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.

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.

Surgery of malignant gliomas: advances and perspectives.

PURPOSE OF REVIEW: One of the most controversial issues in the combined treatment of malignant gliomas is the role of surgical resection, even though the relevance of surgery in obtaining tissue diagnosis and alleviating clinical symptoms is well defined; more debated is the importance of radical surgery in improving the patient final outcome. This review aims to present an overview of the recommendations for surgical treatment of malignant gliomas, and to describe the potential role of locoregional treatments. RECENT FINDINGS: An increasing series of data are being collected in favour of radical surgical removal, with the support of intraoperative imaging and fluorescence guide. More controversial, but theoretically relevant, are the experiences of locoregional treatments, mainly in the contest of present combined modality treatments; different interesting approaches are being studied, without any significant therapeutical advantage in phase III studies, and only biodegradable carmustine wafers entered in the clinical practice. SUMMARY: The gold standard of surgical treatment of malignant gliomas has to include well tolerated and radical tumour removal, taking advantage of the introduction of new technological tools. The future role of neurosurgical treatment of malignant glioma is linked to intratumoural administration of antiblastic agents and the development of more efficient delivery systems; localized therapies have to be considered in a well defined multistep therapeutic strategy.

Low-dose fotemustine for recurrent malignant glioma: a multicenter phase II study.

Fotemustine at the conventional dose of 100 mg/m(2) is an active treatment for recurrent malignant gliomas (RMGs). However, it is associated with a relevant incidence of severe myelotoxicity, which is not justified in the palliative setting of this disease. This study was conducted to address whether administration of fotemustine at 60 mg/m(2) (induction) followed by 75 mg/m(2) (maintenance) would preserve clinical activity with the advantage of improved tolerance. Forty patients with RMGs pretreated with ≤2 lines of chemotherapy were enrolled. Median age was 57 years (26-80) and median Karnofsky performance status was 80 (60-100). Thirty-one patients (77.5%) had tissue available for analysis of the O(6)-methylguanine methyltransferase (MGMT) gene promoter which was found to be methylated in 14 cases (45%). Overall, 8 partial responses (20%) and 13 disease stabilizations (32.5%) were observed for a disease-control rate of 52.5%. At 6 months, 21% of patients were free from progression. Grades 3 and 4 platelet and white blood cell toxicity occurred in ≤10% of patients, and no patients discontinued treatment because of toxicity. No significant difference was observed for disease control rate between methylated and unmethylated patients, although a trend toward improved progression-free survival was reported for methylated patients. Low-dose fotemustine has activity comparable with that of the full-dose regimen, therefore it should be preferred for its greater tolerability. The role of MGMT gene promoter methylation status in relation to sensitivity to fotemustine is still unclear and needs further evaluation in future clinical trials.

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.

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.

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.

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.

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.

Gemcitabine treatment of experimental C6 glioma: the effects on cell cycle and apoptotic rate.

Gemcitabine (dFdCyd) is a deoxycytidine analogue showing a broad spectrum of cytotoxic activity; additionally, at non-cytotoxic concentrations, it is a potent radiosensitiser. Its in vitro and in vivo effects were studied on C6 rat glioma. In vitro, dFdCyd induced an increase in S-phase cells at the end of treatment, with a reduction in G1 and G2 cell cycle-phase cells and relevant effects on the apoptotic rate. The in vivo effects of dFdCyd were studied on rats bearing intracranial C6 glioma. The drug was administered at a dose of 120 mg/Kg every 3 days x 4 doses. A significant effect on tumour growth was detected by longitudinal MRI analyses. Furthermore, the drug induced an inhibitory effect on tumour growth, 72 h after a 300 mg/Kg single dose. Analyses performed on tumour specimens showed relevant G1-phase accumulation and about 45% apoptotic cells. The present results justify further studies to determine the potential efficacy of dFdCyd in the treatment of malignant gliomas.

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.

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.

The Role of PET [18F]FDOPA in Evaluating Low-grade Glioma.

AIM: The aim of the present study was to evaluate the prognostic value of 3,4-dihydroxy-6-[(18)F]-fluoro-L-phenylalanine ([(18)F]-FDOPA) positron-emission tomography (PET) in predicting the risk of radiological progression of disease in patients affected by low-grade glioma. PATIENTS AND METHODS: Patients affected by grade II glioma were consecutively enrolled in a prospective observational study at the Department of Neurology of Regina Elena National Cancer Institute in Rome, Italy. At enrolment, all patients underwent PET [(18)F]-FDOPA and Magnetic Resonance Imaging (MRI), and clinical and radiological assessments with MRI every six months to evaluate the progression of disease. RESULTS: A total of 50 patients affected by grade II glioma (30 males and 20 females) were included in the study. The multivariate analysis showed that standardized uptake value greater than 1.75 and disease duration were independent predictors of disease progression. CONCLUSION: These findings suggest that the PET [(18)F]-FDOPA may play an important prognostic role in evaluation of low-grade glioma.

Brain metastases from solid tumors: disease outcome according to type of treatment and therapeutic resources of the treating center.

BACKGROUND: To evaluate the therapeutic strategies commonly employed in the clinic for the management of brain metastases (BMs) and to correlate disease outcome with type of treatment and therapeutic resources available at the treating center. METHODS: Four Cancer centres participated to the survey. Data were collected through a questionnaire filled in by one physician for each centre. RESULTS: Clinical data regarding 290 cancer patients with BMs from solid tumors were collected. Median age was 59 and 59% of patients had ≤ 3 brain metastases. A local approach (surgery and stereotactic radiosurgery) was adopted in 31% of patients. The local approach demonstrated to be superior in terms of survival compared to the regional/systemic approach (whole brain radiotherapy and chemotherapy, p = <.0001 for survival at 2 years). In the multivariate analysis local treatment was an independent prognostic factor for survival. When patients were divided into 2 groups whether they were treated in centers where local approaches were available or not (group A vs group B respectively, 58% of patients with ≤ 3 BMs in both cohorts), more patients in group A received local strategies although no difference in time to brain progression at 1 year was observed between the two groups of patients. CONCLUSIONS: In clinical practice, local strategies should be integrated in the management of brain metastases. Proper selection of patients who are candidate to local treatments is of crucial importance.

Phase II study of fixed dose rate gemcitabine as radiosensitizer for newly diagnosed glioblastoma multiforme.

PURPOSE: In order to evaluate the activity of gemcitabine as radiosensitizer for newly diagnosed glioblastoma multiforme (GBM), a prospective single-center phase II study was conducted. METHODS: Eligible patients were required to have histologically proven GBM with evaluable and/or measurable disease after surgery. They were treated by standard cranial irradiation plus concomitant fixed dose rate gemcitabine given intravenously at 175 mg/m(2) weekly for 6 weeks. After chemo-radiotherapy, irrespective of tumor response, patients went on to receive oral temozolomide at 150-200 mg/m(2) for 5 days every 28 days. RESULTS: Twenty-three patients were enrolled. Median age was 57 years (range 43-72) and median Karnofsky performance status was 90 (range 70-100). Seventeen patients had received subtotal resection of the tumor, while six patients had biopsied-only tumors. Four patients responded to treatment (17.5%) with additional 14 (61%) experiencing stable disease for an overall disease control rate of 78.5%. Median progression-free and overall survival were 6.8 and 10.1 months, respectively. The concomitant radiotherapy-gemcitabine combination was well tolerated and severe adverse events were rare, consisting of grade 3 neutropenia and hypertransaminasemia in two cases each. Twenty patients were assessable for methylguanine methyltransferase (MGMT) promoter methylation, 11 of which were found methylated. In the methylated and unmethylated cohorts, disease control was obtained in 10/11 patients (91%) and 7/9 patients (77.5%), respectively. CONCLUSIONS: Concomitant radiotherapy-gemcitabine is active and well tolerated in newly diagnosed glioblastoma multiforme. Activity is observed both in tumors with methylated and unmethylated MGMT promoter.

End of life issues in brain tumor patients.

Despite aggressive antitumor treatment, the prognosis of brain tumor (BT) patients remains poor. In the last stage of disease, BT patients present severe symptoms due to the growing tumor or to treatment side-effects, which require adequate palliative management and supportive therapy. However, studies specifically addressing palliative care and end-of-life (EoL) issues in BT patients are lacking. This study explores symptoms experienced by BT patients in the last weeks of disease and EoL issues observed in a population of brain tumor patients followed at home until death by a neuro-oncological home care palliative unit set up in our Institution in 2000. From October 2000 to December 2005, 324 patients affected by brain tumor and discharged from our Institution were enrolled in a comprehensive program of neuro-oncological home care supported by the Regional Health System. Out of 324 patients enrolled in the home care program, 260 patients died of which 169 (65%) were assisted at home until the end of life and have been included in this study. Clinical symptoms, palliative treatments and EoL treatment decisions were collected from home clinical records. Among the 169 patients assisted at home until death, the most frequent symptoms observed in the last four weeks of life were: epilepsy 30%, headache 36%, drowsiness 85%, dysphagia 85%, death rattle 12%, agitation and delirium 15%. Palliative management of brain tumor patients requires a multidisciplinary approach performed by a well trained neuro-oncology team. Development of home care models of assistance may represent an alternative to in-hospital care for the management of patients dying of brain tumor and may improve the quality of end-of-life care.