightly increased the diagnostic accuracy compared to histopathology. However, DWI and PWI were prognostic markers independent of histological grade.

Radiosurgery reirradiation for high-grade glioma recurrence: a retrospective analysis.

Despite various treatment strategies being available, recurrent high-grade gliomas (r-HGG) are difficult to manage. To obtain local control, radiosurgery (SRS) reirradiation has been considered as potential treatment. In the present study, a retrospective analysis was performed on r-HGG patients treated with salvage single- (s-SRS) or multi-fraction SRS (m-SRS). The aim of this study was to evaluate the effectiveness of salvage SRS in terms of overall survival (OS); toxicity was analyzed as well. Between 2004 May and 2011 December, 128 r-HGG patients (161 lesions) treated with CyberKnife(®) SRS reirradiation were retrospectively analyzed. Toxicity was graded according to Radiation Therapy Oncology Group and by Common Terminology Criteria for Adverse Events v.3 criteria. OS from the diagnosis date and OS from reirradiation were estimated using the Kaplan-Meier method. Median follow-up was 9 months (range 15 days-82 months). All patients completed SRS without high-grade toxicity. Radiation necrosis was observed in seven patients (6 %) with large volume lesions. The median survival from initial diagnosis was 32 months. The 1-, 2-, and 3-years survival rates from diagnosis were 95, 62, and 45 % respectively. Median survival following SRS was 11.5 months. The 1-, 2-, and 3-years survival rate following SRS was 48, 20, and 17 % respectively. On multivariate analysis, age <40 years, salvage surgery before SRS, and other post-SRS therapies (second-line chemotherapy and/or surgery) were found to significantly improve survival (p = 0.03). SRS represents a safe and feasible option to treat r-HGG patients with low complication rates and potential survival benefit.

The natural killer cell response and tumor debulking are associated with prolonged survival in recurrent glioblastoma patients receiving dendritic cells loaded with autologous tumor lysates.

Recurrent glioblastomas (GBs) are highly aggressive tumors associated with a 6-8 mo survival rate. In this study, we evaluated the possible benefits of an immunotherapeutic strategy based on mature dendritic cells (DCs) loaded with autologous tumor-cell lysates in 15 patients affected by recurrent GB. The median progression-free survival (PFS) of this patient cohort was 4.4 mo, and the median overall survival (OS) was 8.0 mo. Patients with small tumors at the time of the first vaccination (< 20 cm3; n = 8) had significantly longer PFS and OS than the other patients (6.0 vs. 3.0 mo, p = 0.01; and 16.5 vs. 7.0 mo, p = 0.003, respectively). CD8+ T cells, CD56+ natural killer (NK) cells and other immune parameters, such as the levels of transforming growth factor ß, vascular endothelial growth factor, interleukin-12 and interferon γ (IFNγ), were measured in the peripheral blood and serum of patients before and after immunization, which enabled us to obtain a vaccination/baseline ratio (V/B ratio). An increased V/B ratio for NK cells, but not CD8+ T cells, was significantly associated with prolonged PFS and OS. Patients exhibiting NK-cell responses were characterized by high levels of circulating IFNγ and E4BP4, an NK-cell transcription factor. Furthermore, the NK cell V/B ratio was inversely correlated with the TGFß2 and VEGF V/B ratios. These results suggest that tumor-loaded DCs may increase the survival rate of patients with recurrent GB after effective tumor debulking, and emphasize the role of the NK-cell response in this therapeutic setting.

FABP4 is a candidate marker of cerebellar liponeurocytomas.

Cerebellar liponeurocytoma (cLPN) is a very rare central nervous system (CNS) tumour recently recognized as a clinical and pathological entity distinct from medulloblastoma (MB), and included in the WHO classification of CNS tumours under the heading "glioneuronal tumours". cLPN typically develop in adult age and have a favourable prognosis compared with MB. In this work, we reviewed the clinical and neuroradiological data of two novel cases of adult cLPN diagnosed at our institution; one patient developed distant metastases. We tried to identify novel molecular markers for this malignancy. We found that the transcription factor NEUROG1 (but not ATOH1) is expressed in cLPN, unlike normal adult cerebellum, and that fatty acid binding protein 4 (FABP4), typically found in adipocytes, is significantly overexpressed compared with both normal adult cerebellum and human MB. These findings suggest cLPN occur as a result of transformation of cerebellar progenitors, which are distinct from cerebellar granule progenitors, and aberrantly differentiate into adipocyte-like tumour cells. They also suggest that analysis of FABP4 expression is of help to differentiate cLPN from MB.