Eribulin in brain metastases of breast cancer: outcomes of the EBRAIM prospective observational trial.

Background: Eribulin shows some activity in controlling brain metastasis in breast cancer. Methods: This observational, multicenter study evaluated brain disease control rates, survival and safety in patients with brain metastatic breast cancer treated with eribulin in clinical practice. Results: A total of 34 patients were enrolled (mean age 49 years, 91% with visceral metastases) and 29 were evaluable for brain disease. Fourteen achieved disease control and showed a longer time without progression: 10 months (95% CI: 2.3-17.7) versus 4 months (95% CI: 3.3-4.7) in the control group (p = 0.029). Patients with clinical benefits at 6 months had longer survival. Leukopenia and neutropenia were the most frequent grade 3-4 toxicities. Conclusion: Eribulin confirms its effectiveness in patients with brain metastatic breast cancer. Further studies on larger cohorts are needed to confirm the results.

Italian consensus and recommendations on diagnosis and treatment of low-grade gliomas. An intersociety (SINch/AINO/SIN) document.

In 2018, the SINch (Italian Society of Neurosurgery) Neuro-Oncology Section, AINO (Italian Association of Neuro-Oncology) and SIN (Italian Association of Neurology) Neuro-Oncology Section formed a collaborative Task Force to look at the diagnosis and treatment of low-grade gliomas (LGGs). The Task Force included neurologists, neurosurgeons, neuro-oncologists, pathologists, radiologists, radiation oncologists, medical oncologists, a neuropsychologist and a methodologist. For operational purposes, the Task Force was divided into five Working Groups: diagnosis, surgical treatment, adjuvant treatments, supportive therapies, and follow-up. The resulting guidance document is based on the available evidence and provides recommendations on diagnosis and treatment of LGG patients, considering all aspects of patient care along their disease trajectory.

Correction to: Efficacy of initial temozolomide for high­risk low grade gliomas in a phase II AINO (Italian Association for Neuro­Oncology) study: a post­hoc analysis within molecular subgroups of WHO 2016.

The third and fourth authors' affiliation was incorrectly specified in the original publication. It is correctly shown here.

Efficacy of initial temozolomide for high-risk low grade gliomas in a phase II AINO (Italian Association for Neuro-Oncology) study: a post-hoc analysis within molecular subgroups of WHO 2016.

INTRODUCTION: The optimal management of high risk WHO grade II gliomas after surgery is debated including the role of initial temozolomide to delay radiotherapy and risk of cognitive defects. METHODS: A post-hoc analysis of a phase II multicenter study on high risk WHO grade II gliomas, receiving initial temozolomide alone, has re-evaluated the long-term results within the molecular subgroups of WHO 2016. The primary endpoint of the study was response according to RANO, being seizure response, PFS and OS secondary endpoints. RESULTS: Response rate among oligodendrogliomas IDH-mutant and 1p/19q codeleted (76%) was significantly higher than that among diffuse astrocytomas either mutant (55%) or wild-type (36%). A reduction of seizure frequency > 50% was observed in 87% of patients and a seizure freedom in 72%. The probability of seizure reduction > 50% was significantly associated with the presence of an IDH mutation. Median PFS, PFS at 5 and 10 years, median OS and OS at 5 and 10 years were significantly longer in oligodendrogliomas IDH-mutant and 1p/19q codeleted. Sixty-seven percent of patients with oligodendroglioma IDH mutant and 1p/19q codeleted did not recur with a median follow up of 9.3 years, while 59% did not receive radiotherapy at recurrence with a median follow up of 8.2 years. CONCLUSIONS: The beneficial effects of initial temozolomide prevail in oligodendrogliomas IDH-mutant and 1p/19q codeleted: thus, these tumors, when incompletely resected or progressive after surgery alone, or with intractable seizures, should receive temozolomide as initial treatment with salvage radiotherapy and/o reoperation and/or second-line chemotherapy at recurrence.

The kinase inhibitor SI113 induces autophagy and synergizes with quinacrine in hindering the growth of human glioblastoma multiforme cells.

BACKGROUND: Glioblastoma multiforme (GBM), due to its location, aggressiveness, heterogeneity and infiltrative growth, is characterized by an exceptionally dismal clinical outcome. The small molecule SI113, recently identified as a SGK1 inhibitor, has proven to be effective in restraining GBM growth in vitro and in vivo, showing also encouraging results when employed in combination with other antineoplastic drugs or radiotherapy. Our aim was to explore the pharmacological features of SI113 in GBM cells in order to elucidate the pivotal molecular pathways affected by the drug. Such knowledge would be of invaluable help in conceiving a rational offensive toward GBM. METHODS: We employed GBM cell lines, either established or primary (neurospheres), and used a Reverse-Phase Protein Arrays (RPPA) platform to assess the effect of SI113 upon 114 protein factors whose post-translational modifications are associated with activation or repression of specific signal transduction cascades. RESULTS: SI113 strongly affected the PI3K/mTOR pathway, evoking a pro-survival autophagic response in neurospheres. These results suggested the use of SI113 coupled, for maximum efficiency, with autophagy inhibitors. Indeed, the association of SI113 with an autophagy inhibitor, the antimalarial drug quinacrine, induced a strong synergistic effect in inhibiting GBM growth properties in all the cells tested, including neurospheres. CONCLUSIONS: RPPA clearly identified the molecular pathways influenced by SI113 in GBM cells, highlighting their vulnerability when the drug was administered in association with autophagy inhibitors, providing a strong molecular rationale for testing SI113 in clinical trials in associative GBM therapy.

A multicenter real-world study of bevacizumab in heavily pretreated malignant gliomas: clinical benefit is a plausible end point?

Aim: This multicenter, retrospective study evaluates the clinical benefit (CB) of bevacizumab, alone or in combination, in recurrent gliomas (RG). Patients & methods: The CB was measured as a reduction of corticosteroid dosage and an improvement ≥20 points in the Karnofsky Performance Status lasting ≥3 months. Results: We collected data of 197 RG patients. A CB was observed in 120, patients without significant differences between patients treated with bevacizumab alone or in combination. The rate of patients who achieved a CB and free from progression at 1 year was 21.5 versus 1.4% in patients who did not report CB. Conclusion: The majority of RG patients treated with bevacizumab reported CB. Moreover, patients with CB showed improved survival.

Comorbidities in elderly patients with glioblastoma: a field-practice study.

AIM: This single-center study evaluated the effect of comorbidities on progression-free and overall survival in elderly patients with glioblastoma multiforme (GBM). PATIENTS & METHODS: Comorbid conditions were identified in each patient with the modified version of the cumulative illness rating scale (CIRS). RESULTS:  Total of 118 patients with GBM were enrolled. An age of >75 years at diagnosis, high CIRS, comorbidity index and performance status play a predictive role on survival. CONCLUSION: Comorbidities play an important prognostic role in elderly patients with GBM, a factor too often neglected in clinical practice. If the prognostic role of comorbidity measured by CIRS on outcome will be confirmed, it would be interesting to add it in the algorithm for treatment choice in elderly GBM patients.

A Survey on Pituitary Surgery in Italy.

BACKGROUND: Pituitary tumors are a heterogeneous group of lesions that are usually benign. Therefore, a proper understanding of the anatomy, physiology, and pathology is mandatory to achieve favorable outcomes. Accordingly, diagnostic tests and treatment guidelines should be determined and implemented. Thus, we decided to perform a multicenter study among Italian neurosurgical centers performing pituitary surgery to provide an actual depiction from the neurosurgical standpoint. METHODS: On behalf of the SINch (Società Italiana di Neurochirurgia), a survey was undertaken with the participants to explore the activities in the field of pituitary surgery within 41 public institutions. RESULTS: Of the 41 centers, 37 participated in the present study. The total number of neurosurgical procedures performed in 2016 was 1479. Most of the procedures were performed using the transsphenoidal approach (1320 transsphenoidal [1204 endoscopic, 53 microscopic, 53 endoscope-assisted microscopic] vs. 159 transcranial). A multidisciplinary tumor board is convened regularly in 32 of 37 centers, and a research laboratory is present in 18 centers. CONCLUSIONS: Diagnosing pituitary/hypothalamus disorders and treating them is the result of teamwork, composed of several diverse experts. Regarding neurosurgery, our findings have confirmed the central role of the transsphenoidal approach, with preference toward the endoscopic technique. Better outcomes can be expected at centers with a multidisciplinary team and a full, or part of a, residency program, with a greater surgical caseload.

How is stereotactic brain biopsy evolving? A multicentric analysis of a series of 421 cases treated in Rome over the last sixteen years.

OBJECTIVE: In recent decades, frame-based (FBB) and frame-less stereotactic brain biopsy (FLB) have played a crucial role in defining the diagnosis and management of expanding intracranial lesions in critical areas. During the same period, there have been significant advances in diagnostic imaging, a shift in surgical strategies towards extensive resection in gliomas and new molecular classification of brain tumors. Taking these advances into account, we have evaluated whether significant changes have occurred over the last sixteen years of our clinical practice in terms of frequency, indications, target selection, and the histologic results of stereotactic brain biopsy (SBB) procedures. PATIENTS AND METHODS: We analyzed a series of 421 SBB cases treated between January 2002 and June 2017 in three major neurosurgical institutes in Rome, serving a total of 1.5 million people. Within this series, 94.8% of patients underwent FBB, while, more recently, FLB was performed in 5.2% of cases. The entire period under consideration, running from 2002 to 2017, has been further stratified into four-year time-frames (2002-2005, 2006-2009, 2010-2013, 2014-2017) for the purpose of analysis. RESULTS: The diagnostic yield was 97%. Final diagnoses revealed tumors in 90% of cases and non-neoplastic masses in 7%, while 3% of cases were not conclusive. The morbidity rate was 3% (12 cases) and mortality was 0.7% (3 cases). Intra-operative frozen sections were made in 78% of biopsies. In our three institutes, the number of SBBs decreased steadily throughout the time-frames under consideration. We have also observed a statistically significant reduction in biopsy procedures in lobar lesions, while those performed on the basal ganglia increased and the number of SBBs of multiple masses and lesions of the corpus callosum remained stable. Primary central nervous system diagnosis of lymphomas (PCNSL) was the sole diagnosis whose incidence increased significantly. CONCLUSIONS: Over the last sixteen years, we have witnessed a significant decrease in SBB procedures and a modification in target selection and histologic results. Despite the significant evolution of neuroimaging, an accurate non-invasive diagnosis of intracranial expanding lesions has not yet been achieved. Furthermore, the most recent WHO classification of brain tumors (2016), which incorporates molecular and morphological features, has boosted the need for molecular processing of tissue samples in all expanding brain lesions. For these reasons, it is likely that SBBs will continue to be performed in specific cases, playing a significant role in diagnostic confirmation by providing tissue samples, so as to better assess the biology and the prognosis of cerebral lesions, as well as their sensitivity to standard radio-chemotherapy or to new molecular target therapies.

The role of surgical resection in patients with brain metastases.

PURPOSE OF REVIEW: Treatment of brain metastases represent a critical issue and different options have to be considered according to patients and tumour characteristics; in recent years, new therapeutic strategies have been proposed. In this review, we discuss the role of surgical resection on the basis of patient selection, new surgical techniques and the use of intraoperative adjuncts. The integration with postoperative whole brain radiotherapy will be also outlined because alternative treatment options are currently available. RECENT FINDINGS: Surgical removal has been considered the mainstay in the treatment of brain metastases, in selected patients, with limited number of intracranial lesions and controlled primary disease, mainly in combination with whole brain radiotherapy. In the last few years, the increasing role of stereotactic focal radiotherapy has deeply modified the indications to open surgical procedures and whole brain radiotherapy. SUMMARY: The appearance of brain metastases is considered a sign of bad prognosis. Treatment of these lesions is important for quality of life, providing local tumour control, preventing death from neurological causes and improving survival, although potentially only in a minority of patients. Careful patient selection, with adequate evaluation of clinical prognostic score, the use of appropriate surgical techniques and surgical adjuncts are major determinants of favourable outcome in patients undergoing resection of brain metastases.

Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO).

The management of patients with brain metastases has become a major issue due to the increasing frequency and complexity of the diagnostic and therapeutic approaches. In 2014, the European Association of Neuro-Oncology (EANO) created a multidisciplinary Task Force to draw evidence-based guidelines for patients with brain metastases from solid tumors. Here, we present these guidelines, which provide a consensus review of evidence and recommendations for diagnosis by neuroimaging and neuropathology, staging, prognostic factors, and different treatment options. Specifically, we addressed options such as surgery, stereotactic radiosurgery/stereotactic fractionated radiotherapy, whole-brain radiotherapy, chemotherapy and targeted therapy (with particular attention to brain metastases from non-small cell lung cancer, melanoma and breast and renal cancer), and supportive care.

Overexpression of syndecan-1, MUC-1, and putative stem cell markers in breast cancer leptomeningeal metastasis: a cerebrospinal fluid flow cytometry study.

BACKGROUND: Cancer is a mosaic of tumor cell subpopulations, where only a minority is responsible for disease recurrence and cancer invasiveness. We focused on one of the most aggressive circulating tumor cells (CTCs) which, from the primitive tumor, spreads to the central nervous system (CNS), evaluating the expression of prognostic and putative cancer stem cell markers in breast cancer (BC) leptomeningeal metastasis (LM). METHODS: Flow cytometry immunophenotypic analysis of cerebrospinal fluid (CSF) samples (4.5 ml) was performed in 13 consecutive cases of BCLM. Syndecan-1 (CD138), MUC-1 (CD227) CD45, CD34, and the putative cancer stem cell markers CD15, CD24, CD44, and CD133 surface expression were evaluated on CSF floating tumor cells. The tumor-associated leukocyte population was also characterized. RESULTS: Despite a low absolute cell number (8 cell/µl, range 1-86), the flow cytometry characterization was successfully conducted in all the samples. Syndecan-1 and MUC-1 overexpression was documented on BC cells in all the samples analyzed; CD44, CD24, CD15, and CD133 in 77%, 75%, 70%, and 45% of cases, respectively. A strong syndecan-1 and MUC-1 expression was also documented by immunohistochemistry on primary breast cancer tissues, performed in four patients. The CSF tumor population was flanked by T lymphocytes, with a different immunophenotype between the CSF and peripheral blood samples (P ≤ 0.02). CONCLUSIONS: Flow cytometry can be successfully employed for solid tumor LM characterization even in CSF samples with low cell count. This in vivo study documents that CSF floating BC cells overexpress prognostic and putative cancer stem cell biomarkers related to tumor invasiveness, potentially representing a molecular target for circulating tumor cell detection and LM treatment monitoring, as well as a primary target for innovative treatment strategies. The T lymphocyte infiltration, documented in all CSF samples, suggests a possible involvement of the CNS lymphatic system in both lymphoid and cancer cell migration into and out of the meninges, supporting the extension of a new form of cellular immunotherapy to LM. Due to the small number of cases, validation on large cohorts of patients are warranted to confirm these findings and to evaluate the impact and value of these results for diagnosis and management of LM.

Temozolomide low-dose chemotherapy in newly diagnosed low-grade gliomas: activity, safety, and long-term follow-up.

PURPOSE: To explore the efficacy and toxicity of an extended schedule of temozolomide (50 mg/mq 1 week on/1 week off) in a population of newly diagnosed low-grade gliomas (LGG). METHODS: Primary endpoints were progression-free survival (PFS) at 12 and 24 months and response rate evaluated with Response Assessment in Neuro-Oncology Criteria. Secondary endpoints were clinical benefit (reduction of seizures frequency), reduction of steroid, and modifications of Karnofsky Performance Status. RESULTS: From 2006 to 2009, we enrolled 14 consecutive patients with newly diagnosed LGG: 8 grade II astrocytomas, 2 oligodendroglioma, and 4 oligo-astrocytoma. Temozolomide was administered for 18 cycles (mean) per patient (range 3-24 cycles). In 57.5% (n = 8), we observed stable disease, 28.5% (n = 4) presented a minor response, and 14% (n = 2) showed progression. Five patients presented early progression during the first year of treatment and the study was stopped. A relevant clinical benefit was observed in 85% of patients (seizure control). After 6 years of follow-up, only 4 patients died. Prolonged PFS was associated with 1p-19q codeletion over 1p-19q intact (35 vs 4 months; p<0.04) and IDH1 mutation over IDH1 wild-type (36 vs 6 months; p<0.009). CONCLUSIONS: The study was interrupted for the high rate of progression observed in the first 14 patients enrolled. However, our results show that an extended low dose of temozolomide presents interesting activity with objective response and clinical benefit, but does not seem to prevent progression in patients presenting unfavorable molecular prognostic factors.

Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging.

Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading to neurological damage has not been completely elucidated. Innovative strategies of investigation are needed to more precisely define this pathological process. By longitudinal in vivo bioluminescence imaging, we noninvasively visualized the brain response to hyperbilirubinemia in the MITO-Luc mouse, in which light emission is restricted to the regions of active cell proliferation. We assessed that acute hyperbilirubinemia promotes bioluminescence in the brain region, indicating an increment in the cell proliferation rate. Immunohistochemical detection in brain sections of cells positive for both luciferase and the microglial marker allograft inflammatory factor 1 suggests proliferation of microglial cells. In addition, we demonstrated that brain induction of bioluminescence was altered by pharmacological displacement of bilirubin from its albumin binding sites and by modulation of the blood-brain barrier permeability, all pivotal factors in the development of bilirubin-induced neurologic dysfunction. We also determined that treatment with minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, or administration of bevacizumab, an anti-vascular endothelial growth factor antibody, blunts bilirubin-induced bioluminescence. Overall the study supports the use of the MITO-Luc mouse as a valuable tool for the rapid response monitoring of drugs aiming at preventing acute bilirubin-induced neurological dysfunction.

A restricted signature of serum miRNAs distinguishes glioblastoma from lower grade gliomas.

BACKGROUND: Malignant gliomas are the most common primary brain tumors in adults and challenging cancers for diagnosis and treatment. They remain a disease for which non-invasive, diagnostic and/or prognostic novel biomarkers are highly desirable. Altered microRNA (miRNA) profiles have been observed in tumor tissues and biological fluids. To date only a small set of circulating/serum miRNA is found to be differentially expressed in brain tumors compared to normal controls. Here a restricted signature of circulating/serum miRNA including miR-15b*,-23a, -99a, -125b, -133a, -150*, -197, -340, -497, -548b-5p and let-7c were investigated as potential non-invasive biomarkers in the diagnosis of glioma patients. METHODS: Serum and tissues miRNAs expression in patients with brain cancers (n = 30) and healthy controls (n = 15) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Relative expression was calculated using the comparative Ct method. Statistical significance (p ≤ 0,05) was determined using the Mann-Whitney rank sum and Fisher's exact test. Diagnostic accuracy of miRNAs in distinguishing glioblastoma multiforme (GBM) from lower grade cancer was assessed by the Receiver Operating Characteristic (ROC) curve analysis. To validate the role of the identified miRNAs in cancer a comprehensive literature search was conducted using PubMed, Web of Science (Core Collection) and Scopus databases. RESULTS: We observed a decrease of miR-497 and miR-125b serum levels depending on tumor stages with reduced level in GBM than lower grade tumors. The ROC curve analysis distinguishing GBM from lower grade cases yielded an area under the curve (AUC) of 0.87 (95 % confidence interval (CI) = 0.712-1) and of 0.75 (95 % CI = 0.533-0.967) for miR-497 and -125b, respectively. GBM patients are more likely to show a miR-497 and -125b down-regulation than the lower grade group (p = 0.002 and p = 0.024, respectively). These results were subsequently compared with evidence from 19 studies included in the final systematic review. CONCLUSIONS: Although multiple biomarkers are currently leveraged in the clinic to detect specific cancer types, no such standard blood biomolecules are used as yet in gliomas. Our data suggest that serum miR-497 and -125b could be a novel diagnostic markers with good perspectives for future clinical applications in patients with glioma.

Brain stereotactic biopsy flow cytometry for central nervous system lymphoma characterization: advantages and pitfalls.

BACKGROUND: Brain stereotactic biopsy (SB) followed by conventional histopathology and immunohistochemistry (IHC) is the gold standard approach for primary central nervous system lymphoma (PCNSL) diagnosis. Flow cytometry (FCM) characterization of fine-needle aspiration cytology and core needle biopsies are increasingly utilized to diagnose lymphomas however, no biological data have been published on FCM characterization of fresh single cell suspension from PCNSL SB. The aim of this study was to establish the feasibility and utility of FCM for the diagnosis and characterization of brain lymphomas from a tissue samples obtained by a single SB disaggregation. METHODS: Twenty-nine patients with a magnetic resonance suggestive for PCNSL entered the study. A median of 6 SB were performed for each patient. A cell suspension generated from manual tissue disaggregation of a single, unfixed, brain SB, was characterized by FCM. The FCM versus standard approach was prospectively compared. RESULTS: FCM and IHC showed an high degree of agreement (89 %) in brain lymphoma identification. By FCM, 16 out of 18 PCNSL were identified within 2 h from biopsy. All were of B cell type, with a heterogeneous CD20 mean fluorescence intensity (MFI), CD10 positive in 3 cases (19 %) with surface Ig light chain restriction documented in 11 cases (69 %). No false positive lymphomas cases were observed. Up to 38 % of the brain leukocyte population consisted of CD8 reactive T cells, in contrast with the CD4 positive lymphocytes of the peripheral blood samples (P < 0.001). By histopathology, 18 B-PCNSL, only one CD10 positive (5 %), 1 primitive neuroectodermal tumor (PNET) and 10 gliomas were diagnosed. A median of 6 days was required for IHC diagnosis. CONCLUSION: Complementary to histopathology FCM can contribute to a better characterization of PCNSL, although necrosis and previous steroid treatment can represent a pitfall of this approach. A single brain SB is a valid source for accurate FCM characterization of both lymphoma and reactive lymphocyte population, routinely applicable for antigen intensity quantification and consistently documenting an active mechanism of reactive CD8 T-lymphocytes migration in brain lymphomas. Moreover, FCM confirmed to be more sensitive than IHC for the identification of selected markers.

Spine Surgery in Patients with Metastatic Breast Cancer: A Retrospective Analysis.

BACKGROUND: Pathologic or iatrogenic symptomatic spinal lesions are common in metastatic breast cancer. Given the longer duration of overall survival provided by modern oncologic therapies, a prompt and effective treatment of such lesions may have a significant impact on patient's quality of life, improving pain and preventing deterioration of neurologic functions. METHODS: A retrospective review was conducted on patients with breast cancer operated to the spine between 2005 and 2013. The series includes 41 patients and 57 vertebral levels treated (4 cervical, 35 dorsal, and 18 lumbar). There were 28 patients who received palliative surgery and 13 who received excisional surgery, according to their clinical conditions, Spinal Instability Neoplastic Score, and Tokuhashi scores. RESULTS: Of the 41 patients, 38 presented with a median survival of 50 months (95% confidence interval [CI], 39-61), still preserving a Karnofsky Performance Status Scale score ≥60 and a retained ability to ambulate independently. The median overall survival after the first spine surgery was also 50 months (95% CI, 35-65), suggesting that in this cohort of patients, a reasonable quality of life was preserved almost to the end of their clinical history. In patients treated with palliative surgery, the median survival was 37 months (95% CI, 26-48). In those treated with complex surgery, it was 57 months (95% CI, 41-73; P = 0.03). CONCLUSIONS: Major excisional surgery, albeit associated with an increased length of hospital stay, allowed in our series a prolonged survival compared with less aggressive types of surgery. However, percutaneous or open balloon kyphoplasty techniques have expanded indications for palliative surgery and even patients with lower Tokuhashi scores may benefit from rapid and sustained pain relief, preservation of neurologic function, and early mobilization.

The Prognostic Value of Pyrosequencing-Detected MGMT Promoter Hypermethylation in Newly Diagnosed Patients with Glioblastoma.

O6-methylguanine-DNA-methyltransferase (MGMT) has emerged as a relevant predictor of therapeutic response and good prognosis in patients with glioblastoma (GBM). Transcriptionally active MGMT rapidly removes the alkyl adducts, preventing the formation of cross-links and thereby causing resistance to alkylating drugs. Studies with pyrosequencing (PSQ) showed that this technique has a higher reproducibility and sensitivity than other techniques. However, the definition of a prognostically relevant threshold for the percentage of MGMT methylation remains one of the most critical issues in the use of PSQ analysis. The aim of this study was to define the cut-off value correlated with good favourable prognostic outcomes. We retrospectively analyzed 51 patients (33 males, 18 females) with GBM who underwent surgery or biopsy. The Receiver Operating Characteristics analysis showed that the best possible criteria for PSQ-detected percentage of MGMT methylation that predicted progression-free survival (PFS) and overall survival (OS) were 19% and 13%, respectively. Patients with ≤ 19% of PSQ-detected MGMT had a shorter PFS (HR: 0.24, p < 0.01); those ones with ≤ 13% had a shorter OS (HR: 0.33, p < 0.05). Our study reinforces the importance of MGMT in the management of GBM patients, but future studies with larger sample sizes are warranted to confirm our findings.

Early biomarkers from dynamic contrast-enhanced magnetic resonance imaging to predict the response to antiangiogenic therapy in high-grade gliomas.

INTRODUCTION: The aim of this study is to investigate whether early changes in tumor volume and perfusion measurements derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may predict response to antiangiogenic therapy in recurrent high-grade gliomas. METHODS: Twenty-seven patients who received bevacizumab every 3 weeks were enrolled in the study. For each patient, three MRI scans were performed: at baseline, after the first dose, and after the fourth dose of bevacizumab. The entire tumor volume (V(tot)), as well as contrast-enhanced and noncontrast-enhanced tumor subvolumes (V(CE-T1) and V(NON-CE-T1), respectively) were outlined using post-contrast T1-weighted images as a guide for the tumor location. Histogram analysis of normalized IAUGC (nIAUGC) and transfer constant K(trans) maps were performed. Each patient was classified as a responder patient if he/she had a partial response or a stable disease or as a nonresponder patient if he/she had progressive disease. RESULTS: Responding patients showed a larger reduction in V(NON-CE-T1) after a single dose, compared to nonresponding patients. Tumor subvolumes with increased values of nIAUGC and K(trans), after a single dose, significantly differed between responders and nonresponders. The radiological response was found to be significantly associated to the clinical outcome. After a single dose, V(tot) was predictive of overall survival (OS), while V(CE-T1) showed a tendency of correlation with OS. CONCLUSION: Tumor subvolumes with increased nIAUGC and K(trans) showed the potential for improving the diagnostic accuracy of DCE. Early assessments of the entire tumor volume, including necrotic areas, may provide complementary information of tumor behavior in response to anti-VEGF therapies and is worth further investigation.