Second surgery for relapsed glioblastoma: an observational study on criteria for patient selection in real life.

Aim: There is little consensus on salvage management of glioblastoma after recurrence, for lack of evidence. Materials & methods: A retrospective study of treatments in patients with recurrent glioblastoma. Results: Surgery at recurrence was related to better overall survival (OS) and progression-free survival (PFS). Surgery at recurrence, Karnofsky index, MGMT methylation status, younger age at diagnosis and number of chemotherapy cycles were positive factors for OS and PFS. The benefit of OS was relevant for a second surgery performed at least 9 months after the first one. Systemic treatments after the second surgery were linked to an improved PFS. Conclusion: Younger age, Karnofsky index, MGMT methylation status and a median time between surgeries ≥9 months may be criteria for eligibility for surgery at recurrence.

[Box: see text].

Novel Advances in Treatment of Meningiomas: Prognostic and Therapeutic Implications.

Meningiomas are the most frequent histotypes of tumors of the central nervous system. Their incidence is approximately 35% of all primary brain tumors. Although they have the status of benign lesions, meningiomas are often associated with a decreased quality of life due to focal neurological deficits that may be related. The optimal treatment is total resection. Histological grading is the most important prognostic factor. Recently, molecular alterations have been identified that are specifically related to particular phenotypes and, probably, are also responsible for grading, site, and prognostic trend. Meningiomas recur in 10-25% of cases. In these cases, and in patients with atypical or anaplastic meningiomas, the methods of approach are relatively insufficient. To date, data on the molecular biology, genetics, and epigenetics of meningiomas are insufficient. To achieve an optimal treatment strategy, it is necessary to identify the mechanisms that regulate tumor formation and progression. Combination therapies affecting multiple molecular targets are currently opening up and have significant promise as adjuvant therapeutic options. We review the most recent literature to identify studies investigating recent therapeutic treatments recently used for meningiomas.

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

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

Cranial sonolucent prosthesis: a window of opportunity for neuro-oncology (and neuro-surgery).

INTRODUCTION: Ultrasound (US) is a versatile technology, able to provide a real-time and multiparametric intraoperative imaging, and a promising way to treat neuro-oncological patients outside the operating room. Anyhow, its potential is limited both in imaging and therapeutic purposes by the existence of the bone shielding. To enhance the spectrum of uses, our group has designed a dedicated US-translucent cranial prosthesis. Herein, we provide the proof of concept of a long-term US-based follow-up and a potential bedside therapeutic exploitation of US. METHODS: The prosthesis was first implanted in a cadaveric specimen to record any issue related to the cranioplasty procedure. Hence, the device was implanted in a patient undergoing surgery for a multi-recurrent anaplastic oligodendroglioma. US multiparametric scans through the device were acquired at 3, 6, 9, and 30 months after the procedure. RESULTS: The prosthesis could be modeled and implanted through ordinary instruments, with no concerns over safety and feasibility. Trans-prosthesis multiparametric US imaging was feasible, with image quality comparable to intraoperative US. Long-term follow-up in an outpatient setting was possible with no adverse events. Trans-prosthesis mechanical interaction with microbubbles was also feasible during follow-up. CONCLUSIONS: This report provides the first proof of concept for a potential breakthrough in the management of neuro-oncological patients. Indeed, through the implantation of an artificial acoustic window, the road is set to employ US both for a more dynamic long-term follow-up, and for US-guided therapeutic applications.

Adjuvant chemotherapy after severe myelotoxicity during chemoradiation phase in malignant gliomas. Is it feasibile? Results from AINO study (Italian Association for Neuro-Oncology).

BACKGROUND: Malignant gliomas (MG) are aggressive brain tumours in adults. The standard of care is concurrent radiation plus temozolomide (TMZ) [chemo-radiotherapy (CRT)] followed by TMZ maintenance up to 6 months. TMZ is considered to have a low toxicity profile, but several studies reported occurrence of severe myelosuppression, especially during the concomitant phase. Toxicity may be prolonged, thus treatment should be discontinued. PURPOSE: To evaluate the risk of recurrente myelotoxicity during adjuvant chemotherapy (CT) in patients who recovered from severe myelotoxicity during CRT. METHODS: We retrospectively collected data on patients with MG who developed and recovered from severe myelotoxicity during CRT from eight Italian neuro-oncology centers. RESULTS: We included 87 patients. Histology was Glioblastoma (GBM) in 78 patients (89.7%); 60% of patients were female. After myelotoxicity recovery, 54 (62%) received treatment. The majority of them (82%, n = 44) received adjuvant TMZ and 18% (n = 10) others treatments. Out of 44 patients who received adjuvant TMZ, 34% experienced the re-occurrence of grade 3-4 myelotoxicity which required permanent CT discontinuation in 6 (13%) cases. Patients who received TMZ or other treatments had longer overall (OS) (adjusted HR 0.46, p = 0.008) and progression free survival (PFS) (adjusted HR 0.57, p = 0.034) than those who remained untreated. CONCLUSION: Our study suggests that after severe myelotoxicity the majority of patients received treatment, particularly with TMZ. Only a fraction of patients experienced toxicity recurrence, suggesting that TMZ is well tolerated and had an impact on PFS and OS.

Medulloblastoma of the adult: results from a multicenter retrospective study by AINO (Italian Association of Neuro-Oncology) and SIN (Italian Society of Neurology).

INTRODUCTION: Medulloblastoma (MB) is the most common primary malignant intracranial tumor in childhood, but it is very rare in adults, and for this reason, the optimal treatment has not yet been defined. We designed a multicentric study in order to define relevant outcome measures for future prospective studies. MATERIALS AND METHODS: The project involved 10 Italian centers. The database shared among the centers contains epidemiological, diagnostic (radiological and histological/molecular), therapeutic, recurrence information, and survival data. RESULTS: A total of 152 patients (102 males and 50 females, median age 32) were included in the study. Twenty-three of 152 patients had a diagnosis of classic medulloblastoma, 52/152 had desmoplastic/extensive nodularity, 2/152 had large-cell anaplastic medulloblastoma, and the remaining had diagnoses not otherwise specified. Almost all patients underwent craniospinal irradiation after surgery; in 85.5% of patients, adjuvant chemotherapy, mainly platinum- and etoposide-based chemotherapy, was performed immediately after RT. Upon recurrence, most patients were retreated with various chemotherapy regimens, including intrathecal chemotherapy in patients with leptomeningeal dissemination. The overall survival (OS) rate at 5 years was 73.3% (95% CI, 65.0-80.0%). The median OS for the whole group of patients was 112 months. CONCLUSIONS: The data collected were mainly consistent with the literature. A limitation of this study was the large number of patients lost to follow-up and the lack of molecular data for most patients diagnosed until 2010. An important challenge for the future will be MB biologic characterization in adults, with the identification of specific genetic patterns. It will be important to have more national and international collaborations to provide evidence-based management strategies that attempt to obtain a standard of care.

Biweekly fotemustine schedule for recurrent glioblastoma in the elderly: activity and toxicity assessment of a multicenter study.

Aim: To assess the efficacy and safety of alternative fotemustine administration schedule in elderly patients with recurrent glioblastoma. Patients & methods: Patients aged >65 years with recurrent glioblastoma received fotemustine (80 mg/m2; days 1, 15, 30, 45 and 60, and subsequently every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months. Main secondary end point was safety. Results: 58 patients were enrolled at two centers. PFS at 6 months was 47% (27 patients) and overall response rate was 29%. Median PFS and survival were 6 and 7 months, respectively, and longer in responders versus nonresponders. No grade 3-4 hematological toxicities occurred. Conclusion: The alternative fotemustine administration schedule was an effective and safe treatment for recurrent glioblastoma in elderly patients.

Multicenter, single arm, phase II trial on the efficacy of ortataxel in recurrent glioblastoma.

BACKGROUND AND PURPOSE: Glioblastoma (GBM) is the most aggressive and frequent subtype of all malignant gliomas. At the time of recurrence, therapeutic options are lacking. Ortataxel, a second-generation taxane was reported to be effective in pre-clinical and phase I clinical studies. The aim of this study was to evaluate a potential therapeutic activity of ortataxel in patients with GBM recurring after surgery and first line treatment. METHODS: In this phase II study, according to a two stage design, adult patients with histologically confirmed GBM in recurrence after surgery or biopsy, standard radiotherapy and chemotherapy with temozolomide were considered eligible. Patients included were treated with ortataxel 75 mg/m2 i.v. every 3 weeks until disease progression. The primary objective of the study was to evaluate the activity of ortataxel in terms of progression free survival (PFS) at 6 months after the enrollment. PFS, overall survival at 9 months after the enrollment, objective response rate, compliance and safety were evaluated as secondary endpoints. RESULTS: Between Nov 26, 2013 and Dec 12, 2015, 40 patients were recruited across six centres. The number of patients alive and free from progression at 6 months after the enrollment, observed in the first stage was four (11.4%), out of 35 patients included in the analysis, below the minimum number of events (7 out of 33) required to continue the study with the second stage The most important toxicities were neutropenia and hepatotoxicity that occurred in 13.2% of patients and leukopenia that occurred in 15.8% of patients. CONCLUSION: Overall ortataxel treatment fail to demonstrate a significant activity in recurrent GBM patients. However in a limited number of patients the drug produced a benefit that lasted for a long time. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT01989884.

Antiepileptic treatment and survival in newly diagnosed glioblastoma patients: Retrospective multicentre study in 285 Italian patients.

Glioblastoma multiforme (GBM) has a dismal prognosis even with the best available treatment. Different studies have suggested a possible impact of antiepileptic drugs (AED) on survival in patients with GBM. A recent pooled analysis of prospective clinical trials in newly diagnosed GBM found no significant survival benefit in GBM patients treated with AED. We performed a retrospective study on adult patients with GBM in order to evaluate the impact of AED therapy on overall survival (OS), after adjusting for known prognostic factor (age, extent of surgery, Karnofsky performance status, radiochemotherapy). A total of 285 patients were analyzed. Of them 144 received a non-enzyme-inducing (NEIAED) and 95 an enzyme-inducing AED (EIAED). At univariate analysis the OS of patients receiving AED was not significantly different from that of patients not receiving an AED (HR 0.98, 95%CI 0.69-1.4, p = 0.925), moreover OS was not significantly different between patients receiving EIAED or NEIAED. At multivariate analysis a trend to more prolonged survival (HR 0.8, 95% CI 0.59-1.08, p = 0.15) was detected in patients treated with NEIAED. The question whether treatment with AED may increase OS in GBM patients remains unanswered and randomized extremely large controlled clinical trial would be necessary to elucidate the possible impact of AED on prognosis. In the meantime the use of AED in GBM patients, based on the presumed potential antitumour activity, is not recommended.

Differentiating brain radionecrosis from tumour recurrence: a role for contrast-enhanced ultrasound?

Differentiating radionecrosis from tumour recurrence is a major issue in neuro-oncology. Conventional imaging is far from being validated as an alternative to histological assessment. We report the case of a patient operated on for suspected recurrence of brain metastasis 9 months after cyberknife radiosurgery. While magnetic resonance imaging showed strong enhancement of the lesion, intraoperative contrast-enhanced ultrasonography (CEUS) surprisingly did not-different from what is expected for brain metastases. Histopathological examination documented radionecrosis. For the first time, we describe radionecrosis with CEUS; further investigation is needed; however, the lack of enhancement could represent an important hallmark in differential diagnosis with neoplastic tissue.

Short course radiotherapy concomitant with temozolomide in GBM patients: a phase II study.

PURPOSE: Despite recent advances, the prognosis of glioblastoma (GBM) remains poor. The aim of this study was to assess the efficacy and tolerability of multiple daily fraction radiotherapy performed with multiple temozolomide (TMZ) administrations in newly diagnosed patients with GBM. METHODS: This trial was a prospective, open-label, monocentric, nonrandomized, single arm, phase II study. The primary endpoint was the proportion of progression-free patients at 12 months, and the secondary endpoints were overall survival (OS) and toxicity. Thirty-five patients underwent two radiotherapy courses concomitant with TMZ after surgery. At each course, radiation was delivered 3 times daily, 2 Gy/fraction, for 5 consecutive days, and the total dose was 60 Gy; concurrent TMZ was administered in a total dose of 150-200 mg/m2/day. RESULTS: The primary endpoint failed to be applied; Macdonald criteria could be used in 16 (46%) patients with local or intracerebral recurrence (group A). In 12 patients, due to suspicion of radiation necrosis vs recurrence, Macdonald criteria were not applied (group B). The OS was 22 months, and OS probabilities at 12, 18, and 24 months were 82%, 59%, and 44%, respectively. Hematologic toxicities generally did not exceed grade 2. The quality of life and cognitive functioning did not significantly change between baseline and the first follow-up. In the multivariate analysis, necrosis and pseudoprogression were significant prognostic factors of OS. CONCLUSIONS: To improve local control and OS, a more aggressive treatment schedule should be explored. The related higher necrosis risk and its implications regarding local control deserve further investigation.

Pattern of care and outcome in elderly patients with glioblastoma: Data in 151 patients from 3 Lombardia Hospitals.

The appropriate treatment approach for elderly patients with glioblastoma multiforme (GBM) is unclear, although different studies suggest survival benefit in fit patients treated with radiotherapy and chemiotherapy after surgery. We performed a retrospective analysis of 151 patients older than 65years with GBM treated in 3 Lombardia Hospitals. In univariate regression analysis higher KPS (p=0.02), macroscopical total resection (p<0.003), radiotherapy (p<0.0001), chemotherapy (p<0.0001) and second line chemotheraphy (p=0.02) were of positive prognostic value. On the contrary older age (>70years), presence of seizure at onset and additional resection after tumor recurrence did not influence OS. Multivariate analysis revealed radiotherapy (HR 0.2 p<0.0001) and extent of surgery (HR 0.3, p=0,0063) as positive independent prognostic factors. Patients receiving radio-chemiotherapy displayed more treatment-related toxicities with a slightly prolonged OS versus those receiving hypofractionated radiotherapy. With the limits of a retrospective study, our data suggest that in elderly fit patients extensive surgery should be considered, moreover adjuvant treatments led to an increase in OS. Randomized controlled study are needed to develop treatment guidelines for elderly GBM patients and to assess whether the combination of post-surgical radio and chemiotherapy may be superior to hypofractionated radiotherapy and chemiotherapy in fit patients.

A case of medulloblastoma in adult patient affected by anaplastic oligoastrocytoma.

Medulloblastomas and high-grade gliomas (HGG) are two distinct brain tumor, with different peculiarities in terms of age of onset, localizations and prognosis. The coexistence of the two neoplasms in the same adult patient is an extremely rare event. We present the case of a woman treated with radio-chemotherapy for an HGG, who developed a cerebellar medulloblastoma 7 years later. Considering the poor prognosis of these tumors, the lack of knowledge about the mechanisms of onset as well as effective therapies, it is necessary to determine the exact role of irradiation and the presence of any potential molecular genetic abnormalities in the developing of the two tumors.

Safety and efficacy of primary central nervous system lymphoma treatment in elderly population.

Elderly patients represent an important subgroup in primary central nervous system lymphoma (PCNSL) that accounts for approximately half the cases. Furthermore age represents one of the heaviest prognostic factors and in some cases it has more effect on survival than therapies. We performed a retrospective analysis to assess the toxicity and the efficacy of high-dose methotrexate (HDMTX) chemotherapy in a PCNSL population older than 70 years. Seventeen consecutive immunocompetent patients older than 70 years, with histologically confirmed PCNSL, without systemic involvement, treated with HDMTX at our institution between May 2005 and April 2013, were retrospectively evaluated. Main outcome measures were acute toxicity and tumour response. No evidence of haematological toxicity was recorded in 47 % of patients and no deaths related to toxicity grade were reported. Patients achieved a partial response after 3 cycles of chemotherapy in 53 % of cases. The median overall survival (m-OS) from diagnosis was 20.9 months (range 5.2-34 months), with OS-12 of 58.8 % and an OS-24 of 45.4 %. Since there is no standard of care in the treatment of PCNSL in elderly population, it should be taken into account that elderly patients not always can be considered "fragile" and the general tendency to less treat to avoid severe toxicity should not be the rule.

Intrathecal synthesis of onconeural antibodies in patients with paraneoplastic syndromes.

Paraneoplastic neurological syndromes (PNSs) are a group of immune-mediated neurological disorders occurring in patients with systemic cancers which are associated with the presence of anti-neuronal antibodies. In this retrospective study, serum and cerebrospinal fluid of 489 patients were analyzed for the presence of well characterized onconeural antibodies. The 18 PNS patients positive for onconeural antibodies were reanalyzed to evaluate possible intrathecal synthesis. Intrathecal synthesis of onconeural antibodies, was detected in 10/15 patients affected by PNSs involving the CNS and in 1/3 cases with peripheral syndromes. Our data confirm that onconeural antibodies are produced within the CNS in most PNS patients. Evaluation of intrathecal synthesis of onconeural antibodies on a larger cohort of PNS patients and the correlation with disease course might elucidate whether this marker has a value in predicting the prognosis of the neurological disease.

Herpes simplex encephalitis in glioma patients: a challenging diagnosis.

OBJECTIVES: In recent years, herpes simplex encephalitis (HSE) has been reported with increasing frequency in settings of immunosuppression, such as acquired immunodeficiency, transplantation and cancer. As observed, in immunocompromised individuals HSE presents peculiar clinical and paraclinical features, and poorer prognosis. METHODS: Here we describe a retrospective series of seven cases of HSE in patients with high-grade glioma (HGG), collected among three institutions in a 5-year period (during this time, a total of 1750 patients with HGG were treated). RESULTS: Diagnosis of the condition was particularly challenging due to the confounding clinical presentation and the atypical biological findings. As a result, antiviral treatment was started with a sharp delay compared with immunocompetent hosts. Prognosis was poor, with high short-term mortality and severe residual disability in survivors. CONCLUSIONS: The substantial incidence of HSE observed in our centres together with the difficulty in diagnosing the condition suggest that the incidence of this complication may be highly underestimated. The aim of our report is to strengthen the observation of HSE in patients with HGG and outline the key elements that may allow its diagnosis.

Acute late-onset encephalopathy after radiotherapy: an unusual life-threatening complication.

Unusual late-onset complications of brain irradiation, characterized by reversible neurologic focal signs, seizures, and MRI alterations, have recently been reported and classified as stroke-like migraine attacks after radiation therapy (SMART)(1) and peri-ictal pseudoprogression (PIPG).(2.)

Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL): a new report of an Italian woman and review of the literature.

We report the clinical case of a 43year old Italian woman and her family with Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL), also known as Nasu-Hakola disease. PLOSL is a unique disease clinically characterized by a progressive presenile frontal-lobe dementia and multiple cystic bone lesions, typically leading to fractures of the limbs in the third decade of life. This rare recessively inherited disease is caused by mutations in one of two genes encoding different subunits of a receptor signalling complex, TYROBP and TREM2. In the present case fractures after microtrauma were not diagnosed, despite a radiological demonstration of the characteristic bone lesions in PLOSL. Further investigation led to the same diagnosis in her brother, with similar clinical presentation and the same mutation. Therefore a diagnosis of PLOSL should be considered in cases of presenile frontal-lobe dementia, even if the hallmark of pathological fractures is absent.

Prospective study of carmustine wafers in combination with 6-month metronomic temozolomide and radiation therapy in newly diagnosed glioblastoma: preliminary results.

OBJECT: Locoregional chemotherapy with carmustine wafers, positioned at surgery and followed by radiation therapy, has been shown to prolong survival in patients with newly diagnosed glioblastoma, as has concomitant radiochemotherapy with temozolomide. A combination of carmustine wafers with the Stupp treatment regimen has only been investigated in retrospective studies. METHODS: In a single-institution prospective study, the authors assessed 12-month progression-free survival (PFS), toxicity, and overall survival in patients with glioblastoma treated with surgery, carmustine wafers, radiotherapy, and 6-month metronomic temozolomide chemotherapy. Thirty-five patients with de novo glioblastoma, between the ages of 18 and 70 years, and with Karnofsky Performance Scale scores of at least 70, were included in the study. Patients were followed monthly and assessed using MRI every 2 months. RESULTS: After a median follow-up of 15 months, the median time to tumor progression was 12.5 months and median survival was 17.8 months. Due to toxicity (mostly hematological), 7 patients had to prematurely stop temozolomide treatment. Twenty-two patients developed Grade 3 CD4(+) lymphocytopenia. Three patients developed oral-esophageal candidiasis, 2 developed pneumonia, and 1 developed a dorsolumbar zoster. Early intracranial hypertension was observed in 1 patient, and 1 was treated empirically for suspected brain abscess. One patient died of Legionella pneumonia soon after repeat surgery. CONCLUSIONS: Overall, this treatment schedule produced promising results in terms of PFS without a marked increase in toxicities as compared with the Stupp regimen. However, the gain in median survival using this schedule was less clear. Only prospective comparative trials will determine whether these preliminary results will translate into a long-term survival advantage with an acceptable toxicity profile.